Endometrial cancer

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 Summer B. Dewdney, MD
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35 regimens on this page
55 variants on this page


Guidelines

ESMO

NCCN

Neoadjuvant therapy

Placebo

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Regimen

Study Evidence Comparator Comparative Efficacy
Kitson et al. 2018 (PREMIUM) Phase III (C) Metformin Seems not superior

No active antineoplastic treatment prior to surgery.

Subsequent treatment

References

  1. PREMIUM: Kitson SJ, Maskell Z, Sivalingam VN, Allen JL, Ali S, Burns S, Gilmour K, Latheef R, Slade RJ, Pemberton PW, Shaw J, Ryder WD, Kitchener HC, Crosbie EJ. PRE-surgical Metformin In Uterine Malignancy (PREMIUM): a Multi-Center, Randomized Double-Blind, Placebo-Controlled Phase III Trial. Clin Cancer Res. 2019 Apr 15;25(8):2424-2432. Epub 2018 Dec 18. link to original article PubMed

Adjuvant therapy

Carboplatin & Paclitaxel

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Regimen

Study Evidence Comparator Comparative Efficacy
Matei et al. 2019 (GOG 258) Phase III (C) Cisplatin & RT, then Carboplatin & Paclitaxel x 4 Seems not superior

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

References

  1. GOG 258: Matei D, Filiaci V, Randall ME, Mutch D, Steinhoff MM, DiSilvestro PA, Moxley KM, Kim YM, Powell MA, O'Malley DM, Spirtos NM, Small W Jr, Tewari KS, Richards WE, Nakayama J, Matulonis UA, Huang HQ, Miller DS. Adjuvant chemotherapy plus radiation for locally advanced endometrial cancer. N Engl J Med. 2019 Jun 13;380(24):2317-2326. link to original article contains verified protocol PubMed
  2. JGOG2043: Nomura H, Aoki D, Michimae H, Mizuno M, Nakai H, Arai M, Sasagawa M, Ushijima K, Sugiyama T, Saito M, Tokunaga H, Matoda M, Nakanishi T, Watanabe Y, Takahashi F, Saito T, Yaegashi N; Japanese Gynecologic Oncology Group. Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression: A Randomized Clinical Trial. JAMA Oncol. 2019 Mar 21. [Epub ahead of print] link to original article contains verified protocol link to PMC article PubMed

CIM

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CIM: Cisplatin, Ifosfamide, Mesna

Regimen

Study Evidence Comparator Comparative Efficacy
Wolfson et al. 2007 (GOG 150) Phase III (E) Whole abdominal irradiation Might have superior OS

Preceding treatment

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 120 mg/m2 IV over 15 minutes once on day 1, then 1500 mg/m2/day IV continuous infusion over 96 hours, given second, with Ifosfamide (Ifex)
  • Suggested hydration: 1 liter of NS or 1/2 NS over several hours once per day on days 1 to 4, prior to chemotherapy

21-day cycle for 3 cycles

References

  1. GOG 150: Wolfson AH, Brady MF, Rocereto T, Mannel RS, Lee YC, Futoran RJ, Cohn DE, Ioffe OB. A Gynecologic Oncology Group randomized phase III trial of whole abdominal irradiation (WAI) vs cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcoma (CS) of the uterus. Gynecol Oncol. 2007 Nov;107(2):177-85. Epub 2007 Sep 5. link to original article contains verified protocol link to PMC article PubMed

Cisplatin & Doxorubicin

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CD: Cisplatin & Doxorubicin
AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Variant #1, 50/45, capped BSA

Study Evidence Comparator Comparative Efficacy
Homesley et al. 2008 (GOG 184) Phase III (C) CDP Seems not superior

Note: Treatment was to start within 8 weeks of completion of RT.

Preceding treatment

Chemotherapy

Supportive medications

21-day cycle for 6 cycles

Variant #2, 50/60 x 6

Study Evidence Comparator Comparative Efficacy
Nomura et al. 2019 (JGOG2043) Phase III (C) 1. Carboplatin & Paclitaxel
2. Cisplatin & Docetaxel 		Seems not superior

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

Variant #3, 50/60 x 8

Study Evidence Comparator Comparative Efficacy
Randall et al. 2006 (GOG 122) Phase III (E) Whole abdominal irradiation Superior OS

Preceding treatment

Chemotherapy

Supportive hydration

21-day cycle for 8 cycles

References

  1. GOG 122: Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J, Thigpen JT, Benda JA; Gynecologic Oncology Group study. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2006 Jan 1;24(1):36-44. Epub 2005 Dec 5. link to original article contains verified protocol PubMed
  2. GOG 184: Homesley HD, Filiaci V, Gibbons SK, Long HJ, Cella D, Spirtos NM, Morris RT, DeGeest K, Lee R, Montag A. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study. Gynecol Oncol. 2009 Mar;112(3):543-52. Epub 2008 Dec 23. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Spirtos NM, Enserro D, Homesley HD, Gibbons SK, Cella D, Morris RT, DeGeest K, Lee RB, Miller DS. The addition of paclitaxel to doxorubicin and cisplatin and volume-directed radiation does not improve overall survival (OS) or long-term recurrence-free survival (RFS) in advanced endometrial cancer (EC): a randomized phase III NRG/Gynecologic Oncology Group (GOG) study. Gynecol Oncol. 2019 Jul;154(1):13-21. Epub 2019 Apr 30. link to original article PubMed
  3. JGOG2043: Nomura H, Aoki D, Michimae H, Mizuno M, Nakai H, Arai M, Sasagawa M, Ushijima K, Sugiyama T, Saito M, Tokunaga H, Matoda M, Nakanishi T, Watanabe Y, Takahashi F, Saito T, Yaegashi N; Japanese Gynecologic Oncology Group. Effect of Taxane Plus Platinum Regimens vs Doxorubicin Plus Cisplatin as Adjuvant Chemotherapy for Endometrial Cancer at a High Risk of Progression: A Randomized Clinical Trial. JAMA Oncol. 2019 Mar 21. [Epub ahead of print] link to original article contains verified protocol link to PMC article PubMed

Observation

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Regimen

Study Evidence Comparator Comparative Efficacy
Omura et al. 1985 (GOG 20) Phase III (C) Doxorubicin Seems not superior
Keys et al. 2004 (GOG 99) Phase III (C) RT Inferior RFS
Hogberg et al. 2010 (EORTC 55991) Phase III (C) 1. Cisplatin & Doxorubicin
2. Cisplatin & Epirubicin
3. Epirubicin & Paclitaxel
4. Carboplatin & Doxorubicin
5. Carboplatin & Paclitaxel 		Seems to have inferior PFS
Hogberg et al. 2010 (MaNGO ILIADE-III) Phase III (C) Cisplatin & Doxorubicin Seems not superior

No further treatment.

Preceding treatment

Subsequent treatment

  • MaNGO ILIADE-III: RT

References

  1. GOG 20: Omura GA, Blessing JA, Major F, Lifshitz S, Ehrlich CE, Mangan C, Beecham J, Park R, Silverberg S. A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group study. J Clin Oncol. 1985 Sep;3(9):1240-5. link to original article PubMed
  2. GOG 99: Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, Pearlman A, Maiman MA, Bell JG; Gynecologic Oncology Group. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004 Mar;92(3):744-51. Erratum in: Gynecol Oncol. 2004 Jul;94(1):241-2. link to original article PubMed
  3. EORTC 55991/MaNGO ILIADE-III: Hogberg T, Signorelli M, de Oliveira CF, Fossati R, Lissoni AA, Sorbe B, Andersson H, Grenman S, Lundgren C, Rosenberg P, Boman K, Tholander B, Scambia G, Reed N, Cormio G, Tognon G, Clarke J, Sawicki T, Zola P, Kristensen G. Sequential adjuvant chemotherapy and radiotherapy in endometrial cancer--results from two randomised studies. Eur J Cancer. 2010 Sep;46(13):2422-31. Epub 2010 Jul 7. link to SD article link to PMC article PubMed

Radiation therapy

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Comparative Efficacy
Keys et al. 2004 (GOG 99) Phase III (E) Observation Superior RFS
Maggi et al. 2006 Phase III (C) CAP Seems not superior
Susumu et al. 2007 Phase III (C) CAP Seems not superior
Homesley et al. 2008 (GOG 184) Non-randomized portion of RCT
de Boer et al. 2018 (PORTEC-3) Phase III (C) Cisplatin & RT, then Carboplatin & Paclitaxel Inferior FFS

Note: in PORTEC-3, radiation is to start within 4 to 6 weeks after surgery, and no later than 8 weeks; although the co-primary endpoint of FFS was met, OS was not different between the arms and chemoradiotherapy was not recommended. See individual papers for exact dosing details.

Preceding treatment

Radiotherapy

One course

Subsequent treatment

  • GOG 184: CD x 6 versus CDP x 6

References

  1. GOG 99: Keys HM, Roberts JA, Brunetto VL, Zaino RJ, Spirtos NM, Bloss JD, Pearlman A, Maiman MA, Bell JG; Gynecologic Oncology Group. A phase III trial of surgery with or without adjunctive external pelvic radiation therapy in intermediate risk endometrial adenocarcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004 Mar;92(3):744-51. Erratum in: Gynecol Oncol. 2004 Jul;94(1):241-2. link to original article PubMed
  2. Maggi R, Lissoni A, Spina F, Melpignano M, Zola P, Favalli G, Colombo A, Fossati R. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomised trial. Br J Cancer. 2006 Aug 7;95(3):266-71. Epub 2006 Jul 25. link to original article link to PMC article PubMed
  3. Susumu N, Sagae S, Udagawa Y, Niwa K, Kuramoto H, Satoh S, Kudo R; Japanese Gynecologic Oncology Group. Randomized phase III trial of pelvic radiotherapy versus cisplatin-based combined chemotherapy in patients with intermediate- and high-risk endometrial cancer: a Japanese Gynecologic Oncology Group study. Gynecol Oncol. 2008 Jan;108(1):226-33. Epub 2007 Nov 9. link to original article PubMed
  4. GOG 184: Homesley HD, Filiaci V, Gibbons SK, Long HJ, Cella D, Spirtos NM, Morris RT, DeGeest K, Lee R, Montag A. A randomized phase III trial in advanced endometrial carcinoma of surgery and volume directed radiation followed by cisplatin and doxorubicin with or without paclitaxel: A Gynecologic Oncology Group study. Gynecol Oncol. 2009 Mar;112(3):543-52. Epub 2008 Dec 23. link to original article contains verified protocol link to PMC article PubMed
    1. Update: Spirtos NM, Enserro D, Homesley HD, Gibbons SK, Cella D, Morris RT, DeGeest K, Lee RB, Miller DS. The addition of paclitaxel to doxorubicin and cisplatin and volume-directed radiation does not improve overall survival (OS) or long-term recurrence-free survival (RFS) in advanced endometrial cancer (EC): a randomized phase III NRG/Gynecologic Oncology Group (GOG) study. Gynecol Oncol. 2019 Jul;154(1):13-21. Epub 2019 Apr 30. link to original article PubMed
  5. PORTEC-3: de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, Colombo A, Fyles A, Baron MH, Jürgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Carinelli S, Provencher D, Hanzen C, Lutgens LCHW, Smit VTHBM, Singh N, Do V, D'Amico R, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC study group. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Mar;19(3):295-309. Epub 2018 Feb 12. link to original article link to PMC article PubMed

Whole abdominal radiation (WAI)

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Regimen

Study Evidence Comparator Comparative Efficacy
Randall et al. 2006 (GOG 122) Phase III (E) Cisplatin & Doxorubicin Inferior OS
Wolfson et al. 2007 (GOG 150) Phase III (C) CIM Might have inferior OS

Not commonly used but was a comparator arm; here for reference purposes only.

Radiotherapy

References

  1. GOG 122: Randall ME, Filiaci VL, Muss H, Spirtos NM, Mannel RS, Fowler J, Thigpen JT, Benda JA; Gynecologic Oncology Group study. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2006 Jan 1;24(1):36-44. Epub 2005 Dec 5. link to original article contains verified protocol PubMed
  2. GOG 150: Wolfson AH, Brady MF, Rocereto T, Mannel RS, Lee YC, Futoran RJ, Cohn DE, Ioffe OB. A Gynecologic Oncology Group randomized phase III trial of whole abdominal irradiation (WAI) vs cisplatin-ifosfamide and mesna (CIM) as post-surgical therapy in stage I-IV carcinosarcoma (CS) of the uterus. Gynecol Oncol. 2007 Nov;107(2):177-85. Epub 2007 Sep 5. link to original article contains verified protocol link to PMC article PubMed

Chemotherapy for advanced, recurrent, or metastatic disease

Bevacizumab monotherapy

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Regimen

Study Evidence
Aghajanian et al. 2011 Phase II

Chemotherapy

21-day cycles

References

  1. Aghajanian C, Sill MW, Darcy KM, Greer B, McMeekin DS, Rose PG, Rotmensch J, Barnes MN, Hanjani P, Leslie KK. Phase II trial of bevacizumab in recurrent or persistent endometrial cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2011 Jun 1;29(16):2259-65. Epub 2011 May 2. link to original article contains verified protocol link to PMC article PubMed

Carboplatin monotherapy

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Variant #1, 300 mg/m2

Study Evidence Efficacy
van Wijk et al. 2003 Phase II ORR: 13% (95% CI 6-25%)

This dosing is intended for patients previously treated with chemotherapy.

Chemotherapy

28-day cycles

Variant #2, 400 mg/m2

Study Evidence Efficacy
van Wijk et al. 2003 Phase II ORR: 13% (95% CI 6-25%)

Chemotherapy

28-day cycles

References

  1. van Wijk FH, Lhommé C, Bolis G, Scotto di Palumbo V, Tumolo S, Nooij M, de Oliveira CF, Vermorken JB; European Organization for Research and Treatment of Cancer Gynaecological Cancer Group. Phase II study of carboplatin in patients with advanced or recurrent endometrial carcinoma: a trial of the EORTC Gynaecological Cancer Group. Eur J Cancer. 2003 Jan;39(1):78-85. link to original article contains verified protocol PubMed

Carboplatin & Doxorubicin liposomal

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Regimen

Study Evidence
Pignata et al. 2007 (END-1) Phase II

Chemotherapy

Supportive medications

  • "No prophylactic use of G-CSF was recommended. In case of grade 4 neutropaenia, even without fever, therapeutic and prophylactic use of G-CSF was allowed."

28-day cycle for 3 to 6 cycles

All patients received 3 cycles of therapy. If there was no unacceptable toxicity, patients with stable or responsive disease received an additional 3 cycles.

References

  1. END-1: Pignata S, Scambia G, Pisano C, Breda E, Di Maio M, Greggi S, Ferrandina G, Lorusso D, Zagonel V, Febbraro A, Riva N, De Rosa V, Gallo C, Perrone F; Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies Group. A multicentre phase II study of carboplatin plus pegylated liposomal doxorubicin as first-line chemotherapy for patients with advanced or recurrent endometrial carcinoma: the END-1 study of the MITO (Multicentre Italian Trials in Ovarian Cancer and Gynecologic Malignancies) group. Br J Cancer. 2007 Jun 4;96(11):1639-43. Epub 2007 May 8. contains verified protocol link to PMC article PubMed

Carboplatin & Paclitaxel

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Variant #1, 5/175, finite duration

Study Evidence
Pectasides et al. 2008 Phase II

Chemotherapy

21-day cycle for 6 to 9 cycles

Variant #2, 5/175, indefinite

Study Evidence
Hoskins et al. 2001 Phase II
Sorbe et al. 2008 Phase II

Note: this is the lower limit of carboplatin dosing allowed in Hoskins et al. 2001.

Chemotherapy

21-day cycles

Variant #3, 7/175

Study Evidence
Hoskins et al. 2001 Phase II

Note: this is the upper limit of carboplatin dosing allowed in Hoskins et al. 2001.

Chemotherapy

21-day cycles

References

  1. Hoskins PJ, Swenerton KD, Pike JA, Wong F, Lim P, Acquino-Parsons C, Lee N. Paclitaxel and carboplatin, alone or with irradiation, in advanced or recurrent endometrial cancer: a phase II study. J Clin Oncol. 2001 Oct 15;19(20):4048-53. link to original article contains verified protocol PubMed
  2. Pectasides D, Xiros N, Papaxoinis G, Pectasides E, Sykiotis C, Koumarianou A, Psyrri A, Gaglia A, Kassanos D, Gouveris P, Panayiotidis J, Fountzilas G, Economopoulos T. Carboplatin and paclitaxel in advanced or metastatic endometrial cancer. Gynecol Oncol. 2008 May;109(2):250-4. Epub 2008 Mar 4. link to original article contains verified protocol PubMed content property of HemOnc.org
  3. Sorbe B, Andersson H, Boman K, Rosenberg P, Kalling M. Treatment of primary advanced and recurrent endometrial carcinoma with a combination of carboplatin and paclitaxel-long-term follow-up. Int J Gynecol Cancer. 2008 Jul-Aug;18(4):803-8. Epub 2007 Oct 18. link to original article contains verified protocol PubMed
  4. Retrospective: Shechter-Maor G, Bruchim I, Ben-Harim Z, Altaras M, Fishman A. Combined chemotherapy regimen of carboplatin and paclitaxel as adjuvant treatment for papillary serous and clear cell endometrial cancer. Int J Gynecol Cancer. 2009 May;19(4):662-4. link to original article PubMed

CIM

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CIM: Cisplatin, Ifosfamide, Mesna

Regimen

Study Evidence Comparator Comparative Efficacy
Sutton et al. 2000 (GOG 108) Phase III (E) Ifosfamide Seems to have superior PFS

Chemotherapy

Supportive medications

References

  1. GOG 108: Sutton G, Brunetto VL, Kilgore L, Soper JT, McGehee R, Olt G, Lentz SS, Sorosky J, Hsiu JG. A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group study. Gynecol Oncol. 2000 Nov;79(2):147-53. link to original article PubMed

Cisplatin & Doxorubicin

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AP: Adriamycin (Doxorubicin) & Platinol (Cisplatin)

Variant #1, 50/45

Study Evidence Comparator Comparative Efficacy
Fleming et al. 2004a (GOG 177) Phase III (C) Cisplatin, Doxorubicin, Paclitaxel Seems to have inferior OS

Note: body surface area was capped at 2 m2. This dosage was for patients with previous pelvic radiation or who were greater than 65 years old.

Chemotherapy

21-day cycle for 7 cycles

Variant #2, 50/60, capped BSA

Study Evidence Comparator Comparative Efficacy
Fleming et al. 2004a (GOG 177) Phase III (C) Cisplatin, Doxorubicin, Paclitaxel Seems to have inferior OS

Note: body surface area was capped at 2 m2.

Chemotherapy

21-day cycle for 7 cycles

Variant #3, 50/60, no cap on BSA

Study Evidence Comparator Comparative Efficacy
Fleming et al. 2004b (GOG 163) Phase III (C) Doxorubicin & Paclitaxel Seems not superior
Thigpen et al. 2004 (GOG 107) Phase III (E) Doxorubicin Seems to have superior PFS

Chemotherapy

Supportive hydration

21-day cycle for up to 8 cycles

Variant #4, 60/60

Study Evidence Comparator Comparative Efficacy
Gallion et al. 2003 (GOG 139) Phase III (C) Chronomodulated Cisplatin & Doxorubicin Seems not superior

Chemotherapy

21-day cycle for up to 8 cycles

References

  1. GOG 139: Gallion HH, Brunetto VL, Cibull M, Lentz SS, Reid G, Soper JT, Burger RA, Andersen W; Gynecologic Oncology Group study. Randomized phase III trial of standard timed doxorubicin plus cisplatin versus circadian timed doxorubicin plus cisplatin in stage III and IV or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2003 Oct 15;21(20):3808-13. link to original article contains protocol PubMed
  2. GOG 177: Fleming GF, Brunetto VL, Cella D, Look KY, Reid GC, Munkarah AR, Kline R, Burger RA, Goodman A, Burks RT. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004 Jun 1;22(11):2159-66. link to original article contains verified protocol PubMed
  3. GOG 163: Fleming GF, Filiaci VL, Bentley RC, Herzog T, Sorosky J, Vaccarello L, Gallion H. Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study. Ann Oncol. 2004 Aug;15(8):1173-8. link to original article contains protocol PubMed
  4. GOG 107: Thigpen JT, Brady MF, Homesley HD, Malfetano J, DuBeshter B, Burger RA, Liao S. Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004 Oct 1;22(19):3902-8. link to original article contains protocol PubMed

Cisplatin, Doxorubicin, Paclitaxel

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TAP: Taxol (Paclitaxel), Adriamycin (Doxorubicin), Platinol (Cisplatin)

Regimen

Study Evidence Comparator Comparative Efficacy
Fleming et al. 2004 (GOG 177) Phase III (E) Cisplatin & Doxorubicin Seems to have superior OS

Note: body surface area capped at 2.0 m2.

Chemotherapy

Supportive medications

21-day cycle for 7 cycles

References

  1. GOG 177: Fleming GF, Brunetto VL, Cella D, Look KY, Reid GC, Munkarah AR, Kline R, Burger RA, Goodman A, Burks RT. Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004 Jun 1;22(11):2159-66. link to original article contains verified protocol PubMed

Cisplatin & Paclitaxel

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Regimen

Study Evidence
Dimopoulos et al. 2000 Phase II

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

References

  1. Dimopoulos MA, Papadimitriou CA, Georgoulias V, Moulopoulos LA, Aravantinos G, Gika D, Karpathios S, Stamatelopoulos S. Paclitaxel and cisplatin in advanced or recurrent carcinoma of the endometrium: long-term results of a phase II multicenter study. Gynecol Oncol. 2000 Jul;78(1):52-7. link to original article contains verified protocol PubMed

Dactinomycin monotherapy

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Regimen

Study Evidence
Moore et al. 1999 Phase II

Chemotherapy

28-day cycles

References

  1. Moore DH, Blessing JA, Dunton C, Buller RE, Reid GC. Dactinomycin in the treatment of recurrent or persistent endometrial carcinoma: A Phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 1999 Dec;75(3):473-5. link to original article contains verified protocol PubMed

Doxorubicin monotherapy

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Variant #1, 7 cycles

Study Evidence Comparator Comparative Efficacy
van Wijk et al. 2003 (EORTC 55872) Phase III (C) Cisplatin & Doxorubicin Might have inferior OS

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

Chemotherapy

28-day cycle for up to 7 cycles

Variant #2, 8 cycles

Study Evidence Comparator Comparative Efficacy
Thigpen et al. 1979 Phase II
Omura et al. 1983 (GOG 21) Phase III (C) Dacarbazine & Doxorubicin Seems not superior
Muss et al. 1985 (GOG 42) Phase III (C) AC Seems not superior
Thigpen et al. 1994 (GOG 48) Phase III (C) AC Seems not superior
Thigpen et al. 2004 (GOG 107) Phase III (C) Cisplatin & Doxorubicin Seems to have inferior PFS

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

Chemotherapy

21-day cycle for up to 8 cycles

References

  1. Thigpen JT, Buchsbaum HJ, Mangan C, Blessing JA. Phase II trial of adriamycin in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. Cancer Treat Rep. 1979 Jan;63(1):21-7. PubMed
  2. GOG 21: Omura GA, Major FJ, Blessing JA, Sedlacek TV, Thigpen JT, Creasman WT, Zaino RJ. A randomized study of adriamycin with and without dimethyl triazenoimidazole carboxamide in advanced uterine sarcomas. Cancer. 1983 Aug 15;52(4):626-32. link to original article PubMed
  3. GOG 42: Muss HB, Bundy B, DiSaia PJ, Homesley HD, Fowler WC Jr, Creasman W, Yordan E. Treatment of recurrent or advanced uterine sarcoma: a randomized trial of doxorubicin versus doxorubicin and cyclophosphamide (a phase III trial of the Gynecologic Oncology Group). Cancer. 1985 Apr 15;55(8):1648-53. link to original article PubMed
  4. GOG 48: Thigpen JT, Blessing JA, DiSaia PJ, Yordan E, Carson LF, Evers C. A randomized comparison of doxorubicin alone versus doxorubicin plus cyclophosphamide in the management of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 1994 Jul;12(7):1408-14. link to original article contains protocol PubMed
  5. EORTC 55872: van Wijk FH, Aapro MS, Bolis G, Chevallier B, van der Burg ME, Poveda A, de Oliveira CF, Tumolo S, Scotto di Palumbo V, Piccart M, Franchi M, Zanaboni F, Lacave AJ, Fontanelli R, Favalli G, Zola P, Guastalla JP, Rosso R, Marth C, Nooij M, Presti M, Scarabelli C, Splinter TA, Ploch E, Beex LV, ten Bokkel Huinink W, Forni M, Melpignano M, Blake P, Kerbrat P, Mendiola C, Cervantes A, Goupil A, Harper PG, Madronal C, Namer M, Scarfone G, Stoot JE, Teodorovic I, Coens C, Vergote I, Vermorken JB; European Organisation for Research and Treatment of Cancer Gynaecological Cancer Group. Doxorubicin versus doxorubicin and cisplatin in endometrial carcinoma: definitive results of a randomised study (55872) by the EORTC Gynaecological Cancer Group. Ann Oncol. 2003 Mar;14(3):441-8. Erratum in: Ann Oncol. 2003 May;14(5):811. link to original article contains verified protocol PubMed
  6. GOG 107: Thigpen JT, Brady MF, Homesley HD, Malfetano J, DuBeshter B, Burger RA, Liao S. Phase III trial of doxorubicin with or without cisplatin in advanced endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2004 Oct 1;22(19):3902-8. link to original article contains protocol PubMed

Ifosfamide monotherapy

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Variant #1, 1200 mg/m2 (3 days/cycle)

Study Evidence Comparator Comparative Efficacy
Homesley et al. 2007 (GOG 161) Phase III (C) Ifosfamide & Paclitaxel Seems to have inferior OS

Note: GOG 161 specifies that PO Mesna (Mesnex) is to be taken in 3 divided doses, but only lists 2 time points for its use. The timing of the middle dose is estimated based on other references. This dosage is intended for patients with previous radiation.

Chemotherapy

Supportive medications

  • Mesna (Mesnex) 2000 mg IV over 12 hours once per day on days 1 to 3, starting 15 minutes before Ifosfamide (Ifex) (total dose per cycle: 6000 mg/m2)
    • Alternate PO dosing: 1330 mg PO three times per day on days 1 to 3, taken 1 hour before, 4 hours after, and 8 hours after Ifosfamide (Ifex) (total dose per cycle: 11,970 mg)
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 4, to continue until ANC is greater than or equal to 2000/uL

21-day cycle for 8 cycles

Variant #2, 1500 mg/m2 (5 days/cycle)

Study Evidence Comparator Comparative Efficacy
Sutton et al. 2000 (GOG 108) Phase III (C) CIM Seems to have inferior PFS

Chemotherapy

Supportive medications

21-day cycle for 8 cycles

Variant #3, 1600 mg/m2 (3 days/cycle)

Study Evidence Comparator Comparative Efficacy
Homesley et al. 2007 (GOG 161) Phase III (C) Ifosfamide & Paclitaxel Seems to have inferior OS

Note: GOG 161 specifies that PO Mesna (Mesnex) is to be taken in 3 divided doses, but only lists 2 time points for its use. The timing of the middle dose is estimated based on other references.

Chemotherapy

  • Ifosfamide (Ifex) 1600 mg/m2 IV once per day on days 1 to 3
    • Dosage for patients with previous radiation: 1200 mg/m2 IV once per day on days 1 to 3

Supportive medications

  • Mesna (Mesnex) 2000 mg IV over 12 hours once per day on days 1 to 3, starting 15 minutes before Ifosfamide (Ifex) (total dose per cycle: 6000 mg/m2)
    • Alternate PO dosing: 1330 mg PO three times per day on days 1 to 3, taken 1 hour before, 4 hours after, and 8 hours after Ifosfamide (Ifex) (total dose per cycle: 11,970 mg)
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 4, to continue until ANC is greater than or equal to 2000/uL

21-day cycle for 8 cycles

References

  1. GOG 108: Sutton G, Brunetto VL, Kilgore L, Soper JT, McGehee R, Olt G, Lentz SS, Sorosky J, Hsiu JG. A phase III trial of ifosfamide with or without cisplatin in carcinosarcoma of the uterus: A Gynecologic Oncology Group study. Gynecol Oncol. 2000 Nov;79(2):147-53. link to original article contains verified protocol PubMed
  2. GOG 161: Homesley HD, Filiaci V, Markman M, Bitterman P, Eaton L, Kilgore LC, Monk BJ, Ueland FR; Gynecologic Oncology Group. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group study. J Clin Oncol. 2007 Feb 10;25(5):526-31. link to original article contains verified protocol PubMed

Ifosfamide & Paclitaxel

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Regimen

Study Evidence Comparator Comparative Efficacy
Homesley et al. 2007 (GOG 161) Phase III (E) Ifosfamide Seems to have superior OS

Note: GOG 161 specifies that PO Mesna (Mesnex) is to be taken in 3 divided doses, but only lists 2 time points for its use. The timing of the middle dose is estimated based on other references.

Chemotherapy

  • Ifosfamide (Ifex) 1600 mg/m2 IV once per day on days 1 to 3
    • Dosage for patients with previous radiation: 1200 mg/m2 IV once per day on days 1 to 3
  • Paclitaxel (Taxol) 135 mg/m2 IV over 3 hours once on day 1

Supportive medications

21-day cycle for 8 cycles

References

  1. GOG 161: Homesley HD, Filiaci V, Markman M, Bitterman P, Eaton L, Kilgore LC, Monk BJ, Ueland FR; Gynecologic Oncology Group. Phase III trial of ifosfamide with or without paclitaxel in advanced uterine carcinosarcoma: a Gynecologic Oncology Group study. J Clin Oncol. 2007 Feb 10;25(5):526-31. link to original article contains verified protocol PubMed

Lenvatinib & Pembrolizumab

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Regimen

Study Evidence
Makker et al. 2019 (KEYNOTE-146) Phase II (RT)

Chemotherapy

Immunotherapy

21-day cycles

References

  1. KEYNOTE-146: Makker V, Rasco D, Vogelzang NJ, Brose MS, Cohn AL, Mier J, Di Simone C, Hyman DM, Stepan DE, Dutcus CE, Schmidt EV, Guo M, Sachdev P, Shumaker R, Aghajanian C, Taylor M. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019 May;20(5):711-718. Epub 2019 Mar 25. link to original article contains protocol PubMed

Paclitaxel monotherapy

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Variant #1, 175 mg/m2

Study Evidence Comparator Comparative Efficacy
Lissoni et al. 1996 Phase II
Lincoln et al. 2003 Phase II
McMeekin et al. 2015 Phase III (C) Ixabepilone Seems to have superior OS

Note: in Lincoln et al. 2003, this was the dosage for patients with previous pelvic radiation.

Chemotherapy

Supportive medications

21-day cycles

Variant #2, 200 mg/m2

Study Evidence
Ball et al. 1996 Phase II
Lincoln et al. 2003 Phase II

Note: in Ball et al. 1996, this was the dosage for patients with previous pelvic radiation.

Chemotherapy

  • Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
    • Ball et al. 1996 gave as a 24 hour continuous infusion
    • Dose can be changed to 135 or 110 mg/m2 depending on toxicity

Supportive medications

21-day cycles

Variant #3, 250 mg/m2

Study Evidence
Ball et al. 1996 Phase II

Chemotherapy

  • Paclitaxel (Taxol) 250 mg/m2 IV continuous infusion over 24 hours, started on day 1
    • Dosage for patients with previous pelvic radiation: 200 mg/m2 IV continuous infusion over 24 hours, started on day 1
    • Dose can be changed to 200, 170, 135, 110 mg/m2 depending on toxicity

Supportive medications

21-day cycles

References

  1. Ball HG, Blessing JA, Lentz SS, Mutch DG. A phase II trial of paclitaxel in patients with advanced or recurrent adenocarcinoma of the endometrium: a Gynecologic Oncology Group study. Gynecol Oncol. 1996 Aug;62(2):278-81. link to original article contains verified protocol PubMed
  2. Lissoni A, Zanetta G, Losa G, Gabriele A, Parma G, Mangioni C. Phase II study of paclitaxel as salvage treatment in advanced endometrial cancer. Ann Oncol. 1996 Oct;7(8):861-3. link to original article contains verified protocol PubMed
  3. Lincoln S, Blessing JA, Lee RB, Rocereto TF. Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2003 Mar;88(3):277-81. link to original article contains verified protocol PubMed
  4. McMeekin S, Dizon D, Barter J, Scambia G, Manzyuk L, Lisyanskaya A, Oaknin A, Ringuette S, Mukhopadhyay P, Rosenberg J, Vergote I. Phase III randomized trial of second-line ixabepilone versus paclitaxel or doxorubicin in women with advanced endometrial cancer. Gynecol Oncol. 2015 Jul;138(1):18-23. Epub 2015 Apr 26. link to original article contains protocol PubMed

Pembrolizumab monotherapy

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Regimen

Study Evidence
Ott et al. 2017 (KEYNOTE-028) Phase II
Le et al. 2017 (KEYNOTE-016) Phase II, <20 pts of this subtype

Note: KEYNOTE-016 was an expansion to a CRC-specific trial.

Immunotherapy

14-day cycle for up to 52 cycles (2 years)

References

  1. KEYNOTE-028: Ott PA, Bang YJ, Berton-Rigaud D, Elez E, Pishvaian MJ, Rugo HS, Puzanov I, Mehnert JM, Aung KL, Lopez J, Carrigan M, Saraf S, Chen M, Soria JC. Safety and antitumor activity of pembrolizumab in advanced programmed death ligand 1-positive endometrial cancer: results from the KEYNOTE-028 study. J Clin Oncol. 2017 Aug 1;35(22):2535-2541. Epub 2017 May 10. link to original article contains protocol PubMed
  2. KEYNOTE-016: Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017 Jul 28;357(6349):409-413. Epub 2017 Jun 8. link to original article link to PMC article contains verified protocol in supplement PubMed

Temsirolimus monotherapy

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Regimen

Study Evidence
Oza et al. 2011 Phase II

Chemotherapy

28-day cycles

References

  1. Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, Gotlieb WH, Hoskins PJ, Ghatage P, Tonkin KS, Mackay HJ, Mazurka J, Sederias J, Ivy P, Dancey JE, Eisenhauer EA. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J Clin Oncol. 2011 Aug 20;29(24):3278-85. Epub 2011 Jul 25. link to original article contains verified protocol link to PMC article PubMed

Topotecan monotherapy

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Regimen

Study Evidence
Wadler et al. 2003 (ECOG E3E93) Phase II

Chemotherapy

  • Topotecan (Hycamtin) 1.5 mg/m2 IV once per day on days 1 to 5
    • Dosage for patients with previous pelvic radiation: 1.2 mg/m2, which can be increased to the 1.5 mg/m2 dose in later cycles if there are no toxicities higher than grade 1

21-day cycles

References

  1. ECOG E3E93: Wadler S, Levy DE, Lincoln ST, Soori GS, Schink JC, Goldberg G. Topotecan is an active agent in the first-line treatment of metastatic or recurrent endometrial carcinoma: Eastern Cooperative Oncology Group Study E3E93. J Clin Oncol. 2003 Jun 1;21(11):2110-4. link to original article contains verified protocol PubMed

Endocrine therapy for advanced, recurrent, or metastatic disease

Anastrozole monotherapy

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Regimen

Study Evidence
Rose et al. 2000 Phase II

Hormonotherapy

Continued indefinitely

References

  1. Rose PG, Brunetto VL, VanLe L, Bell J, Walker JL, Lee RB. A phase II trial of anastrozole in advanced recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2000 Aug;78(2):212-6. link to original article contains verified protocol PubMed

Medroxyprogesterone monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Kelley & Baker 1961 Non-randomized
Thigpen et al. 1999 Phase III (C) High-dose medroxyprogesterone Seems not superior

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm. Kelley & Baker 1961 examined a variety of progestins and is included for historic interest.

Hormonotherapy

Continued indefinitely

References

  1. Kelley RM, Baker WH. Progestational agents in the treatment of carcinoma of the endometrium. N Engl J Med. 1961 Feb 2;264:216-22. link to original article PubMed
  2. Thigpen JT, Brady MF, Alvarez RD, Adelson MD, Homesley HD, Manetta A, Soper JT, Given FT. Oral medroxyprogesterone acetate in the treatment of advanced or recurrent endometrial carcinoma: a dose-response study by the Gynecologic Oncology Group. J Clin Oncol. 1999 Jun;17(6):1736-44. link to original article contains verified protocol PubMed

Medroxyprogesterone & Tamoxifen

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Regimen

Study Evidence
Whitney et al. 2004 Phase II

Hormonotherapy

Continued indefinitely

References

  1. Whitney CW, Brunetto VL, Zaino RJ, Lentz SS, Sorosky J, Armstrong DK, Lee RB; Gynecologic Oncology Group study. Phase II study of medroxyprogesterone acetate plus tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004 Jan;92(1):4-9. link to original article contains verified protocol PubMed

Megestrol monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Kelley & Baker 1961 Non-randomized
Pandya et al. 2001 (ECOG E4882) Randomized Phase II (C) Megestrol & Tamoxifen Seems not superior

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm. Kelley & Baker 1961 examined a variety of progestins and is included for historic interest.

Hormonotherapy

Continued indefinitely

References

  1. Kelley RM, Baker WH. Progestational agents in the treatment of carcinoma of the endometrium. N Engl J Med. 1961 Feb 2;264:216-22. link to original article PubMed
  2. Pandya KJ, Yeap BY, Weiner LM, Krook JE, Erban JK, Schinella RA, Davis TE. Megestrol and tamoxifen in patients with advanced endometrial cancer: an Eastern Cooperative Oncology Group Study (E4882). Am J Clin Oncol. 2001 Feb;24(1):43-6. link to original article contains verified protocol PubMed

Megestrol & Tamoxifen

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Regimen

Study Evidence Comparator Comparative Efficacy
Pandya et al. 2001 (ECOG E4882) Randomized Phase II (E) Megestrol Seems not superior
Fiorica et al. 2004 Phase II

Hormonotherapy, part 1

21-day cycles, alternating with tamoxifen

Hormonotherapy, part 2

21-day cycles, alternating with megestrol

References

  1. ECOG E4882: Pandya KJ, Yeap BY, Weiner LM, Krook JE, Erban JK, Schinella RA, Davis TE. Megestrol and tamoxifen in patients with advanced endometrial cancer: an Eastern Cooperative Oncology Group Study (E4882). Am J Clin Oncol. 2001 Feb;24(1):43-6. link to original article contains verified protocol PubMed
  2. Fiorica JV, Brunetto VL, Hanjani P, Lentz SS, Mannel R, Andersen W; Gynecologic Oncology Group study. Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2004 Jan;92(1):10-4. link to original article contains verified protocol PubMed

Tamoxifen monotherapy

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Regimen

Study Evidence
Quinn et al. 1989 Phase II
Thigpen et al. 2001 (GOG-81F) Phase II

Hormonotherapy

Continued indefinitely

References

  1. Quinn MA, Campbell JJ. Tamoxifen therapy in advanced/recurrent endometrial carcinoma. Gynecol Oncol. 1989 Jan;32(1):1-3. link to original article PubMed
  2. GOG-81F: Thigpen T, Brady MF, Homesley HD, Soper JT, Bell J. Tamoxifen in the treatment of advanced or recurrent endometrial carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2001 Jan 15;19(2):364-7. link to original article contains verified protocol PubMed
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