Melanoma - null regimens

From HemOnc.org - A Hematology Oncology Wiki
Revision as of 20:39, 7 February 2020 by Jwarner (talk | contribs) (Created page with "The purpose of this page is to provide references to "null therapy" such as placebo and observation. While not clinically relevant, these references provide further insight in...")
(diff) ← Older revision | Latest revision (diff) | Newer revision → (diff)
Jump to navigation Jump to search

The purpose of this page is to provide references to "null therapy" such as placebo and observation. While not clinically relevant, these references provide further insight into the historical development of the treatment landscape. See the main melanoma page for current regimens.


Adjuvant therapy

Observation

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Eilber et al. 1976 Randomized (C) BCG Seems to have inferior MFS
Veronesi et al. 1982 Phase III (C) 1. BCG Did not meet efficacy endpoints
2. BCG & Dacarbazine Did not meet efficacy endpoints
3. Dacarbazine Did not meet efficacy endpoints
Quirt et al. 1991 Phase III (C) 1. BCG
2. BCG/Levamisole
 Did not meet primary endpoint of OS60
3. Levamisole Might have inferior OS
Meyskens et al. 1994 (SWOG S8049) Phase III (C) Vitamin A Did not meet primary endpoints of DFS/OS
Creagan et al. 1995 Phase III (C) Interferon alfa-2a x 12 wk Did not meet primary endpoints of DFS/OS
Meyskens et al. 1995 (SWOG S8642) Phase III (C) Interferon gamma Did not meet primary endpoints of DFS/OS
Kirkwood et al. 1996 (ECOG E1684) Phase III (C) Interferon alfa-2b Seems to have inferior OS
Pehamberger et al. 1998 Phase III (C) Interferon alfa-2a x 12 m Seems to have inferior DFS
Grob et al. 1998 Phase III (C) Interferon alfa-2a x 18 m Might have inferior OS
Koops et al. 1998 (EORTC 18832) Phase III (C) Prophylactic ILP Did not meet primary endpoints of DFS/OS
Kirkwood et al. 2000 (ECOG E1690) Phase III (C) 1. HD-Interferon alfa-2b x 12 m Seems to have inferior RFS
2. LD-Interferon alfa-2b x 24 m Did not meet primary endpoint of RFS
Cameron et al. 2001 (The Scottish study) Phase III (C) Interferon alfa-2b Did not meet primary endpoint of RFS
Cascinelli et al. 2001 Phase III (C) Interferon alfa-2a Did not meet primary endpoint of OS
Sondak et al. 2002 Phase III (C) Allogeneic tumor vaccine Did not meet primary endpoints of DFS/OS
Hersey et al. 2002 Phase III (C) VMCL Might have inferior OS
Hancock et al. 2003 (AIM HIGH) Phase III (C) Interferon alfa-2a x 24 mo Did not meet primary endpoints of RFS/OS
Kleeberg et al. 2004 (EORTC 18871/DKG 80-1) Phase III (C) 1. Interferon alfa-2b x 12 mo
2. Interferon gamma
3. Iscador M 		Did not meet primary endpoint of DFI
Agarwala et al. 2004 (ECOG E1673) Phase III (C) BCG Did not meet primary endpoints of DFS/OS
Eggermont et al. 2005 (EORTC 18952) Phase III (C) Interferon alfa-2b Might have inferior OS
Eggermont et al. 2008 (EORTC 18991) Phase III (C) Pegylated interferon alfa-2b Seems to have inferior RFS
Hansson et al. 2011 (Nordic IFN trial) Phase III (C) 1. Interferon alfa-2b x 12 mo
2. Interferon alfa-2b x 24 mo 		Did not meet primary endpoint of OS
Corrie et al. 2014 (AVAST-M) Phase III (C) Bevacizumab Did not meet primary endpoint of OS
Agarwala et al. 2017 (ECOG-ACRIN E1697) Phase III (C) Interferon alfa-2b Did not meet primary endpoint of RFS

No treatment after primary resection.

Preceding treatment

References

  1. Eilber FR, Morton DL, Holmes EC, Sparks FC, Ramming KP. Adjuvant immunotherapy with BCG in treatment of regional-lymph-node metastases from malignant melanoma. N Engl J Med. 1976 Jan 29;294(5):237-40. link to original article PubMed
  2. Veronesi U, Adamus J, Aubert C, Bajetta E, Beretta G, Bonadonna G, Bufalino R, Cascinelli N, Cocconi G, Durand J, De Marsillac J, Ikonopisov RL, Kiss B, Lejeune F, MacKie R, Madej G, Mulder H, Mechl Z, Milton GW, Morabito A, Peter H, Priario J, Paul E, Rumke P, Sertoli R, Tomin R. A randomized trial of adjuvant chemotherapy and immunotherapy in cutaneous melanoma. N Engl J Med. 1982 Oct 7;307(15):913-6. link to original article PubMed
  3. Quirt IC, Shelley WE, Pater JL, Bodurtha AJ, McCulloch PB, McPherson TA, Paterson AH, Prentice R, Silver HK, Willan AR, Wilson K, Zee B. Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1991 May;9(5):729-35. link to original article PubMed
  4. SWOG S8049: Meyskens FL Jr, Liu PY, Tuthill RJ, Sondak VK, Fletcher WS, Jewell WR, Samlowski W, Balcerzak SP, Rector DJ, Noyes RD, Costanzi JJ. Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group study. J Clin Oncol. 1994 Oct;12(10):2060-5. link to original article PubMed
  5. Creagan ET, Dalton RJ, Ahmann DL, Jung SH, Morton RF, Langdon RM Jr, Kugler J, Rodrigue LJ. Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clin Oncol. 1995 Nov;13(11):2776-83. link to original article PubMed
  6. SWOG S8642: Meyskens FL Jr, Kopecky KJ, Taylor CW, Noyes RD, Tuthill RJ, Hersh EM, Feun LG, Doroshow JH, Flaherty LE, Sondak VK. Randomized trial of adjuvant human interferon gamma versus observation in high-risk cutaneous melanoma: a Southwest Oncology Group study. J Natl Cancer Inst. 1995 Nov 15;87(22):1710-3. link to original article PubMed
  7. 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 verified protocol PubMed
  8. 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 verified protocol PubMed
  9. 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 verified protocol PubMed
  10. EORTC 18832: Koops HS, Vaglini M, Suciu S, Kroon BB, Thompson JF, Göhl J, Eggermont AM, Di Filippo F, Krementz ET, Ruiter D, Lejeune FJ; European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593. Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. J Clin Oncol. 1998 Sep;16(9):2906-12. link to original article PubMed
  11. 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
  12. 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 verified protocol link to PMC article PubMed
  13. Cascinelli N, Belli F, MacKie RM, Santinami M, Bufalino R, Morabito A. Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet. 2001 Sep 15;358(9285):866-9. link to original article PubMed
  14. Sondak VK, Liu PY, Tuthill RJ, Kempf RA, Unger JM, Sosman JA, Thompson JA, Weiss GR, Redman BG, Jakowatz JG, Noyes RD, Flaherty LE. Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group. J Clin Oncol. 2002 Apr 15;20(8):2058-66. link to original article PubMed
  15. Hersey P, Coates AS, McCarthy WH, Thompson JF, Sillar RW, McLeod R, Gill PG, Coventry BJ, McMullen A, Dillon H, Simes RJ. Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial. J Clin Oncol. 2002 Oct 15;20(20):4181-90. link to original article PubMed
  16. AIM HIGH: Hancock BW, Wheatley K, Harris S, Ives N, Harrison G, Horsman JM, Middleton MR, Thatcher N, Lorigan PC, Marsden JR, Burrows L, Gore M. 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. J Clin Oncol. 2004 Jan 1;22(1):53-61. Epub 2003 Dec 9. link to original article PubMed
  17. EORTC 18871/DKG 80-1: Kleeberg UR, Suciu S, Bröcker EB, Ruiter DJ, Chartier C, Liénard D, Marsden J, Schadendorf D, Eggermont AM; EORTC Melanoma Group in cooperation with the German Cancer Society (DKG). Final results of the EORTC 18871/DKG 80-1 randomised phase III trial: rIFN-alpha2b versus rIFN-gamma versus ISCADOR M versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer. 2004 Feb;40(3):390-402. link to original article PubMed
  18. ECOG E1673: Agarwala SS, Neuberg D, Park Y, Kirkwood JM. Mature results of a phase III randomized trial of bacillus Calmette-Guerin (BCG) versus observation and BCG plus dacarbazine versus BCG in the adjuvant therapy of American Joint Committee on Cancer Stage I-III melanoma (E1673): a trial of the Eastern Oncology Group. Cancer. 2004 Apr 15;100(8):1692-8. link to original article PubMed
  19. 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
    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. link to original article PubMed
  20. 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 verified protocol PubMed
    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 verified protocol PubMed
  21. Nordic IFN trial: Hansson J, Aamdal S, Bastholt L, Brandberg Y, Hernberg M, Nilsson B, Stierner U, von der Maase H; Nordic Melanoma Cooperative Group. Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial. Lancet Oncol. 2011 Feb;12(2):144-52. Epub 2011 Jan 20. link to original article PubMed
  22. 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
  23. 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 PubMed

Placebo

back to top

Regimen

Study Evidence Comparator Comparative Efficacy Comparative Toxicity
Spitler & Sagabiel 1980 Phase III (C) Levamisole Did not meet efficacy endpoints
Wallack et al. 1995 Phase III (C) VMO Did not meet primary endpoints of DFS/OS
Markovic et al. 2002 Phase III (C) Megestrol acetate Did not meet primary endpoint of OS
Eggermont et al. 2015 (EORTC 18071) Phase III (C) Ipilimumab Inferior OS (*) Similar HRQoL
Lawson et al. 2015 (ECOG-ACRIN E4697) Phase III (C) 1. GM-CSF
2. GM-CSF & Peptide vaccine
3. Peptide vaccine 		Did not meet primary endpoints of RFS/OS
Eggermont et al. 2018 (EORTC 1325) Phase III (C) Pembrolizumab Inferior RFS
Dreno et al. 2018 (DERMA) Phase III (C) MAGE-A3 antigen Did not meet primary endpoint of DFS

No active antineoplastic treatment after primary resection. Placed here because one or more randomized clinical trials included a placebo in this disease context. Efficacy in EORTC 18071 is based on the 2016 update. While there was a statistically significant difference in EORTC QLC-C30 scores in EORTC 18071 (in favor of placebo), this difference did not meet the pre-determined threshold for clinically relevance.

Preceding treatment

References

  1. Spitler LE, Sagebiel R. A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma. N Engl J Med. 1980 Nov 13;303(20):1143-7. link to original article PubMed
  2. Wallack MK, Sivanandham M, Balch CM, Urist MM, Bland KI, Murray D, Robinson WA, Flaherty LE, Richards JM, Bartolucci AA, Rosen L. A phase III randomized, double-blind multiinstitutional trial of vaccinia melanoma oncolysate-active specific immunotherapy for patients with stage II melanoma. Cancer. 1995 Jan 1;75(1):34-42. link to original article PubMed
    1. Update: Wallack MK, Sivanandham M, Ditaranto K, Shaw P, Balch CM, Urist MM, Bland KI, Murray D, Robinson WA, Flaherty L, Richards JM, Rosen L, Bartolucci AA. Increased survival of patients treated with a vaccinia melanoma oncolysate vaccine: second interim analysis of data from a phase III, multi-institutional trial. Ann Surg. 1997 Aug;226(2):198-206. link to original article link to PMC article PubMed
  3. Markovic S, Suman VJ, Dalton RJ, Woods JE, Fitzgibbons RJ Jr, Wold LE, Buckner JC, Kugler JW, Mailliard JA, Rowland KM, Krook JE, Brown DW, Tirona MT, Creagan ET. Randomized, placebo-controlled, phase III surgical adjuvant clinical trial of megestrol acetate (Megace) in selected patients with malignant melanoma. Am J Clin Oncol. 2002 Dec;25(6):552-6. link to original article PubMed
  4. EORTC 18071: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Konto C, Hoos A, de Pril V, Gurunath RK, de Schaetzen G, Suciu S, Testori A. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015 May;16(5):522-30. Erratum: Lancet Oncol. 2015 Jun;16(6):e262. Epub 2015 May 27. link to original article contains verified protocol PubMed
    1. Update: Eggermont AM, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bastholt L, Mortier L, Thomas L, Tahir S, Hauschild A, Hassel JC, Hodi FS, Taitt C, de Pril V, de Schaetzen G, Suciu S, Testori A. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016 Nov 10;375(19):1845-1855. Epub 2016 Oct 7. link to original article contains verified protocol PubMed
    2. HRQoL analysis: Coens C, Suciu S, Chiarion-Sileni V, Grob JJ, Dummer R, Wolchok JD, Schmidt H, Hamid O, Robert C, Ascierto PA, Richards JM, Lebbé C, Ferraresi V, Smylie M, Weber JS, Maio M, Bottomley A, Kotapati S, de Pril V, Testori A, Eggermont AM. Health-related quality of life with adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): secondary outcomes of a multinational, randomised, double-blind, phase 3 trial. Lancet Oncol. 2017 Mar;18(3):393-403. Epub 2017 Feb 3. link to PMC article PubMed
  5. ECOG-ACRIN E4697: Lawson DH, Lee S, Zhao F, Tarhini AA, Margolin KA, Ernstoff MS, Atkins MB, Cohen GI, Whiteside TL, Butterfield LH, Kirkwood JM. Randomized, placebo-controlled, phase III trial of yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) versus peptide vaccination versus GM-CSF plus peptide vaccination versus placebo in patients with no evidence of disease after complete surgical resection of locally advanced and/or stage IV melanoma: a trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network cancer research group (E4697). J Clin Oncol. 2015 Dec 1;33(34):4066-76. Epub 2015 Sep 8. link to original article link to PMC article PubMed
  6. EORTC 1325: Eggermont AMM, Blank CU, Mandala M, Long GV, Atkinson V, Dalle S, Haydon A, Lichinitser M, Khattak A, Carlino MS, Sandhu S, Larkin J, Puig S, Ascierto PA, Rutkowski P, Schadendorf D, Koornstra R, Hernandez-Aya L, Maio M, van den Eertwegh AJM, Grob JJ, Gutzmer R, Jamal R, Lorigan P, Ibrahim N, Marreaud S, van Akkooi ACJ, Suciu S, Robert C. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018 May 10;378(19):1789-1801. Epub 2018 Apr 15. link to original article contains verified protocol PubMed
  7. DERMA: Dreno B, Thompson JF, Smithers BM, Santinami M, Jouary T, Gutzmer R, Levchenko E, Rutkowski P, Grob JJ, Korovin S, Drucis K, Grange F, Machet L, Hersey P, Krajsova I, Testori A, Conry R, Guillot B, Kruit WHJ, Demidov L, Thompson JA, Bondarenko I, Jaroszek J, Puig S, Cinat G, Hauschild A, Goeman JJ, van Houwelingen HC, Ulloa-Montoya F, Callegaro A, Dizier B, Spiessens B, Debois M, Brichard VG, Louahed J, Therasse P, Debruyne C, Kirkwood JM. MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2018 Jul;19(7):916-929. Epub 2018 Jun 13. link to original article PubMed

Metastatic or unresectable disease

Placebo

back to top

Regimen

Study Evidence Comparator Comparative Efficacy
Eisen et al. 2010 (MEL-002) Phase III (C) Lenalidomide Did not meet primary endpoint of OS

No active antineoplastic treatment.

References

  1. MEL-002: Eisen T, Trefzer U, Hamilton A, Hersey P, Millward M, Knight RD, Jungnelius JU, Glaspy J. Results of a multicenter, randomized, double-blind phase 2/3 study of lenalidomide in the treatment of pretreated relapsed or refractory metastatic malignant melanoma. Cancer. 2010 Jan 1;116(1):146-54. link to original article PubMed
Retrieved from "https://hemonc.org/w/index.php?title=Melanoma_-_null_regimens&oldid=42750"