Melanomas represent 4% of all malignant tumors of the skin, yet account for 80% of deaths from skin cancer.While in the early stages patients can be successfully treated with surgical resection, metastatic melanoma prognosis is dismal. Several oncogenes have been identified in melanoma as BRAF, NRAS, c-Kit, and GNA11 GNAQ, each capable of activating MAPK pathway that increases cell proliferation and promotes angiogenesis, although NRAS and c-Kit also activate PI3 kinase pathway, including being more commonly BRAF activated oncogene. The treatment of choice for localised primary cutaneous melanoma is surgery plus lymphadenectomy if regional lymph nodes are involved. The justification for treatment in addition to surgery is based on the poor prognosis for high risk melanomas with a relapse index of 50–80%. Patients included in the high risk group should be assessed for adjuvant treatment with high doses of Interferon-α2b, as it is the only treatment shown to significantly improve disease free and possibly global survival. In the future we will have to analyze all these therapeutic possibilities on specific targets, probably associated with chemotherapy and/or interferon in the adjuvant treatment, if we want to change the natural history of melanomas. 1. Introduction Melanomas constitute 2-3% of all cancers, 95% presented as skin cancer and only 5% in nonskin locations. It represents 4% of all malignant tumors of the skin, yet account for 80% of deaths from skin cancer. The incidence in Spain adjusted per 100,000 populations is 5.85 for men and 7.50 for women, according to published data. In the U.S. 76,250 new cases are expected for 2012 (44,250 men and 32,000 women) and a mortality rate of 9180 patients. Using data from 2005–2009 the age-adjusted incidence was 21.0 per 100,000 (27.2 for men and 16.7 for women). The highest incidence occurs in Australia and New Zealand (38/100.000 inhabitants) and Japan has just 0.47 per 100,000 population, which is indicative of the different incidence rates by geographic areas. Globocan’s data from 2008 shows an incidence of 199.627 cases and a mortality of 46.372 (M: 101.807/25.860 and W: 97.820/20512), when in 2002 the incident was 160.000 (M？:？F sex ratio, 0.97) and the mortality 41.000 (M？:？F sex ratio, 1.2) [1]. Melanoma is one of the neoplasms that is increasing the most, both young and old, exceeded only by the liver and thyroid cancer. It is currently the fifth most common cancer in men and the seventh in women. While in the early stages patients can be successfully treated with surgical resection, metastatic
References
[1]
GLOBOCAN 2008 (IARC). Section of Cancer. 2011.
[2]
S. W. Dyson, J. Bass, J. Pomeranz, C. Jaworsky, J. Sigel, and S. Somach, “Impact of thorough block sampling in the histologic evaluation of melanomas,” Archives of Dermatology, vol. 141, no. 6, pp. 734–736, 2005.
[3]
P. Saiag, M. Bernard, A. Beauchet, M. L. Bafounta, I. Bourgault-Villada, and S. Chagnon, “Ultrasonography using simple diagnostic criteria vs palpation for the detection of regional lymph node metastases of melanoma,” Archives of Dermatology, vol. 141, no. 2, pp. 183–189, 2005.
[4]
M. Alvarez-Mon Soto, F. Camacho Martinez, J. L. Diaz Perez, et al., “Tratamiento quirúrgico del melanoma cutáneo,” Melanomas, pp. 123–145, 2005.
[5]
C. M. Balch, S. J. Soong, J. E. Gershenwald et al., “Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system,” Journal of Clinical Oncology, vol. 19, no. 16, pp. 3622–3634, 2001.
[6]
S. B. Edge, D. R. Byrd, C. C. Compton, A. G. Fritz, F. L. Greene, and A. Trotti, Eds., AJCC Cancer Staging Manual, Springer Science and Business Media, Dordrecht, The Netherlands, 7th edition, 2010.
[7]
W. Liu, J. P. Dowling, W. K. Murray, et al., “Rate of growth in melanoma,” Archives of Dermatology, vol. 142, no. 12, pp. 1551–1558, 2006.
[8]
H. Schmidt, J. S. Johansen, P. Sjoegren et al., “Serum YKL-40 predicts relapse-free and overall survival in patients with American Joint Committee on Cancer stage I and II melanoma,” Journal of Clinical Oncology, vol. 24, no. 5, pp. 798–804, 2006.
[9]
M. Mikhail, E. Velazquez, R. Shapiro, et al., “PTEN expression in melanoma: relationship with patient survival, bcl-2 expression, and proliferation,” Clinical Cancer Research, no. 11, pp. 5153–5157, 2005.
[10]
P. A. Gimotty, P. van Belle, D. E. Elder et al., “Biologic and prognostic significance of dermal Ki67 expression, mitoses, and tumorigenicity in thin invasive cutaneous melanoma,” Journal of Clinical Oncology, vol. 23, no. 31, pp. 8048–8056, 2005.
[11]
D. G. Coit, C. Q. Zhou, A. Patel, and K. Panageas, “Estimating survival probability in stage III melanoma: a multivariable individualized patient risk assessment nomogram,” Journal of Clinical Oncology, vol. 24, no. 18S, abstract 8020, 2006.
[12]
C. M. Balch, J. E. Gershenwald, S. J. Soong et al., “Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases,” Journal of Clinical Oncology, vol. 28, no. 14, pp. 2452–2459, 2010.
[13]
M. Alvarez-Mon Soto, F. Camacho Martinez, J. L. Diaz Perez, et al., “Diagnostico de extensión. Estadiaje. Enfermedad metastásica,” Melanomas, pp. 101–110, 2005.
[14]
S. Suciu, G. Ghanem, W. Kruit, et al., “Serum S-100B protein is a strong independent prognostic marker for distant-metastasis free survival in stage III melanoma patients: an evaluation of the EORTC randomized trial 18952 comparing IFN versus observation,” Journal of Clinical Oncology, vol. 25, no. 18S, abstract 8518, 2007.
[15]
T. John, M. A. Black, T. Toro, et al., “Predicting clinical outcome through gene expression profiling in stage III melanoma,” Journal of Clinical Oncology, vol. 25, no. 18S, abstract 8502, 2007.
[16]
S. Mocellin, D. Hoon, A. Ambrosi, D. Nitti, and C. R. Rossi, “The prognostic value of circulating tumor cells in patients with melanoma: a systematic review and meta-analysis,” Clinical Cancer Research, vol. 12, no. 15, pp. 4605–4613, 2006.
[17]
L. A. Fecher, S. D. Cummings, M. J. Keefe, and R. M. Alani, “Toward a molecular classification of melanoma,” Journal of Clinical Oncology, vol. 25, no. 12, pp. 1606–1620, 2007.
[18]
A. A. Tarhini, J. Stuckert, S. Lee, C. Sander, and J. M. Kirkwood, “Prognostic significance of serum s100b protein in high-risk surgically resected melanoma patients participating in intergroup trial ECOG 1694,” Journal of Clinical Oncology, vol. 27, no. 1, pp. 38–44, 2009.
[19]
J. A. Sosman, “Translating BRAF mutations into effective therapy for patients with melanoma,” in Educational Book, pp. 367–372, ASCO, 2011.
[20]
S. J. Moschos and J. M. Kirkwood, “Adjuvant therapy for cutaneous melanoma,” in Cancer of the Skin, D. S. Rigel, R. J. Friedman, L. M. Dzubow, D. S. Reinterg, J.-C. Bystryn, and R. Marks, Eds., chapter 52, pp. 641–654, Elsevier Saunders, Philadelphia, Pa, USA, 2005.
[21]
K. B. Kim, S. S. Legha, R. Gonzalez, et al., “A phase III randomized trial of adjuvant biochemotherapy (BC) versus interferon- -2b (IFN) in patients (pts) with high risk for melanoma recurrence,” Journal of Clinical Oncology, vol. 24, no. 18S, abstract 8003, 2006.
[22]
R. Stadler and T. Luger, “Long term survival benefit adjuvant treatment of high risk cutaneous with dacarbazine and low dose natural interferon alpha: a controlled, randomised, multicentre trial,” Journal of Clinical Oncology, vol. 23, no. 16S, abstract 7516, 2005.
[23]
C. Garbe, P. Radny, R. Linse et al., “Adjuvant low-dose interferon 2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis,” Annals of Oncology, vol. 19, no. 6, pp. 1195–1201, 2008.
[24]
L. E. Flaherty, J. Moon, M. B. Atkins, et al., “Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with high-risk melanoma (SWOG S0008): an intergroup study of CALGB, COG, ECOG, and SWOG,” Journal of Clinical Oncology, vol. 30, supplement, abstract 8504, 2012.
[25]
K. D. Lewis, A. Lane, C. Anderson, et al., “Phase II study neoadjuvant biochemotherapy for stage III malignant melanoma: results of long-term fallow-up,” Journal of Clinical Oncology, vol. 24, no. 18S, abstract 8035, 2006.
[26]
A. M. Eggermont, S. Suciu, P. Rutkowski, et al., “Randomized phase III trial comparing postoperative adjuvant ganglioside GM2-KLH/QS-21 vaccination versus observation in stage II, (T3-T4N0M0) melanoma: final results of study EORTC, 18961,” Journal of Clinical Oncology, vol. 28, no. 15s, abstract 8505, 2010.
[27]
J. A. Sosman, J. M. Unger, P. Y. Liu et al., “Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: impact of HLA class I antigen expression on outcome,” Journal of Clinical Oncology, vol. 20, no. 8, pp. 2067–2075, 2002.
[28]
J. M. Kirkwood, J. G. Ibrahim, J. A. Sosman et al., “High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801,” Journal of Clinical Oncology, vol. 19, no. 9, pp. 2370–2380, 2001.
[29]
M. S. Mitchell, J. Abrams, J. A. Thompson et al., “Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon alfa-2b compared with high-dose interferon alfa-2b for resected stage III cutaneous melanoma,” Journal of Clinical Oncology, vol. 25, no. 15, pp. 2078–2085, 2007.
[30]
M. Arroyo Yustos, T. de Portugal Fernández del Rivero, F. Albarrán Hernández, and M. Alvarez-Mon Soto, “Estado actual del empleo de citoquinas,” Medicine, vol. 7, no. 126, pp. 5925–5935, 1999.
[31]
C. R. Faltynek, G. L. Princler, J. L. Rossio, et al., “Relationship of the clinical response and binding of recombinant interferon alpha in patients with lymphoproliferative diseases,” Blood, vol. 67, no. 4, pp. 1077–1082, 1986.
[32]
S. Pestka, “The interferon receptors,” Seminars in Oncology, vol. 24, supplement 9, no. 3, pp. 18–40, 1997.
[33]
J. M. Kirkwood, J. Manola, J. Ibrahim, et al., “Análisis conjunto de los estudios del Eastern Cooperative Oncology Group e Intergroup sobre altas dosis de IFN como adjuvante para el melanoma,” Clinical Cancer Research, vol. 10, pp. 1670–1677, 2004.
[34]
A. González Martín and A. J. Moyano Jato, “La inmunoterapia,” in El Siglo de la Oncología Médica, E. Díaz-Rubio, Ed., pp. 55–70, You&Us S. A., Tres Cantos, Madrid, 2000.
[35]
F. M. Foss, “Immunologic mechanisms of antitumor activity,” Seminars in Oncology, vol. 29, 3, supplement 7, pp. 5–11, 2002.
[36]
A. Rodríguez Quesada, M. Medina Torres, and R. Mu？oz-Chápuli, “Modulación farmacológica de la angiogénesis. Terapia antiangiogénica y terapia antivascular,” in Cap. III. Angiogénesis, pp. 85–119, Consejo Social de la Universidad de Málaga, 2004.
[37]
E. Jonasch and F. G. Haluska, “El interferón en la practica clínica oncológica: revisión de la biología, las aplicaciones practicas y los efectos tóxicos del interferón,” The Oncologist, vol. 6, no. 1, pp. 37–59, 2001.
[38]
J. M. Kirkwoo, C. Bender, S. Agarwala, et al., “Mechanisms and management of toxicities associated with high-dose Interferon alpha-2b therapy,” Journal of Clinical Oncology, vol. 20, no. 17, pp. 3703–3718, 2002.
[39]
P. C. Trask, P. Esper, M. Riba, and B. Redman, “Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions,” Journal of Clinical Oncology, vol. 18, no. 11, pp. 2316–2326, 2000.
[40]
K. L. Kilbridge, B. F. Cole, J. M. Kirkwood et al., “Quality-of-life-adjusted survival analysis of high-dose adjuvant interferon alfa-2b for high-risk melanoma patients using intergroup clinical trial data,” Journal of Clinical Oncology, vol. 20, no. 5, pp. 1311–1318, 2002.
[41]
J. L. Gonzalez-Larriba, S. Serrano, and M. Alvarez-Mon, “Análisis coste-efectividad de interferón como tratamiento adjuvante en pacientes con melanoma de alto riesgo en Espa？a,” The European Journal of Cancer, vol. 1, pp. 191–199, 2001.
[42]
J. N. Cormier, Y. Xing, M. Ding, et al., “Cost effectiveness of adjuvant interferon in node-positive melanomas,” Journal of Clinical Oncology, vol. 25, no. 17, pp. 2442–2448, 2007.
[43]
H. Gogas, U. Dafni, D. Bafaloukos, et al., “A randomized phase III trial of 1 month versus 1 year adjuvant high-dose Interferon alfa-2b in patients with resected high risk melanoma,” Journal of Clinical Oncology, vol. 25, no. 18S, abstract 8505, 2007.
[44]
R. J. Sullivan, A. Frankenthaler, W. Wang, et al., “A retrospective comparison of 12 weeks versus 52 weeks of adjuvant interferon for patients with stage IIB, IIC and IIIA melanoma,” Journal of Clinical Oncology, vol. 28, no. 15S, abstract 19013, 2010.
[45]
D. Pectasides, U. Dafni, D. Bafaloukos et al., “Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma,” Journal of Clinical Oncology, vol. 27, no. 6, pp. 939–944, 2009.
[46]
P. Mohr, A. Hauschild, A. Enk, et al., “Intermittent high-dose intranenous interferon alpha 2b for adjuvant treatment of stage III malignant melanoma: an interim analysis of a randomized phase III study (NCT226408),” Journal of Clinical Oncology, vol. 26, abstract 9040, 2008.
[47]
A. M. Eggermont, S. Suciu, R. MacKie, et al., “Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC, 18952): randomised controlled trial,” The Lancet, vol. 366, pp. 1189–1196, 2005.
[48]
B. W. Hancock, K. Wheatley, S. Harris, et al., “Adjuvant interferon in high-risk melanoma: the AIM HIGH Study—United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended-duration interferon Alfa-2a in high-risk resected malignant melanoma,” Journal of Clinical Oncology, vol. 22, no. 1, pp. 53–61, 2004.
[49]
D. A. Cameron, M. C. Cornbleet, R. M. Mackie, et al., “Adjuvant interferon alpha 2b in high risk melanoma- the Scottish study,” British Journal of Cancer, vol. 84, no. 9, pp. 1146–1149, 2001.
[50]
N. Cascinelli, F. Belli, R. M. MacKie, et al., “Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial,” The Lancet, vol. 358, no. 9285, pp. 866–869, 2001.
[51]
E. Richtig, H. P. Soyer, M. Posch, et al., “Prospective, randomized, multicenter, double-blind placebo-controlled trial comparing adjuvant interferon alfa and isotretinoin with interferon alfa alone in stage IIA and IIB melanoma: European Cooperative Adjuvant Melanoma Treatment Study Group,” Journal of Clinical Oncology, vol. 23, no. 34, pp. 8655–8663, 2005.
[52]
S. J. Moschos, H. D. Edington, S. R. Land et al., “Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses,” Journal of Clinical Oncology, vol. 24, no. 19, pp. 3164–3171, 2006.
[53]
A. M. M. Eggermont, S. Suciu, R. Mackie et al., “Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial,” The Lancet, vol. 366, no. 9492, pp. 1189–1196, 2005.
[54]
S. Verma, I. Quirt, D. Mccready, et al., “Systematic review of systemic adjuvant therapy for patients at high risk for recurrent melanoma,” Archives of Dermatology, vol. 143, no. 6, pp. 779–782, 2007.
[55]
K. Wheatley, N. Ives, A. M. Eggermont, et al., “Interferon- as adjuvant therapy for melanoma: an individual patient data meta-analysis of randomized trial,” Journal of Clinical Oncology, vol. 25, no. 18S, abstract 8526, 2007.
[56]
A. Hauschild, M. Weichenthal, K. Rass et al., “Efficacy of low-dose interferon 2a 18 versus 60 months of treatment in patients with primary melanoma of ≥1.5？mm tumor thickness: results of a randomized phase III DeCOG trial,” Journal of Clinical Oncology, vol. 28, no. 5, pp. 841–846, 2010.
[57]
A. M. Eggermont, S. Suciu, M. Santinami et al., “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,” The Lancet, vol. 372, no. 9633, pp. 117–126, 2008.
[58]
A. M. Eggermont, S. Suciu, M. Santimani, et al., “EORTC, 18991: long-term adjuvant pegylated Interferon-alpha 2b (PEG-IFN) compared to observation in resected satege III melanoma, final results of a randomized phase III trial,” Journal of Clinical Oncology, vol. 25, no. 18S, abstract 8504, 2007.
[59]
A. Bottomley, C. Coens, S. Suciu et al., “Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma: a phase III randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group,” Journal of Clinical Oncology, vol. 27, no. 18, pp. 2916–2923, 2009.
[60]
J. J. Grob, T. Jouary, B. Dreno, et al., “Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macro-metastatic nodes: EADO trial,” Journal of Clinical Oncology, vol. 28, no. 15S, abstract LBA8506, 2010.
[61]
S. Mocellin, S. Pasquali, C. R. Rossi, and D. Nitti, “Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis,” Journal of the National Cancer Institute, vol. 102, no. 7, pp. 493–501, 2010.
[62]
B. Lian, L. L. Mao, C. L. Cui, et al., “Phase II randomized study of high-dose interferon alfa-2b (HDI) versus chemotherapy as adjuvant therapy in patients with resected mucosal melanoma,” Journal of Clinical Oncology, vol. 30, supplement, abstact 8506, 2012.
[63]
H. Gogas, J. Ioannovich, U. Dafni, et al., “Prognostic significance of autoimmunity during treatment of melanoma with interferon,” The New England Journal of Medicine, vol. 354, pp. 709–718, 2006.
[64]
M. G. Bouwhuis, S. Suciu, A. Testori et al., “Phase III trial comparing adjuvant treatment with pegylated interferon alfa-2b versus observation: prognostic significance of autoantibodies - EORTC 18991,” Journal of Clinical Oncology, vol. 28, no. 14, pp. 2460–2466, 2010.
[65]
H. Gogas, M. Spyropoulou-Vlachou, U. Dafni, et al., “Correlation of molecular HLA typing and outcome in high-risk melanoma patients receiving adjuvant interferon,” Journal of Clinical Oncology, vol. 24, no. 18S, Abstract 8029, 2006.
[66]
L. E. Spitler, M. L. Grossbard, M. S. Ernstoff et al., “Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor,” Journal of Clinical Oncology, vol. 18, no. 8, pp. 1614–1621, 2000.
[67]
L. E. Spitier, R. W. Weber, S. Cruickshank, et al., “Granulocyte-macrophage colony stimulating factor as adjuvant therapy of melanoma,” Journal of Clinical Oncology, vol. 26, 18S, Abstract 20006, 2008.
[68]
D. H. Lawson, S. J. Lee, A. A. Tarhini, et al., “E4697: phase III cooperative group study of yeast-derived granulocyte macorphage colony-stimulating factor (GM-CSF)versus placebo as adjuvant treatment of patients with completely resected stage III-IV melanoma,” Journal of Clinical Oncology, vol. 28, no. 15S, abstract 8504, 2010.
[69]
M. A. Henderson, B. Burmeister, J. F. Thompson, et al., “Adjuvant radiotherapy and regional lymph node field control in melanoma patients after lymphadenectomy: results of an intergroup randomized trial (ANZMTG 01. 02/TROG 02. 01),” Journal of Clinical Oncology, vol. 27, no. 18S, abstract LBA9084, 2009.
[70]
A. M. M. Eggermont, A. Testori, M. Maio, et al., “Anti-CTLA-4 antibody adjuvant therapy in melanoma,” Seminars in Oncology, vol. 27, no. 5, pp. 455–459, 2010.
[71]
L. H. Camacho, S. Antonia, J. Sosman et al., “Phase I/II trial of tremelimumab in patients with metastatic melanoma,” Journal of Clinical Oncology, vol. 27, no. 7, pp. 1075–1081, 2009.
[72]
A. A. Tarhini, S. J. Moschos, H. Tawbi, et al., “Phase II evaluation of tremelimumab combined with high-dose interferon alpha-2b for metastatic melanoma,” Journal of Clinical Oncology, vol. 28, no. 15S, abstract 8524, 2010.
[73]
F. S. Hodi, S. J. O'Day, D. F. Mcdermott, et al., “Improved survival with Ipilimumab in patients with metastatic melanoma,” The New England Journal of Medicine, vol. 363, no. 8, pp. 711–723, 2010.
[74]
S. Kotapati, P. Lorigan, C. Verduyn, et al., “Overall survival in treatment naive patients with unresectable stage III/IV melanoma: a systematic literature review and network meta-analysis,” Journal of Clinical Oncology, vol. 30, supplement, no. 15, article e19010, 2012.
[75]
L. Thomas, J. D. Wolchok, C. Garbe, et al., “Safety of ipilimumab in patients (pts) with untreated, advanced melanoma alive beyond 2 years: results from a phase III study,” Journal of Clinical Oncology, vol. 30, supplement, no. 15, abstract 8512, 2012.
[76]
S. P. Patel, W.-J. Hwu, K. B. Kim, et al., “Phase II study of the frontlime combination of ipilimumab and temozolamide in patients with metastatic melanoma,” Journal of Clinical Oncology, vol. 30, supplement, no. 15, abstract 8514, 2012.
[77]
A. M. Giacomo, P. A. Ascierto, L. Pilla, et al., “Phase II multicenter trial of ipilimumab combined with fotemustine in patients with metastatic melanoma: the Italian Network for Tumor Biotherapy (NIBI)-M1 trial,” Journal of Clinical Oncology, vol. 30, supplement, no. 15, abstract 8513, 2012.
[78]
J. A. Sosman, K. B. Kim, L. Schuchter, et al., “Survival in BRAF V600-mutant advanced melanoma treated with Vemurafenib,” The New England Journal of Medicine, vol. 366, pp. 707–714, 2012.
[79]
P. B. Chapman, A. Hauschild, C. Robert et al., “Improved survival with vemurafenib in melanoma with BRAF V600E mutation,” New England Journal of Medicine, vol. 364, no. 26, pp. 2507–2516, 2011.
[80]
K. T. Flaherty, C. Robert, P. Hersey, et al., “Improved survival with MEK inhibition in BRAF-mutated melanoma,” The New England Journal of Medicine, vol. 367, pp. 107–114, 2012.
[81]
J. P. Fruehauf, B. Alger, B. Parmakhtiar, et al., “A phase II single arm study of pazopanib and paclitaxel as first-line treatment for unresectable stage III and IV melanoma: interim analysis,” Journal of Clinical Oncology, vol. 30, supplement, no. 15, abstract 8524, 2012.
[82]
K. B. Kim, J. A. Sosman, J. P. Fruehauf, et al., “BEAM: an andomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma,” Journal of Clinical Oncology, vol. 30, no. 1, pp. 34–41, 2012.
[83]
M. Weiss, C. L. Loprinzi, E. T. Creagan, R. J. Dalton, P. Novotny, and J. R. O'Fallon, “Utility of follow-up tests for detecting recurrent disease in patients with malignant melanomas,” Journal of the American Medical Association, vol. 274, no. 21, pp. 1703–1705, 1995.
[84]
M. M. Mooney, M. Kulas, B. McKinley, A. M. Michalek, and W. G. Kraybill, “Impact on survival by method of recurrence detection in stage I and II cutaneous melanoma,” Annals of Surgical Oncology, vol. 5, no. 1, pp. 54–63, 1998.
[85]
D. B. Solit and N. Rosen, “Resistance to BRAF inhibition in melanoma,” The New England Journal of Medicine, vol. 364, no. 8, pp. 772–774, 2011.
