Cervical cancer

Section editor
	Alaina J. Brown, MD, MPH Vanderbilt University Nashville, TN LinkedIn

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45 regimens on this page 60 variants on this page

Guidelines

ASCO

• 2022: Chuang et al. Management and Care of Patients With Invasive Cervical Cancer: ASCO Resource-Stratified Guideline Rapid Recommendation Update
  • 2016: Chuang et al. Management and Care of Women With Invasive Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Clinical Practice Guideline

ESMO

• 2017: Marth et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Older

• 2012: Colombo et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

NCCN

• NCCN Guidelines - Cervical Cancer

Older

• 2015: Koh et al. Cervical Cancer, Version 2.2015 PubMed

Neoadjuvant chemotherapy

Cisplatin & Paclitaxel

Regimen

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

Chemotherapy

• Cisplatin (Platinol) 60 mg/m² IV over 2 hours once on day 1, given second
• Paclitaxel (Taxol) 60 mg/m² IV over 3 hours once on day 1, given first

Supportive therapy

• Dexamethasone (Decadron) 20 mg PO twice on day 1; 12 and 6 hours prior to paclitaxel
• Cimetidine (Tagamet) 300 mg IV once on day 1; 30 minutes prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once on day 1; 30 minutes prior to paclitaxel
• Antiemetics before and 3 days after chemotherapy

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

Carboplatin & RT

Carboplatin & RT: Carboplatin & Radiation Therapy

Regimen

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

Chemotherapy

• Carboplatin (Paraplatin) 100 mg/m² IV over 30 to 60 minutes once on day 1

7-day cycle for 5 to 6 cycles, according to RT duration

Radiotherapy

• Concurrent radiation therapy

One 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: Clinical Trial Registry

Cisplatin & RT

Cisplatin & RT: Cisplatin & Radiation Therapy

Protocol variant #1, weekly cisplatin x 5, no cap

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 OS60: 54% vs 46% (HR 0.82, 95% CI 0.68-0.98)

Chemotherapy

• Cisplatin (Platinol) 40 mg/m² IV once on day 1

Supportive therapy

• Ondansetron (Zofran) 16 mg (route not specified) once on day 1, prior to cisplatin
• Dexamethasone (Decadron) 8 mg (route not specified) once on day 1, prior to cisplatin
• Pre- and post- cisplatin hydration

7-day cycle for 5 cycles

Radiotherapy, part 1

• Concurrent radiation therapy: 2 Gy x 25 fractions, for a dose of 50 Gy

5-week course, followed by:

Radiotherapy, part 2

• See paper for details

Protocol variant #2, 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 primary endpoints of PFS/OS
			2. Hydroxyurea & RT	Superior OS
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 (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, part 1

• Concurrent radiation therapy by the following study-specific criteria:
  • GOG 120, stage IIB: 1.7 Gy x 24 fractions, for an initial dose of 40.8 Gy
  • GOG 219: Concurrent radiation therapy: 1.8 Gy x 23 to 25 fractions, for an initial dose of 41.4 to 45 Gy
  • Pearcey et al. 2002 & Zuliani et al. 2014: 1.8 Gy x 25 fractions, for an initial dose of 45 Gy
  • B9E-MC-JHQS & Sehouli et al. 2012: 1.8 Gy x 28 fractions, for an initial dose of 50.4 Gy
  • GOG 120, stage III or IVA: 1.7 Gy x 30 fractions, for an initial dose of 51 Gy
  • Yang et al. 2022: 1.8 Gy/fraction/day, 5 days/week, a total of 25-28 fractions

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

Radiotherapy, part 2

• 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: 30 Gy for a total dose of 81 Gy to point A
    • Patients that could not receive brachytherapy underwent additional external beam radiation therapy for a total dose of 61.2 Gy
  • B9E-MC-JHQS & Sehouli et al. 2012: 30 to 35 Gy delivered to point A
  • GOG 219: 35 to 43.6 Gy to point A
  • GOG 120, stage IIB: 40 Gy for a total dose of 80.8 Gy to point A
    • Patients that could not receive brachytherapy underwent additional external beam radiation therapy for a total dose of 61.2 Gy

Protocol variant #3, 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
Lanciano et al. 2005 (GOG 165)	1997-2000	Phase 3 (E-switch-ic)	Fluorouracil & RT	Might have superior ORR

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, part 1

• Concurrent radiation therapy: 1.8 Gy x 25 fractions, for an initial dose of 45 Gy

6-week course, followed by:

Radiotherapy, part 2

• Brachytherapy by the following study-specific criteria:
  • GOG 123: 30 Gy to point A for a total dose of 75 Gy
  • GOG 165: ONE of the following:
    • Low-dose rate intracavitary brachytherapy of 40 Gy to point A given in 1 to 2 fractions
    • High-dose rate intracavitary brachytherapy of 30 Gy to point A given in 5 fractions, starting week 4 of XRT
  • GOG 165: Parametrial boost of 5.4 to 9 Gy was administered to the involved parametrium after whole pelvic RT was complete

Subsequent treatment

• GOG 123: Adjuvant hysterectomy

Regimen variant #4, 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

• Cisplatin (Platinol) 75 mg/m² IV once on day 1

21-day cycle for 3 cycles

Radiotherapy

• Concurrent radiation therapy: 1.8 to 2 Gy, for an initial dose of 50 Gy
• Brachytherapy, see paper for details

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
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 Clinical Trial Registry
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 Clinical Trial Registry
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 Clinical Trial Registry
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 Clinical Trial Registry
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 Clinical Trial Registry
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. CALLA: Clinical Trial Registry

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
Peters et al. 2000 (GOG 109/SWOG-8797)	1991-1996	Phase 3 (E-esc)	Radiation therapy	Superior OS

Chemotherapy

• Cisplatin (Platinol) 70 mg/m² IV over 2 hours once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose: 4000 mg/m²)

21-day cycle for 4 cycles

Radiotherapy

• Concurrent radiation therapy: 1.7 Gy x 29 fractions, for a total dose of 49.3 Gy, starting on cycle 1 day 1
  • Patients with positive high common iliac lymph nodes also received 1.5 Gy x 30 fractions, for a total dose of 45 Gy

6-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

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV over 4 hours once on day 1, given first
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose: 4000 mg/m²)

21-day cycle for 3 cycles

Radiotherapy

• Concurrent radiation therapy: 1.8 Gy x 25 fractions, for a total dose of 45 Gy, starting on cycle 1 day 0 or 1

5-week course

Subsequent treatment

• Brachytherapy (see paper for details)

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

Protocol

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 primary endpoints of PFS/OS
			2. Hydroxyurea & RT	Superior OS

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m²)
• Hydroxyurea (Hydrea) 2000 mg/m² PO two times per week, given 2 hours before radiation on weeks 1 to 6

28-day cycle for 2 cycles

Radiotherapy, part 1

• Concurrent radiation therapy by the following stage-based criteria:
  • Stage IIB: 1.7 Gy x 24 fractions, for an initial dose of 40.8 Gy
  • Stage III or IVA: 1.7 Gy x 30 fractions, for an initial dose of 51 Gy

5- to 6-week course, followed by:

Radiotherapy, part 2

• Stage IIB patients received 40 Gy by intracavitary brachytherapy, for a total dose of 80.8 Gy to point A
• Stage III or IVA disease received 30 Gy by intracavitary brachytherapy, for a total dose of 81 Gy to point A
  • Patients that could not receive brachytherapy underwent additional external beam radiation therapy for a total dose of 61.2 Gy

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 OS Median OS: NYR vs NYR (HR 0.68, 95% CI 0.49-0.95)
Cetina et al. 2013	2004-2009	Non-randomized part of 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: 1.8 Gy x 28 fractions, for an initial dose of 50.4 Gy

6-week course

Subsequent treatment

• B9E-MC-JHQS: Brachytherapy (30 to 35 Gy delivered to point A), then adjuvant GC, in 2 weeks
• Cetina et al. 2013: Brachytherapy verus radical hysterectomy

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 Clinical Trial Registry
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

Protocol

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

Chemotherapy

• Fluorouracil (5-FU) 225 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 1125 mg/m²)

7-day cycle for 6 cycles

Radiotherapy, part 1

• Concurrent radiation therapy, 1.8 Gy x 25 fractions, for an initial dose of 40.8 Gy

6-week course, followed by:

Radiotherapy, part 2

• • EITHER Low-dose rate intracavitary brachytherapy of 40 Gy to point A given in 1 to 2 fractions
  • OR High-dose rate intracavitary brachytherapy of 30 Gy to point A given in 5 fractions, starting week 4 of XRT
• Parametrial boost of 5.4 to 9 Gy 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 Clinical Trial Registry

Hydroxyurea & RT

Hydroxyurea & RT: Hydroxyurea & Radiation Therapy

Protocol

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
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

Chemotherapy

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

Radiotherapy, part 1

• Concurrent radiation therapy by the following stage-based criteria:
  • Stage IIB: 1.7 Gy x 24 fractions, for an initial dose of 40.8 Gy
  • Stage III or IVA: 1.7 Gy x 30 fractions, for an initial dose of 51 Gy

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

Radiotherapy, part 2

• Intracavitary brachytherapy by the following stage-based criteria:
  • Stage IIB: 40 Gy for a total dose of 80.8 Gy to point A
• Stage III or IVA: 30 Gy for a total dose of 81 Gy to point A
• Patients that could not receive brachytherapy underwent additional external beam radiation therapy for a total dose of 61.2 Gy

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 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
3. 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 PFS Median PFS: 30 vs 28 mo (HR 0.25, 95% CI 0.08-0.77)

Chemotherapy

• Nedaplatin (Aqupla) 30 mg/m² IV once on day 1

7-day cycle for 5 to 6 cycles

Radiotherapy

• Concurrent radiation therapy 1.8 Gy/fraction/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.

Preceding treatment

• Wertheim-Meigs radical abdominal hysterectomy

Chemotherapy

• Carboplatin (Paraplatin) AUC 4 IV over 60 minutes once on day 1
• Ifosfamide (Ifex) 1600 mg/m² IV over 6 hours once per day on days 1 to 3, with mesa

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

• Pelvic EBRT x 50.4 Gy

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 RCT

Preceding treatment

• Cisplatin, Gemcitabine, RT

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

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 Clinical Trial Registry

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

• Surgery, then Carboplatin & Ifosfamide x 4

Radiotherapy

• External beam radiotherapy: 1.8 Gy for 28 fractions, for a total dose of 50.4 Gy
• If resection margins positive, patients received one of the following:
  • EBRT boost of 2 x 5 Gy
  • 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

Carboplatin monotherapy

Regimen

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

Chemotherapy

• Carboplatin (Paraplatin) 400 mg/m² IV once on day 1

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 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

• Carboplatin (Paraplatin) AUC 6 IV over 60 minutes once on day 1, given second
• Docetaxel (Taxotere) 60 mg/m² IV over 60 minutes once on day 1, given first

Supportive therapy

• Dexamethasone (Decadron)
• Ondansetron (Zofran) or Granisetron
• Filgrastim (Neupogen) 5 mcg/kg once per day for patients with grade 4 neutropenia or febrile neutropenia

21-day cycle for up to 6 cycles

Regimen variant #2, indefinite

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

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV over 60 minutes once on day 1, given second
• Docetaxel (Taxotere) 60 mg/m² IV over 60 minutes once on day 1, given first

Supportive therapy

• Dexamethasone (Decadron)
• Ondansetron (Zofran) or Granisetron
• Filgrastim (Neupogen) 5 mcg/kg once per day for patients with grade 4 neutropenia or febrile neutropenia

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
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

• Carboplatin (Paraplatin) AUC 5 IV over 60 minutes once on day 1, given second
• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1, given first

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 Clinical Trial Registry
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 Clinical Trial Registry
   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

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

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

Chemotherapy

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6 (see note): AUC 5 IV once on day 1
• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 6 (see note): 175 mg/m² IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

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 Clinical Trial Registry
   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

Carboplatin & Paclitaxel (CP), Bevacizumab, Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826) ESMO-MCBS (4)	2018-2020	Phase 3 (E-RT-esc)	1a. CP 1b. CP & Bevacizumab 1c. Cisplatin & Paclitaxel 1d. Cisplatin, Paclitaxel, Bevacizumab	Superior OS1 (co-primary endpoint) OS24: 50.4% vs 40.4% (HR 0.67, 95% CI 0.54-0.84)

¹Reported efficacy is for the ITT population
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

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6 (see note): AUC 5 IV once on day 1
• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 6 (see note): 175 mg/m² IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

Immunotherapy

• Pembrolizumab (Keytruda) as follows:
  • Cycles 1 up to 35: 200 mg IV once on day 1

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 Clinical Trial Registry
   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

Carboplatin & Paclitaxel (CP) & Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826) ESMO-MCBS (4)	2018-2020	Phase 3 (E-RT-esc)	1a. CP 1b. CP & Bevacizumab 1c. Cisplatin & Paclitaxel 1d. Cisplatin, Paclitaxel, Bevacizumab	Superior OS1 (co-primary endpoint) OS24: 50.4% vs 40.4% (HR 0.67, 95% CI 0.54-0.84)

¹Reported efficacy is for the ITT population
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

• Carboplatin (Paraplatin) as follows:
  • Cycles 1 to 6 (see note): AUC 5 IV once on day 1
• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 6 (see note): 175 mg/m² IV once on day 1

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

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 Clinical Trial Registry
   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

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)	Cisplatin & Ifosfamide	Inferior PFS
			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

• Cisplatin (Platinol) 50 mg/m² IV once on day 1

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 Clinical Trial Registry
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 Clinical Trial Registry

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
			2. Cisplatin & Topotecan	Did not meet primary endpoint of OS
			3. Cisplatin & Vinorelbine	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

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 Clinical Trial Registry

Cisplatin & Ifosfamide

Regimen

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

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Ifosfamide (Ifex) 5000 mg/m² IV continuous infusion over 24 hours, started on day 1 concurrent with mesna

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

• Cisplatin (Platinol) 50 mg/m² IV once on day 1, given second
• Mitomycin (Mutamycin) 6 mg/m² IV push once on day 1, given first

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

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Paclitaxel (Taxol) 135 mg/m² IV once on day 1

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
Monk et al. 2009 (GOG 204)	2003-2007	Phase 3 (C)	1. Cisplatin & Gemcitabine	Seems to have superior PFS
			2. Cisplatin & Topotecan	Did not meet primary endpoint of OS
			3. Cisplatin & Vinorelbine	Might have superior PFS
Kitagawa et al. 2015 (JCOG0505)	2006-2009	Phase 3 (C)	Carboplatin & Paclitaxel	Non-inferior OS Median OS: 18.3 vs 17.5 mo (HR 0.994, 90% CI 0.79-1.25)

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

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once on day 2
• Paclitaxel (Taxol) 135 mg/m² IV continuous infusion over 24 hours, started on day 1

Supportive therapy

• (varies depending on reference):
• Dexamethasone (Decadron)
• Diphenhydramine (Benadryl)
• H2 receptor antagonist such as Cimetidine (Tagamet) or Ranitidine (Zantac)
• Prophylactic antiemetics
• "Adequate IV hydration and electrolyte replacement"

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

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

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 Clinical Trial Registry
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 Clinical Trial Registry
   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 Clinical Trial Registry
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 Clinical Trial Registry
   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

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) ESMO-MCBS (3)	2009-2012	Phase 3 (E-RT-esc)	1. Cisplatin & Paclitaxel	Superior OS1 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

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Paclitaxel (Taxol) 135 mg/m² IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

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) ESMO-MCBS (3)	2009-2012	Phase 3 (E-RT-esc)	1. Cisplatin & Paclitaxel	Superior OS1 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

¹Reported efficacy marked 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. The decision to give bevacizumab in KEYNOTE-826 was at the discretion of the treating institution and was not a randomization.

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

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 Clinical Trial Registry
   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 Clinical Trial Registry
   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
3. BEATcc: Clinical Trial Registry

Cisplatin, Paclitaxel, Bevacizumab, Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826) ESMO-MCBS (4)	2018-2020	Phase 3 (E-RT-esc)	1a. CP 1b. CP & Bevacizumab 1c. Cisplatin & Paclitaxel 1d. Cisplatin, Paclitaxel, Bevacizumab	Superior OS1 (co-primary endpoint) OS24: 50.4% vs 40.4% (HR 0.67, 95% CI 0.54-0.84)

¹Reported efficacy is for the ITT population
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

• Cisplatin (Platinol) as follows:
  • Cycles 1 to 6 (see note): 50 mg/m² IV once on day 1
• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 6 (see note): 175 mg/m² IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

Immunotherapy

• Pembrolizumab (Keytruda) as follows:
  • Cycles 1 up to 35: 200 mg IV once on day 1

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 Clinical Trial Registry
   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

Cisplatin, Paclitaxel, Pembrolizumab

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826) ESMO-MCBS (4)	2018-2020	Phase 3 (E-RT-esc)	1a. CP 1b. CP & Bevacizumab 1c. Cisplatin & Paclitaxel 1d. Cisplatin, Paclitaxel, Bevacizumab	Superior OS1 (co-primary endpoint) OS24: 50.4% vs 40.4% (HR 0.67, 95% CI 0.54-0.84)

¹Reported efficacy is for the ITT population
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

• Cisplatin (Platinol) as follows:
  • Cycles 1 to 6 (see note): 50 mg/m² IV once on day 1
• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 6 (see note): 175 mg/m² IV once on day 1

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV once on day 1

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 Clinical Trial Registry
   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

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
			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

• Cisplatin (Platinol) 50 mg/m² IV once on day 1, given second
• Topotecan (Hycamtin) 0.75 mg/m² IV over 30 minutes once per day on days 1 to 3, given first

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 Clinical Trial Registry
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 Clinical Trial Registry
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 Clinical Trial Registry

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
			3. Cisplatin & Topotecan	Did not meet primary endpoint of OS

Chemotherapy

• Cisplatin (Platinol) 50 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

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 Clinical Trial Registry

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 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

• Paclitaxel (Taxol) 135 mg/m² IV continuous infusion over 24 hours, started on day 1

Supportive therapy

• Dexamethasone (Decadron) 20 mg IV or PO for two doses on day 1; 14 and 7 hours prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once on day 1; 30 minutes prior to paclitaxel
• Ranitidine (Zantac) 50 mg IV once on day 1; 30 minutes prior to paclitaxel

21-day cycles

Dose modifications

• Paclitaxel (Taxol) dose could be changed to 110 or 200 mg/m² depending on toxicity

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

• Dexamethasone (Decadron) 20 mg IV or PO for 2 doses on day 1; 14 and 7 hours prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once on day 1; 30 minutes prior to paclitaxel
• Ranitidine (Zantac) 50 mg IV once on day 1; 30 minutes prior to paclitaxel

21-day cycles

Dose modifications

• Paclitaxel (Taxol) dose could be changed to 110 or 200 mg/m² depending on toxicity

Regimen variant #3, 250 mg/m²

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

Chemotherapy

• Paclitaxel (Taxol) 250 mg/m² IV over 3 hours once on day 1

Supportive therapy

• Dexamethasone (Decadron) 20 mg PO for two doses on day 1; 14 and 7 hours prior to paclitaxel
• Cimetidine (Tagamet) 300 mg IV once on day 1; 60 minutes prior to paclitaxel
• Diphenhydramine (Benadryl) 50 mg IV once on day 1; 60 minutes prior to paclitaxel
• Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 2, 24 hours after paclitaxel, given until day 19 or until ANC greater or equal to 10,000/μL

21-day cycles

Dose modifications

• Paclitaxel (Taxol) dose could be changed to 275, 225, or 200 mg/m² depending on toxicity

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

• Paclitaxel (Taxol) 175 mg/m² IV once on day 1
• Topotecan (Hycamtin) 0.75 mg/m² IV once per day on days 1 to 3

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 Clinical Trial Registry
   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) ESMO-MCBS (3)	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

• Paclitaxel (Taxol) 175 mg/m² IV once on day 1
• Topotecan (Hycamtin) 0.75 mg/m² IV once per day on days 1 to 3

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

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 Clinical Trial Registry
   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

• Topotecan (Hycamtin) 1.5 mg/m² IV over 30 minutes once per day on days 1 to 5

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

• Topotecan (Hycamtin) 1.5 mg/m² IV over 30 minutes once per day on days 1 to 5

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

• Vinorelbine (Navelbine) 30 mg/m² IV once on day 1

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

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

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) ESMO-MCBS (4)	2017-2020 (C)	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

• Cemiplimab (Libtayo) 350 mg IV once on day 1

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 Clinical Trial Registry

Cisplatin & Gemcitabine (GC)

GC: Gemcitabine, Cisplatin

Regimen

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

Chemotherapy

• Cisplatin (Platinol) 30 mg/m² IV once on day 1, given first
• Gemcitabine (Gemzar) 800 mg/m² IV once per day on days 1 & 8, given second

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

• Docetaxel (Taxotere) 36 mg/m² IV over 60 minutes once per day on days 1, 8, 15

Supportive therapy

• Dexamethasone (Decadron) 8 mg PO the evening before, morning of, and evening of each dose of docetaxel

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

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

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 (Folinic acid)

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

• Fluorouracil (5-FU) 370 mg/m² IV over 5 minutes once per day on days 1 to 5, given second
• Folinic acid (Leucovorin) 200 mg/m² IV bolus once on day 1 (see note), given first

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

• Fluorouracil (5-FU) 425 mg/m² IV once per day on days 1 to 5, given second
• Folinic acid (Leucovorin) 20 mg/m² IV once per day on days 1 to 5, given first

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

• Gemcitabine (Gemzar) 800 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycles

Regimen variant #2

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

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

• Gemcitabine (Gemzar) 1000 mg/m² IV once per day on days 1 & 8

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 Clinical Trial Registry
4. innovaTV 301: Clinical Trial Registry

Irinotecan monotherapy

Regimen variant #1

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

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

• Irinotecan (Camptosar) 100 mg/m² IV once per day on days 1, 8, 15, 22

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

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

• Irinotecan (Camptosar) 125 mg/m² IV over 90 minutes once per day on days 1, 8, 15, 22

Supportive therapy

• Diphenhydramine (Benadryl) 25 to 50 mg IV or PO every 6 hours as needed for diarrhea during irinotecan infusion
• Atropine (Atropen) 1 mg IV every 6 hours as needed for diarrhea during irinotecan infusion
• Loperamide (Imodium) 4 mg PO as needed for each episode of delayed diarrhea between irinotecan infusions

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 Clinical Trial Registry
3. innovaTV 301: Clinical Trial Registry

Pembrolizumab monotherapy

Regimen

FDA-recommended dose

Study	Dates of enrollment	Evidence
Chung et al. 2019 (KEYNOTE-158)	2016	Phase 2 (RT)

Immunotherapy

• Pembrolizumab (Keytruda) 200 mg IV over 30 minutes once on day 1

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

References

1. KEYNOTE-158: 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 Clinical Trial Registry

Pemetrexed monotherapy

Regimen variant #1

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

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

• Pemetrexed (Alimta) 500 mg/m² IV once on day 1

21-day cycles

Regimen variant #2

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

Chemotherapy

• Pemetrexed (Alimta) 900 mg/m² IV over 10 minutes once on day 1

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 Clinical Trial Registry
3. innovaTV 301: Clinical Trial Registry

Tisotumab vedotin monotherapy

Regimen

FDA-recommended dose

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

Antibody-drug conjugate therapy

• Tisotumab vedotin (Tivdak) 2 mg/kg (maximum dose of 200 mg) IV over 30 minutes once on day 1

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 Clinical Trial Registry

Topotecan monotherapy

Regimen variant #1

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

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

• Topotecan (Hycamtin) 1 mg/m² IV once per day on days 1 to 5

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

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

• Topotecan (Hycamtin) 1.25 mg/m² IV once per day on days 1 to 5

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 Clinical Trial Registry
2. innovaTV 301: Clinical Trial Registry

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 (C)	Phase 3 (C)	Cemiplimab	Inferior OS
Awaiting publication (innovaTV 301)	2021-ongoing	Phase 3 (C)	Tisotumab vedotin	TBD

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

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

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 Clinical Trial Registry
4. innovaTV 301: Clinical Trial Registry