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Adjuvant Interferon Therapy for Patients at High Risk for Recurrent Melanoma: An Updated Systematic Review
Clinical Oncology 24 (2012) 410e412 Contents lists available at SciVerse ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Editorial
Adjuvant Interferon Therapy for Patients at High Risk for Recurrent Melanoma: An Updated Systematic Review J.M.G. Larkin*, R.A. Fisher, M.E. Gore Melanoma Unit, Department of Medicine, Royal Marsden Hospital, London, UK Received 21 February 2012; accepted 27 March 2012
The systematic review of studies published between July 2005 and July 2010 reported by Petrella and colleagues [1] addresses an important and controversial area in melanoma therapy: adjuvant interferon for those at high risk of recurrent disease. There remains widespread variation in practice globally with regard to the administration of adjuvant interferon in melanoma, and in some countries, such as the USA, there is variation between academic centres. In the UK, adjuvant interferon is rarely given; observation is regarded as the standard of care and clinical trial participation is recommended wherever possible [2]. To take a broad perspective, the adjuvant setting is arguably the most important situation in which systemic therapy is given to treat solid tumours, as it is generally the only setting in which drugs are given with curative intent. Counselling patients regarding adjuvant systemic therapies is, in our experience, complex. A fundamental problem is our current inability to predict those patients who are destined to relapse and those who are not, and the consequent need to rely on historical statistical estimates to advise patients. From a patient’s viewpoint, they may never be destined to relapse and the administration of adjuvant therapy would then be at best a waste of time and at worst significantly impair quality of life or even cause lifethreatening side-effects. In this context, the fact that some adjuvant therapies have been shown to worsen survival from melanoma in clinical trials [3] cannot be ignored. Another scenario is one in which the patient is destined to relapse but the disease is not sensitive to the treatment, so again the administration of adjuvant therapy is futile and potentially toxic. Therefore, the only situation in which the administration of adjuvant therapy is worthwhile is in the patient who is destined to relapse and whose disease is Author for correspondence: J.M.G. Larkin, Melanoma Unit, Department of Medicine, Royal Marsden Hospital, London SW3 6JJ, UK. Tel: þ44-207808-2198; Fax: þ44-207-808-2688. E-mail address: [email protected] (J.M.G. Larkin).
sensitive to the drug. Identification of this scenario is clearly where our research efforts should be focussed. A further critical question for adjuvant therapy is how success should be measured. The downside of treatment is obvious: side-effects of variable degrees are guaranteed from any drug therapy. As oncologists, our primary aim is to cure cancer and this should be reflected in the primary objective of adjuvant therapy: prolongation of (overall) survival. Prolongation of disease- (or relapse-) free survival is another important therapeutic goal, but it cannot necessarily be assumed that prolongation of disease-free survival equates to prolongation of overall survival. Furthermore, a drug with significant side-effects may significantly worsen quality of life for the duration of therapy (perhaps a year or longer) and if the benefit is an average prolongation of disease-free survival of the order of a few months, is this a price worth paying? Seven randomised trials were identified in the systematic review of Petrella and colleagues [1]: three of high-dose (one pegylated) [4e6], one of intermediate-dose [7] and three trials of low-dose interferon [8e10]. One of the low-dose interferon trials was a three-arm study comparing interferon alone and interferon plus chemotherapy with observation alone [9]. Two meta-analyses of adjuvant interferon, one an individual patient data analysis [11,12], and two reports of quality of life data were also included [13,14]. Of the 12 reports included, two have not been fully published and are available only as presentations at meetings. To summarise a complex body of data, many of the trials were too small to detect anything except relatively large differences between treatment arms. In terms of outcome, interferon at low and intermediate doses does not have significant efficacy; the same is true for the combination of immunotherapy and chemotherapy. High-dose interferon (20 106 U/m2/day intravenously for 5 days per week for 4 weeks, then 10 106 U/m2 subcutaneously three times weekly for 48 weeks) unquestionably leads to prolonged disease-free survival, but any effect on overall survival is at
0936-6555/$36.00 Ó 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2012.03.010
J.M.G. Larkin et al. / Clinical Oncology 24 (2012) 410e412
best small. Furthermore, therapy with high-dose interferon is toxic and frequently leads to treatment discontinuation; 45% of patients treated with high-dose, long-term pegylated interferon in the EORTC 18991 trial experienced grade 3 or 4 toxicities, and a third of patients stopped treatment prematurely because of interferon side-effects. A similar range of constitutional side-effects, such as fatigue, anorexia and mood changes, affected 20% of patients treated with moderate-dose interferon, and the same proportion stopped or interrupted treatment for toxicity. Two trials assessed quality of life during low-dose interferon treatment, which was associated with significantly lower functional, global and symptom scores in patients treated with low-dose interferon compared with observation in one report, and worsened fatigue scores in the other. Pegylated interferon (6 mg/kg subcutaneously per week for 8 weeks followed by 3 mg/kg subcutaneously per week for 5 years) also leads to prolonged disease-free survival, but has no effect on overall survival and is associated with inferior quality of life in comparison with observation. We agree with much of the analysis of Petrella and colleagues [1], but would highlight one major issue. It is stated that ‘[disease-free survival] is an appropriate end point in melanoma as it is expected that recurrence of disease would lead to mortality in the majority of cases. It is a meaningful end point in adjuvant melanoma trials as postponing when disease recurs or prolonging the diseasefree period has substantial effects on quality of life’. We disagree, for reasons already discussed, with these contentions and it is our view that disease-free survival should be used as an end point only when it has been proven to be a valid surrogate for overall survival, such as in the case of adjuvant therapy for colorectal cancer [15,16]. In fact, the adjuvant interferon data demonstrate clearly that a significant effect on disease-free survival does not in general translate into a major effect on overall survival. We agree with Petrella and colleagues [1] that recurrence of melanoma in most cases will probably lead to death, but it would appear (on average) that adjuvant interferon can delay melanoma recurrence but have little effect on survival. Furthermore, ‘postponing when disease recurs’ may have ‘substantial effects on quality of life’ but if in order to achieve this, quality of life has been worsened as a consequence of taking adjuvant interferon for 1 year or even 5 years, then this would seem to us to be moot. Controversy surrounding the use of adjuvant interferon will no doubt continue, but ultimately, if this were a very effective treatment, then it would have been widely adopted as a standard of care some time ago. Furthermore, modest efficacy is acceptable for treatments with manageable toxicity, but adjuvant interferon does not meet this criterion. Again, to take a wider view, effective adjuvant systemic therapies have been developed for both breast and colorectal cancer by the use of agents with significant activity in the metastatic setting to treat early stage disease. Interferon does not have significant activity in metastatic melanoma, so it might have been a surprise to find major efficacy in the adjuvant setting, although of course if adjuvant therapy works by eliminating micrometastatic disease
411
then from first principles the setting of low volume disease might be one in which a disproportionate benefit for an immunotherapy might be anticipated. An important message overall in our view is that effective systemic treatments have now finally been developed for advanced melanoma after decades without major progress. Much of the foundation for the development of these treatments is the realisation that melanoma growth and progression is driven by somatic activating mutations in signalling molecules such as BRAF, KIT, NRAS and GNAQ/ GNA11 [17e20]. Active drugs targeting BRAF and KIT are available [21e23] and the anti-CTLA4 antibody ipilimumab has shown an overall survival benefit and the possibility of prolonged disease control in the metastatic setting [24,25]. Clinical trials of these agents in the adjuvant setting are being planned, but what should be the control arm in these studies? We would argue that it should be observation; although we discuss the potential benefits and risks of adjuvant interferon with our patients, we do not recommend it and regard the standard of care in 2012 as clinical trial entry.
References [1] Petrella T, Verma S, Spithoff K, et al. Adjuvant interferon therapy for patients at high risk for recurrent melanoma: an updated systematic review. Clin Oncol 2012;24(6):413e423. [2] Fisher R, Cahalin P, Gore M, et al. A tale of two tumours and a plea for progress. Lancet Oncol 2012;13(2):124e125. [3] Eggermont AM, Suciu S, Ruka W, et al. EORTC 18961: post-operative adjuvant ganglioside GM2-KLH21 vaccination treatment vs observation in stage II (T3-T4N0M0) melanoma: 2nd interim analysis led to an early disclosure of the results. J Clin Oncol 2008;26(Suppl.). abstract 9004. [4] Eggermont AM, Suciu S, Santinami M, 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. Lancet 2008;372(9633):117e126. [5] McMasters KM, Ross MI, Reintgen DS, et al. Final results of the Sunbelt Melanoma Trial. J Clin Oncol 2008;26(Suppl.). abstract 9003. [6] Pectasides D, Dafni U, Bafaloukos D, 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. J Clin Oncol 2009;27(6):939e944. [7] Eggermont AM, Suciu S, MacKie R, 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. Lancet 2005;366(9492): 1189e1196. [8] Stadler R, Luger T, Bieber T, et al. Long-term survival benefit after adjuvant treatment of cutaneous melanoma with dacarbazine and low dose natural interferon alpha: a controlled, randomised multicentre trial. Acta Oncol 2006;45(4):389e399. [9] Garbe C, Radny P, Linse R, et al. Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis. Ann Oncol 2008;19(6):1195e1201. [10] Hauschild A, Weichenthal M, Rass K, et al. Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >¼ 1.5 mm tumor
412
[11]
[12]
[13]
[14]
[15]
[16]
J.M.G. Larkin et al. / Clinical Oncology 24 (2012) 410e412 thickness: results of a randomized phase III DeCOG trial. J Clin Oncol 2010;28(5):841e846. Wheatley K, Ives N, Eggermont AM, et al. Interferon-a as adjuvant therapy for melanoma: an individual patient data meta-analysis of randomised trials. J Clin Oncol 2007;25(18s). abstract 8526. Mocellin S, Pasquali S, Ross CR, et al. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2010;102(7): 493e501. Dixon S, Walters SJ, Turner L, et al. Quality of life and costeffectiveness of interferon-alpha in malignant melanoma: results from randomised trial. Br J Cancer 2006;94(4):492e498. Bottomley A, Coens C, Suciu S, 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. J Clin Oncol 2009; 27(18):2916e2923. Sargent DJ, Patiyil S, Yothers G, et al. End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 2007;25(29):4569e4574. de Gramont A, Hubbard J, Shi Q, et al. Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: simulations based on the
[17] [18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
20,800 patient ACCENT data set. J Clin Oncol 2009;28(3): 460e465. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949e954. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353(20): 2135e2147. Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006;24(26): 4340e4346. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010; 363(23):2191e2199. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507e2516. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011;305(22): 2327e2334. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011; 29(21):2904e2909. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711e723. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364(26):2517e2526.
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Editorial
Adjuvant Interferon Therapy for Patients at High Risk for Recurrent Melanoma: An Updated Systematic Review J.M.G. Larkin*, R.A. Fisher, M.E. Gore Melanoma Unit, Department of Medicine, Royal Marsden Hospital, London, UK Received 21 February 2012; accepted 27 March 2012
The systematic review of studies published between July 2005 and July 2010 reported by Petrella and colleagues [1] addresses an important and controversial area in melanoma therapy: adjuvant interferon for those at high risk of recurrent disease. There remains widespread variation in practice globally with regard to the administration of adjuvant interferon in melanoma, and in some countries, such as the USA, there is variation between academic centres. In the UK, adjuvant interferon is rarely given; observation is regarded as the standard of care and clinical trial participation is recommended wherever possible [2]. To take a broad perspective, the adjuvant setting is arguably the most important situation in which systemic therapy is given to treat solid tumours, as it is generally the only setting in which drugs are given with curative intent. Counselling patients regarding adjuvant systemic therapies is, in our experience, complex. A fundamental problem is our current inability to predict those patients who are destined to relapse and those who are not, and the consequent need to rely on historical statistical estimates to advise patients. From a patient’s viewpoint, they may never be destined to relapse and the administration of adjuvant therapy would then be at best a waste of time and at worst significantly impair quality of life or even cause lifethreatening side-effects. In this context, the fact that some adjuvant therapies have been shown to worsen survival from melanoma in clinical trials [3] cannot be ignored. Another scenario is one in which the patient is destined to relapse but the disease is not sensitive to the treatment, so again the administration of adjuvant therapy is futile and potentially toxic. Therefore, the only situation in which the administration of adjuvant therapy is worthwhile is in the patient who is destined to relapse and whose disease is Author for correspondence: J.M.G. Larkin, Melanoma Unit, Department of Medicine, Royal Marsden Hospital, London SW3 6JJ, UK. Tel: þ44-207808-2198; Fax: þ44-207-808-2688. E-mail address: [email protected] (J.M.G. Larkin).
sensitive to the drug. Identification of this scenario is clearly where our research efforts should be focussed. A further critical question for adjuvant therapy is how success should be measured. The downside of treatment is obvious: side-effects of variable degrees are guaranteed from any drug therapy. As oncologists, our primary aim is to cure cancer and this should be reflected in the primary objective of adjuvant therapy: prolongation of (overall) survival. Prolongation of disease- (or relapse-) free survival is another important therapeutic goal, but it cannot necessarily be assumed that prolongation of disease-free survival equates to prolongation of overall survival. Furthermore, a drug with significant side-effects may significantly worsen quality of life for the duration of therapy (perhaps a year or longer) and if the benefit is an average prolongation of disease-free survival of the order of a few months, is this a price worth paying? Seven randomised trials were identified in the systematic review of Petrella and colleagues [1]: three of high-dose (one pegylated) [4e6], one of intermediate-dose [7] and three trials of low-dose interferon [8e10]. One of the low-dose interferon trials was a three-arm study comparing interferon alone and interferon plus chemotherapy with observation alone [9]. Two meta-analyses of adjuvant interferon, one an individual patient data analysis [11,12], and two reports of quality of life data were also included [13,14]. Of the 12 reports included, two have not been fully published and are available only as presentations at meetings. To summarise a complex body of data, many of the trials were too small to detect anything except relatively large differences between treatment arms. In terms of outcome, interferon at low and intermediate doses does not have significant efficacy; the same is true for the combination of immunotherapy and chemotherapy. High-dose interferon (20 106 U/m2/day intravenously for 5 days per week for 4 weeks, then 10 106 U/m2 subcutaneously three times weekly for 48 weeks) unquestionably leads to prolonged disease-free survival, but any effect on overall survival is at
0936-6555/$36.00 Ó 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.clon.2012.03.010
J.M.G. Larkin et al. / Clinical Oncology 24 (2012) 410e412
best small. Furthermore, therapy with high-dose interferon is toxic and frequently leads to treatment discontinuation; 45% of patients treated with high-dose, long-term pegylated interferon in the EORTC 18991 trial experienced grade 3 or 4 toxicities, and a third of patients stopped treatment prematurely because of interferon side-effects. A similar range of constitutional side-effects, such as fatigue, anorexia and mood changes, affected 20% of patients treated with moderate-dose interferon, and the same proportion stopped or interrupted treatment for toxicity. Two trials assessed quality of life during low-dose interferon treatment, which was associated with significantly lower functional, global and symptom scores in patients treated with low-dose interferon compared with observation in one report, and worsened fatigue scores in the other. Pegylated interferon (6 mg/kg subcutaneously per week for 8 weeks followed by 3 mg/kg subcutaneously per week for 5 years) also leads to prolonged disease-free survival, but has no effect on overall survival and is associated with inferior quality of life in comparison with observation. We agree with much of the analysis of Petrella and colleagues [1], but would highlight one major issue. It is stated that ‘[disease-free survival] is an appropriate end point in melanoma as it is expected that recurrence of disease would lead to mortality in the majority of cases. It is a meaningful end point in adjuvant melanoma trials as postponing when disease recurs or prolonging the diseasefree period has substantial effects on quality of life’. We disagree, for reasons already discussed, with these contentions and it is our view that disease-free survival should be used as an end point only when it has been proven to be a valid surrogate for overall survival, such as in the case of adjuvant therapy for colorectal cancer [15,16]. In fact, the adjuvant interferon data demonstrate clearly that a significant effect on disease-free survival does not in general translate into a major effect on overall survival. We agree with Petrella and colleagues [1] that recurrence of melanoma in most cases will probably lead to death, but it would appear (on average) that adjuvant interferon can delay melanoma recurrence but have little effect on survival. Furthermore, ‘postponing when disease recurs’ may have ‘substantial effects on quality of life’ but if in order to achieve this, quality of life has been worsened as a consequence of taking adjuvant interferon for 1 year or even 5 years, then this would seem to us to be moot. Controversy surrounding the use of adjuvant interferon will no doubt continue, but ultimately, if this were a very effective treatment, then it would have been widely adopted as a standard of care some time ago. Furthermore, modest efficacy is acceptable for treatments with manageable toxicity, but adjuvant interferon does not meet this criterion. Again, to take a wider view, effective adjuvant systemic therapies have been developed for both breast and colorectal cancer by the use of agents with significant activity in the metastatic setting to treat early stage disease. Interferon does not have significant activity in metastatic melanoma, so it might have been a surprise to find major efficacy in the adjuvant setting, although of course if adjuvant therapy works by eliminating micrometastatic disease
411
then from first principles the setting of low volume disease might be one in which a disproportionate benefit for an immunotherapy might be anticipated. An important message overall in our view is that effective systemic treatments have now finally been developed for advanced melanoma after decades without major progress. Much of the foundation for the development of these treatments is the realisation that melanoma growth and progression is driven by somatic activating mutations in signalling molecules such as BRAF, KIT, NRAS and GNAQ/ GNA11 [17e20]. Active drugs targeting BRAF and KIT are available [21e23] and the anti-CTLA4 antibody ipilimumab has shown an overall survival benefit and the possibility of prolonged disease control in the metastatic setting [24,25]. Clinical trials of these agents in the adjuvant setting are being planned, but what should be the control arm in these studies? We would argue that it should be observation; although we discuss the potential benefits and risks of adjuvant interferon with our patients, we do not recommend it and regard the standard of care in 2012 as clinical trial entry.
References [1] Petrella T, Verma S, Spithoff K, et al. Adjuvant interferon therapy for patients at high risk for recurrent melanoma: an updated systematic review. Clin Oncol 2012;24(6):413e423. [2] Fisher R, Cahalin P, Gore M, et al. A tale of two tumours and a plea for progress. Lancet Oncol 2012;13(2):124e125. [3] Eggermont AM, Suciu S, Ruka W, et al. EORTC 18961: post-operative adjuvant ganglioside GM2-KLH21 vaccination treatment vs observation in stage II (T3-T4N0M0) melanoma: 2nd interim analysis led to an early disclosure of the results. J Clin Oncol 2008;26(Suppl.). abstract 9004. [4] Eggermont AM, Suciu S, Santinami M, 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. Lancet 2008;372(9633):117e126. [5] McMasters KM, Ross MI, Reintgen DS, et al. Final results of the Sunbelt Melanoma Trial. J Clin Oncol 2008;26(Suppl.). abstract 9003. [6] Pectasides D, Dafni U, Bafaloukos D, 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. J Clin Oncol 2009;27(6):939e944. [7] Eggermont AM, Suciu S, MacKie R, 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. Lancet 2005;366(9492): 1189e1196. [8] Stadler R, Luger T, Bieber T, et al. Long-term survival benefit after adjuvant treatment of cutaneous melanoma with dacarbazine and low dose natural interferon alpha: a controlled, randomised multicentre trial. Acta Oncol 2006;45(4):389e399. [9] Garbe C, Radny P, Linse R, et al. Adjuvant low-dose interferon {alpha}2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis. Ann Oncol 2008;19(6):1195e1201. [10] Hauschild A, Weichenthal M, Rass K, et al. Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >¼ 1.5 mm tumor
412
[11]
[12]
[13]
[14]
[15]
[16]
J.M.G. Larkin et al. / Clinical Oncology 24 (2012) 410e412 thickness: results of a randomized phase III DeCOG trial. J Clin Oncol 2010;28(5):841e846. Wheatley K, Ives N, Eggermont AM, et al. Interferon-a as adjuvant therapy for melanoma: an individual patient data meta-analysis of randomised trials. J Clin Oncol 2007;25(18s). abstract 8526. Mocellin S, Pasquali S, Ross CR, et al. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 2010;102(7): 493e501. Dixon S, Walters SJ, Turner L, et al. Quality of life and costeffectiveness of interferon-alpha in malignant melanoma: results from randomised trial. Br J Cancer 2006;94(4):492e498. Bottomley A, Coens C, Suciu S, 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. J Clin Oncol 2009; 27(18):2916e2923. Sargent DJ, Patiyil S, Yothers G, et al. End points for colon cancer adjuvant trials: observations and recommendations based on individual patient data from 20,898 patients enrolled onto 18 randomized trials from the ACCENT Group. J Clin Oncol 2007;25(29):4569e4574. de Gramont A, Hubbard J, Shi Q, et al. Association between disease-free survival and overall survival when survival is prolonged after recurrence in patients receiving cytotoxic adjuvant therapy for colon cancer: simulations based on the
[17] [18]
[19]
[20]
[21]
[22]
[23]
[24]
[25]
20,800 patient ACCENT data set. J Clin Oncol 2009;28(3): 460e465. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949e954. Curtin JA, Fridlyand J, Kageshita T, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353(20): 2135e2147. Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol 2006;24(26): 4340e4346. Van Raamsdonk CD, Griewank KG, Crosby MB, et al. Mutations in GNA11 in uveal melanoma. N Engl J Med 2010; 363(23):2191e2199. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507e2516. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011;305(22): 2327e2334. Guo J, Si L, Kong Y, et al. Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 2011; 29(21):2904e2909. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363(8):711e723. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364(26):2517e2526.