Ovarian cancer - null regimens

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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 ovarian cancer page for current regimens.


Adjuvant therapy for early stage disease

Observation

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Young et al. 1990 1976-1984 Phase III (C) Melphalan Did not meet efficacy endpoints
Trimbos et al. 2003 (ACTION) 1990-2000 Phase III (C) Platinum-based chemotherapy Inferior OS (*)
Colombo et al. 2003 (ICON1) 1991-2000 Phase III (C) Platinum-based chemotherapy Inferior OS (*)
Mannel et al. 2011 (GOG-0175) 1998-2006 Phase III (C) Paclitaxel Did not meet primary endpoint of RR

No further treatment. Reported efficacy for ACTION and ICON1 is based on the 2003 pooled update.

Preceding treatment

References

  1. Young RC, Walton LA, Ellenberg SS, Homesley HD, Wilbanks GD, Decker DG, Miller A, Park R, Major F Jr. Adjuvant therapy in stage I and stage II epithelial ovarian cancer: results of two prospective randomized trials. N Engl J Med. 1990 Apr 12;322(15):1021-7. link to original article PubMed
  2. ACTION: Trimbos JB, Vergote I, Bolis G, Vermorken JB, Mangioni C, Madronal C, Franchi M, Tateo S, Zanetta G, Scarfone G, Giurgea L, Timmers P, Coens C, Pecorelli S; EORTC-ACTION collaborators. Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst. 2003 Jan 15;95(2):113-25. link to original article PubMed
    1. Pooled analysis: Trimbos JB, Parmar M, Vergote I, Guthrie D, Bolis G, Colombo N, Vermorken JB, Torri V, Mangioni C, Pecorelli S, Lissoni A, Swart AM; International Collaborative Ovarian Neoplasm 1; EORTC Collaborators-Adjuvant ChemoTherapy un Ovarian Neoplasm. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst. 2003 Jan 15;95(2):105-12. link to original article PubMed
  3. ICON1: Colombo N, Guthrie D, Chiari S, Parmar M, Qian W, Swart AM, Torri V, Williams C, Lissoni A, Bonazzi C; ICON. International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst. 2003 Jan 15;95(2):125-32. link to original article PubMed
    1. Pooled analysis: Trimbos JB, Parmar M, Vergote I, Guthrie D, Bolis G, Colombo N, Vermorken JB, Torri V, Mangioni C, Pecorelli S, Lissoni A, Swart AM; International Collaborative Ovarian Neoplasm 1; EORTC Collaborators-Adjuvant ChemoTherapy un Ovarian Neoplasm. International Collaborative Ovarian Neoplasm trial 1 and Adjuvant ChemoTherapy In Ovarian Neoplasm trial: two parallel randomized phase III trials of adjuvant chemotherapy in patients with early-stage ovarian carcinoma. J Natl Cancer Inst. 2003 Jan 15;95(2):105-12. link to original article PubMed
  4. GOG-0175: Mannel RS, Brady MF, Kohn EC, Hanjani P, Hiura M, Lee R, Degeest K, Cohn DE, Monk BJ, Michael H. A randomized phase III trial of IV carboplatin and paclitaxel × 3 courses followed by observation versus weekly maintenance low-dose paclitaxel in patients with early-stage ovarian carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2011 Jul;122(1):89-94. Epub 2011 May 6. link to original article link to PMC article PubMed NCT00003644

Maintenance after first-line therapy

Observation

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Piccart et al. 2003 (EORTC 55875) 1988-1997 Phase III (C) IP Cisplatin Did not meet primary endpoint of OS
Hall et al. 2004 1990-1997 Phase III (C) IFN alfa-2a Did not meet primary endpoint of OS
De Placido et al. 2004 (MITO-1) 1998-2002 Phase III (C) Topotecan Did not meet primary endpoint of PFS
Pfisterer et al. 2006 (AGO-OVAR 7) 1999-2002 Phase III (C) Topotecan Did not meet primary endpoint of OS
Pecorelli et al. 2009 (After-6 protocol 1) 1999-2006 Phase III (C) Paclitaxel Did not meet primary endpoint of PFS
Berek et al. 2008 (OVA-Gy-17) 2002-NR Phase III (C) Oregovomab Did not meet primary endpoint of TTR
Vergote et al. 2013 (EORTC 55041) 2005-2008 Phase III (C) Erlotinib Did not meet primary endpoint of PFS

No further treatment.

Preceding treatment

References

  1. EORTC 55875: Piccart MJ, Floquet A, Scarfone G, Willemse PH, Emerich J, Vergote I, Giurgea L, Coens C, Awada A, Vermorken JB. Intraperitoneal cisplatin versus no further treatment: 8-year results of EORTC 55875, a randomized phase III study in ovarian cancer patients with a pathologically complete remission after platinum-based intravenous chemotherapy. Int J Gynecol Cancer. 2003 Nov-Dec;13 Suppl 2:196-203. link to original article PubMed
  2. MITO-1: De Placido S, Scambia G, Di Vagno G, Naglieri E, Lombardi AV, Biamonte R, Marinaccio M, Cartenì G, Manzione L, Febbraro A, De Matteis A, Gasparini G, Valerio MR, Danese S, Perrone F, Lauria R, De Laurentiis M, Greggi S, Gallo C, Pignata S. Topotecan compared with no therapy after response to surgery and carboplatin/paclitaxel in patients with ovarian cancer: Multicenter Italian Trials in Ovarian Cancer (MITO-1) randomized study. J Clin Oncol. 2004 Jul 1;22(13):2635-42. link to original article PubMed
  3. Hall GD, Brown JM, Coleman RE, Stead M, Metcalf KS, Peel KR, Poole C, Crawford M, Hancock B, Selby PJ, Perren TJ. Maintenance treatment with interferon for advanced ovarian cancer: results of the Northern and Yorkshire gynaecology group randomised phase III study. Br J Cancer. 2004 Aug 16;91(4):621-6. link to original article link to PMC article PubMed
  4. AGO-OVAR 7: Pfisterer J, Weber B, Reuss A, Kimmig R, du Bois A, Wagner U, Bourgeois H, Meier W, Costa S, Blohmer JU, Lortholary A, Olbricht S, Stähle A, Jackisch C, Hardy-Bessard AC, Möbus V, Quaas J, Richter B, Schröder W, Geay JF, Lück HJ, Kuhn W, Meden H, Nitz U, Pujade-Lauraine E; AGO-OVAR; GINECO. Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst. 2006 Aug 2;98(15):1036-45. link to original article contains verified protocol PubMed
  5. OVA-Gy-17: Berek J, Taylor P, McGuire W, Smith LM, Schultes B, Nicodemus CF. Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer. J Clin Oncol. 2009 Jan 20;27(3):418-25. Epub 2008 Dec 15. link to original article PubMed NCT00050375
  6. After-6 protocol 1: Pecorelli S, Favalli G, Gadducci A, Katsaros D, Panici PB, Carpi A, Scambia G, Ballardini M, Nanni O, Conte P; After 6 Italian Cooperative Group. Phase III trial of observation versus six courses of paclitaxel in patients with advanced epithelial ovarian cancer in complete response after six courses of paclitaxel/platinum-based chemotherapy: final results of the After-6 protocol 1. J Clin Oncol. 2009 Oct 1;27(28):4642-8. Epub 2009 Aug 24. link to original article PubMed
  7. EORTC 55041: Vergote IB, Jimeno A, Joly F, Katsaros D, Coens C, Despierre E, Marth C, Hall M, Steer CB, Colombo N, Lesoin A, Casado A, Reinthaller A, Green J, Buck M, Ray-Coquard I, Ferrero A, Favier L, Reed NS, Curé H, Pujade-Lauraine E. Randomized phase III study of erlotinib versus observation in patients with no evidence of disease progression after first-line platin-based chemotherapy for ovarian carcinoma: a European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group, and Gynecologic Cancer Intergroup study. J Clin Oncol. 2014 Feb 1;32(4):320-6. Epub 2013 Dec 23. link to original article PubMed NCT00263822

Placebo

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hirte et al. 2006 1998-1999 Phase III (C) Tanomastat Did not meet primary endpoint of TTP
Sabbatini et al. 2013 (MIMOSA) 2006-2009 Phase III (C) Abagovomab Did not meet primary endpoint of RFS
Du Bois et al. 2014 (AGO-OVAR 16) 2009-2010 Phase III (C) Pazopanib Inferior PFS
Moore et al. 2018 (SOLO-1) 2013-2015 Phase III (C) Olaparib Inferior PFS

No active antineoplastic treatment after initial treatment.

Preceding treatment

  • MIMOSA: Debulking surgery, then platinum-taxane-based chemotherapy x 6 to 8, with CR
  • AGO-OVAR 16: Debulking surgery (primary or interval) & platinum-taxane-based chemotherapy for at least 5 cycles, with SD or better

References

  1. Hirte H, Vergote IB, Jeffrey JR, Grimshaw RN, Coppieters S, Schwartz B, Tu D, Sadura A, Brundage M, Seymour L; National Cancer Institute of Canada Clinical Trials Group. A phase III randomized trial of BAY 12-9566 (tanomastat) as maintenance therapy in patients with advanced ovarian cancer responsive to primary surgery and paclitaxel/platinum containing chemotherapy: a National Cancer Institute of Canada Clinical Trials Group study. Gynecol Oncol. 2006 Aug;102(2):300-8. Epub 2006 Jan 25. link to original article PubMed
  2. MIMOSA: Sabbatini P, Harter P, Scambia G, Sehouli J, Meier W, Wimberger P, Baumann KH, Kurzeder C, Schmalfeldt B, Cibula D, Bidzinski M, Casado A, Martoni A, Colombo N, Holloway RW, Selvaggi L, Li A, del Campo J, Cwiertka K, Pinter T, Vermorken JB, Pujade-Lauraine E, Scartoni S, Bertolotti M, Simonelli C, Capriati A, Maggi CA, Berek JS, Pfisterer J. Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: a phase III trial of the AGO OVAR, COGI, GINECO, and GEICO--the MIMOSA study. J Clin Oncol. 2013 Apr 20;31(12):1554-61. Epub 2013 Mar 11. link to original article link to PMC article PubMed NCT00418574
  3. AGO-OVAR 16: du Bois A, Floquet A, Kim JW, Rau J, del Campo JM, Friedlander M, Pignata S, Fujiwara K, Vergote I, Colombo N, Mirza MR, Monk BJ, Kimmig R, Ray-Coquard I, Zang R, Diaz-Padilla I, Baumann KH, Mouret-Reynier MA, Kim JH, Kurzeder C, Lesoin A, Vasey P, Marth C, Canzler U, Scambia G, Shimada M, Calvert P, Pujade-Lauraine E, Kim BG, Herzog TJ, Mitrica I, Schade-Brittinger C, Wang Q, Crescenzo R, Harter P. Incorporation of pazopanib in maintenance therapy of ovarian cancer. J Clin Oncol. 2014 Oct 20;32(30):3374-82. Epub 2014 Sep 15. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Kim JW, Mahner S, Wu LY, Shoji T, Kim BG, Zhu JQ, Takano T, Park SY, Kong BH, Wu Q, Wang KL, Ngan HY, Liu JH, Wei LH, Mitrica I, Zhang P, Crescenzo R, Wang Q, Cox CJ, Harter P, du Bois A. Pazopanib maintenance therapy in East Asian women with advanced epithelial ovarian cancer: results from AGO-OVAR16 and an East Asian Study. Int J Gynecol Cancer. 2018 Jan;28(1):2-10. link to original article PubMed
    2. Update: Vergote I, du Bois A, Floquet A, Rau J, Kim JW, Del Campo JM, Friedlander M, Pignata S, Fujiwara K, Colombo N, Mirza MR, Monk BJ, Tsibulak I, Calvert PM, Herzog TJ, Hanker LC, Meunier J, Lee JY, Bologna A, Carrasco-Alfonso MJ, Harter P. Overall survival results of AGO-OVAR16: A phase 3 study of maintenance pazopanib versus placebo in women who have not progressed after first-line chemotherapy for advanced ovarian cancer. Gynecol Oncol. 2019 Nov;155(2):186-191. Epub 2019 Sep 10. link to original article PubMed
  4. SOLO-1: Moore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, Lisyanskaya A, Floquet A, Leary A, Sonke GS, Gourley C, Banerjee S, Oza A, González-Martín A, Aghajanian C, Bradley W, Mathews C, Liu J, Lowe ES, Bloomfield R, DiSilvestro P. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2018 Dec 27;379(26):2495-2505. Epub 2018 Oct 21. link to original article contains protocol PubMed

Maintenance after second-line therapy for platinum-sensitive disease

Placebo

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Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ledermann et al. 2016 (ICON6) 2007-2011 Phase III (C) Cediranib Inferior PFS
Ledermann et al. 2012 (Study 19) 2008-2010 Randomized Phase II (C) Olaparib Might have inferior OS (*)
Mirza et al. 2016 (NOVA) 2013-NR Phase III (C) Niraparib Inferior PFS
Pujade-Lauraine et al. 2017 (SOLO2) 2013-2014 Phase III (C) Olaparib Inferior PFS
Coleman et al. 2017 (ARIEL3) 2014-2016 Phase III (C) Rucaparib Inferior PFS

No further active antineoplastic treatment. Reported efficacy for Study 19 is based on the 2018 update; although p=0.02, the authors state that "the predefined threshold for statistical significance was not met."

Preceding treatment

References

  1. Study 19: Ledermann J1, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Macpherson E, Watkins C, Carmichael J, Matulonis U. Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer. N Engl J Med. 2012 Apr 12;366(15):1382-92. link to original article contains verified protocol PubMed
    1. Update: Ledermann JA, Harter P, Gourley C, Friedlander M, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Fielding A, Spencer S, Rowe P, Lowe E, Hodgson D, Sovak MA, Matulonis U. Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol. 2016 Nov;17(11):1579-1589. Epub 2016 Sep 8. link to orignal article PubMed
    2. Update: Friedlander M, Matulonis U, Gourley C, du Bois A, Vergote I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D, Shirinkin V, Selle F, Fielding A, Lowe ES, McMurtry EL, Spencer S, Rowe P, Mann H, Parry D, Ledermann J. Long-term efficacy, tolerability and overall survival in patients with platinum-sensitive, recurrent high-grade serous ovarian cancer treated with maintenance olaparib capsules following response to chemotherapy. Br J Cancer. 2018 Oct;119(9):1075-1085. Epub 2018 Oct 24. link to original article PubMed
  2. ICON6: Ledermann JA, Embleton AC, Raja F, Perren TJ, Jayson GC, Rustin GJS, Kaye SB, Hirte H, Eisenhauer E, Vaughan M, Friedlander M, González-Martín A, Stark D, Clark E, Farrelly L, Swart AM, Cook A, Kaplan RS, Parmar MKB; ICON. Cediranib in patients with relapsed platinum-sensitive ovarian cancer (ICON6): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016 Mar 12;387(10023):1066-1074. Erratum in: Lancet. 2016 Apr 23;387(10029):1722. link to original article PubMed NCT00532194
  3. NOVA: Mirza MR, Monk BJ, Herrstedt J, Oza AM, Mahner S, Redondo A, Fabbro M, Ledermann JA, Lorusso D, Vergote I, Ben-Baruch NE, Marth C, Mądry R, Christensen RD, Berek JS, Dørum A, Tinker AV, du Bois A, González-Martín A, Follana P, Benigno B, Rosenberg P, Gilbert L, Rimel BJ, Buscema J, Balser JP, Agarwal S, Matulonis UA; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer. N Engl J Med. 2016 Dec 1;375(22):2154-64. Epub 2016 Oct 7. link to original article contains verified protocol PubMed
    1. Subgroup analysis: Del Campo JM, Matulonis UA, Malander S, Provencher D, Mahner S, Follana P, Waters J, Berek JS, Woie K, Oza AM, Canzler U, Gil-Martin M, Lesoin A, Monk BJ, Lund B, Gilbert L, Wenham RM, Benigno B, Arora S, Hazard SJ, Mirza MR. Niraparib Maintenance Therapy in Patients With Recurrent Ovarian Cancer After a Partial Response to the Last Platinum-Based Chemotherapy in the ENGOT-OV16/NOVA Trial. J Clin Oncol. 2019 Nov 10;37(32):2968-2973. Epub 2019 Jun 7. link to original article PubMed
  4. SOLO2: Pujade-Lauraine E, Ledermann JA, Selle F, Gebski V, Penson RT, Oza AM, Korach J, Huzarski T, Poveda A, Pignata S, Friedlander M, Colombo N, Harter P, Fujiwara K, Ray-Coquard I, Banerjee S, Liu J, Lowe ES, Bloomfield R, Pautier P; SOLO2/ENGOT-Ov21 investigators. Olaparib tablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1274-1284. Epub 2017 Jul 25. link to original article contains protocol PubMed
  5. ARIEL3: Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, Colombo N, Weberpals JI, Clamp A, Scambia G, Leary A, Holloway RW, Gancedo MA, Fong PC, Goh JC, O'Malley DM, Armstrong DK, Garcia-Donas J, Swisher EM, Floquet A, Konecny GE, McNeish IA, Scott CL, Cameron T, Maloney L, Isaacson J, Goble S, Grace C, Harding TC, Raponi M, Sun J, Lin KK, Giordano H, Ledermann JA; ARIEL3 investigators. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Oct 28;390(10106):1949-1961. Epub 2017 Sep 12. link to original article link to PMC article PubMed