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Adjuvant therapy of melanoma: is pegylated interferon alfa-2b what we've been waiting for?
Comment
Adjuvant therapy of melanoma: is pegylated interferon alfa-2b what we’ve been waiting for?
www.thelancet.com Vol 372 July 12, 2008
interferon alfa-2b had improved recurrence-free and distant metastasis-free survival, and a non-significant improvement in overall survival. Because more and more patients with stage III melanoma are now diagnosed worldwide with N1 disease, these findings represent a very relevant subset for therapy. Eggermont and coworkers suggest that the effect of therapy is confined to this subset, but, as with any subset analysis, this observation cannot be considered a conclusive guide for therapeutic decision-making. Nonetheless, the idea that adjuvant treatment was beneficial for patients with microscopic nodal disease should focus our attention on whether more patients with microscopic nodal involvement or with sentinel-node-negative melanoma should be receiving adjuvant interferon. In this respect, the results of the Eastern Cooperative Oncology Group E1697 trial (which is evaluating 1 month of high-dose intravenous interferon versus observation in patients with node-negative primary melanomas at least 2 mm in thickness or with any thickness primary and positive sentinel nodes) will be important to better define the spectrum of patients who should be considered for adjuvant therapy. The disparate findings in the microscopic and macroscopic node-positive patients in Eggermont and coworkers’ study and in a previous EORTC trial9 serve as a reminder that our understanding of melanoma’s biology continues to evolve. The observation that primary tumour ulceration was associated with benefit
See Articles page 117
Photolibrary
Although adjuvant therapy of melanoma with interferon alfa is widely used in different doses, schedules, and routes of administration throughout the world, the regimen remains highly controversial.1,2 The controversy centres on whether the efficacy (particularly in terms of improved survival) relative to the toxicity of therapy is sufficient to justify such routine use. Pegylated interferon, widely used for the treatment of hepatitis, seems to be at least equally efficacious as standard recombinant interferon in the treatment of metastatic melanoma, and the available evidence suggests that equi-efficacious doses have somewhat lower acute toxicity.3,4 Moreover, the favourable pharmacokinetic properties of pegylated interferon allow administration on a weekly basis, with sustained exposure to interferon during that entire period. In today’s Lancet, Lex Eggermont and colleagues now show, in a large well-conducted trial from the European Organisation for Research and Treatment of Cancer (EORTC), that pegylated interferon alfa-2b improved recurrence-free survival in patients with resected stage III (lymph-node metastatic) cutaneous melanoma.5 So is this result what the world has been waiting for? Recurrence-free survival is an appropriate endpoint—many patients with melanoma are willing to accept significant toxicity in exchange for a modest improvement in recurrence-free survival, even in the absence of an overall survival effect6—and the weight of evidence that adjuvant interferon in various forms improves recurrence-free survival is now overwhelming.7 But is the lesser toxicity of pegylated interferon alfa2b compared with the high-dose interferon regimen currently used in the USA8 sufficient to persuade sceptical clinicians who demand an overall survival benefit? Will patients accept 5 years of treatment for an absolute benefit in recurrence-free survival of about 6% at 4 years? On the basis of the data in this new study, the strongest case can be made in favour of treatment of the N1 subset, those patients whose metastatic melanoma was discovered on sentinel-node biopsy rather than as a clinically palpable node (N2/3). In the study, patients with N1 disease who were randomised to pegylated
Metastatic melanoma in human lymph node
89
Comment
from pegylated interferon is particularly intriguing, and must be evaluated in the context of other clinical trial data before it can be accepted, but echoes a similar finding from a meta-analysis.7 Ultimately, however, these crude clinicopathological predictors of responsiveness need to be replaced by molecular and immunological markers if we are truly to move toward personalised therapy, as we are seeing in other adjuvant therapy settings such as breast and colon cancer. Looking to the near future, the prospects for combining pegylated interferon alfa-2b with other agents in the adjuvant setting, such as anti-CTLA4 antibodies,10 in an attempt to enhance the generation of autoimmunity (which is strongly associated with a favourable outcome with adjuvant interferon therapy11) are brighter than for the standard 1-year high-dose regimen. It might also be logical to evaluate maintenance therapy with pegylated interferon alfa2b after an initial month of intravenous interferon as used in the high-dose regimen, particularly in patients with clinically evident nodal disease, the subset that appeared to benefit least in the new EORTC trial. So is this pegylated interferon alfa-2b regimen a real advance, a minor variation on the high-dose interferon theme, or a non-starter? For the large group of patients with melanoma found in their sentinel node, we believe this regimen will be an attractive alternative to highdose interferon. Some patients with macroscopic nodal disease who would not tolerate or accept high-dose interferon will also want to consider this approach. But we clearly still need to do better and clinical trials must continue, with pegylated interferon alfa-2b and with other therapies. The so-called final results of Eggermont and co-workers’ trial are not so final yet: 3·8 years median follow-up is too short for final conclusions, especially about the N1 population of patients. The
effect on recurrence-free survival could yet disappear after therapy ends, but further follow-up might show a significant survival advantage for the N1 population— and that would represent the real advance we’ve been waiting for. *Vernon K Sondak, Lawrence E Flaherty H Lee Moffitt Cancer Center and University of South Florida College of Medicine, Tampa, FL 33612, USA (VK); and Karmanos Cancer Institute and Wayne State University School of Medicine, MI, Detroit, USA (LEF) vernon.sondak@moffitt.org We have been paid consultants to and on speakers’ bureaus for Schering-Plough. 1 2
3
4
5
6
7
8
9
10
11
Schucter LM. Adjuvant interferon therapy for melanoma: high-dose, low-dose, no dose, which dose? J Clin Oncol 2004; 22: 7–10. Kirkwood JM, Tarhini AA, Moschos SJ, Panelli MC. Adjuvant therapy with interferon α2b in patients with high-risk stage IIB/III melanoma. Nat Clin Pract Oncol 2008; 5: 2–3. Bukowski R, Ernstoff MS, Gore ME, et al. Pegylated interferon alfa-2b treatment for patients with solid tumors: a phase I/II study. J Clin Oncol 2002; 20: 3841–49. Sondak VK, Daud AI. Pharmacology of cancer biotherapeutics: interferons. In: DeVita VT Jr, Laurence TS, Rosenberg SA, eds. Cancer: principles and practice of oncology, 8th edn. Philadelphia: Lippincott Williams & Wilkins, 2008: 497–505. Eggermont AMM, Suciu S, Santinami M, et al, for the EORTC Melanoma Group. 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: 117–26. Kilbridge KL, Cole BF, Kirkwood JM, 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. J Clin Oncol 2002; 20: 1311–18. Wheatley K, Ives N, Eggermont A, et al. Interferon-α as adjuvant therapy for melanoma: an individual patient data meta-analysis of randomized trials. J Clin Oncol 2007; 25: 478s (abstr). Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U. A pooled analysis of ECOG and Intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 2004; 10: 1670–77. Eggermont AMM, Suciu S, MacKie R, et al, for the EORTC Melanoma Group. 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: 1189–96. Tarhini AA, Moschos SS, Schlesselman JJ, et al. Phase II trial of combination biotherapy of high-dose interferon alfa-2b and tremelimumab for recurrent inoperable stage III or stage IV melanoma. J Clin Oncol 2008; 26: 485s (abstr). Gogas H, Ioannovich J, Dafni U, et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 2006; 354: 709–18.
Global surgery—defining a research agenda Published Online June 25, 2008 DOI:10.1016/S01406736(08)60924-1 See Articles page 139
90
In today’s Lancet, Thomas Weiser and colleagues1 report that there are 234 million major surgical procedures worldwide each year, one for every 25 people. This figure is more than twice the number of yearly births, and seven times the 33·2 million2 people infected with HIV. Because this estimate was
based solely on major procedures, and did not include minor procedures or non-operative surgical care (eg, management of most blunt injuries), the actual surgical workload may be much higher. This massive volume of procedures, along with the attendant risks, clearly qualifies surgical diseases (any illness that www.thelancet.com Vol 372 July 12, 2008
Adjuvant therapy of melanoma: is pegylated interferon alfa-2b what we’ve been waiting for?
www.thelancet.com Vol 372 July 12, 2008
interferon alfa-2b had improved recurrence-free and distant metastasis-free survival, and a non-significant improvement in overall survival. Because more and more patients with stage III melanoma are now diagnosed worldwide with N1 disease, these findings represent a very relevant subset for therapy. Eggermont and coworkers suggest that the effect of therapy is confined to this subset, but, as with any subset analysis, this observation cannot be considered a conclusive guide for therapeutic decision-making. Nonetheless, the idea that adjuvant treatment was beneficial for patients with microscopic nodal disease should focus our attention on whether more patients with microscopic nodal involvement or with sentinel-node-negative melanoma should be receiving adjuvant interferon. In this respect, the results of the Eastern Cooperative Oncology Group E1697 trial (which is evaluating 1 month of high-dose intravenous interferon versus observation in patients with node-negative primary melanomas at least 2 mm in thickness or with any thickness primary and positive sentinel nodes) will be important to better define the spectrum of patients who should be considered for adjuvant therapy. The disparate findings in the microscopic and macroscopic node-positive patients in Eggermont and coworkers’ study and in a previous EORTC trial9 serve as a reminder that our understanding of melanoma’s biology continues to evolve. The observation that primary tumour ulceration was associated with benefit
See Articles page 117
Photolibrary
Although adjuvant therapy of melanoma with interferon alfa is widely used in different doses, schedules, and routes of administration throughout the world, the regimen remains highly controversial.1,2 The controversy centres on whether the efficacy (particularly in terms of improved survival) relative to the toxicity of therapy is sufficient to justify such routine use. Pegylated interferon, widely used for the treatment of hepatitis, seems to be at least equally efficacious as standard recombinant interferon in the treatment of metastatic melanoma, and the available evidence suggests that equi-efficacious doses have somewhat lower acute toxicity.3,4 Moreover, the favourable pharmacokinetic properties of pegylated interferon allow administration on a weekly basis, with sustained exposure to interferon during that entire period. In today’s Lancet, Lex Eggermont and colleagues now show, in a large well-conducted trial from the European Organisation for Research and Treatment of Cancer (EORTC), that pegylated interferon alfa-2b improved recurrence-free survival in patients with resected stage III (lymph-node metastatic) cutaneous melanoma.5 So is this result what the world has been waiting for? Recurrence-free survival is an appropriate endpoint—many patients with melanoma are willing to accept significant toxicity in exchange for a modest improvement in recurrence-free survival, even in the absence of an overall survival effect6—and the weight of evidence that adjuvant interferon in various forms improves recurrence-free survival is now overwhelming.7 But is the lesser toxicity of pegylated interferon alfa2b compared with the high-dose interferon regimen currently used in the USA8 sufficient to persuade sceptical clinicians who demand an overall survival benefit? Will patients accept 5 years of treatment for an absolute benefit in recurrence-free survival of about 6% at 4 years? On the basis of the data in this new study, the strongest case can be made in favour of treatment of the N1 subset, those patients whose metastatic melanoma was discovered on sentinel-node biopsy rather than as a clinically palpable node (N2/3). In the study, patients with N1 disease who were randomised to pegylated
Metastatic melanoma in human lymph node
89
Comment
from pegylated interferon is particularly intriguing, and must be evaluated in the context of other clinical trial data before it can be accepted, but echoes a similar finding from a meta-analysis.7 Ultimately, however, these crude clinicopathological predictors of responsiveness need to be replaced by molecular and immunological markers if we are truly to move toward personalised therapy, as we are seeing in other adjuvant therapy settings such as breast and colon cancer. Looking to the near future, the prospects for combining pegylated interferon alfa-2b with other agents in the adjuvant setting, such as anti-CTLA4 antibodies,10 in an attempt to enhance the generation of autoimmunity (which is strongly associated with a favourable outcome with adjuvant interferon therapy11) are brighter than for the standard 1-year high-dose regimen. It might also be logical to evaluate maintenance therapy with pegylated interferon alfa2b after an initial month of intravenous interferon as used in the high-dose regimen, particularly in patients with clinically evident nodal disease, the subset that appeared to benefit least in the new EORTC trial. So is this pegylated interferon alfa-2b regimen a real advance, a minor variation on the high-dose interferon theme, or a non-starter? For the large group of patients with melanoma found in their sentinel node, we believe this regimen will be an attractive alternative to highdose interferon. Some patients with macroscopic nodal disease who would not tolerate or accept high-dose interferon will also want to consider this approach. But we clearly still need to do better and clinical trials must continue, with pegylated interferon alfa-2b and with other therapies. The so-called final results of Eggermont and co-workers’ trial are not so final yet: 3·8 years median follow-up is too short for final conclusions, especially about the N1 population of patients. The
effect on recurrence-free survival could yet disappear after therapy ends, but further follow-up might show a significant survival advantage for the N1 population— and that would represent the real advance we’ve been waiting for. *Vernon K Sondak, Lawrence E Flaherty H Lee Moffitt Cancer Center and University of South Florida College of Medicine, Tampa, FL 33612, USA (VK); and Karmanos Cancer Institute and Wayne State University School of Medicine, MI, Detroit, USA (LEF) vernon.sondak@moffitt.org We have been paid consultants to and on speakers’ bureaus for Schering-Plough. 1 2
3
4
5
6
7
8
9
10
11
Schucter LM. Adjuvant interferon therapy for melanoma: high-dose, low-dose, no dose, which dose? J Clin Oncol 2004; 22: 7–10. Kirkwood JM, Tarhini AA, Moschos SJ, Panelli MC. Adjuvant therapy with interferon α2b in patients with high-risk stage IIB/III melanoma. Nat Clin Pract Oncol 2008; 5: 2–3. Bukowski R, Ernstoff MS, Gore ME, et al. Pegylated interferon alfa-2b treatment for patients with solid tumors: a phase I/II study. J Clin Oncol 2002; 20: 3841–49. Sondak VK, Daud AI. Pharmacology of cancer biotherapeutics: interferons. In: DeVita VT Jr, Laurence TS, Rosenberg SA, eds. Cancer: principles and practice of oncology, 8th edn. Philadelphia: Lippincott Williams & Wilkins, 2008: 497–505. Eggermont AMM, Suciu S, Santinami M, et al, for the EORTC Melanoma Group. 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: 117–26. Kilbridge KL, Cole BF, Kirkwood JM, 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. J Clin Oncol 2002; 20: 1311–18. Wheatley K, Ives N, Eggermont A, et al. Interferon-α as adjuvant therapy for melanoma: an individual patient data meta-analysis of randomized trials. J Clin Oncol 2007; 25: 478s (abstr). Kirkwood JM, Manola J, Ibrahim J, Sondak V, Ernstoff MS, Rao U. A pooled analysis of ECOG and Intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 2004; 10: 1670–77. Eggermont AMM, Suciu S, MacKie R, et al, for the EORTC Melanoma Group. 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: 1189–96. Tarhini AA, Moschos SS, Schlesselman JJ, et al. Phase II trial of combination biotherapy of high-dose interferon alfa-2b and tremelimumab for recurrent inoperable stage III or stage IV melanoma. J Clin Oncol 2008; 26: 485s (abstr). Gogas H, Ioannovich J, Dafni U, et al. Prognostic significance of autoimmunity during treatment of melanoma with interferon. N Engl J Med 2006; 354: 709–18.
Global surgery—defining a research agenda Published Online June 25, 2008 DOI:10.1016/S01406736(08)60924-1 See Articles page 139
90
In today’s Lancet, Thomas Weiser and colleagues1 report that there are 234 million major surgical procedures worldwide each year, one for every 25 people. This figure is more than twice the number of yearly births, and seven times the 33·2 million2 people infected with HIV. Because this estimate was
based solely on major procedures, and did not include minor procedures or non-operative surgical care (eg, management of most blunt injuries), the actual surgical workload may be much higher. This massive volume of procedures, along with the attendant risks, clearly qualifies surgical diseases (any illness that www.thelancet.com Vol 372 July 12, 2008