Cervical cancer

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Alaina J. Brown, MD, MPH
Vanderbilt University
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Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!

48 regimens on this page
64 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO

ESMO

NCCN

Neoadjuvant chemotherapy

Cisplatin & Paclitaxel

Regimen

Study Dates of enrollment Evidence
Park et al. 2004 2000-10 to 2002-01 Phase 2

Chemotherapy

Supportive therapy

10-day cycle for 3 cycles

Subsequent treatment

  • Clinical response assessed after 3 cycles with pelvic examination and MRI. Treatment followed by surgery or radiation therapy.

References

  1. Park DC, Kim JH, Lew YO, Kim DH, Namkoong SE. Phase II trial of neoadjuvant paclitaxel and cisplatin in uterine cervical cancer. Gynecol Oncol. 2004 Jan;92(1):59-63. link to original article contains dosing details in manuscript PubMed

Definitive therapy for locally advanced disease

Brachytherapy protocol

Regimen

To be completed

Radiotherapy

  • Intracavitary brachytherapy with radium or its equivalent by the following study-specific criteria:
    • Pearcey et al. 2002: See paper for details
    • GOG 120, stage III or IVA: 3000 cGy for a total dose of 8100 cGy to point A
      • Patients that could not receive brachytherapy underwent additional external beam radiation therapy for a total dose of 6120 cGy
    • B9E-MC-JHQS & Sehouli et al. 2012: 30 to 3500 cGy delivered to point A
    • GOG 219: 35 to 4360 cGy to point A
    • GOG 120, stage IIB: 4000 cGy for a total dose of 8080 cGy to point A
      • Patients that could not receive brachytherapy underwent additional external_beam_radiotherapy for a total dose of 6120 cGy
    • GOG 123: 3000 cGy to point A for a total dose of 7500 cGy
    • GOG 165: ONE of the following:
    • GOG 165: Parametrial boost of 5.4 to 900 cGy was administered to the involved parametrium after whole pelvic RT was complete

References

  1. GOG 165: Lanciano R, Calkins A, Bundy BN, Parham G, Lucci JA 3rd, Moore DH, Monk BJ, O'Connor DM. Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2005 Nov 20;23(33):8289-95. Epub 2005 Oct 17. link to original article contains dosing details in manuscript PubMed NCT00003078

Carboplatin & RT

Carboplatin & RT: Carboplatin & Radiation Therapy

Regimen variant #1, AUC-based carboplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Monk et al. 2023 (CALLA) 2019-02-15 to 2020-12-10 Phase 3 (C) 1a. Carboplatin, Durvalumab, RT
1b. Cisplatin, Durvalumab, RT
Did not meet primary endpoint of PFS

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 180 cGy per fraction on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (4500 cGy total in 25 fractions)

5-week course

Subsequent treatment


Regimen variant #2, BSA-based carboplatin

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Veerasarn et al. 2006 2001-2003 Phase 3 (C) Carboplatin, UFT, RT Did not meet co-primary endpoints of TTP/OS

Chemotherapy

Radiotherapy

5- to 6-week course

References

  1. Veerasarn V, Lorvidhaya V, Kamnerdsupaphon P, Suntornpong N, Sangruchi S, Lertsanguansinchai P, Khorprasert C, Sookpreedee L, Udompunturak S. A randomized phase III trial of concurrent chemoradiotherapy in locally advanced cervical cancer: preliminary results. Gynecol Oncol. 2007 Jan;104(1):15-23. Epub 2006 Sep 25. link to original article contains dosing details in manuscript PubMed
  2. CALLA: Monk BJ, Toita T, Wu X, Vázquez Limón JC, Tarnawski R, Mandai M, Shapira-Frommer R, Mahantshetty U, Del Pilar Estevez-Diz M, Zhou Q, Limaye S, Godinez FJR, Oppermann Kussler C, Varga S, Valdiviezo N, Aoki D, Leiva M, Lee JY, Sulay R, Kreynina Y, Cheng WF, Rey F, Rong Y, Ke G, Wildsmith S, Lloyd A, Dry H, Tablante Nunes A, Mayadev J. Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1334-1348. link to original article contains dosing details in abstract PubMed NCT03830866

Cisplatin & RT

Cisplatin & RT: Cisplatin & Radiation Therapy

Regimen variant #1, weekly cisplatin x 5, no cap + 4500 cGy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kenter et al. 2023 (EORTC-55994) 2002-05 to 2014-01 Phase 3 (C) Neoadjuvant chemotherapy, then surgery Did not meet primary endpoint of OS60
Monk et al. 2023 (CALLA) 2019-02-15 to 2020-12-10 Phase 3 (C) 1a. Carboplatin, Durvalumab, RT
1b. Cisplatin, Durvalumab, RT
Did not meet primary endpoint of PFS

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
    • Total number of fractions: 25
    • Total dose: 4500 cGy

5-week course

Subsequent treatment


Regimen variant #2, weekly cisplatin x 5, no cap + 5000 cGy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lutgens et al. 2016 (RADCHOC) 2003-2009 Phase 3 (C) RT-HT Did not meet primary endpoint of EFS
Shrivastava et al. 2018 (CRACx) 2003-2011 Phase 3 (E-esc) RT Seems to have superior OS (secondary endpoint)
OS60: 54% vs 46%
(HR 0.82, 95% CI 0.68-0.98)

Chemotherapy

Supportive therapy

Radiotherapy

  • Concurrent radiation therapy: 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
    • Total number of fractions: 25
    • Total dose: 5000 cGy

5-week course

Subsequent treatment


Regimen variant #3, weekly cisplatin x 6, no cap

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pearcey et al. 2002 1991-1996 Phase 3 (E-esc) RT Did not meet primary endpoint of OS36
Rose et al. 1999 (GOG 120) 1992-1997 Phase 3 (E-esc) 1. Cisplatin, Fluorouracil, Hydroxyurea, RT Did not meet co-primary endpoints of PFS/OS
2. Hydroxyurea & RT Superior OS (co-primary endpoint)
Dueñas-González et al. 2011 (B9E-MC-JHQS) 2002-2004 Phase 3 (C) Cisplatin, Gemcitabine, RT Seems to have inferior OS
Sehouli et al. 2012 2003-2008 Phase 3 (C) Carboplatin & Paclitaxel, then RT Did not meet primary endpoint of PFS
Zuliani et al. 2014 2003-2010 Phase 3 (E-esc) RT Superior OS1 (co-primary endpoint)
(HR 0.53, 95% CI 0.31-0.92)
DiSilvestro et al. 2014 (GOG 219) 2006-2009 Phase 3 (C) Cisplatin, Tirapazamine, RT Did not meet primary endpoint of PFS
Yang et al. 2022 2018-2020 Phase 3 (C) Nedaplatin & RT Inferior PFS

1Reported efficacy is based on the 2020 update.
Note: In GOG 120, this regimen was intended for disease.

Chemotherapy

  • Cisplatin (Platinol) 40 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, given 1 to 4 hours prior to radiation

Radiotherapy

  • Concurrent radiation therapy by the following study-specific criteria:
    • GOG 120, stage IIB: 170 cGy x 24 fractions, for an initial dose of 4080 cGy
    • GOG 219: 180 cGy x 23 to 25 fractions, for an initial dose of 41.4 to 4500 cGy
    • Pearcey et al. 2002 & Zuliani et al. 2014: 180 cGy x 25 fractions, for an initial dose of 4500 cGy
    • B9E-MC-JHQS & Sehouli et al. 2012: 180 cGy x 28 fractions, for an initial dose of 5040 cGy
    • GOG 120, stage III or IVA: 170 cGy x 30 fractions, for an initial dose of 5100 cGy
    • Yang et al. 2022: 180 cGy/fraction/day, 5 days/week, a total of 25-28 fractions

6-week course, followed in 1 to 3 weeks by:

Subsequent treatment


Regimen variant #4, weekly cisplatin x 6, capped

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Keys et al. 1999 (GOG 123) 1992-1997 Phase 3 (E-esc) RT Superior OS (co-primary endpoint)
OS36: 83% vs 74%
(RR 0.54, 95% CI 0.34-0.86)
Lanciano et al. 2005 (GOG 165) 1997-2000 Phase 3 (E-switch-ic) Fluorouracil & RT Might have superior ORR (secondary endpoint)

Chemotherapy

  • Cisplatin (Platinol) 40 mg/m2 (maximum dose of 70 mg) IV once per day on days 1, 8, 15, 22, 29, 36, given 4 hours before radiation

Radiotherapy

  • Concurrent radiation therapy: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
    • Total number of fractions: 25
    • Total dose: 4500 cGy

6-week course, followed by:

Subsequent treatment


Regimen variant #5, q3wk cisplatin x 3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ryu et al. 2011 (KCCH GY 1005) 2002-2004 Phase 3 (E-switch-ic) Cisplatin & RT; weekly cisplatin Superior OS60
OS60: 89% vs 66.5%
(HR 0.375, 95% CI 0.15-0.91)

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy: 1.8 to 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, (35 to 37)
    • Total number of fractions: 25 to 28
    • Total dose: 5000 cGy

9-week course

Subsequent treatment

References

  1. GOG 120: Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, Clarke-Pearson DL, Insalaco S. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999 Apr 15;340(15):1144-53. link to original article contains dosing details in manuscript PubMed
    1. Update: Rose PG, Ali S, Watkins E, Thigpen JT, Deppe G, Clarke-Pearson DL, Insalaco S; Gynecologic Oncology Group. Long-term follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007 Jul 1;25(19):2804-10. Epub 2007 May 14. link to original article PubMed
  2. GOG 123: Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL 3rd, Walker JL, Gersell D. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999 Apr 15;340(15):1154-61. link to original article contains dosing details in manuscript PubMed
  3. NCIC-CTG: Pearcey R, Brundage M, Drouin P, Jeffrey J, Johnston D, Lukka H, MacLean G, Souhami L, Stuart G, Tu D. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol. 2002 Feb 15;20(4):966-72. link to original article contains dosing details in manuscript PubMed
  4. GOG 165: Lanciano R, Calkins A, Bundy BN, Parham G, Lucci JA 3rd, Moore DH, Monk BJ, O'Connor DM. Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2005 Nov 20;23(33):8289-95. Epub 2005 Oct 17. link to original article contains dosing details in manuscript PubMed NCT00003078
  5. B9E-MC-JHQS: Dueñas-González A, Zarbá JJ, Patel F, Alcedo JC, Beslija S, Casanova L, Pattaranutaporn P, Hameed S, Blair JM, Barraclough H, Orlando M. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol. 2011 May 1;29(13):1678-85. Epub 2011 Mar 28. link to original article contains dosing details in manuscript PubMed NCT00191100
  6. KCCH GY 1005: Ryu SY, Lee WM, Kim K, Park SI, Kim BJ, Kim MH, Choi SC, Cho CK, Nam BH, Lee ED. Randomized clinical trial of weekly vs triweekly cisplatin-based chemotherapy concurrent with radiotherapy in the treatment of locally advanced cervical cancer. Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e577-81. Epub 2011 Aug 11. link to original article contains dosing details in manuscript PubMed NCT01097252
  7. Sehouli J, Runnebaum IB, Fotopoulou C, Blohmer U, Belau A, Leber H, Hanker LC, Hartmann W, Richter R, Keyver-Paik MD, Oberhoff C, Heinrich G, du Bois A, Olbrich C, Simon E, Friese K, Kimmig R, Boehmer D, Lichtenegger W, Kuemmel S; NOGGO; AGO. A randomized phase III adjuvant study in high-risk cervical cancer: simultaneous radiochemotherapy with cisplatin (S-RC) versus systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R): a NOGGO-AGO Intergroup Study. Ann Oncol. 2012 Sep;23(9):2259-64. Epub 2012 Feb 21. link to original article contains dosing details in manuscript PubMed
  8. GOG 219: DiSilvestro PA, Ali S, Craighead PS, Lucci JA, Lee YC, Cohn DE, Spirtos NM, Tewari KS, Muller C, Gajewski WH, Steinhoff MM, Monk BJ. Phase III randomized trial of weekly cisplatin and irradiation versus cisplatin and tirapazamine and irradiation in stages IB2, IIA, IIB, IIIB, and IVA cervical carcinoma limited to the pelvis: a Gynecologic Oncology Group study. J Clin Oncol. 2014 Feb 10;32(5):458-64. Epub 2014 Jan 6. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00262821
  9. Zuliani AC, Esteves SC, Teixeira LC, Teixeira JC, de Souza GA, Sarian LO. Concomitant cisplatin plus radiotherapy and high-dose-rate brachytherapy versus radiotherapy alone for stage IIIB epidermoid cervical cancer: a randomized controlled trial. J Clin Oncol. 2014 Feb 20;32(6):542-7. Epub 2014 Jan 21. link to original article PubMed
    1. Update: Fachini AMD, Zuliani AC, Sarian LO, Teixeira JC, Esteves SCB, da Costa Machado H, Zeferino LC. Long-term outcomes of concomitant cisplatin plus radiotherapy versus radiotherapy alone in patients with stage IIIB squamous cervical cancer: A randomized controlled trial. Gynecol Oncol. 2021 Feb;160(2):379-383. Epub 2020 Dec 16. link to original article PubMed
  10. RADCHOC: Lutgens LC, Koper PC, Jobsen JJ, van der Steen-Banasik EM, Creutzberg CL, van den Berg HA, Ottevanger PB, van Rhoon GC, van Doorn HC, Houben R, van der Zee J. Radiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial. Radiother Oncol. 2016 Sep;120(3):378-382. Epub 2016 Feb 17. link to original article contains dosing details in abstract PubMed
  11. CRACx: Shrivastava S, Mahantshetty U, Engineer R, Chopra S, Hawaldar R, Hande V, Kerkar RA, Maheshwari A, Shylasree TS, Ghosh J, Bajpai J, Gurram L, Gulia S, Gupta S; Gynecologic Disease Management Group. Cisplatin chemoradiotherapy vs radiotherapy in FIGO stage IIIB squamous cell carcinoma of the uterine cervix: a randomized clinical trial. JAMA Oncol. 2018 Apr 1;4(4):506-513. link to original article contains dosing details in supplement link to PMC article PubMed NCT00193791
  12. Yang X, Ren H, Li Z, Zhang L, Shao Y, Li H, Yang X, Sun Y, Zhang X, Wang Z, Fu J. A phase III randomized, controlled trial of nedaplatin versus cisplatin concurrent chemoradiotherapy in patients with cervical cancer. ESMO Open. 2022 Oct;7(5):100565. Epub 2022 Aug 19. link to original article link to PMC article contains dosing details in manuscript PubMed ChiCTR1800017108
  13. EORTC-55994: Kenter GG, Greggi S, Vergote I, Katsaros D, Kobierski J, van Doorn H, Landoni F, van der Velden J, Reed N, Coens C, van Luijk I, Colombo N, Steen-Banasik EV, Ottevanger N, Casado A; EORTC-55994 Study Group. Randomized Phase III Study Comparing Neoadjuvant Chemotherapy Followed by Surgery Versus Chemoradiation in Stage IB2-IIB Cervical Cancer: EORTC-55994. J Clin Oncol. 2023 Nov 10;41(32):5035-5043. Epub 2023 Sep 1. link to original article PubMed NCT00039338
  14. CALLA: Monk BJ, Toita T, Wu X, Vázquez Limón JC, Tarnawski R, Mandai M, Shapira-Frommer R, Mahantshetty U, Del Pilar Estevez-Diz M, Zhou Q, Limaye S, Godinez FJR, Oppermann Kussler C, Varga S, Valdiviezo N, Aoki D, Leiva M, Lee JY, Sulay R, Kreynina Y, Cheng WF, Rey F, Rong Y, Ke G, Wildsmith S, Lloyd A, Dry H, Tablante Nunes A, Mayadev J. Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1334-1348. link to original article contains dosing details in abstract PubMed NCT03830866

Cisplatin & Fluorouracil (CF) & RT

CF & RT: Cisplatin, Fluorouracil Radiation Therapy

Regimen variant #1, 70/4000 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Whitney et al. 1999 (GOG 85/SWOG 8695) 1986-1990 Phase 3 (E-esc) Hydroxyurea & RT Seems to have superior OS (co-primary endpoint)
Median OS: NYR vs 59.8 mo
(RR 0.74, 90% CI 0.58-0.95)
Peters et al. 2000 (GOG 109/SWOG-8797) 1991-1996 Phase 3 (E-esc) Radiation therapy Superior OS (co-primary endpoint)
OS48: 81% vs 71%
(HR 0.51)

Chemotherapy

  • Cisplatin (Platinol) 70 mg/m2 IV over 2 hours once per day on days 1, 22, 43, 64
  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on days 1, 22, 43, 64 (total dose: 16,000 mg/m2)

Radiotherapy

  • Concurrent radiation therapy 170 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 39 (29 fractions, for a total dose of 4930 cGy)
    • Patients with positive high common iliac lymph nodes also received 150 cGy x 30 fractions, for a total dose of 4500 cGy

12-week course


Regimen variant #2, 75/4000 x 3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Morris et al. 1999 (RTOG 9001) 1990-1997 Phase 3 (E-esc) Radiation therapy Superior OS (primary endpoint)
OS60: 73% vs 58%

Note: radiation could start one day before chemotherapy, on "day 0".

Chemotherapy

  • Cisplatin (Platinol) 75 mg/m2 IV over 4 hours once per day on days 1, 22, 43, given first
  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on days 1, 22, 43 (total dose: 12,000 mg/m2)

Radiotherapy

  • Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for a total dose of 4500 cGy)

9-week course

Subsequent treatment

References

  1. RTOG 9001: Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, Rotman M, Gershenson DM, Mutch DG. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999 Apr 15;340(15):1137-43. link to original article contains dosing details in manuscript PubMed
  2. GOG 85/SWOG 8695: Whitney CW, Sause W, Bundy BN, Malfetano JH, Hannigan EV, Fowler WC Jr, Clarke-Pearson DL, Liao SY. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999 May;17(5):1339-48. link to original article PubMed
  3. GOG 109/SWOG-8797: Peters WA 3rd, Liu PY, Barrett RJ 2nd, Stock RJ, Monk BJ, Berek JS, Souhami L, Grigsby P, Gordon W Jr, Alberts DS. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. 2000 Apr;18(8):1606-13. link to original article contains dosing details in manuscript PubMed

Cisplatin & Fluorouracil (CF) & Hydroxyurea, RT

Cisplatin, Fluorouracil, Hydroxyurea, RT: Cisplatin, Fluorouracil, Hydroxyurea, Radiation Therapy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rose et al. 1999 (GOG 120) 1992-1997 Phase 3 (E-esc) 1. Cisplatin & RT Did not meet co-primary endpoints of PFS/OS
2. Hydroxyurea & RT Superior OS (co-primary endpoint)

Definitive therapy

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy by the following stage-based criteria:
    • Stage IIB: 170 cGy once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 25 (24 fractions, for an initial dose of 4080 cGy)
    • Stage III or IVA: 170 cGy once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (30 fractions, for an initial dose of 5100 cGy)

5- to 6-week course, followed by:


Consolidation

Radiotherapy

One course

References

  1. GOG 120: Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, Clarke-Pearson DL, Insalaco S. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999 Apr 15;340(15):1144-53. link to original article contains dosing details in manuscript PubMed
    1. Update: Rose PG, Ali S, Watkins E, Thigpen JT, Deppe G, Clarke-Pearson DL, Insalaco S; Gynecologic Oncology Group. Long-term follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007 Jul 1;25(19):2804-10. Epub 2007 May 14. link to original article PubMed

Cisplatin & Gemcitabine (GC) & RT

Cisplatin, Gemcitabine, RT: Cisplatin, Gemcitabine, Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Dueñas-González et al. 2011 (B9E-MC-JHQS) 2002-2004 Phase 3 (E-esc) Cisplatin & RT Seems to have superior PFS (primary endpoint)
PFS36: 74.4% vs 65%
(HR 0.68, 95% CI 0.49-0.95)

Seems to have superior OS (secondary endpoint)
Median OS: NYR vs NYR
(HR 0.68, 95% CI 0.49-0.95)
Cetina et al. 2013 2004-2009 Non-randomized part of phase 3 RCT

Chemotherapy

  • Cisplatin (Platinol) 40 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, given first, 1 to 2 hours before radiation
  • Gemcitabine (Gemzar) 125 mg/m2 IV over 30 to 60 minutes once per day on days 1, 8, 15, 22, 29, 36, given second, 1 to 2 hours before radiation

Radiotherapy

  • Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38 (28 fractions, for an initial dose of 5040 cGy)

6-week course

Subsequent treatment

References

  1. B9E-MC-JHQS: Dueñas-González A, Zarbá JJ, Patel F, Alcedo JC, Beslija S, Casanova L, Pattaranutaporn P, Hameed S, Blair JM, Barraclough H, Orlando M. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol. 2011 May 1;29(13):1678-85. Epub 2011 Mar 28. link to original article contains dosing details in manuscript PubMed NCT00191100
  2. Cetina L, González-Enciso A, Cantú D, Coronel J, Pérez-Montiel D, Hinojosa J, Serrano A, Rivera L, Poitevin A, Mota A, Trejo E, Montalvo G, Muñoz D, Robles-Flores J, de la Garza J, Chanona J, Jiménez-Lima R, Wegman T, Dueñas-González A. Brachytherapy versus radical hysterectomy after external beam chemoradiation with gemcitabine plus cisplatin: a randomized, phase III study in IB2-IIB cervical cancer patients. Ann Oncol. 2013 Aug;24(8):2043-7. Epub 2013 Apr 21. link to original article contains dosing details in abstract PubMed

Fluorouracil & RT

5-FU & RT: 5-FluouroUracil & Radiation Therapy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lanciano et al. 2005 (GOG 165) 1997-2000 Phase 3 (E-switch-ic) Cisplatin & RT Might have inferior ORR (secondary endpoint)

Definitive therapy

Chemotherapy

  • Fluorouracil (5-FU) 225 mg/m2/day IV continuous infusion over 120 hours, started on days 1, 8, 15, 22, 29, 36 (total dose: 6750 mg/m2)

Radiotherapy

  • Concurrent radiation therapy: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for an initial dose of 4080 cGy)

6-week course, followed by:


Consolidation

Radiotherapy

  • Parametrial boost of 5.4 to 900 cGy was administered to the involved parametrium after whole pelvic RT was complete

References

  1. GOG 165: Lanciano R, Calkins A, Bundy BN, Parham G, Lucci JA 3rd, Moore DH, Monk BJ, O'Connor DM. Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2005 Nov 20;23(33):8289-95. Epub 2005 Oct 17. link to original article contains dosing details in manuscript PubMed NCT00003078

Hydroxyurea & RT

Hydroxyurea & RT: Hydroxyurea & Radiation Therapy

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hreshchyshyn et al. 1979 (GOG 04) 1970-1976 Phase 3 (E-esc) Radiation therapy Seems to have superior OS
Stehman et al. 1988 (GOG 56) 1981-06 to 1985-12 Randomized Misonidazole & RT Seems to have superior PFS1
Whitney et al. 1999 (GOG 85/SWOG 8695) 1986-1990 Phase 3 (C) Cisplatin, Fluorouracil, RT Seems to have inferior OS
Rose et al. 1999 (GOG 120) 1992-1997 Phase 3 (C) 1. Cisplatin & RT Inferior OS
2. Cisplatin, Fluorouracil, Hydroxyurea, RT Inferior OS

1Reported efficacy for GOG 56 is based on the 1993 update.

Definitive therapy

Chemotherapy

  • Hydroxyurea (Hydrea) 2000 mg/m2 PO two times per week, given 2 hours before radiation on weeks 1 to 6

Radiotherapy

  • Concurrent radiation therapy by the following stage-based criteria:
    • Stage IIB: 170 cGy x 24 fractions, for an initial dose of 4080 cGy
    • Stage III or IVA: 170 cGy x 30 fractions, for an initial dose of 5100 cGy

6-week course, followed in 1 to 3 weeks by:


Consolidation

Radiotherapy

  • Intracavitary brachytherapy by the following stage-based criteria:
    • Stage IIB: 4000 cGy for a total dose of 8080 cGy to point A
  • Stage III or IVA: 3000 cGy for a total dose of 8100 cGy to point A
  • Patients that could not receive brachytherapy underwent additional external beam radiation therapy for a total dose of 6120 cGy

References

  1. Hreshchyshyn MM, Aron BS, Boronow RC, Franklin EW 3rd, Shingleton HM, Blessing JA. Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Int J Radiat Oncol Biol Phys. 1979 Mar;5(3):317-22. link to original article PubMed
  2. GOG 56: Stehman FB, Bundy BN, Keys H, Currie JL, Mortel R, Creasman WT. A randomized trial of hydroxyurea versus misonidazole adjunct to radiation therapy in carcinoma of the cervix: A preliminary report of a Gynecologic Oncology Group study. Am J Obstet Gynecol. 1988 Jul;159(1):87-94. link to original article PubMed
    1. Update: Stehman FB, Bundy BN, Thomas G, Keys HM, d'Ablaing G 3rd, Fowler WC Jr, Mortel R, Creasman WT. Hydroxyurea versus misonidazole with radiation in cervical carcinoma: long-term follow-up of a Gynecologic Oncology Group trial. J Clin Oncol. 1993 Aug;11(8):1523-8. link to original article PubMed
  3. GOG 120: Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, Clarke-Pearson DL, Insalaco S. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999 Apr 15;340(15):1144-53. link to original article contains dosing details in manuscript PubMed
    1. Update: Rose PG, Ali S, Watkins E, Thigpen JT, Deppe G, Clarke-Pearson DL, Insalaco S; Gynecologic Oncology Group. Long-term follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007 Jul 1;25(19):2804-10. Epub 2007 May 14. link to original article PubMed
  4. GOG 85/SWOG 8695: Whitney CW, Sause W, Bundy BN, Malfetano JH, Hannigan EV, Fowler WC Jr, Clarke-Pearson DL, Liao SY. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol. 1999 May;17(5):1339-48. link to original article PubMed

Nedaplatin & RT

Nedaplatin & RT: Nedaplatin & Radiation Therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2022 2018-2020 Phase 3 (E-switch-ic) Cisplatin & RT Superior PFS36 (primary endpoint)
Median PFS: 30 vs 28 mo
(HR 0.25, 95% CI 0.08-0.77)

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy 180 cGy per day, 5 days/week, a total of 25-28 fractions

References

  1. Yang X, Ren H, Li Z, Zhang L, Shao Y, Li H, Yang X, Sun Y, Zhang X, Wang Z, Fu J. A phase III randomized, controlled trial of nedaplatin versus cisplatin concurrent chemoradiotherapy in patients with cervical cancer. ESMO Open. 2022 Oct;7(5):100565. Epub 2022 Aug 19. link to original article link to PMC article contains dosing details in manuscript PubMed ChiCTR1800017108

Adjuvant therapy

Carboplatin & Ifosfamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Blohmer et al. 2011 (NOGGO-AGO) 1999-2001 Phase 3 (C) See link See link

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

  • Mesna (Mesnex) 1600 mg/m2 IV over 6 hours once per day on days 1 to 3, with ifosfamide

21-day cycle for 4 cycles

Subsequent treatment

References

  1. NOGGO-AGO: Blohmer JU, Paepke S, Sehouli J, Boehmer D, Kolben M, Würschmidt F, Petry KU, Kimmig R, Elling D, Thomssen C, von Minckwitz G, Möbus V, Hinke A, Kümmel S, Budach V, Lichtenegger W, Schmid P; NOGGO; AGO. Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study. J Clin Oncol. 2011 Oct 1;29(28):3791-7. Epub 2011 Aug 22. link to original article contains dosing details in manuscript PubMed

Cisplatin & Gemcitabine (GC)

Regimen

Study Dates of enrollment Evidence
Dueñas-González et al. 2011 (B9E-MC-JHQS) 2002-2004 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

References

  1. B9E-MC-JHQS: Dueñas-González A, Zarbá JJ, Patel F, Alcedo JC, Beslija S, Casanova L, Pattaranutaporn P, Hameed S, Blair JM, Barraclough H, Orlando M. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol. 2011 May 1;29(13):1678-85. Epub 2011 Mar 28. link to original article contains dosing details in manuscript PubMed NCT00191100

Radiation therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Blohmer et al. 2011 (NOGGO-AGO) 1999-2001 Phase 3 (C) See link See link

Preceding treatment

Radiotherapy

  • External beam radiotherapy: 180 cGy for 28 fractions, for a total dose of 5040 cGy
  • If resection margins positive, patients received one of the following:
    • EBRT boost of 2 x 500 cGy
    • Low-dose brachytherapy

6-week course

References

  1. NOGGO-AGO: Blohmer JU, Paepke S, Sehouli J, Boehmer D, Kolben M, Würschmidt F, Petry KU, Kimmig R, Elling D, Thomssen C, von Minckwitz G, Möbus V, Hinke A, Kümmel S, Budach V, Lichtenegger W, Schmid P; NOGGO; AGO. Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study. J Clin Oncol. 2011 Oct 1;29(28):3791-7. Epub 2011 Aug 22. link to original article contains dosing details in manuscript PubMed

Persistent, recurrent, or metastatic disease, first-line therapy

ABCP

ABCP: Atezolizumab, Bevacizumab, Carboplatin, Paclitaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Oaknin et al. 2023 (BEATcc) 2018-10-08 to 2021-08-20 Phase 3 (E-esc) 1a. CP & Bevacizumab
1b. Cisplatin, Paclitaxel, Bevacizumab
Superior OS (co-primary endpoint)
Median OS: 32.1 vs 22.8 mo
(HR 0.68, 95% CI 0.52-0.88)

Superior PFS (co-primary endpoint)
Median PFS: 13.7 vs 10.4 mo
(HR 0.62, 95% CI 0.49-0.78)

Note: Patients with a complete response after at least six cycles could discontinue chemotherapy and continue atezolizumab & bevacizumab maintenance.

Chemotherapy

Immunotherapy

Targeted therapy

21-day cycles

References

  1. BEATcc: Oaknin A, Gladieff L, Martínez-García J, Villacampa G, Takekuma M, De Giorgi U, Lindemann K, Woelber L, Colombo N, Duska L, Leary A, Godoy-Ortiz A, Nishio S, Angelergues A, Rubio MJ, Fariñas-Madrid L, Yamaguchi S, Lorusso D, Ray-Coquard I, Manso L, Joly F, Alarcón J, Follana P, Romero I, Lebreton C, Pérez-Fidalgo JA, Yunokawa M, Dahlstrand H, D'Hondt V, Randall LM; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2024 Jan 6;403(10421):31-43. Epub 2023 Dec 1. link to original article contains dosing details in manuscript PubMed NCT03556839

Carboplatin monotherapy

Regimen

Study Dates of enrollment Evidence
Weiss et al. 1990 NR Phase 2

Chemotherapy

28-day cycles

References

  1. Weiss GR, Green S, Hannigan EV, Boutselis JG, Surwit EA, Wallace DL, Alberts DS; SWOG. A phase II trial of carboplatin for recurrent or metastatic squamous carcinoma of the uterine cervix: a Southwest Oncology Group study. Gynecol Oncol. 1990 Dec;39(3):332-6. link to original article contains dosing details in abstract PubMed

Carboplatin & Docetaxel

Regimen variant #1, 6 cycles

Study Dates of enrollment Evidence
Takekida et al. 2010 2004-01 to 2005-12 Phase 2

Chemotherapy

Supportive therapy

21-day cycle for up to 6 cycles


Regimen variant #2, indefinite

Study Dates of enrollment Evidence
Nagao et al. 2005 2001-2004 Pilot, fewer than 20 pts

Chemotherapy

Supportive therapy

21-day cycles

References

  1. Nagao S, Fujiwara K, Oda T, Ishikawa H, Koike H, Tanaka H, Kohno I. Combination chemotherapy of docetaxel and carboplatin in advanced or recurrent cervix cancer: a pilot study. Gynecol Oncol. 2005 Mar;96(3):805-9. link to original article contains dosing details in manuscript PubMed
  2. Takekida S, Fujiwara K, Nagao S, Yamaguchi S, Yoshida N, Kitada F, Kigawa J, Terakawa N, Nishimura R. Phase II study of combination chemotherapy with docetaxel and carboplatin for locally advanced or recurrent cervical cancer. Int J Gynecol Cancer. 2010 Dec;20(9):1563-8. link to original article PubMed

Carboplatin & Paclitaxel (CP)

TC: Taxol (Paclitaxel) & Carboplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pectasides et al. 2009a NR Phase 2
Kitagawa et al. 2015 (JCOG0505) 2006-2009 Phase 3 (E-switch-ic) Cisplatin & Paclitaxel Non-inferior OS (primary endpoint)
Median OS: 17.5 vs 18.3 mo
(HR 0.994, 90% CI 0.79-1.25)
Colombo et al. 2021 (KEYNOTE-826) 2018-2020 Phase 3 (C) 1a. CP & Pembrolizumab
1b. CP, Bevacizumab, Pembrolizumab
1c. Cisplatin, Paclitaxel, Pembrolizumab
1d. Cisplatin, Paclitaxel, Bevacizumab, Pembrolizumab
Inferior OS

Note: Pectasides et al. 2009a allowed the regimen to be given up to 9 cycles. Patients in KEYNOTE-826 were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects.

Chemotherapy

21-day cycle for 6 or more cycles (see note)

References

  1. Pectasides D, Fountzilas G, Papaxoinis G, Pectasides E, Xiros N, Sykiotis C, Koumarianou A, Psyrri A, Panayiotides J, Economopoulos T. Carboplatin and paclitaxel in metastatic or recurrent cervical cancer. Int J Gynecol Cancer. 2009 May;19(4):777-81. link to original article contains dosing details in abstract PubMed
  2. JCOG0505: Kitagawa R, Katsumata N, Shibata T, Kamura T, Kasamatsu T, Nakanishi T, Nishimura S, Ushijima K, Takano M, Satoh T, Yoshikawa H. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505. J Clin Oncol. 2015 Jul 1;33(19):2129-35. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00295789
  3. KEYNOTE-826: Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ; KEYNOTE-826 Investigators. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med. 2021 Nov 11;385(20):1856-1867. Epub 2021 Sep 18. link to original article contains dosing details in manuscript PubMed NCT03635567
    1. HRQoL analysis: Monk BJ, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Hurtado de Mendoza MO, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Martin Nguyen A, Monberg MJ, Colombo N, Lorusso D. Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):392-402. Epub 2023 Mar 3. link to original article PubMed
    2. Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article PubMed

Carboplatin & Paclitaxel (CP) & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826) 2018-2020 Phase 3 (C) 1a. CP & Pembrolizumab
1b. CP, Bevacizumab, Pembrolizumab
1c. Cisplatin, Paclitaxel, Pembrolizumab
1d. Cisplatin, Paclitaxel, Bevacizumab, Pembrolizumab
Inferior OS
Oaknin et al. 2023 (BEATcc) 2018-10-08 to 2021-08-20 Phase 3 (C) 1a. ABCP
1b. Cisplatin, Paclitaxel, Atezolizumab, Bevacizumab
Inferior PFS/OS

Note: In KEYNOTE-826, the decision to give bevacizumab was at the discretion of the treating institution and was not a randomization. Patients in KEYNOTE-826 were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects. Patients in BEATcc with a complete response after at least six cycles could discontinue chemotherapy and continue bevacizumab maintenance. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. KEYNOTE-826: Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ; KEYNOTE-826 Investigators. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med. 2021 Nov 11;385(20):1856-1867. Epub 2021 Sep 18. link to original article contains dosing details in manuscript PubMed NCT03635567
    1. HRQoL analysis: Monk BJ, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Hurtado de Mendoza MO, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Martin Nguyen A, Monberg MJ, Colombo N, Lorusso D. Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):392-402. Epub 2023 Mar 3. link to original article PubMed
    2. Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article PubMed
  2. BEATcc: Oaknin A, Gladieff L, Martínez-García J, Villacampa G, Takekuma M, De Giorgi U, Lindemann K, Woelber L, Colombo N, Duska L, Leary A, Godoy-Ortiz A, Nishio S, Angelergues A, Rubio MJ, Fariñas-Madrid L, Yamaguchi S, Lorusso D, Ray-Coquard I, Manso L, Joly F, Alarcón J, Follana P, Romero I, Lebreton C, Pérez-Fidalgo JA, Yunokawa M, Dahlstrand H, D'Hondt V, Randall LM; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2024 Jan 6;403(10421):31-43. Epub 2023 Dec 1. link to original article contains dosing details in manuscript PubMed NCT03556839

Carboplatin & Paclitaxel (CP), Bevacizumab, Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826) 2018-2020 Phase 3 (E-RT-esc) 1a. CP
1b. CP & Bevacizumab
1c. Cisplatin & Paclitaxel
1d. Cisplatin, Paclitaxel, Bevacizumab
Superior OS1 (co-primary endpoint)
Median OS: 26.4 vs 16.8 mo
(HR 0.63, 95% CI 0.52-0.77)

1Reported efficacy is based on the 2023 update for all patients.
Note: The decision to give bevacizumab was at the discretion of the treating institution and was not a randomization. Patients were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects.

Chemotherapy

Targeted therapy

Immunotherapy

21-day cycles

References

  1. KEYNOTE-826: Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ; KEYNOTE-826 Investigators. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med. 2021 Nov 11;385(20):1856-1867. Epub 2021 Sep 18. link to original article contains dosing details in manuscript PubMed NCT03635567
    1. HRQoL analysis: Monk BJ, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Hurtado de Mendoza MO, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Martin Nguyen A, Monberg MJ, Colombo N, Lorusso D. Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):392-402. Epub 2023 Mar 3. link to original article PubMed
    2. Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article PubMed

Carboplatin & Paclitaxel (CP) & Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826) 2018-2020 Phase 3 (E-RT-esc) 1a. CP
1b. CP & Bevacizumab
1c. Cisplatin & Paclitaxel
1d. Cisplatin, Paclitaxel, Bevacizumab
Superior OS1 (co-primary endpoint)
Median OS: 26.4 vs 16.8 mo
(HR 0.63, 95% CI 0.52-0.77)

1Reported efficacy is based on the 2023 update for all patients.
Note: Patients were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects.

Chemotherapy

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. KEYNOTE-826: Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ; KEYNOTE-826 Investigators. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med. 2021 Nov 11;385(20):1856-1867. Epub 2021 Sep 18. link to original article contains dosing details in manuscript PubMed NCT03635567
    1. HRQoL analysis: Monk BJ, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Hurtado de Mendoza MO, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Martin Nguyen A, Monberg MJ, Colombo N, Lorusso D. Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):392-402. Epub 2023 Mar 3. link to original article PubMed
    2. Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article PubMed

Cisplatin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thigpen et al. 1979a NR in abstract Phase 2
Bonomi et al. 1985 (GOG 43) 1978-1982 Phase 3 (C) 1. Cisplatin; higher dose
2. Cisplatin; higher dose, split doses
Did not meet primary endpoint of ORR
Thigpen et al. 1989 (GOG 64) 1982-1985 Phase 3 (C) Cisplatin; CI Did not meet primary efficacy endpoints
Omura et al. 1997 (GOG 110) 1990-1994 Phase 3 (C) 1. Cisplatin & Ifosfamide Inferior PFS
2. Cisplatin & Mitolactol Did not meet primary endpoint of ORR
Vermorken et al. 2001 1986-1991 Phase 3 (C) BEMP Did not meet primary endpoint of ORR
Moore et al. 2004 (GOG 169) 1997-1999 Phase 3 (C) Cisplatin & Paclitaxel Inferior PFS
Long et al. 2005 (GOG 179) 1999-2002 Phase 3 (C) 1. Cisplatin & Topotecan Seems to have inferior OS
2. MVAC Not reported
Aoki et al. 2018 (Taiho 10020380) 2008-2011 Phase 3 (C) Cisplatin & S-1 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

21-day cycles; if not responding, given for maximum of 6 cycles

References

  1. Thigpen T, Shingleton H, Homesley H, LaGasse L, Blessing J; Gynecologic Oncology Group. cis-Dichlorodiammineplatinum(II) in the treatment of gynecologic malignancies: phase II trials by the Gynecologic Oncology Group. Cancer Treat Rep. 1979 Sep-Oct;63(9-10):1549-55. PubMed
  2. GOG 43: Bonomi P, Blessing JA, Stehman FB, DiSaia PJ, Walton L, Major FJ. Randomized trial of three cisplatin dose schedules in squamous-cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 1985 Aug;3(8):1079-85. link to original article PubMed
  3. GOG 64: Thigpen JT, Blessing JA, DiSaia PJ, Fowler WC Jr, Hatch KD. A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1989 Feb;32(2):198-202. link to original article contains dosing details in abstract PubMed
  4. GOG 110: Omura GA, Blessing JA, Vaccarello L, Berman ML, Clarke-Pearson DL, Mutch DG, Anderson B. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 1997 Jan;15(1):165-71. link to original article contains dosing details in abstract PubMed
  5. Vermorken JB, Zanetta G, Freire de Oliveira C, van der Burg ME, Lacave AJ, Teodorovic I, Boes GH, Colombo N; EORTC Gynecological Cancer Cooperative Group. Randomized phase III trial of bleomycin, vindesine, mitomycin-C, and cisplatin (BEMP) versus cisplatin (P) in disseminated squamous-cell carcinoma of the uterine cervix: an EORTC Gynecological Cancer Cooperative Group study. Ann Oncol. 2001 Jul;12(7):967-74. link to original article PubMed
  6. GOG 169: Moore DH, Blessing JA, McQuellon RP, Thaler HT, Cella D, Benda J, Miller DS, Olt G, King S, Boggess JF, Rocereto TF. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2004 Aug 1;22(15):3113-9. link to original article contains dosing details in manuscript PubMed
  7. GOG 179: Long HJ 3rd, Bundy BN, Grendys EC Jr, Benda JA, McMeekin DS, Sorosky J, Miller DS, Eaton LA, Fiorica JV; Gynecologic Oncology Group. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2005 Jul 20;23(21):4626-33. Epub 2005 May 23. link to original article contains dosing details in manuscript PubMed NCT00003945
  8. Taiho 10020380: Aoki Y, Ochiai K, Lim S, Aoki D, Kamiura S, Lin H, Katsumata N, Cha SD, Kim JH, Kim BG, Hirashima Y, Fujiwara K, Kim YT, Kim SM, Chung HH, Chang TC, Kamura T, Takizawa K, Takeuchi M, Kang SB. Phase III study of cisplatin with or without S-1 in patients with stage IVB, recurrent, or persistent cervical cancer. Br J Cancer. 2018 Aug;119(5):530-537. Epub 2018 Aug 3. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00770874

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine, Cisplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Monk et al. 2009 (GOG 204) 2003-2007 Phase 3 (E-switch-ic) 1. Cisplatin & Paclitaxel Seems to have inferior PFS (secondary endpoint)
2. Cisplatin & Topotecan Did not meet primary endpoint of OS
3. Cisplatin & Vinorelbine Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

References

  1. GOG 204: Monk BJ, Sill MW, McMeekin DS, Cohn DE, Ramondetta LM, Boardman CH, Benda J, Cella D. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009 Oct 1;27(28):4649-55. Epub 2009 Aug 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00064077

Cisplatin & Ifosfamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Omura et al. 1997 (GOG 110) 1990-1994 Phase 3 (E-esc) 1. Cisplatin Superior PFS (secondary endpoint)
2. Cisplatin & Mitolactol Not reported
Bloss et al. 2002 (GOG 149) 1994-1997 Phase 3 (C) CIB Did not meet primary endpoint of ORR

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) 6000 mg/m2 IV continuous infusion over 36 hours, started on day 1 concurrent with ifosfamide

21-day cycle for up to 6 cycles

References

  1. GOG 110: Omura GA, Blessing JA, Vaccarello L, Berman ML, Clarke-Pearson DL, Mutch DG, Anderson B. Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 1997 Jan;15(1):165-71. link to original article contains dosing details in abstract PubMed
  2. GOG 149: Bloss JD, Blessing JA, Behrens BC, Mannel RS, Rader JS, Sood AK, Markman M, Benda J. Randomized trial of cisplatin and ifosfamide with or without bleomycin in squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2002 Apr 1;20(7):1832-7. link to original article PubMed

Cisplatin & Mitomycin

Regimen

Study Dates of enrollment Evidence Efficacy
Wagenaar et al. 2001 NR Phase 2 ORR: 42% (95% CI: 26-61%)

Chemotherapy

Supportive therapy

  • 1 liter NS over 1 hour once on day 1, prior to chemotherapy, then 1 liter NS over 1 hour once on day 1, after cisplatin
  • Furosemide (Lasix) (route/dose not specified) once on day 1, prior to chemotherapy
  • Mannitol IV push once on day 1, prior to cisplatin

28-day cycle for 9 cycles

References

  1. Wagenaar HC, Pecorelli S, Mangioni C, van der Burg ME, Rotmensz N, Anastasopoulou A, Zola P, Veenhof CH, Lacave AJ, Neijt JP, van Oosterom AT, Einhorn N, Vermorken JB; EORTC Gynecological Cancer Group. Phase II study of mitomycin-C and cisplatin in disseminated, squamous cell carcinoma of the uterine cervix: a European Organisation for Research and Treatment of Cancer (EORTC) Gynecological Cancer Group study. Eur J Cancer. 2001 Sep;37(13):1624-8. link to original article contains dosing details in manuscript PubMed

Cisplatin & Paclitaxel

PC: Paclitaxel & Cisplatin
CP: Cisplatin & Paclitaxel
TP: Taxol (Paclitaxel) & Platinol (Cisplatin)

Regimen variant #1, 50/135, 3 hr paclitaxel

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tewari et al. 2014 (GOG 240) 2009-2012 Phase 3 (C) 1. Cisplatin, Paclitaxel, Bevacizumab Inferior OS1
2. Paclitaxel & Topotecan Did not meet primary endpoint of OS
3. Paclitaxel, Topotecan, Bevacizumab Not reported

1Reported efficacy is based on the 2017 update.

Chemotherapy

21-day cycles until CR or indefinitely


Regimen variant #2, 50/135, CI paclitaxel

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Moore et al. 2004 (GOG 169) 1997-1999 Phase 3 (E-esc) Cisplatin Superior PFS (secondary endpoint)

Superior ORR (primary endpoint)
Monk et al. 2009 (GOG 204) 2003-2007 Phase 3 (C) 1. Cisplatin & Gemcitabine Seems to have superior PFS (secondary endpoint)
2. Cisplatin & Topotecan Did not meet primary endpoint of OS
3. Cisplatin & Vinorelbine Might have superior PFS (secondary endpoint)
Kitagawa et al. 2015 (JCOG0505) 2006-2009 Phase 3 (C) Carboplatin & Paclitaxel Non-inferior OS

Note: patients in JCOG0505 received a maximum of 6 cycles.

Chemotherapy

Supportive therapy

21-day cycles; if not responding, given for maximum of 6 cycles.


Regimen variant #3, 50/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tewari et al. 2014 (GOG 240) 2009-2012 Phase 3 (C) 1. Cisplatin, Paclitaxel, Bevacizumab Inferior OS1
2. Paclitaxel & Topotecan Did not meet primary endpoint of OS
3. Paclitaxel, Topotecan, Bevacizumab Not reported
Colombo et al. 2021 (KEYNOTE-826) 2018-2020 Phase 3 (C) 1a. CP & Pembrolizumab
1b. CP, Bevacizumab, Pembrolizumab
1c. Cisplatin, Paclitaxel, Pembrolizumab
1d. Cisplatin, Paclitaxel, Bevacizumab, Pembrolizumab
Inferior OS

1Reported efficacy is based on the 2017 update.
Note: Treatment in GOG 240 was given until CR or indefinitely. Patients in KEYNOTE-826 were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects.

Chemotherapy

21-day cycle for 6 or more cycles (see note)

References

  1. GOG 169: Moore DH, Blessing JA, McQuellon RP, Thaler HT, Cella D, Benda J, Miller DS, Olt G, King S, Boggess JF, Rocereto TF. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2004 Aug 1;22(15):3113-9. link to original article contains dosing details in manuscript PubMed
  2. GOG 204: Monk BJ, Sill MW, McMeekin DS, Cohn DE, Ramondetta LM, Boardman CH, Benda J, Cella D. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009 Oct 1;27(28):4649-55. Epub 2009 Aug 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00064077
  3. GOG 240: Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014 Feb 20;370(8):734-43. link to original article link to supplementary appendix contains dosing details in manuscript link to PMC article PubMed NCT00803062
    1. Update: Tewari KS, Sill MW, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, DiSaia PJ, Copeland LJ, Creasman WT, Stehman FB, Brady MF, Burger RA, Thigpen JT, Birrer MJ, Waggoner SE, Moore DH, Look KY, Koh WJ, Monk BJ. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017 Oct 7;390(10103):1654-1663. Epub 2017 Jul 27. link to original article link to PMC article PubMed
    2. Update: Tewari KS, Sill MW, Birrer MJ, Penson RT, Huang H, Moore DH, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Final survival analysis of topotecan and paclitaxel for first-line treatment of advanced cervical cancer: An NRG oncology randomized study. Gynecol Oncol. 2023 Apr;171:141-150. Epub 2023 Mar 8. link to original article PubMed
  4. JCOG0505: Kitagawa R, Katsumata N, Shibata T, Kamura T, Kasamatsu T, Nakanishi T, Nishimura S, Ushijima K, Takano M, Satoh T, Yoshikawa H. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505. J Clin Oncol. 2015 Jul 1;33(19):2129-35. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00295789
  5. KEYNOTE-826: Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ; KEYNOTE-826 Investigators. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med. 2021 Nov 11;385(20):1856-1867. Epub 2021 Sep 18. link to original article contains dosing details in manuscript PubMed NCT03635567
    1. HRQoL analysis: Monk BJ, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Hurtado de Mendoza MO, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Martin Nguyen A, Monberg MJ, Colombo N, Lorusso D. Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):392-402. Epub 2023 Mar 3. link to original article PubMed
    2. Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article PubMed

Cisplatin, Paclitaxel, Bevacizumab

CP+Bev: Cisplatin, Paclitaxel, Bevacizumab

ESMO-preferred (I-A, 2017)

Regimen variant #1, 135 mg/m2 paclitaxel

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tewari et al. 2014 (GOG 240) 2009-2012 Phase 3 (E-RT-esc) 1. Cisplatin & Paclitaxel Superior OS1 (primary endpoint)
Median OS: 16.8 vs 13.3 mo
(HR 0.77, 95% CI 0.62-0.95)
2. Paclitaxel & Topotecan Did not meet primary endpoint of OS1
3. Paclitaxel, Topotecan, Bevacizumab Not reported

1Reported efficacy is based on the 2017 update.

Chemotherapy

Targeted therapy

21-day cycles until CR or indefinitely


Regimen variant #2, 175 mg/m2 paclitaxel

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tewari et al. 2014 (GOG 240) 2009-2012 Phase 3 (E-RT-esc) 1. Cisplatin & Paclitaxel Superior OS1 (primary endpoint)
Median OS: 16.8 vs 13.3 mo
(HR 0.77, 95% CI 0.62-0.95)
2. Paclitaxel & Topotecan Did not meet primary endpoint of OS1
3. Paclitaxel, Topotecan, Bevacizumab Not reported
Colombo et al. 2021 (KEYNOTE-826) 2018-2020 Phase 3 (C) 1a. CP & Pembrolizumab
1b. CP, Bevacizumab, Pembrolizumab
1c. Cisplatin, Paclitaxel, Pembrolizumab
1d. Cisplatin, Paclitaxel, Bevacizumab, Pembrolizumab
Inferior OS
Oaknin et al. 2023 (BEATcc) 2018-10-08 to 2021-08-20 Phase 3 (C) 1a. ABCP
1b. Cisplatin, Paclitaxel, Atezolizumab, Bevacizumab
Inferior PFS/OS

1Reported efficacy for this comparison in GOG 240 is based on the 2017 update.
Note: Treatment in GOG 240 was given until CR or indefinitely. Patients in KEYNOTE-826 were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects. Patients in BEATcc with a complete response after at least six cycles could discontinue chemotherapy and continue bevacizumab maintenance. The decision to give bevacizumab in KEYNOTE-826 was at the discretion of the treating institution and was not a randomization.

Chemotherapy

Targeted therapy

21-day cycle for 6 or more cycles (see note)

References

  1. GOG 240: Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014 Feb 20;370(8):734-43. link to original article link to supplementary appendix contains dosing details in manuscript link to PMC article PubMed NCT00803062
    1. Update: Tewari KS, Sill MW, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, DiSaia PJ, Copeland LJ, Creasman WT, Stehman FB, Brady MF, Burger RA, Thigpen JT, Birrer MJ, Waggoner SE, Moore DH, Look KY, Koh WJ, Monk BJ. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017 Oct 7;390(10103):1654-1663. Epub 2017 Jul 27. link to original article link to PMC article PubMed
    2. Update: Tewari KS, Sill MW, Birrer MJ, Penson RT, Huang H, Moore DH, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Final survival analysis of topotecan and paclitaxel for first-line treatment of advanced cervical cancer: An NRG oncology randomized study. Gynecol Oncol. 2023 Apr;171:141-150. Epub 2023 Mar 8. link to original article PubMed
  2. KEYNOTE-826: Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ; KEYNOTE-826 Investigators. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med. 2021 Nov 11;385(20):1856-1867. Epub 2021 Sep 18. link to original article contains dosing details in manuscript PubMed NCT03635567
    1. HRQoL analysis: Monk BJ, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Hurtado de Mendoza MO, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Martin Nguyen A, Monberg MJ, Colombo N, Lorusso D. Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):392-402. Epub 2023 Mar 3. link to original article PubMed
    2. Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article PubMed
  3. BEATcc: Oaknin A, Gladieff L, Martínez-García J, Villacampa G, Takekuma M, De Giorgi U, Lindemann K, Woelber L, Colombo N, Duska L, Leary A, Godoy-Ortiz A, Nishio S, Angelergues A, Rubio MJ, Fariñas-Madrid L, Yamaguchi S, Lorusso D, Ray-Coquard I, Manso L, Joly F, Alarcón J, Follana P, Romero I, Lebreton C, Pérez-Fidalgo JA, Yunokawa M, Dahlstrand H, D'Hondt V, Randall LM; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2024 Jan 6;403(10421):31-43. Epub 2023 Dec 1. link to original article contains dosing details in manuscript PubMed NCT03556839

Cisplatin, Paclitaxel, Atezolizumab, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Oaknin et al. 2023 (BEATcc) 2018-10-08 to 2021-08-20 Phase 3 (E-esc) 1a. CP & Bevacizumab
1b. Cisplatin, Paclitaxel, Bevacizumab
Superior OS (co-primary endpoint)
Median OS: 32.1 vs 22.8 mo
(HR 0.68, 95% CI 0.52-0.88)

Superior PFS (co-primary endpoint)
Median PFS: 13.7 vs 10.4 mo
(HR 0.62, 95% CI 0.49-0.78)

Note: Patients with a complete response after at least six cycles could discontinue chemotherapy and continue atezolizumab & bevacizumab maintenance.

Chemotherapy

Immunotherapy

Targeted therapy

21-day cycles

References

  1. BEATcc: Oaknin A, Gladieff L, Martínez-García J, Villacampa G, Takekuma M, De Giorgi U, Lindemann K, Woelber L, Colombo N, Duska L, Leary A, Godoy-Ortiz A, Nishio S, Angelergues A, Rubio MJ, Fariñas-Madrid L, Yamaguchi S, Lorusso D, Ray-Coquard I, Manso L, Joly F, Alarcón J, Follana P, Romero I, Lebreton C, Pérez-Fidalgo JA, Yunokawa M, Dahlstrand H, D'Hondt V, Randall LM; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2024 Jan 6;403(10421):31-43. Epub 2023 Dec 1. link to original article contains dosing details in manuscript PubMed NCT03556839

Cisplatin, Paclitaxel, Bevacizumab, Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826) 2018-2020 Phase 3 (E-RT-esc) 1a. CP
1b. CP & Bevacizumab
1c. Cisplatin & Paclitaxel
1d. Cisplatin, Paclitaxel, Bevacizumab
Superior OS1 (co-primary endpoint)
Median OS: 26.4 vs 16.8 mo
(HR 0.63, 95% CI 0.52-0.77)

1Reported efficacy is based on the 2023 update for all patients.
Note: The decision to give bevacizumab was at the discretion of the treating institution and was not a randomization. Patients were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects.

Chemotherapy

Targeted therapy

Immunotherapy

21-day cycles

References

  1. KEYNOTE-826: Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ; KEYNOTE-826 Investigators. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med. 2021 Nov 11;385(20):1856-1867. Epub 2021 Sep 18. link to original article contains dosing details in manuscript PubMed NCT03635567
    1. HRQoL analysis: Monk BJ, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Hurtado de Mendoza MO, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Martin Nguyen A, Monberg MJ, Colombo N, Lorusso D. Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):392-402. Epub 2023 Mar 3. link to original article PubMed
    2. Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article PubMed

Cisplatin, Paclitaxel, Pembrolizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826) 2018-2020 Phase 3 (E-RT-esc) 1a. CP
1b. CP & Bevacizumab
1c. Cisplatin & Paclitaxel
1d. Cisplatin, Paclitaxel, Bevacizumab
Superior OS1 (co-primary endpoint)
Median OS: 26.4 vs 16.8 mo
(HR 0.63, 95% CI 0.52-0.77)

1Reported efficacy is based on the 2023 update for all patients.
Note: Patients were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects.

Chemotherapy

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. KEYNOTE-826: Colombo N, Dubot C, Lorusso D, Caceres MV, Hasegawa K, Shapira-Frommer R, Tewari KS, Salman P, Hoyos Usta E, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Toker S, Li K, Keefe SM, Monk BJ; KEYNOTE-826 Investigators. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. N Engl J Med. 2021 Nov 11;385(20):1856-1867. Epub 2021 Sep 18. link to original article contains dosing details in manuscript PubMed NCT03635567
    1. HRQoL analysis: Monk BJ, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Hurtado de Mendoza MO, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Martin Nguyen A, Monberg MJ, Colombo N, Lorusso D. Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2023 Apr;24(4):392-402. Epub 2023 Mar 3. link to original article PubMed
    2. Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article PubMed

Cisplatin & Topotecan

TC: Topotecan & Cisplatin
CT: Cisplatin & Topotecan

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Long et al. 2005 (GOG 179) 1999-2002 Phase 3 (E-RT-esc) 1. Cisplatin Seems to have superior OS (primary endpoint)
Median OS: 9.4 vs 6.5 mo
(RR 0.76, 95% CI 0.59-0.98)
2. MVAC Not reported
Monk et al. 2009 (GOG 204) 2003-2007 Phase 3 (E-switch-ic) 1. Cisplatin & Gemcitabine Did not meet primary endpoint of OS
2. Cisplatin & Paclitaxel Did not meet primary endpoint of OS
3. Cisplatin & Vinorelbine Did not meet primary endpoint of OS
Coronel et al. 2010 (006/027/ICI) 2007-2009 Phase 3 (C) CT + HV Seems to have inferior PFS

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. GOG 179: Long HJ 3rd, Bundy BN, Grendys EC Jr, Benda JA, McMeekin DS, Sorosky J, Miller DS, Eaton LA, Fiorica JV; Gynecologic Oncology Group. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2005 Jul 20;23(21):4626-33. Epub 2005 May 23. link to original article contains dosing details in manuscript PubMed NCT00003945
  2. GOG 204: Monk BJ, Sill MW, McMeekin DS, Cohn DE, Ramondetta LM, Boardman CH, Benda J, Cella D. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009 Oct 1;27(28):4649-55. Epub 2009 Aug 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00064077
  3. 006/027/ICI: Coronel J, Cetina L, Pacheco I, Trejo-Becerril C, González-Fierro A, de la Cruz-Hernandez E, Perez-Cardenas E, Taja-Chayeb L, Arias-Bofill D, Candelaria M, Vidal S, Dueñas-González A. A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer: preliminary results. Med Oncol. 2011 Dec;28 Suppl 1:S540-6. Epub 2010 Oct 8. link to original article contains dosing details in manuscript PubMed NCT00532818

Cisplatin & Vinorelbine (CVb)

CVb: Cisplatin & Vinorelbine
VC: Vinorelbine, Cisplatin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Monk et al. 2009 (GOG 204) 2003-2007 Phase 3 (E-switch-ic) 1. Cisplatin & Gemcitabine Did not meet primary endpoint of OS
2. Cisplatin & Paclitaxel Might have inferior PFS (primary endpoint)
3. Cisplatin & Topotecan Did not meet primary endpoint of OS

Chemotherapy

21-day cycles; if not responding, given for maximum of 6 cycles

References

  1. GOG 204: Monk BJ, Sill MW, McMeekin DS, Cohn DE, Ramondetta LM, Boardman CH, Benda J, Cella D. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009 Oct 1;27(28):4649-55. Epub 2009 Aug 31. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00064077

Ifosfamide monotherapy

Regimen

Study Dates of enrollment Evidence
Coleman et al. 1986 NR Phase 2
Sutton et al. 1993b 1985-07 to 1990-12 Phase 2
Sutton et al. 1993a 1988-01 to 1990-02 Phase 2

Chemotherapy

  • Ifosfamide (Ifex) by the following exposure-based criteria:
  • No previous pelvic radiation or other chemotherapy: 1500 mg/m2 IV once per day on days 1 to 5
  • Previous pelvic radiation or other chemotherapy: 1200 mg/m2 IV once per day on days 1 to 5

Supportive therapy

  • Mesna (Mesnex) at 20% of ifosfamide dose (for example, 300 mg/m2 for 1500 mg/m2 dose of ifosfamide) IV given at 0, 4, and 8 hours after each dose of ifosfamide on days 1 to 5

21-day cycles

Dose and schedule modifications

  • Ifosfamide (Ifex) dose could be increased by 300 mg/m2 or decreased by 20% depending on toxicity

References

  1. Coleman RE, Harper PG, Gallagher C, Osborne R, Rankin EM, Silverstone AC, Slevin ML, Souhami RL, Tobias JS, Trask CW, Wiltshaw E. A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemother Pharmacol. 1986;18(3):280-3. link to original article PubMed
  2. Sutton GP, Blessing JA, McGuire WP, Patton T, Look KY; Gynecologic Oncology Group. Phase II trial of ifosfamide and mesna in patients with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy: a Gynecologic Oncology Group study. Am J Obstet Gynecol. 1993 Mar;168(3 Pt 1):805-7. link to original article PubMed
  3. Sutton GP, Blessing JA, DiSaia PJ, McGuire WP; Gynecologic Oncology Group. Phase II study of ifosfamide and mesna in nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1993 Apr;49(1):48-50. link to original article contains dosing details in manuscript PubMed

Paclitaxel monotherapy

Regimen variant #1, 135 mg/m2

Study Dates of enrollment Evidence
McGuire et al. 1996 1990 Phase 2
Curtin et al. 2001 1994 Phase 2

Note: this was the dosage used for patients with previous pelvic radiation.

Chemotherapy

Supportive therapy

21-day cycles

Dose and schedule modifications


Regimen variant #2, 170 mg/m2

Study Dates of enrollment Evidence
McGuire et al. 1996 1990 Phase 2
Curtin et al. 2001 1994 Phase 2

Chemotherapy

  • Paclitaxel (Taxol) by the following exposure-based criteria:
    • No previous pelvic radiation: 170 mg/m2 IV continuous infusion over 24 hours, started on day 1
    • Previous pelvic radiation: 135 mg/m2 IV continuous infusion over 24 hours, started on day 1

Supportive therapy

21-day cycles

Dose and schedule modifications


Regimen variant #3, 250 mg/m2

Study Dates of enrollment Evidence
Kudelka et al. 1996 NR Phase 2

Chemotherapy

Supportive therapy

21-day cycles

Dose and schedule modifications

References

  1. McGuire WP, Blessing JA, Moore D, Lentz SS, Photopulos G; Gynecologic Oncology Group. Paclitaxel has moderate activity in squamous cervix cancer: a Gynecologic Oncology Group study. J Clin Oncol. 1996 Mar;14(3):792-5. link to original article contains dosing details in manuscript PubMed
  2. Kudelka AP, Winn R, Edwards CL, Downey G, Greenberg H, Dakhil SR, Freedman RS, Loyer E, Rusinkiewicz J, Gacrama P, Fueger R, Kavanagh JJ. Activity of paclitaxel in advanced or recurrent squamous cell cancer of the cervix. Clin Cancer Res. 1996 Aug;2(8):1285-8. link to original article contains dosing details in manuscript PubMed content property of HemOnc.org
    1. Update: Kudelka AP, Winn R, Edwards CL, Downey G, Greenberg H, Dakhil SR, Freedman RS, LoCoco S, Umbreit J, Delmore JE, Arbuck S, Loyer E, Gacrama P, Fueger R, Kavanagh JJ. An update of a phase II study of paclitaxel in advanced or recurrent squamous cell cancer of the cervix. Anticancer Drugs. 1997 Aug;8(7):657-61. link to original article PubMed
  3. Curtin JP, Blessing JA, Webster KD, Rose PG, Mayer AR, Fowler WC Jr, Malfetano JH, Alvarez RD; Gynecologic Oncology Group. Paclitaxel, an active agent in nonsquamous carcinomas of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2001 Mar 1;19(5):1275-8. link to original article contains dosing details in manuscript PubMed

Paclitaxel & Topotecan

TP: Topotecan, Paclitaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tewari et al. 2014 (GOG 240) 2009-2012 Phase 3 (C) 1. Cisplatin & Paclitaxel Did not meet primary endpoint of OS
2. Cisplatin, Paclitaxel, Bevacizumab Not reported
3. Paclitaxel, Topotecan, Bevacizumab Did not meet primary endpoint of OS1

1Reported efficacy is based on the 2017 update.
Note: per the initial report, topotecan & paclitaxel +/- bevacizumab regimens were "associated with a significantly higher risk of progression" as compared to cisplatin & paclitaxel +/- bevacizumab regimens.

Chemotherapy

21-day cycles

References

  1. GOG 240: Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014 Feb 20;370(8):734-43. link to original article link to supplementary appendix contains dosing details in manuscript link to PMC article PubMed NCT00803062
    1. Update: Tewari KS, Sill MW, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, DiSaia PJ, Copeland LJ, Creasman WT, Stehman FB, Brady MF, Burger RA, Thigpen JT, Birrer MJ, Waggoner SE, Moore DH, Look KY, Koh WJ, Monk BJ. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017 Oct 7;390(10103):1654-1663. Epub 2017 Jul 27. link to original article link to PMC article PubMed
    2. Update: Tewari KS, Sill MW, Birrer MJ, Penson RT, Huang H, Moore DH, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Final survival analysis of topotecan and paclitaxel for first-line treatment of advanced cervical cancer: An NRG oncology randomized study. Gynecol Oncol. 2023 Apr;171:141-150. Epub 2023 Mar 8. link to original article PubMed

Paclitaxel, Topotecan, Bevacizumab

TP+Bev: Topotecan, Paclitaxel, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tewari et al. 2014 (GOG 240) 2009-2012 Phase 3 (E-RT-esc) 1. Cisplatin & Paclitaxel Not reported
2. Cisplatin, Paclitaxel, Bevacizumab Not reported
3. Paclitaxel & Topotecan Did not meet primary endpoint of OS1

1Reported efficacy is based on the 2017 update.
Note: in the initial report, topotecan & paclitaxel +/- bevacizumab regimens were "associated with a significantly higher risk of progression" as compared to cisplatin & paclitaxel +/- bevacizumab regimens.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. GOG 240: Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014 Feb 20;370(8):734-43. link to original article link to supplementary appendix contains dosing details in manuscript link to PMC article PubMed NCT00803062
    1. Update: Tewari KS, Sill MW, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, DiSaia PJ, Copeland LJ, Creasman WT, Stehman FB, Brady MF, Burger RA, Thigpen JT, Birrer MJ, Waggoner SE, Moore DH, Look KY, Koh WJ, Monk BJ. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017 Oct 7;390(10103):1654-1663. Epub 2017 Jul 27. link to original article link to PMC article PubMed
    2. Update: Tewari KS, Sill MW, Birrer MJ, Penson RT, Huang H, Moore DH, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Final survival analysis of topotecan and paclitaxel for first-line treatment of advanced cervical cancer: An NRG oncology randomized study. Gynecol Oncol. 2023 Apr;171:141-150. Epub 2023 Mar 8. link to original article PubMed

Topotecan monotherapy

Regimen variant #1, q3wk

Study Dates of enrollment Evidence
Bookman et al. 2000 (GOG 127-F) 1994-12 to NR Phase 2

Chemotherapy

21-day cycles


Regimen variant #2, q4wk

Study Dates of enrollment Evidence
Muderspach et al. 2001 (GOG 76-U) 1994-01 to 1995-12 Phase 2

Chemotherapy

28-day cycles

References

  1. Bookman MA, Blessing JA, Hanjani P, Herzog TJ, Andersen WA; Gynecologic Oncology Group. Topotecan in squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2000 Jun;77(3):446-9. link to original article contains dosing details in manuscript PubMed
  2. GOG 76-U: Muderspach LI, Blessing JA, Levenback C, Moore JL Jr; Gynecologic Oncology Group. A phase II study of topotecan in patients with squamous cell carcinoma of the cervix: a Gynecologic Oncology Gxroup study. Gynecol Oncol. 2001 May;81(2):213-5. link to original article contains dosing details in manuscript PubMed

Vinorelbine monotherapy

Regimen

Study Dates of enrollment Evidence Efficacy
Morris et al. 1998 1993-1995 Phase 2 ORR: 18%

Chemotherapy

7-day cycles

References

  1. Morris M, Brader KR, Levenback C, Burke TW, Atkinson EN, Scott WR, Gershenson DM. Phase II study of vinorelbine in advanced and recurrent squamous cell carcinoma of the cervix. J Clin Oncol. 1998 Mar;16(3):1094-8. link to original article contains dosing details in manuscript PubMed

Advanced or metastatic disease, subsequent lines of therapy

Bevacizumab monotherapy

Regimen

Study Dates of enrollment Evidence
Monk et al. 2009 (GOG 227-C) 2002-2006 Phase 2

Targeted therapy

21-day cycles

References

  1. Monk BJ, Sill MW, Burger RA, Gray HJ, Buekers TE, Roman LD; Gynecologic Oncology Group. Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2009 Mar 1;27(7):1069-74. Epub 2009 Jan 12. link to original article contains dosing details in manuscript link to PMC article PubMed

Cemiplimab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tewari et al. 2022 (EMPOWER-Cervical 1) 2017-2020 Phase 3 (E-switch-ooc) 1a. Pemetrexed
1b. Topotecan
1c. Irinotecan
1d. Gemcitabine
1e. Vinorelbine
Superior OS (primary endpoint)
Median OS: 12 vs 8.5 mo
(HR 0.69, 95% CI 0.56-0.84)

Immunotherapy

21-day cycle for up to 32 cycles (96 weeks)

References

  1. EMPOWER-Cervical 1: Tewari KS, Monk BJ, Vergote I, Miller A, de Melo AC, Kim HS, Kim YM, Lisyanskaya A, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin EA, Takahashi S, Ramone D, Pikiel J, Maćkowiak-Matejczyk B, Guerra Alía EM, Colombo N, Makarova Y, Rischin D, Lheureux S, Hasegawa K, Fujiwara K, Li J, Jamil S, Jankovic V, Chen CI, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Mathias M, Fury MG, Oaknin A; Investigators for GOG Protocol 3016 and ENGOT Protocol En-Cx9. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med. 2022 Feb 10;386(6):544-555. link to original article contains dosing details in manuscript PubMed NCT03257267

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine, Cisplatin

Regimen

Study Dates of enrollment Evidence
Brewer et al. 2006 2001-2002 Phase 2

Chemotherapy

28-day cycles

References

  1. Brewer CA, Blessing JA, Nagourney RA, McMeekin DS, Lele S, Zweizig SL; Gynecologic Oncology Group. Cisplatin plus gemcitabine in previously treated squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2006 Feb;100(2):385-8. Epub 2005 Nov 4. link to original article contains dosing details in manuscript PubMed

Docetaxel monotherapy

Regimen variant #1, 36 mg/m2, 3 weeks out of 4

Study Dates of enrollment Evidence
Garcia et al. 2008 2004-07 to 2005-04 Phase 2

Chemotherapy

Supportive therapy

28-day cycles


Regimen variant #2, 100 mg/m2, q3wk

Study Dates of enrollment Evidence
Garcia et al. 2007 2002-06 to 2004-12 Phase 2

Chemotherapy

21-day cycles

References

  1. Garcia AA, Blessing JA, Vaccarello L, Roman LD; Gynecologic Oncology Group. Phase II clinical trial of docetaxel in refractory squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Am J Clin Oncol. 2007 Aug;30(4):428-31. link to original article contains dosing details in abstract PubMed
  2. Garcia AA, Blessing JA, Nolte S, Mannel RS; Gynecologic Oncology Group. A phase II evaluation of weekly docetaxel in the treatment of recurrent or persistent endometrial carcinoma: a study by the Gynecologic Oncology Group. Gynecol Oncol. 2008 Oct;111(1):22-6. link to original article contains dosing details in manuscript PubMed

FULV

FULV: 5-FU & LeucoVorin

Regimen variant #1, 1850/200

Study Dates of enrollment Evidence
Look et al. 1996 1990-1992 Phase 2
Look et al. 1997 1993-1995 Phase 2

Note: it is not entirely clear from these publications whether leucovorin is given on day 1 only, versus on days 1 to 5.

Chemotherapy

28-day cycle for 2 cycles, then 35-day cycles


Regimen variant #2, 2125/100

Study Dates of enrollment Evidence
Look et al. 1992 1989-09 to 1990-04 Phase 2

Chemotherapy

28-day cycle for 2 cycles, then 35-day cycles

References

  1. Look KY, Blessing JA, Muss HB, Partridge EE, Malfetano JH; Gynecologic Oncology Group. 5-fluorouracil and low-dose leucovorin in the treatment of recurrent squamous cell carcinoma of the cervix: a phase II trial of the Gynecologic Oncology Group. Am J Clin Oncol. 1992 Dec;15(6):497-9. link to original article PubMed
  2. Look KY, Blessing JA, Gallup DG, Lentz SS; Gynecologic Oncology Group. A phase II trial of 5-fluorouracil and high-dose leucovorin in patients with recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Am J Clin Oncol. 1996 Oct;19(5):439-41. link to original article contains dosing details in manuscript PubMed
  3. Look KY, Blessing JA, Valea FA, McGehee R, Manetta A, Webster KD, Andersen WA; Gynecologic Oncology Group. Phase II trial of 5-fluorouracil and high-dose leucovorin in recurrent adenocarcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1997 Dec;67(3):255-8. link to original article contains dosing details in manuscript PubMed

Gemcitabine monotherapy

Regimen variant #1

Study Dates of enrollment Evidence
Schilder et al. 2000 (GOG 127-K) NR Phase 2
Schilder et al. 2005 NR Phase 2

Chemotherapy

28-day cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tewari et al. 2022 (EMPOWER-Cervical 1) 2017-2020 Phase 3 (C) Cemiplimab Inferior OS
Awaiting publication (innovaTV 301) 2021-ongoing Phase 3 (C) Tisotumab vedotin TBD if different 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

21-day cycles

References

  1. GOG 127-K: Schilder RJ, Blessing JA, Morgan M, Mangan CE, Rader JS; Gynecologic Oncology Group. Evaluation of gemcitabine in patients with squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2000 Feb;76(2):204-7. link to original article contains dosing details in manuscript PubMed
  2. Schilder RJ, Blessing J, Cohn DE; Gynecologic Oncology Group. Evaluation of gemcitabine in previously treated patients with non-squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2005 Jan;96(1):103-7. link to original article contains dosing details in manuscript PubMed
  3. EMPOWER-Cervical 1: Tewari KS, Monk BJ, Vergote I, Miller A, de Melo AC, Kim HS, Kim YM, Lisyanskaya A, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin EA, Takahashi S, Ramone D, Pikiel J, Maćkowiak-Matejczyk B, Guerra Alía EM, Colombo N, Makarova Y, Rischin D, Lheureux S, Hasegawa K, Fujiwara K, Li J, Jamil S, Jankovic V, Chen CI, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Mathias M, Fury MG, Oaknin A; Investigators for GOG Protocol 3016 and ENGOT Protocol En-Cx9. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med. 2022 Feb 10;386(6):544-555. link to original article contains dosing details in manuscript PubMed NCT03257267
  4. innovaTV 301: NCT04697628

Irinotecan monotherapy

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tewari et al. 2022 (EMPOWER-Cervical 1) 2017-2020 Phase 3 (C) Cemiplimab Inferior OS
Awaiting publication (innovaTV 301) 2021-ongoing Phase 3 (C) Tisotumab vedotin TBD if different 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

42-day cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Verschraegen et al. 1997 1993-1995 Phase 2
Awaiting publication (innovaTV 301) 2021-ongoing Phase 3 (C) Tisotumab vedotin TBD if different 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

Supportive therapy

42-day cycles

References

  1. Verschraegen CF, Levy T, Kudelka AP, Llerena E, Ende K, Freedman RS, Edwards CL, Hord M, Steger M, Kaplan AL, Kieback D, Fishman A, Kavanagh JJ. Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol. 1997 Feb;15(2):625-31. link to original article contains dosing details in manuscript PubMed
  2. EMPOWER-Cervical 1: Tewari KS, Monk BJ, Vergote I, Miller A, de Melo AC, Kim HS, Kim YM, Lisyanskaya A, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin EA, Takahashi S, Ramone D, Pikiel J, Maćkowiak-Matejczyk B, Guerra Alía EM, Colombo N, Makarova Y, Rischin D, Lheureux S, Hasegawa K, Fujiwara K, Li J, Jamil S, Jankovic V, Chen CI, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Mathias M, Fury MG, Oaknin A; Investigators for GOG Protocol 3016 and ENGOT Protocol En-Cx9. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med. 2022 Feb 10;386(6):544-555. link to original article contains dosing details in manuscript PubMed NCT03257267
  3. innovaTV 301: NCT04697628

Pembrolizumab monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence
Chung et al. 2019 (KEYNOTE-158cervical) 2016-01-27 to 2016-08-18 Phase 2 (RT)

Note: KEYNOTE-158 was a basket study with multiple arms of different enrollment periods.

Immunotherapy

21-day cycle for up to 35 cycles (2 years)

References

  1. KEYNOTE-158cervical: Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, Manzuk L, Piha-Paul SA, Xu L, Zeigenfuss S, Pruitt SK, Leary A. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019 Jun 10;37(17):1470-1478. Epub 2019 Apr 3. link to original article contains dosing details in abstract PubMed NCT02628067

Pemetrexed monotherapy

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tewari et al. 2022 (EMPOWER-Cervical 1) 2017-2020 Phase 3 (C) Cemiplimab Inferior OS
Awaiting publication (innovaTV 301) 2021-ongoing Phase 3 (C) Tisotumab vedotin TBD if different 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

21-day cycles


Regimen variant #2

Study Dates of enrollment Evidence
Miller et al. 2008 2004-2006 Phase 2

Chemotherapy

Supportive therapy

  • Folic acid (Folate) 350 to 600 mcg PO once per day, starting 7 days prior to pemetrexed, to continue throughout therapy
  • Cyanocobalamin (Vitamin B12) 1000 mcg IM once, 7 days prior to pemetrexed, then 1000 mcg IM every 9 weeks
  • Dexamethasone (Decadron) 4 mg PO twice per day the day before, the day of, and day after pemetrexed
  • No NSAIDs (nonsteroidal anti-inflammatory drugs) for 2 days before or after pemetrexed

21-day cycles

References

  1. Miller DS, Blessing JA, Bodurka DC, Bonebrake AJ, Schorge JO; Gynecologic Oncology Group. Evaluation of pemetrexed (Alimta, LY231514) as second line chemotherapy in persistent or recurrent carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2008 Jul;110(1):65-70. Epub 2008 May 5. link to original article contains dosing details in manuscript PubMed
  2. EMPOWER-Cervical 1: Tewari KS, Monk BJ, Vergote I, Miller A, de Melo AC, Kim HS, Kim YM, Lisyanskaya A, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin EA, Takahashi S, Ramone D, Pikiel J, Maćkowiak-Matejczyk B, Guerra Alía EM, Colombo N, Makarova Y, Rischin D, Lheureux S, Hasegawa K, Fujiwara K, Li J, Jamil S, Jankovic V, Chen CI, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Mathias M, Fury MG, Oaknin A; Investigators for GOG Protocol 3016 and ENGOT Protocol En-Cx9. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med. 2022 Feb 10;386(6):544-555. link to original article contains dosing details in manuscript PubMed NCT03257267
  3. innovaTV 301: NCT04697628

Tisotumab vedotin monotherapy

Regimen

FDA-recommended dose
Study Dates of enrollment Evidence
Coleman et al. 2021 (innovaTV 204) 2018-06-12 to 2019-04-11 Phase 2 (RT)

Antibody-drug conjugate therapy

21-day cycles

References

  1. innovaTV 204: Coleman RL, Lorusso D, Gennigens C, González-Martín A, Randall L, Cibula D, Lund B, Woelber L, Pignata S, Forget F, Redondo A, Vindeløv SD, Chen M, Harris JR, Smith M, Nicacio LV, Teng MSL, Laenen A, Rangwala R, Manso L, Mirza M, Monk BJ, Vergote I; innovaTV 204/GOG-3023/ENGOT-cx6 Collaborators. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021 May;22(5):609-619. Epub 2021 Apr 9. link to original article contains dosing details in abstract PubMed NCT03438396

Topotecan monotherapy

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tewari et al. 2022 (EMPOWER-Cervical 1) 2017-2020 Phase 3 (C) Cemiplimab Inferior OS
Awaiting publication (innovaTV 301) 2021-ongoing Phase 3 (C) Tisotumab vedotin TBD if different 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

21-day cycles


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Awaiting publication (innovaTV 301) 2021-ongoing Phase 3 (C) Tisotumab vedotin TBD if different 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. Dosing information is from CT.gov.

Chemotherapy

21-day cycles

References

  1. EMPOWER-Cervical 1: Tewari KS, Monk BJ, Vergote I, Miller A, de Melo AC, Kim HS, Kim YM, Lisyanskaya A, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin EA, Takahashi S, Ramone D, Pikiel J, Maćkowiak-Matejczyk B, Guerra Alía EM, Colombo N, Makarova Y, Rischin D, Lheureux S, Hasegawa K, Fujiwara K, Li J, Jamil S, Jankovic V, Chen CI, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Mathias M, Fury MG, Oaknin A; Investigators for GOG Protocol 3016 and ENGOT Protocol En-Cx9. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med. 2022 Feb 10;386(6):544-555. link to original article contains dosing details in manuscript PubMed NCT03257267
  2. innovaTV 301: NCT04697628

Vinorelbine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Muggia et al. 2004 1997-1999 Phase 2 ORR: 14% (95% CI 5-27%)
Muggia et al. 2005 1997-1999 Phase 2 ORR: 7%
Tewari et al. 2022 (EMPOWER-Cervical 1) 2017-2020 Phase 3 (C) Cemiplimab Inferior OS
Awaiting publication (innovaTV 301) 2021-ongoing Phase 3 (C) Tisotumab vedotin TBD if different 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

21-day cycles

References

  1. Muggia FM, Blessing JA, Method M, Miller DS, Johnson GA, Lee RB, Menzin A; Gynecologic Oncology Group. Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2004 Feb;92(2):639-43. link to original article contains dosing details in manuscript PubMed
  2. Muggia FM, Blessing JA, Waggoner S, Berek JS, Monk BJ, Sorosky J, Pearl ML; Gynecologic Oncology Group. Evaluation of vinorelbine in persistent or recurrent nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2005 Jan;96(1):108-11. link to original article contains dosing details in manuscript PubMed
  3. EMPOWER-Cervical 1: Tewari KS, Monk BJ, Vergote I, Miller A, de Melo AC, Kim HS, Kim YM, Lisyanskaya A, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin EA, Takahashi S, Ramone D, Pikiel J, Maćkowiak-Matejczyk B, Guerra Alía EM, Colombo N, Makarova Y, Rischin D, Lheureux S, Hasegawa K, Fujiwara K, Li J, Jamil S, Jankovic V, Chen CI, Seebach F, Weinreich DM, Yancopoulos GD, Lowy I, Mathias M, Fury MG, Oaknin A; Investigators for GOG Protocol 3016 and ENGOT Protocol En-Cx9. Survival with Cemiplimab in Recurrent Cervical Cancer. N Engl J Med. 2022 Feb 10;386(6):544-555. link to original article contains dosing details in manuscript PubMed NCT03257267
  4. innovaTV 301: NCT04697628