Melanoma - historical

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? See the main melanoma page for current regimens.

20 regimens on this page
34 variants on this page


Adjuvant therapy

Bevacizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Corrie et al. 2014 (AVAST-M) 2007-2012 Phase 3 (E-esc) Observation Did not meet primary endpoint of OS1
(HR 0.98, 95% CI 0.82-1.16)

Preceding treatment

Targeted therapy

21-day cycle for 18 cycles (1 year)

References

  1. AVAST-M: Corrie PG, Marshall A, Dunn JA, Middleton MR, Nathan PD, Gore M, Davidson N, Nicholson S, Kelly CG, Marples M, Danson SJ, Marshall E, Houston SJ, Board RE, Waterston AM, Nobes JP, Harries M, Kumar S, Young G, Lorigan P. Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study. Lancet Oncol. 2014 May;15(6):620-30. Epub 2014 Apr 15. Erratum in: Lancet Oncol. 2014 Aug;15(9):e365. Lancet Oncol. 2014 Jun;15(7):e253. link to original article PubMed ISRCTN81261306
    1. Update: Corrie PG, Marshall A, Nathan PD, Lorigan P, Gore M, Tahir S, Faust G, Kelly CG, Marples M, Danson SJ, Marshall E, Houston SJ, Board RE, Waterston AM, Nobes JP, Harries M, Kumar S, Goodman A, Dalgleish A, Martin-Clavijo A, Westwell S, Casasola R, Chao D, Maraveyas A, Patel PM, Ottensmeier CH, Farrugia D, Humphreys A, Eccles B, Young G, Barker EO, Harman C, Weiss M, Myers KA, Chhabra A, Rodwell SH, Dunn JA, Middleton MR; AVAST-M Investigators. Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial. Ann Oncol. 2018 Aug 1;29(8):1843-1852. Erratum in: Ann Oncol. 2019 Dec 1;30(12):2013-2014. Erratum in: Ann Oncol. 2019 Dec;30(12):2013-2014. link to original article link to PMC article PubMed

CVD, IL-2, IFN alfa-2b - sequential biochemotherapy

CVD, IL-2, IFN alfa-2b: Cisplatin, Vinblastine, Dacarbazine, high-dose InterLeukin-2, InterFeroN alfa-2b
bioCT: bioChemoTherapy

Example orders

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Flaherty et al. 2014 (SWOG S0008) 2000-2007 Phase 3 (E-esc) IFN alfa-2b Seems to have superior RFS
Median RFS: 4 vs 1.9 y
(HR 0.75, 95% CI 0.58-0.97)

Did not meet co-primary endpoint of OS
Median OS: 9.9 vs 6.7 y
(HR 0.98, 95% CI 0.74-1.31)

Preceding treatment

Chemotherapy

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36,000,000 units/m2)
  • Interferon alfa-2b (Intron-A) 5,000,000 units/m2 SC once per day on days 1 to 5, 8, 10, 12
    • Doses on days 8, 10, 12 are given as outpatient doses

21-day cycle for 3 cycles

References

  1. SWOG S0008: Flaherty LE, Othus M, Atkins MB, Tuthill RJ, Thompson JA, Vetto JT, Haluska FG, Pappo AS, Sosman JA, Redman BG, Moon J, Ribas A, Kirkwood JM, Sondak VK; CALGB; COG; ECOG; SWOG. Southwest Oncology Group S0008: a phase III trial of high-dose interferon alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup study of Cancer and Leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol. 2014 Nov 20;32(33):3771-8. Epub 2014 Oct 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00006237

Interferon alfa-2a monotherapy

Regimen variant #1, 12 months

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pehamberger et al. 1998 1990-1994 Phase 3 (E-esc) Observation Seems to have superior DFS

Preceding treatment

Immunotherapy

  • Interferon alfa-2a (Roferon-A) as follows:
    • Cycles 1 to 3: 3,000,000 international units SC once per day
    • Cycles 4 to 52: 3,000,000 international units SC once per day on days 1, 3, 5

7-day cycle for 52 cycles (1 year)


Regimen variant #2, 18 months

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Grob et al. 1998 1990-NR Phase 3 (E-esc) Observation Might have superior OS
Hauschild et al. 2010 2001-2004 Phase 3 (C) IFN alfa-2a x 5 y Did not meet primary endpoint of RFS60

Preceding treatment

Immunotherapy

7-day cycle for 78 cycles (18 months)


Regimen variant #3, 24 months

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Garbe et al. 2008 1997-2001 Phase 3 (E-esc) 1. Dacarbazine & IFN alfa-2a Not reported
2. Observation Superior OS
Eigentler et al. 2016 (ML17840) 2004-2007 Phase 3 (C) Peginterferon alfa-2a Did not meet primary endpoint of DMFS Superior toxicity

Preceding treatment

Immunotherapy

7-day cycle for 104 cycles (2 years)

References

  1. Pehamberger H, Soyer HP, Steiner A, Kofler R, Binder M, Mischer P, Pachinger W, Auböck J, Fritsch P, Kerl H, Wolff K; Austrian Malignant Melanoma Cooperative Group. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. J Clin Oncol. 1998 Apr;16(4):1425-9. link to original article contains dosing details in manuscript PubMed
  2. Grob JJ, Dreno B, de la Salmonière P, Delaunay M, Cupissol D, Guillot B, Souteyrand P, Sassolas B, Cesarini JP, Lionnet S, Lok C, Chastang C, Bonerandi JJ; French Cooperative Group on Melanoma. Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. Lancet. 1998 Jun 27;351(9120):1905-10. link to original article contains dosing details in manuscript PubMed
  3. Garbe C, Radny P, Linse R, Dummer R, Gutzmer R, Ulrich J, Stadler R, Weichenthal M, Eigentler T, Ellwanger U, Hauschild A; DeCOG. 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 Jun;19(6):1195-201. Epub 2008 Feb 14. link to original article contains dosing details in abstract PubMed
  4. Hauschild A, Weichenthal M, Rass K, Linse R, Berking C, Böttjer J, Vogt T, Spieth K, Eigentler T, Brockmeyer NH, Stein A, Näher H, Schadendorf D, Mohr P, Kaatz M, Tronnier M, Hein R, Schuler G, Egberts F, Garbe C; DeCOG. Efficacy of low-dose interferon {alpha}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. J Clin Oncol. 2010 Feb 10;28(5):841-6. Epub 2010 Jan 4. link to original article contains dosing details in abstract PubMed
  5. ML17840: Eigentler TK, Gutzmer R, Hauschild A, Heinzerling L, Schadendorf D, Nashan D, Hölzle E, Kiecker F, Becker J, Sunderkötter C, Moll I, Richtig E, Pönitzsch I, Pehamberger H, Kaufmann R, Pföhler C, Vogt T, Berking C, Praxmarer M, Garbe C; Dermatologic Cooperative Oncology Group. Adjuvant treatment with pegylated interferon α-2a versus low-dose interferon α-2a in patients with high-risk melanoma: a randomized phase III DeCOG trial. Ann Oncol. 2016 Aug;27(8):1625-32. Epub 2016 Jun 10. link to original article contains dosing details in manuscript PubMed NCT00204529

Interferon alfa-2b monotherapy

HDI: High-Dose Interferon

Example orders

Regimen variant #1, 3M, 6-month course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cameron et al. 2001 (The Scottish study) NR Phase 3 (E-esc) Observation Did not meet primary endpoint of RFS

Note: The PubMed version of Cameron et al. 2001's abstract says that interferon alfa-2b is given "twice weekly," in contrast to what the actual paper says, "thrice weekly." This is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Preceding treatment

Immunotherapy

6-month course


Regimen variant #2, 3M, 18-month course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Grob et al. 2012 (EADO 2001/CMII) 2003-2005 Phase 3 (C) Peginterferon x 36 mo Did not meet primary endpoint of DFS60

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Immunotherapy

18-month course


Regimen variant #3, 10M/5M, 24-month course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Eggermont et al. 2005 (EORTC 18952) 1996-2000 Phase 3 (E-esc) Observation Might have superior OS1 (secondary endpoint)

1Reported efficacy is based on the 2016 update.

Preceding treatment

Immunotherapy

  • Interferon alfa-2b (Intron-A) as follows:
    • Cycles 1 to 4: 10,000,000 units/m2 (route not specified) once per day on days 1 to 5
    • Cycles 5 to 104: 5,000,000 units/m2 (route not specified) once per day on days 1, 3, 5

7-day cycle for 104 cycles (2 years)


Regimen variant #4, 10M/10M, 12-month course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Eggermont et al. 2005 (EORTC 18952) 1996-2000 Phase 3 (E-esc) Observation Might have superior OS1 (secondary endpoint)

1Reported efficacy is based on the 2016 update.

Preceding treatment

Immunotherapy

  • Interferon alfa-2b (Intron-A) as follows:
    • Cycles 1 to 4: 10,000,000 units/m2 (route not specified) once per day on days 1 to 5
    • Cycles 5 to 52: 10,000,000 units/m2 (route not specified) once per day on days 1, 3, 5

7-day cycle for 52 cycles (1 year)


Regimen variant #5, 15M, 4-week course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pectasides et al. 2009 1998-2004 Phase 3 (E-de-esc) Interferon alfa-2b; 15M/10M x 12 mo Non-inferior RFS (co-primary endpoint)

Preceding treatment

Immunotherapy

7-day cycle for 4 cycles


Regimen variant #6, 15M/9M, 12-month course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lian et al. 2013 2007-2009 Randomized Phase 2 (E-esc) 1. Observation Superior OS (co-primary endpoint)
2. Cisplatin & Temozolomide Inferior RFS (co-primary endpoint)

Preceding treatment

Immunotherapy

  • Interferon alfa-2b (Intron-A) as follows:
    • Cycles 1 to 4: 15,000,000 units/m2 IV once per day on days 1 to 5
    • Cycles 5 to 52: 9,000,000 units/m2 SC once per day on days 1, 3, 5

7-day cycle for 52 cycles (1 year)


Regimen variant #7, 20M, 4-week course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Agarwala et al. 2017 (ECOG-ACRIN E1697) 1998-NR Phase 3 (E-esc) Observation Did not meet primary endpoint of RFS

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Preceding treatment

Immunotherapy

7-day cycle for 4 cycles


Regimen variant #8, 20M/10M, 12-month course

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kirkwood et al. 1996 (ECOG E1684) 1984-1990 Phase 3 (E-RT-esc) Observation Seems to have superior OS (co-primary endpoint)
Kirkwood et al. 2000 (ECOG E1690) 1991-1995 Phase 3 (E-RT-esc) 1. Observation Seems to have superior RFS
2. Interferon alfa-2b; low-dose x 24 mo Not directly compared
Kim et al. 2009 (MDACC ID95-196) 1995-12 to 2003-06 Phase 3 (C) Biochemotherapy Did not meet primary endpoint of RFS
Kirkwood et al. 2001 (ECOG E1694) 1996-1999 Phase 3 (C) GM2-KLH/QS-21 vaccine Superior OS
McMasters et al. 2016 (Sunbelt) 1997-2003 Phase 3 (E-esc) Observation Did not meet co-primary endpoints of DFS/OS
Flaherty et al. 2014 (SWOG S0008) 2000-2007 Phase 3 (C) Biochemotherapy Seems to have inferior RFS
Mohr et al. 2015 (DeCOG MM-ADJ-5) 2003-2009 Phase 3 (C) Intermittent HDI Did not meet primary endpoint of DMFS
Tarhini et al. 2019 (ECOG E1609) 2011-2014 Phase 3 (C) 1. Ipilimumab; 3 mg/kg Seems to have inferior OS
2. Ipilimumab; 10 mg/kg Did not meet primary endpoint of OS

Preceding treatment

Immunotherapy

  • Interferon alfa-2b (Intron-A) as follows:
    • Cycles 1 to 4: 20,000,000 units/m2 IV once per day on days 1 to 5
    • Cycles 5 to 52: 10,000,000 units/m2 SC once per day on days 1, 3, 5

7-day cycle for 52 cycles (1 year)

References

  1. ECOG E1684: Kirkwood JM, Strawderman MH, Ernstoff MS, Smith TJ, Borden EC, Blum RH. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996 Jan;14(1):7-17. link to original article contains dosing details in manuscript PubMed
  2. ECOG E1690: Kirkwood JM, Ibrahim JG, Sondak VK, Richards J, Flaherty LE, Ernstoff MS, Smith TJ, Rao U, Steele M, Blum RH. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000 Jun;18(12):2444-58. link to original article PubMed
  3. ECOG E1694: Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS, Rao U. 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. J Clin Oncol. 2001 May 1;19(9):2370-80. link to original article contains dosing details in manuscript PubMed
  4. The Scottish Study: Cameron DA, Cornbleet MC, Mackie RM, Hunter JA, Gore M, Hancock B, Smyth JF; Scottish Melanoma Group. Adjuvant interferon alpha 2b in high risk melanoma - the Scottish study. Br J Cancer. 2001 May 4;84(9):1146-9. link to original article contains dosing details in manuscript link to PMC article PubMed
  5. EORTC 18952: Eggermont AM, Suciu S, MacKie R, Ruka W, Testori A, Kruit W, Punt CJ, Delauney M, Sales F, Groenewegen G, Ruiter DJ, Jagiello I, Stoitchkov K, Keilholz U, Lienard D; 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 Oct 1;366(9492):1189-96. link to original article PubMed NCT00002763
    1. Update: Eggermont AM, Suciu S, Rutkowski P, Kruit WH, Punt CJ, Dummer R, Salès F, Keilholz U, de Schaetzen G, Testori A; EORTC Melanoma Group. Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB-III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: ulceration of primary is key determinant for IFN-sensitivity. Eur J Cancer. 2016 Mar;55:111-21. Epub 2016 Jan 17. link to original article PubMed
  6. Pectasides D, Dafni U, Bafaloukos D, Skarlos D, Polyzos A, Tsoutsos D, Kalofonos H, Fountzilas G, Panagiotou P, Kokkalis G, Papadopoulos O, Castana O, Papadopoulos S, Stavrinidis E, Vourli G, Ioannovich J, Gogas H. 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 Feb 20;27(6):939-44. Epub 2009 Jan 12. link to original article contains dosing details in abstract PubMed
  7. MDACC ID95-196: Kim KB, Legha SS, Gonzalez R, Anderson CM, Johnson MM, Liu P, Papadopoulos NE, Eton O, Plager C, Buzaid AC, Prieto VG, Hwu WJ, Frost AM, Alvarado G, Hwu P, Ross MI, Gershenwald JE, Lee JE, Mansfield PF, Benjamin RS, Bedikian AY. A randomized phase III trial of biochemotherapy versus interferon-alpha-2b for adjuvant therapy in patients at high risk for melanoma recurrence. Melanoma Res. 2009 Feb;19(1):42-9. link to original article PubMed NCT00002882
  8. EADO 2001/CMII: Grob JJ, Jouary T, Dréno B, Asselineau J, Gutzmer R, Hauschild A, Leccia MT, Landthaler M, Garbe C, Sassolas B, Herbst RA, Guillot B, Chene G, Pehamberger H. Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macrometastatic nodes: an open-label, randomised, phase 3 European Association for Dermato-Oncology (EADO) study. Eur J Cancer. 2013 Jan;49(1):166-74. Epub 2012 Sep 10. link to original article contains dosing details in abstract PubMed NCT00221702
  9. Lian B, Si L, Cui C, Chi Z, Sheng X, Mao L, Li S, Kong Y, Tang B, Guo J. Phase II randomized trial comparing high-dose IFN-α2b with temozolomide plus cisplatin as systemic adjuvant therapy for resected mucosal melanoma. Clin Cancer Res. 2013 Aug 15;19(16):4488-98. Epub 2013 Jul 5. link to original article contains dosing details in manuscript PubMed ChiCTR-TRC-11001798
  10. SWOG S0008: Flaherty LE, Othus M, Atkins MB, Tuthill RJ, Thompson JA, Vetto JT, Haluska FG, Pappo AS, Sosman JA, Redman BG, Moon J, Ribas A, Kirkwood JM, Sondak VK; SWOG; CALGB; COG; ECOG. Southwest Oncology Group S0008: a phase III trial of high-dose interferon alfa-2b versus cisplatin, vinblastine, and dacarbazine, plus interleukin-2 and interferon in patients with high-risk melanoma--an intergroup study of Cancer and Leukemia Group B, Children's Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group. J Clin Oncol. 2014 Nov 20;32(33):3771-8. Epub 2014 Oct 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00006237
  11. DeCOG MM-ADJ-5: Mohr P, Hauschild A, Trefzer U, Enk A, Tilgen W, Loquai C, Gogas H, Haalck T, Koller J, Dummer R, Gutzmer R, Brockmeyer N, Hölzle E, Sunderkötter C, Mauch C, Stein A, Schneider LA, Podda M, Göppner D, Schadendorf D, Weichenthal M. Intermittent high-dose intravenous interferon alfa-2b for adjuvant treatment of stage III melanoma: final analysis of a randomized phase III Dermatologic Cooperative Oncology Group trial. J Clin Oncol. 2015 Dec 1;33(34):4077-84. Epub 2015 Oct 26. link to original article contains dosing details in manuscript PubMed NCT00226408
  12. Sunbelt: McMasters KM, Egger ME, Edwards MJ, Ross MI, Reintgen DS, Noyes RD, Martin RC 2nd, Goydos JS, Beitsch PD, Urist MM, Ariyan S, Sussman JJ, Davidson BS, Gershenwald JE, Hagendoorn LJ, Stromberg AJ, Scoggins CR. Final results of the Sunbelt melanoma trial: a multi-institutional prospective randomized phase III study evaluating the role of adjuvant high-dose interferon alfa-2b and completion lymph node dissection for patients staged by sentinel lymph node biopsy. J Clin Oncol. 2016 Apr 1;34(10):1079-86. Epub 2016 Feb 8. link to original article link to PMC article contains dosing details in manuscript PubMed
  13. ECOG-ACRIN E1697: Agarwala SS, Lee SJ, Yip W, Rao UN, Tarhini AA, Cohen GI, Reintgen DS, Evans TL, Brell JM, Albertini MR, Atkins MB, Dakhil SR, Conry RM, Sosman JA, Flaherty LE, Sondak VK, Carson WE, Smylie MG, Pappo AS, Kefford RF, Kirkwood JM. Phase III randomized study of 4 weeks of high-dose interferon-α-2b in stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) melanoma: a trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017 Mar 10;35(8):885-892. Epub 2017 Jan 30. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003641
  14. ECOG E1609: Tarhini AA, Lee SJ, Hodi FS, Rao UNM, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Phase III Study of Adjuvant Ipilimumab (3 or 10 mg/kg) Versus High-Dose Interferon Alfa-2b for Resected High-Risk Melanoma: North American Intergroup E1609. J Clin Oncol. 2020 Feb 20;38(6):567-575. Epub 2019 Dec 27. link to original article contains dosing details in manuscript PubMed NCT01274338
    1. HRQoL analysis: McLouth LE, Zheng Y, Smith S, Hodi FS, Rao UN, Cohen GI, Amatruda TT, Dakhil SR, Curti BD, Nakhoul I, Chandana SR, Bane CL, Marinier DE, Lee SJ, Sondak VK, Kirkwood JM, Tarhini AA, Wagner LI. Patient-reported tolerability of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk stage III-IV melanoma in phase III trial E1609. Qual Life Res. 2023 Jan;32(1):183-196. Epub 2022 Aug 27. link to original article link to PMC article PubMed

Peginterferon alfa-2b monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Eggermont et al. 2008 (EORTC 18991) 2000-2003 Phase 3 (E-RT-esc) Observation Seems to have superior RFS1 (primary endpoint)
RFS84: 39.1% vs 34.6%
(HR 0.87, 95% CI 0.76-1.00)

No difference in OS (secondary endpoint)

1Reported efficacy is based on the 2012 update.
Patients enrolled in EORTC 18991 had resected stage III melanoma. Given for up to 5 years if ECOG performance status remains 0 or 1.

Preceding treatment

Immunotherapy

7-day cycle for 260 cycles (5 years)

References

  1. EORTC 18991: Eggermont AM, Suciu S, Santinami M, Testori A, Kruit WH, Marsden J, Punt CJ, Salès F, Gore M, Mackie R, Kusic Z, Dummer R, Hauschild A, Musat E, Spatz A, Keilholz U; 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 Jul 12;372(9633):117-26. link to original article contains dosing details in manuscript PubMed NCT00006249
    1. Update: Eggermont AM, Suciu S, Testori A, Santinami M, Kruit WH, Marsden J, Punt CJ, Salès F, Dummer R, Robert C, Schadendorf D, Patel PM, de Schaetzen G, Spatz A, Keilholz U. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012 Nov 1;30(31):3810-8. Epub 2012 Sep 24. link to original article contains dosing details in manuscript PubMed

Metastatic or unresectable disease, first-line

Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ridolfi et al. 2002 1997-1999 Phase 3 (E-esc) Cisplatin, Dacarbazine +/- Carmustine Did not meet primary endpoint of OS

Chemotherapy

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) 4,500,000 units/m2 (Ridolfi et al. 2002 did not clearly specify the frequency and whether this dose was per day or total) SC once per day on days 3 to 5, 8 to 12
  • Interferon alfa-2b (Intron-A) 3,000,000 units/m2 (Ridolfi et al. 2002 did not clearly specify the frequency and whether this dose was per day or total) IM on days 3 to 5 of week 1, then 3 times per week on all later weeks

21-day cycle for 6 cycles

References

  1. Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. link to original article contains dosing details in manuscript PubMed

CVD (Vinblastine)

CVD: Cisplatin, Vinblastine, Dacarbazine

Regimen variant #1, 20/1.2/800

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Atkins et al. 2008 (ECOG E3695) 1997-2002 Phase 3 (C) Sequential biochemotherapy Seems to have inferior PFS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Supportive therapy

21-day cycle for up to 4 cycles


Regimen variant #2, 20/1.6/800

Study Dates of enrollment Evidence
Legha et al. 1989 1986-1987 Phase 2

Chemotherapy

21-day cycles


Regimen variant #3, 20/2/800

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Eton et al. 2002 1993-1999 Phase 3 (C) Sequential biochemotherapy Inferior TTP

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycle for up to 10 cycles

References

  1. Legha SS, Ring S, Papadopoulos N, Plager C, Chawla S, Benjamin R. A prospective evaluation of a triple-drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) for metastatic melanoma. Cancer. 1989 Nov 15;64(10):2024-9. link to original contains dosing details in abstract PubMed
  2. Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002 Apr 15;20(8):2045-52. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
  3. ECOG E3695: Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; ECOG. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008 Dec 10;26(35):5748-54. Epub 2008 Nov 10. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003027

Metastatic or unresectable disease

BCG vaccine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Faries et al. 2017 (MMAIT-IV) 1998-2005 Phase 3 (C) BCG & Canvaxin Did not meet primary endpoint of OS

Immunotherapy

References

  1. MMAIT-IV: Faries MB, Mozzillo N, Kashani-Sabet M, Thompson JF, Kelley MC, DeConti RC, Lee JE, Huth JF, Wagner J, Dalgleish A, Pertschuk D, Nardo C, Stern S, Elashoff R, Gammon G, Morton DL; MMAIT-IV Clinical Trial Group. Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases. Ann Surg Oncol. 2017 Dec;24(13):3991-4000. Epub 2017 Oct 10. link to original article PubMed NCT00052156

BCG & Dacarbazine

BCG & DTIC: Bacillus Calmette-Guérin & Dimethyl Triazeno Imidazole Carboxamide (Dacarbazine)

Regimen

Study Evidence
Gutterman et al. 1974 Non-randomized

Immunotherapy

  • BCG vaccine 600,000,000 viable units by scarification once per day on days 7, 12, 17

Chemotherapy

21-day cycles

References

  1. Gutterman JU, Mavligit G, Gottlieb JA, Burgess MA, McBride CE, Einhorn L, Freireich EJ, Hersh EM. Chemoimmunotherapy of disseminated malignant melanoma with dimethyl triazeno imidazole carboxamide and Bacillus Calmette--Guérin. N Engl J Med. 1974 Sep 19;291(12):592-7. link to original article contains dosing details in manuscript PubMed

BHD

BHD: BCNU (Carmustine), Hydroxyurea, Dacarbazine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Costanzi et al. 1984 (SWOG S7727) NR Phase 3 (C) 1. BHD & Levamisole
2. DTIC & Dactinomycin 		Did not meet endpoint of ORR

Chemotherapy

28-day cycles

References

  1. SWOG S7727: Costanzi JJ, Fletcher WS, Balcerzak SP, Taylor S, Eyre HJ, O'Bryan RM, Al-Sarraf M, Frank J. Combination chemotherapy plus levamisole in the treatment of disseminated malignant melanoma: a Southwest Oncology Group study. Cancer. 1984 Feb 15;53(4):833-6. link to original article contains dosing details in manuscript PubMed

BVD

BVD: BCNU (Carmustine), Vincristine, Dacarbazine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jelić et al. 2002 NR Phase 3 (C) 1. BVD; high-dose
2. Bleomycin, Cisplatin, Vindesine
3. Carmustine & Procarbazine 		Did not meet endpoint of OS

Chemotherapy

28-day cycles

References

  1. Jelić S, Babovic N, Kovcin V, Milicevic N, Milanovic N, Popov I, Radosavljevic D. Comparison of the efficacy of two different dosage dacarbazine-based regimens and two regimens without dacarbazine in metastatic melanoma: a single-centre randomized four-arm study. Melanoma Res. 2002 Feb;12(1):91-8. link to original article contains dosing details in manuscript PubMed

Carboplatin & Dacarbazine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Agarwala et al. 1999 NR Phase 3 (C) Carboplatin, Dacarbazine, Tamoxifen Did not meet primary endpoint of ORR

Chemotherapy

28-day cycle for at least 2 cycles

References

  1. Agarwala SS, Ferri W, Gooding W, Kirkwood JM. A phase III randomized trial of dacarbazine and carboplatin with and without tamoxifen in the treatment of patients with metastatic melanoma. Cancer. 1999 May 1;85(9):1979-84. link to original article contains dosing details in abstract PubMed

CDB

CDB: Cisplatin, Dacarbazine, BCNU (Carmustine)

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Creagan et al. 1999 1991-1996 Phase 3 (C) CDB & Tamoxifen Did not meet co-primary endpoints of PFS/OS
Rusthoven et al. 1996 1992-1995 Phase 3 (E-de-esc) CDB & Tamoxifen Did not meet primary endpoint of ORR

Chemotherapy

42-day cycle for 3 cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ridolfi et al. 2002 1997-1999 Phase 3 (C) Cisplatin, Dacarbazine, IL-2, IFN alfa-2b +/- Carmustine Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for 6 cycles

References

  1. Rusthoven JJ, Quirt IC, Iscoe NA, McCulloch PB, James KW, Lohmann RC, Jensen J, Burdette-Radoux S, Bodurtha AJ, Silver HK, Verma S, Armitage GR, Zee B, Bennett K; National Cancer Institute of Canada Clinical Trials Group. Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. J Clin Oncol. 1996 Jul;14(7):2083-90. link to original article contains dosing details in abstract PubMed
  2. Creagan ET, Suman VJ, Dalton RJ, Pitot HC, Long HJ, Veeder MH, Vukov AM, Rowland KM, Krook JE, Michalak JC. Phase III clinical trial of the combination of cisplatin, dacarbazine, and carmustine with or without tamoxifen in patients with advanced malignant melanoma. J Clin Oncol. 1999 Jun;17(6):1884-90. link to original article contains dosing details in manuscript PubMed
  3. Ridolfi R, Chiarion-Sileni V, Guida M, Romanini A, Labianca R, Freschi A, Lo Re G, Nortilli R, Brugnara S, Vitali P, Nanni O; Italian Melanoma Intergroup. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol. 2002 Mar 15;20(6):1600-7. link to original article contains dosing details in manuscript PubMed

Cisplatin, Dacarbazine, Interferon alfa-2b

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Keilholz et al. 2005 (EORTC 18951) 1995-2000 Phase 3 (C) Cisplatin, Dacarbazine, IFN, IL-2 Did not meet primary endpoint of OS

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Immunotherapy

28-day cycle for up to 4 cycles

References

  1. EORTC 18951: Keilholz U, Punt CJ, Gore M, Kruit W, Patel P, Lienard D, Thomas J, Proebstle TM, Schmittel A, Schadendorf D, Velu T, Negrier S, Kleeberg U, Lehman F, Suciu S, Eggermont AM. Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: a randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol. 2005 Sep 20;23(27):6747-55. link to original article contains dosing details in manuscript PubMed

Cisplatin, Dacarbazine, Tamoxifen

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rosenberg et al. 1999 1993-1997 Phase 3 (C) Cisplatin, Dacarbazine, Tamoxifen, then IFN & IL-2 Did not meet primary endpoint of ORR

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

Endocrine therapy

  • Tamoxifen (Nolvadex) as follows:
    • Cycle 1: 40 mg PO once on day 0, then 10 mg PO twice per day on days 1 to 21
    • Cycle 2: 10 mg PO twice per day on days 1 to 8

21-day cycle for 2 cycles

References

  1. Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, Seipp CA, Einhorn JH, White DE, Steinberg SM. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol. 1999 Mar;17(3):968-75. link to original article contains dosing details in manuscript PubMed

CVD, IL-2, IFN alfa-2b - sequential biochemotherapy

CVD, IL-2, IFN alfa-2b: Cisplatin, Vinblastine, Dacarbazine, high-dose InterLeukin-2, InterFeroN alfa-2b
bioCT: bioChemoTherapy

Example orders

Regimen variant #1, 4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
McDermott et al. 2000 1996-1997 Phase 2
Atkins et al. 2008 (ECOG E3695) 1997-2002 Phase 3 (E-esc) CVD Seems to have superior PFS (co-primary endpoint)

Chemotherapy

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) 9,000,000 units/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36,000,000 units/m2)
  • Interferon alfa-2b (Intron-A) 5,000,000 units/m2 SC once per day on days 1 to 5, 8, 10, 12
    • Doses on days 8, 10, 12 are given as outpatient doses

Supportive therapy

21-day cycle for up to 4 cycles


Regimen variant #2, 5 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Eton et al. 2002 1993-1999 Phase 3 (E-esc) CVD Superior TTP

Chemotherapy

Immunotherapy

42-day cycle for up to 5 cycles


Regimen variant #3, 6 cycles

Study Dates of enrollment Evidence
Legha et al. 1998 1992-1993 Phase 2

Chemotherapy

Immunotherapy

21-day cycle for 6 cycles

References

  1. Legha SS, Ring S, Eton O, Bedikian A, Buzaid AC, Plager C, Papadopoulos N. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 for patients with metastatic melanoma. J Clin Oncol. 1998 May;16(5):1752-9. link to original article contains dosing details in abstract PubMed
  2. McDermott DF, Mier JW, Lawrence DP, van den Brink MR, Clancy MA, Rubin KM, Atkins MB. A phase II pilot trial of concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin 2, and interferon alpha-2B in patients with metastatic melanoma. Clin Cancer Res. 2000 Jun;6(6):2201-8. link to original article contains dosing details in manuscript PubMed
  3. Eton O, Legha SS, Bedikian AY, Lee JJ, Buzaid AC, Hodges C, Ring SE, Papadopoulos NE, Plager C, East MJ, Zhan F, Benjamin RS. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol. 2002 Apr 15;20(8):2045-52. link to original article contains dosing details in manuscript PubMed
  4. ECOG E3695: Atkins MB, Hsu J, Lee S, Cohen GI, Flaherty LE, Sosman JA, Sondak VK, Kirkwood JM; ECOG. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol. 2008 Dec 10;26(35):5748-54. Epub 2008 Nov 10. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00003027

Dacarbazine & Interferon alfa-2a

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Middleton et al. 2000a 1994-1998 Phase 3 (C) DBCT Did not meet primary efficacy endpoints
Hauschild et al. 2001 1994-1998 Phase 3 (C) Dacarbazine, IFN alfa, IL-2 Did not meet primary endpoint of OS

Note: in Hauschild et al. 2001, the interferon is described as "IFN-α2a/b" without further details.

Chemotherapy

Immunotherapy

21-day cycles

References

  1. Middleton MR, Lorigan P, Owen J, Ashcroft L, Lee SM, Harper P, Thatcher N. A randomized phase III study comparing dacarbazine, BCNU, cisplatin and tamoxifen with dacarbazine and interferon in advanced melanoma. Br J Cancer. 2000 Mar;82(6):1158-62. link to original article link to PMC article contains dosing details in manuscript PubMed
  2. Hauschild A, Garbe C, Stolz W, Ellwanger U, Seiter S, Dummer R, Ugurel S, Sebastian G, Nashan D, Linse R, Achtelik W, Mohr P, Kaufmann R, Fey M, Ulrich J, Tilgen W; Dermatologic Cooperative Oncology Group. Dacarbazine and interferon alpha with or without interleukin 2 in metastatic melanoma: a randomized phase III multicentre trial of the Dermatologic Cooperative Oncology Group (DeCOG). Br J Cancer. 2001 Apr 20;84(8):1036-42. link to original article link to PMC article PubMed

Dacarbazine & Tamoxifen

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cocconi et al. 1992 1983-1988 Phase 3 (E-esc) Dacarbazine Seems to have superior OS
Median OS: 48 vs 29 weeks

Chemotherapy

Endocrine therapy

21-day cycles

References

  1. Cocconi G, Bella M, Calabresi F, Tonato M, Canaletti R, Boni C, Buzzi F, Ceci G, Corgna E, Costa P, Lottici R, Papadia F, Sofra MC, Bacchi M. Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen. N Engl J Med. 1992 Aug 20;327(8):516-23. link to original article contains dosing details in manuscript PubMed

Low-dose Interleukin-2

LD IL-2: Low-Dose InterLeukin-2

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Agarwala et al. 2002 1997-1999 Phase 3 (C) LD IL-2 & Histamine Inferior OS

Immunotherapy

  • IL-2 - Aldesleukin (Proleukin) as follows:
    • Weeks 1 & 3: 9,000,000 units SC twice per day on days 1 & 2
    • Weeks 2 & 4: 2,000,000 units SC twice per day on days 1 to 5

6-week cycles

References

  1. Agarwala SS, Glaspy J, O'Day SJ, Mitchell M, Gutheil J, Whitman E, Gonzalez R, Hersh E, Feun L, Belt R, Meyskens F, Hellstrand K, Wood D, Kirkwood JM, Gehlsen KR, Naredi P. Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma. J Clin Oncol. 2002 Jan 1;20(1):125-33. link to original article PubMed

Sargramostim monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Andtbacka et al. 2015 (OPTiM) 2009-2011 Phase 3 (C) T-VEC Inferior DRR

Immunotherapy

28-day cycles

References

  1. OPTiM: Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, Delman KA, Spitler LE, Puzanov I, Agarwala SS, Milhem M, Cranmer L, Curti B, Lewis K, Ross M, Guthrie T, Linette GP, Daniels GA, Harrington K, Middleton MR, Miller WH Jr, Zager JS, Ye Y, Yao B, Li A, Doleman S, VanderWalde A, Gansert J, Coffin RS. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015 Sep 1;33(25):2780-8. Epub 2015 May 26. link to original article contains dosing details in manuscript PubMed NCT00769704
    1. Update: Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, Kaufman HL. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019 Jun 6;7(1):145. link to original article link to PMC article PubMed
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