Cervical cancer

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Last updated on 2024-12-02:50 regimens on this page
71 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==ASCO==
*2022: Chuang et al. Management and Care of Patients With Invasive Cervical Cancer: ASCO Resource-Stratified Guideline Rapid Recommendation Update EuroPMC
**2016: Chuang et al. Management and Care of Women With Invasive Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Clinical Practice Guideline EuroPMC
==ESGO/ESTRO/ESP==
*2023: Cibula et al. ESGO/ESTRO/ESP Guidelines for the management of patients with cervical cancer - Update 2023 EuroPMC
==ESMO==
*2018: Marth et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2017: Marth et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2012: Colombo et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Haie-Meder et al. Cervical cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Haie-Meder et al. Cervical cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2008: Haie-Meder et al. Cervical cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
==NCCN==
*NCCN Guidelines - Cervical Cancer
**2019: Koh et al. Cervical Cancer, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology. EuroPMC
**2015: Koh et al. Cervical Cancer, Version 2.2015 EuroPMC
**2013: Koh et al. Cervical cancer. EuroPMC
**2010: Greer et al. Cervical cancer. EuroPMC
**2008: Greer et al. Cervical cancer. EuroPMC
**2004: Teng et al. Cervical cancer guidelines. Clinical practice guidelines in oncology. EuroPMC
=Induction chemotherapy=
==Carboplatin & Paclitaxel (CP)==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
McCormack et al. 2024 (INTERLACE)	2012-11-08 to 2022-11-17	Phase 3 (E-esc)	No induction therapy	Longer OS (co-primary endpoint)OS60: 80% vs 72%(HR 0.60, 95% CI 0.40-0.91)Longer PFS (co-primary endpoint)PFS60: 72% vs 64%(HR 0.65, 95% CI 0.46-0.91)
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 2 IV once on day 1
*Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
7-day cycle for 6 cycles
====Subsequent treatment====
*Cisplatin & RT consolidation
===References===
#INTERLACE: McCormack M, Eminowicz G, Gallardo D, Diez P, Farrelly L, Kent C, Hudson E, Panades M, Mathew T, Anand A, Persic M, Forrest J, Bhana R, Reed N, Drake A, Adusumalli M, Mukhopadhyay A, King M, Whitmarsh K, McGrane J, Colombo N, Mak C, Mandal R, Chowdhury RR, Alamilla-Garcia G, Chávez-Blanco A, Stobart H, Feeney A, Vaja S, Hacker AM, Hackshaw A, Ledermann JA; INTERLACE investigators. Induction chemotherapy followed by standard chemoradiotherapy versus standard chemoradiotherapy alone in patients with locally advanced cervical cancer (GCIG INTERLACE): an international, multicentre, randomised phase 3 trial. Lancet. 2024 Oct 19;404(10462):1525-1535. Epub 2024 Oct 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01566240
==Cisplatin & Paclitaxel (TP)==
TP: Taxol (Paclitaxel) & Platinol (Cisplatin)
===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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
=Definitive therapy for locally advanced disease=
==Brachytherapy protocol==
===Regimen===
To be completed
====Radiotherapy====
*Intracavitary brachytherapy with radium or its equivalent by the following study-specific criteria:
**Pearcey et al. 2002: See paper for details
**GOG 120, stage III or IVA: 3000 cGy for a total dose of 8100 cGy to point A
***Patients that could not receive brachytherapy underwent additional external beam radiation therapy for a total dose of 6120 cGy
**B9E-MC-JHQS & Sehouli et al. 2012: 3000 to 3500 cGy delivered to point A
**GOG 219: 35 to 4360 cGy to point A
**GOG 120, stage IIB: 4000 cGy for a total dose of 8080 cGy to point A
***Patients that could not receive brachytherapy underwent additional external_beam_radiotherapy for a total dose of 6120 cGy
**GOG 123: 3000 cGy to point A for a total dose of 7500 cGy
**GOG 165: ONE of the following:
***Low-dose rate intracavitary brachytherapy of 4000 cGy to point A given in 1 to 2 fractions
***High-dose rate intracavitary brachytherapy of 3000 cGy to point A given in 5 fractions, starting week 4 of XRT
**GOG 165: Parametrial boost of 540 to 900 cGy was administered to the involved parametrium after whole pelvic RT was complete
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003078
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==Carboplatin & RT==
Carboplatin & RT: Carboplatin & Radiation Therapy
===Regimen variant #1, AUC-based carboplatin===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Monk et al. 2023 (CALLA)	2019-02-15 to 2020-12-10	Phase 3 (C)	1a. Carboplatin, Durvalumab, RT1b. Cisplatin, Durvalumab, RT	Did not meet primary endpoint of PFSMedian PFS: NYR vs NYR(HR 1.19, 95% CI 0.93-1.54)
Note: a sixth dose of carboplatin was optional.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 2 IV once per day on days 1, 8, 15, 22, 29, (36)
====Radiotherapy====
*Concurrent radiation therapy, 180 cGy per fraction on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (4500 cGy total in 25 fractions)
5-week course
====Subsequent treatment====
*Brachytherapy
===Regimen variant #2, BSA-based carboplatin===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Veerasarn et al. 2006	2001-2003 	Phase 3 (C)	Carboplatin, UFT, RT	Did not meet co-primary endpoints of TTP/OS
====Chemotherapy====
*Carboplatin (Paraplatin) 100 mg/m2 IV over 30 to 60 minutes once per day on days 1, 8, 15, 22, 29, +/- 36
====Radiotherapy====
*Concurrent radiation therapy, 4000 to 5000 cGy in 20 to 25 fractions, with an additional parametrium boost of 1000 to 1600 cGy in 5 to 8 fractions
5- to 6-week course
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# CALLA: Monk BJ, Toita T, Wu X, Vázquez Limón JC, Tarnawski R, Mandai M, Shapira-Frommer R, Mahantshetty U, Del Pilar Estevez-Diz M, Zhou Q, Limaye S, Godinez FJR, Oppermann Kussler C, Varga S, Valdiviezo N, Aoki D, Leiva M, Lee JY, Sulay R, Kreynina Y, Cheng WF, Rey F, Rong Y, Ke G, Wildsmith S, Lloyd A, Dry H, Tablante Nunes A, Mayadev J. Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1334-1348. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03830866
==Cisplatin & RT==
Cisplatin & RT: Cisplatin & Radiation Therapy
===Regimen variant #1, weekly cisplatin x 5, no cap + 4500 cGy===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Kenter et al. 2023 (EORTC-55994)	2002-05 to 2014-01 	Phase 3 (C)	Neoadjuvant chemotherapy, then surgery 	Did not meet primary endpoint of OS60
Monk et al. 2023 (CALLA) 	2019-02-15 to 2020-12-10	Phase 3 (C)	1a. Carboplatin, Durvalumab, RT1b. Cisplatin, Durvalumab, RT	Did not meet primary endpoint of PFSMedian PFS: NYR vs NYR(HR 1.19, 95% CI 0.93-1.54)
Note: in CALLA, a sixth dose of cisplatin was optional.
====Chemotherapy====
*Cisplatin (Platinol) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29, (36)
====Radiotherapy====
*Concurrent radiation therapy: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
**Total number of fractions: 25
**Total dose: 4500 cGy
5-week course
====Subsequent treatment====
*Sequential brachytherapy (see paper for details)
===Regimen variant #2, weekly cisplatin x 5, no cap + 5000 cGy===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lutgens et al. 2016 (RADCHOC) 	2003-2009 	Phase 3 (C) 	RT-HT 	Did not meet primary endpoint of EFS
Shrivastava et al. 2018 (CRACx)	2003-2011 	Phase 3 (E-esc)	RT 	Seems to have longer OS (secondary endpoint)OS60: 54% vs 46%(HR 0.82, 95% CI 0.68-0.98)
====Chemotherapy====
*Cisplatin (Platinol) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29
====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
====Radiotherapy====
*Concurrent radiation therapy: 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
**Total number of fractions: 25
**Total dose: 5000 cGy
5-week course
====Subsequent treatment====
*Sequential brachytherapy (see paper for details)
===Regimen variant #3, weekly cisplatin x 6, no cap===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Pearcey et al. 2002 	1991-1996 	Phase 3 (E-esc)	RT 	Did not meet primary endpoint of OS36
Rose et al. 1999 (GOG 120) 	1992-1997 	Phase 3 (E-esc)	1. Cisplatin, Fluorouracil, Hydroxyurea, RT	Did not meet co-primary endpoints of PFS/OS
Rose et al. 1999 (GOG 120) 	1992-1997 	Phase 3 (E-esc)	2. Hydroxyurea & RT 	Longer OS (co-primary endpoint)
Dueñas-González et al. 2011 (B9E-MC-JHQS)	2002-2004 	Phase 3 (C) 	Cisplatin, Gemcitabine, RT 	Seems to have shorter PFS (primary endpoint)PFS36: 65% vs 74.4%(HR 1.47, 95% CI 1.05-2.04)Seems to have shorter OS (secondary endpoint)Median OS: NYR vs NYR(HR 1.47, 95% CI 1.05-2.04)
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 	Longer OS1 (co-primary endpoint)(HR 0.53, 95% CI 0.31-0.92)
DiSilvestro et al. 2014 (GOG 219) 	2006-2009 	Phase 3 (C) 	Cisplatin, Tirapazamine, RT 	Did not meet primary endpoint of PFSPFS36: 64.4% vs 63%
Yang et al. 2022 	2018-2020 	Phase 3 (C) 	Nedaplatin & RT 	Shorter PFSMedian PFS: 28 vs 30 mo(HR 4.00, 95% CI 1.30-12.50)
Lorusson et al. 2024 (KEYNOTE-A18) 	2020-06-09 to 2022-12-15	Phase 3 (C) 	Cisplatin, Pembrolizumab, RT 	Shorter PFS (co-primary endpoint)PFS24: 57% vs 68%(HR 1.43, 95% CI 1.12-1.82)Shorter OS2 (co-primary endpoint)OS36: 74.8% vs 82.6%(HR 1.49, 95% CI 1.11-2.00)
1Reported efficacy for Zuliani et al. 2014 is based on the 2020 update.
2Reported efficacy for KEYNOTE-A18 is based on the 2024 update.
Note: In GOG 120, this regimen was intended for disease.
====Chemotherapy====
*Cisplatin (Platinol) 40 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, (36), given 1 to 4 hours prior to radiation
====Radiotherapy====
*Concurrent radiation therapy by the following study-specific criteria: 
**GOG 120, stage IIB: 170 cGy x 24 fractions, for an initial dose of 4080 cGy
**GOG 219: 180 cGy x 23 to 25 fractions, for an initial dose of 4140 to 4500 cGy
**Pearcey et al. 2002 & Zuliani et al. 2014: 180 cGy x 25 fractions, for an initial dose of 4500 cGy
**B9E-MC-JHQS & Sehouli et al. 2012: 180 cGy x 28 fractions, for an initial dose of 5040 cGy
**GOG 120, stage III or IVA: 170 cGy x 30 fractions, for an initial dose of 5100 cGy
**Yang et al. 2022: 180 cGy/fraction/day, 5 days/week, a total of 25-28 fractions
6-week course, followed in 1 to 3 weeks by:
====Subsequent treatment====
*Sequential brachytherapy
===Regimen variant #4, weekly cisplatin x 6, capped===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Keys et al. 1999 (GOG 123) 	1992-1997 	Phase 3 (E-esc) 	RT 	Longer OS (co-primary endpoint)OS36: 83% vs 74%(RR 0.54, 95% CI 0.34-0.86)
Lanciano et al. 2005 (GOG 165)	1997-2000 	Phase 3 (E-switch-ic)	Fluorouracil & RT	Might have higher ORR (secondary endpoint)
====Chemotherapy====
*Cisplatin (Platinol) 40 mg/m2 (maximum dose of 70 mg) IV once per day on days 1, 8, 15, 22, 29, 36, given 4 hours before radiation
====Radiotherapy====
*Concurrent radiation therapy: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33
**Total number of fractions: 25
**Total dose: 4500 cGy
6-week course, followed by:
====Subsequent treatment====
*GOG 123: Sequential brachytherapy, then adjuvant hysterectomy
*GOG 165: Sequential brachytherapy
===Regimen variant #5, q3wk cisplatin x 3===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ryu et al. 2011 (KCCH GY 1005)	2002-2004 	Phase 3 (E-switch-ic)	Cisplatin & RT; weekly cisplatin	Higher OS60OS60: 89% vs 66.5%(HR 0.375, 95% CI 0.15-0.91)
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once per day on days 1, 22, 43
====Radiotherapy====
*Concurrent radiation therapy: 1.8 to 200 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, (35 to 37)
**Total number of fractions: 25 to 28
**Total dose: 5000 cGy
9-week course
====Subsequent treatment====
*Sequential brachytherapy (see paper for details)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003078
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00191100
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01097252
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00262821
#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 EuroPMC
##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 EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT00193791
#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 dosing details in manuscript have been reviewed by our editors EuroPMC ChiCTR1800017108
#EORTC-55994: Kenter GG, Greggi S, Vergote I, Katsaros D, Kobierski J, van Doorn H, Landoni F, van der Velden J, Reed N, Coens C, van Luijk I, Colombo N, Steen-Banasik EV, Ottevanger N, Casado A; EORTC-55994 Study Group. Randomized Phase III Study Comparing Neoadjuvant Chemotherapy Followed by Surgery Versus Chemoradiation in Stage IB2-IIB Cervical Cancer: EORTC-55994. J Clin Oncol. 2023 Nov 10;41(32):5035-5043. Epub 2023 Sep 1. link to original article EuroPMC NCT00039338
# CALLA: Monk BJ, Toita T, Wu X, Vázquez Limón JC, Tarnawski R, Mandai M, Shapira-Frommer R, Mahantshetty U, Del Pilar Estevez-Diz M, Zhou Q, Limaye S, Godinez FJR, Oppermann Kussler C, Varga S, Valdiviezo N, Aoki D, Leiva M, Lee JY, Sulay R, Kreynina Y, Cheng WF, Rey F, Rong Y, Ke G, Wildsmith S, Lloyd A, Dry H, Tablante Nunes A, Mayadev J. Durvalumab versus placebo with chemoradiotherapy for locally advanced cervical cancer (CALLA): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2023 Dec;24(12):1334-1348. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03830866
#KEYNOTE-A18: Lorusso D, Xiang Y, Hasegawa K, Scambia G, Leiva M, Ramos-Elias P, Acevedo A, Sukhin V, Cloven N, Pereira de Santana Gomes AJ, Contreras Mejía F, Reiss A, Ayhan A, Lee JY, Saevets V, Zagouri F, Gilbert L, Sehouli J, Tharavichitkul E, Lindemann K, Lazzari R, Chang CL, Lampé R, Zhu H, Oaknin A, Christiaens M, Polterauer S, Usami T, Li K, Yamada K, Toker S, Keefe SM, Pignata S, Duska LR; ENGOT-cx11/GOG-3047/KEYNOTE-A18 investigators. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet. 2024 Apr 6;403(10434):1341-1350. Epub 2024 Mar 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04221945
##Update: Lorusso D, Xiang Y, Hasegawa K, Scambia G, Leiva M, Ramos-Elias P, Acevedo A, Cvek J, Randall L, Pereira de Santana Gomes AJ, Contreras Mejía F, Helpman L, Akıllı H, Lee JY, Saevets V, Zagouri F, Gilbert L, Sehouli J, Tharavichitkul E, Lindemann K, Colombo N, Chang CL, Bednarikova M, Zhu H, Oaknin A, Christiaens M, Petru E, Usami T, Liu P, Yamada K, Toker S, Keefe SM, Pignata S, Duska LR; ENGOT-cx11/GOG-3047/KEYNOTE-A18 investigators. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024 Oct 5;404(10460):1321-1332. Epub 2024 Sep 13. link to original article EuroPMC
#NRG-GY006: NCT02466971
==Cisplatin, Pembrolizumab, RT==
Cisplatin, Pembrolizumab, RT: Cisplatin, Pembrolizumab, Radiation Therapy
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Lorusson et al. 2024 (KEYNOTE-A18)	2020-06-09 to 2022-12-15	Phase 3 (E-RT-esc)	Cisplatin & RT	Longer PFS (co-primary endpoint)PFS24: 68% vs 57%(HR 0.70, 95% CI 0.55-0.89)Longer OS1 (co-primary endpoint)OS36: 82.6% vs 74.8%(HR 0.67, 95% CI 0.50-0.90)
1Reported efficacy is based on the 2024 update.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 & 2: 40 mg/m2 IV once per day on days 1, 8, 15
====Radiotherapy====
*Concurrent radiation therapy
====Immunotherapy====
*Pembrolizumab (Keytruda) as follows:
**Cycles 1 to 5: 200 mg IV once on day 1
**Cycles 6 to 20: 400 mg IV once on day 1
21-day cycle for 5 cycles, then 42-day cycle for 15 cycles
===References===
#KEYNOTE-A18: Lorusso D, Xiang Y, Hasegawa K, Scambia G, Leiva M, Ramos-Elias P, Acevedo A, Sukhin V, Cloven N, Pereira de Santana Gomes AJ, Contreras Mejía F, Reiss A, Ayhan A, Lee JY, Saevets V, Zagouri F, Gilbert L, Sehouli J, Tharavichitkul E, Lindemann K, Lazzari R, Chang CL, Lampé R, Zhu H, Oaknin A, Christiaens M, Polterauer S, Usami T, Li K, Yamada K, Toker S, Keefe SM, Pignata S, Duska LR; ENGOT-cx11/GOG-3047/KEYNOTE-A18 investigators. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet. 2024 Apr 6;403(10434):1341-1350. Epub 2024 Mar 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04221945
##Update: Lorusso D, Xiang Y, Hasegawa K, Scambia G, Leiva M, Ramos-Elias P, Acevedo A, Cvek J, Randall L, Pereira de Santana Gomes AJ, Contreras Mejía F, Helpman L, Akıllı H, Lee JY, Saevets V, Zagouri F, Gilbert L, Sehouli J, Tharavichitkul E, Lindemann K, Colombo N, Chang CL, Bednarikova M, Zhu H, Oaknin A, Christiaens M, Petru E, Usami T, Liu P, Yamada K, Toker S, Keefe SM, Pignata S, Duska LR; ENGOT-cx11/GOG-3047/KEYNOTE-A18 investigators. Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024 Oct 5;404(10460):1321-1332. Epub 2024 Sep 13. link to original article EuroPMC
==Cisplatin & Fluorouracil (CF) & RT==
CF & RT: Cisplatin, Fluorouracil Radiation Therapy
===Regimen variant #1, 50/4000 x 2===
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 longer OS (co-primary endpoint)Median OS: NYR vs 59.8 mo(RR 0.74, 90% CI 0.58-0.95)
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1 & 29, given 4 hours prior to radiation
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on days 2 & 30 (total dose: 8,000 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy
8-week course
===Regimen variant #2, 70/4000 x 4===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Peters et al. 2000 (GOG 109/SWOG-8797)	1991-1996 	Phase 3 (E-esc)	Radiation therapy	Longer OS (co-primary endpoint)OS48: 81% vs 71%(HR 0.51)
====Chemotherapy====
*Cisplatin (Platinol) 70 mg/m2 IV over 2 hours once per day on days 1, 22, 43, 64
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on days 1, 22, 43, 64 (total dose: 16,000 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy 170 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 39 (29 fractions, for a total dose of 4930 cGy)
**Patients with positive high common iliac lymph nodes also received 150 cGy x 30 fractions, for a total dose of 4500 cGy
12-week course
===Regimen variant #3, 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	Longer OS (primary endpoint)OS60: 73% vs 58%
Note: radiation could start one day before chemotherapy, on "day 0".
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV over 4 hours once per day on days 1, 22, 43, given first
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on days 1, 22, 43 (total dose: 12,000 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for a total dose of 4500 cGy)
9-week course
====Subsequent treatment====
*Brachytherapy (see paper for details)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Cisplatin & Fluorouracil (CF) & Hydroxyurea, RT==
Cisplatin, Fluorouracil, Hydroxyurea, RT: Cisplatin, Fluorouracil, Hydroxyurea, Radiation Therapy
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rose et al. 1999 (GOG 120)	1992-1997 	Phase 3 (E-esc)	1. Cisplatin & RT 	Did not meet co-primary endpoints of PFS/OS
Rose et al. 1999 (GOG 120)	1992-1997 	Phase 3 (E-esc)	2. Hydroxyurea & RT	Longer OS (co-primary endpoint)
===Definitive therapy===
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV once per day on days 1 & 29
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on days 1 & 29 (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
====Radiotherapy====
*Concurrent radiation therapy by the following stage-based criteria:
**Stage IIB: 170 cGy once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 25 (24 fractions, for an initial dose of 4080 cGy)
**Stage III or IVA: 170 cGy once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (30 fractions, for an initial dose of 5100 cGy)
5- to 6-week course, followed by:
===Consolidation===
====Radiotherapy====
*Stage IIB patients received 4000 cGy by intracavitary brachytherapy, for a total dose of 8080 cGy to point A
*Stage III or IVA disease received 3000 cGy by intracavitary brachytherapy, for a total dose of 8100 cGy to point A
**Patients that could not receive brachytherapy underwent additional external beam radiation therapy for a total dose of 6120 cGy
One course
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
==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 longer PFS (primary endpoint)PFS36: 74.4% vs 65%(HR 0.68, 95% CI 0.49-0.95)Seems to have longer OS (secondary endpoint)Median OS: NYR vs NYR(HR 0.68, 95% CI 0.49-0.95)
Cetina et al. 2013 	2004-2009 	Non-randomized part of phase 3 RCT	 	
====Chemotherapy====
*Cisplatin (Platinol) 40 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, given first, 1 to 2 hours before radiation
*Gemcitabine (Gemzar) 125 mg/m2 IV over 30 to 60 minutes once per day on days 1, 8, 15, 22, 29, 36, given second, 1 to 2 hours before radiation
====Radiotherapy====
*Concurrent radiation therapy 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 38 (28 fractions, for an initial dose of 5040 cGy)
6-week course
====Subsequent treatment====
*B9E-MC-JHQS: Brachytherapy (30 to 3500 cGy delivered to point A), then adjuvant GC, in 2 weeks
*Cetina et al. 2013: Brachytherapy verus radical hysterectomy
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00191100
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
==Fluorouracil & RT==
5-FU & RT: 5-FluouroUracil & Radiation Therapy
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Lanciano et al. 2005 (GOG 165)	1997-2000 	Phase 3 (E-switch-ic)	Cisplatin & RT	Might have lower ORR (secondary endpoint)
===Definitive therapy===
====Chemotherapy====
*Fluorouracil (5-FU) 225 mg/m2/day IV continuous infusion over 120 hours, started on days 1, 8, 15, 22, 29, 36 (total dose: 6750 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy: 180 cGy per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33 (25 fractions, for an initial dose of 4080 cGy)
6-week course, followed by:
===Consolidation===
====Radiotherapy====
**EITHER Low-dose rate intracavitary brachytherapy of 4000 cGy to point A given in 1 to 2 fractions
**OR High-dose rate intracavitary brachytherapy of 3000 cGy to point A given in 5 fractions, starting week 4 of XRT
*Parametrial boost of 5.4 to 900 cGy was administered to the involved parametrium after whole pelvic RT was complete
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003078
==Hydroxyurea & RT==
Hydroxyurea & RT: Hydroxyurea & Radiation Therapy
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hreshchyshyn et al. 1979 (GOG 04) 	1970-1976 	Phase 3 (E-esc)	Radiation therapy 	Seems to have longer OS
Stehman et al. 1988 (GOG 56) 	1981-06 to 1985-12 	Randomized 	Misonidazole & RT 	Seems to have longer PFS1
Whitney et al. 1999 (GOG 85/SWOG 8695)	1986-1990 	Phase 3 (C) 	Cisplatin, Fluorouracil, RT 	Seems to have shorter OS (co-primary endpoint)Median OS: 59.8 vs NYR mo(RR 1.35, 90% CI 1.05-1.72)
Rose et al. 1999 (GOG 120) 	1992-1997 	Phase 3 (C) 	1. Cisplatin & RT 	Shorter OS
Rose et al. 1999 (GOG 120) 	1992-1997 	Phase 3 (C) 	2. Cisplatin, Fluorouracil, Hydroxyurea, RT	Shorter OS
1Reported efficacy for GOG 56 is based on the 1993 update.
===Definitive therapy===
====Chemotherapy====
*Hydroxyurea (Hydrea) as follows:
**Weeks 1 to 6: 2000 mg/m2 PO two times per week, given 2 hours before radiation
====Radiotherapy====
*Concurrent radiation therapy by the following stage-based criteria:
**Stage IIB: 170 cGy x 24 fractions, for an initial dose of 4080 cGy
**Stage III or IVA: 170 cGy x 30 fractions, for an initial dose of 5100 cGy
7- to 9-week course
===Consolidation===
====Radiotherapy====
*Intracavitary brachytherapy by the following stage-based criteria:
**Stage IIB: 4000 cGy for a total dose of 8080 cGy to point A
*Stage III or IVA: 3000 cGy for a total dose of 8100 cGy to point A
*Patients that could not receive brachytherapy underwent additional external beam radiation therapy for a total dose of 6120 cGy
===References===
# 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 EuroPMC
# GOG 56: Stehman FB, Bundy BN, Keys H, Currie JL, Mortel R, Creasman WT. A randomized trial of hydroxyurea versus misonidazole adjunct to radiation therapy in carcinoma of the cervix: A preliminary report of a Gynecologic Oncology Group study. Am J Obstet Gynecol. 1988 Jul;159(1):87-94. link to original article EuroPMC
##Update: Stehman FB, Bundy BN, Thomas G, Keys HM, d'Ablaing G 3rd, Fowler WC Jr, Mortel R, Creasman WT. Hydroxyurea versus misonidazole with radiation in cervical carcinoma: long-term follow-up of a Gynecologic Oncology Group trial. J Clin Oncol. 1993 Aug;11(8):1523-8. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 EuroPMC
==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	Higher PFS36 (primary endpoint)Median PFS: 30 vs 28 mo(HR 0.25, 95% CI 0.08-0.77)
====Chemotherapy====
*Nedaplatin (Aqupla) 30 mg/m2 IV once per day on days 1, 8, 15, 22, 29, +/- 36
====Radiotherapy====
*Concurrent radiation therapy 180 cGy per day, 5 days/week, a total of 25-28 fractions
One course
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 5040 cGy
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Cisplatin & Gemcitabine (GC)==
===Regimen===
Study 	Dates of enrollment	Evidence
Dueñas-González et al. 2011 (B9E-MC-JHQS)	2002-2004 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*Definitive 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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00191100
==Radiation therapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Blohmer et al. 2011 (NOGGO-AGO)	1999-2001 	Phase 3 (C)	See link 	See link
====Preceding treatment====
*Surgery, then adjuvant Carboplatin & Ifosfamide x 4
====Radiotherapy====
*External beam radiotherapy: 180 cGy for 28 fractions, for a total dose of 5040 cGy
*If resection margins positive, patients received one of the following:
**EBRT boost of 2 x 500 cGy
**Low-dose brachytherapy
6-week course
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
=Persistent, recurrent, or metastatic disease, first-line therapy=
==ABCP==
ABCP: Atezolizumab, Bevacizumab, Carboplatin, Paclitaxel
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Oaknin et al. 2023 (BEATcc)	2018-10-08 to 2021-08-20	Phase 3 (E-esc)	1a. CP & Bevacizumab1b. TP & Bevacizumab	Longer OS (co-primary endpoint)Median OS: 32.1 vs 22.8 mo(HR 0.68, 95% CI 0.52-0.88)Longer PFS (co-primary endpoint)Median PFS: 13.7 vs 10.4 mo(HR 0.62, 95% CI 0.49-0.78)
Note: Patients with a complete response after at least six cycles could discontinue chemotherapy and continue atezolizumab & bevacizumab maintenance.
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 5 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
#BEATcc: Oaknin A, Gladieff L, Martínez-García J, Villacampa G, Takekuma M, De Giorgi U, Lindemann K, Woelber L, Colombo N, Duska L, Leary A, Godoy-Ortiz A, Nishio S, Angelergues A, Rubio MJ, Fariñas-Madrid L, Yamaguchi S, Lorusso D, Ray-Coquard I, Manso L, Joly F, Alarcón J, Follana P, Romero I, Lebreton C, Pérez-Fidalgo JA, Yunokawa M, Dahlstrand H, D'Hondt V, Randall LM; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2024 Jan 6;403(10421):31-43. Epub 2023 Dec 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03556839
==Carboplatin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Weiss et al. 1990	Not reported 	Phase 2
====Chemotherapy====
*Carboplatin (Paraplatin) 400 mg/m2 IV once on day 1
28-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Carboplatin & Docetaxel (DCb)==
===Regimen===
Study 	Dates of enrollment	Evidence
Nagao et al. 2005 	2001-2004 	Pilot, fewer than 20 pts
Takekida et al. 2010	2004-01 to 2005-12 	Phase 2
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV over 60 to 120 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
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Carboplatin & Paclitaxel (CP)==
TC: Taxol (Paclitaxel) & Carboplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pectasides et al. 2009a 	Not reported 	Phase 2 	 	
Kitagawa et al. 2015 (JCOG0505) 	2006-2009 	Phase 3 (E-switch-ic)	Cisplatin & Paclitaxel 	Non-inferior OS (primary endpoint)Median OS: 17.5 vs 18.3 mo(HR 0.994, 90% CI 0.79-1.25)
Colombo et al. 2021 (KEYNOTE-826)	2018-2020 	Phase 3 (C) 	1a. CP & Pembrolizumab1b. CP, Bevacizumab, Pembrolizumab1c. TP & Pembrolizumab1d. TP, Bevacizumab, Pembrolizumab	Shorter OS1Median OS: 16.8 vs 26.4 mo(HR 1.59, 95% CI 1.30-1.92)
1Reported efficacy for KEYNOTE-826 is based on the 2023 update for all patients.
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 varying durations: 6 cycles (JCOG0505); 6 to 9 cycles (Pectasides et al. 2009a); 6 or more cycles (KEYNOTE-826)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00295789
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03635567
##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 EuroPMC
##Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article EuroPMC
==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 & Pembrolizumab1b. CP, Bevacizumab, Pembrolizumab1c. TP & Pembrolizumab1d. TP, Bevacizumab, Pembrolizumab	Shorter OS1Median OS: 16.8 vs 26.4 mo(HR 1.59, 95% CI 1.30-1.92)
Oaknin et al. 2023 (BEATcc) 	2018-10-08 to 2021-08-20	Phase 3 (C)	1a. ABCP1b. TP, Atezolizumab, Bevacizumab 	Shorter OSMedian OS: 22.8 vs 32.1 mo(HR 1.47, 95% CI 1.14-1.92)Shorter PFSMedian PFS: 10.4 vs 13.7 mo(HR 1.61, 95% CI 1.28-2.04)
1Reported efficacy for KEYNOTE-826 is based on the 2023 update for all patients.
Note: In KEYNOTE-826, the decision to give bevacizumab was at the discretion of the treating institution and was not a randomization. Patients in KEYNOTE-826 were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects. Patients in BEATcc with a complete response after at least six cycles could discontinue chemotherapy and continue bevacizumab maintenance. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
====Chemotherapy====
*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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03635567
##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 EuroPMC
##Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article EuroPMC
#BEATcc: Oaknin A, Gladieff L, Martínez-García J, Villacampa G, Takekuma M, De Giorgi U, Lindemann K, Woelber L, Colombo N, Duska L, Leary A, Godoy-Ortiz A, Nishio S, Angelergues A, Rubio MJ, Fariñas-Madrid L, Yamaguchi S, Lorusso D, Ray-Coquard I, Manso L, Joly F, Alarcón J, Follana P, Romero I, Lebreton C, Pérez-Fidalgo JA, Yunokawa M, Dahlstrand H, D'Hondt V, Randall LM; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2024 Jan 6;403(10421):31-43. Epub 2023 Dec 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03556839
==Carboplatin & Paclitaxel (CP), Bevacizumab, Pembrolizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826)	2018-2020 	Phase 3 (E-RT-esc)	1a. CP1b. CP & Bevacizumab1c. Cisplatin & Paclitaxel1d. TP & Bevacizumab	Longer OS1 (co-primary endpoint)Median OS: 26.4 vs 16.8 mo(HR 0.63, 95% CI 0.52-0.77)
1Reported efficacy is based on the 2023 update for all patients.
Note: The decision to give bevacizumab was at the discretion of the treating institution and was not a randomization. Patients were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects.
====Chemotherapy====
*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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03635567
##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 EuroPMC
##Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article EuroPMC
==Carboplatin & Paclitaxel (CP) & Pembrolizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826)	2018-2020 	Phase 3 (E-RT-esc)	1a. CP1b. CP & Bevacizumab1c. Cisplatin & Paclitaxel1d. TP & Bevacizumab	Longer OS1 (co-primary endpoint)Median OS: 26.4 vs 16.8 mo(HR 0.63, 95% CI 0.52-0.77)
1Reported efficacy is based on the 2023 update for all patients.
Note: Patients were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects.
====Chemotherapy====
*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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03635567
##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 EuroPMC
##Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article EuroPMC
==Cisplatin monotherapy==
===Regimen variant #1===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Thigpen et al. 1979a 	Not reported in abstract	Phase 2 	 	
Bonomi et al. 1985 (GOG 43) 	1978-1982 	Phase 3 (C)	1. Cisplatin; higher dose2. Cisplatin; higher dose, split doses	Did not meet primary endpoint of ORR
Thigpen et al. 1989 (GOG 64) 	1982-1985 	Phase 3 (C)	Cisplatin; CI 	Did not meet primary efficacy endpoints
Omura et al. 1997 (GOG 110) 	1990-1994 	Phase 3 (C)	1. Cisplatin & Ifosfamide 	Shorter PFS
Omura et al. 1997 (GOG 110) 	1990-1994 	Phase 3 (C)	2. Cisplatin & Mitolactol 	Did not meet primary endpoint of ORR
Moore et al. 2004 (GOG 169) 	1997-1999 	Phase 3 (C)	Cisplatin & Paclitaxel 	Shorter PFS
Long et al. 2005 (GOG 179) 	1999-2002 	Phase 3 (C)	1. Cisplatin & Topotecan 	Seems to have shorter OS
Long et al. 2005 (GOG 179) 	1999-2002 	Phase 3 (C)	2. MVAC 	Not reported
Aoki et al. 2018 (Taiho 10020380)	2008-2011 	Phase 3 (C)	Cisplatin & S-1 	Might have shorter OSMedian OS: 19.5 vs 21.9 mo(HR 1.19, 95% CI 0.95-1.49)
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. The full manuscript for Thigpen et al. 1979a was not available for review.
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV once on day 1
21-day cycle for varying durations: 6 cycles (GOG 110, GOG 169); 6 or more cycles (GOG 179); until cumulative cisplatin dose of 400 mg/m2 (GOG 43); indefinitely (GOG 64, Taiho 10020380, Thigpen et al. 1979a)
===Regimen variant #2, schedule change in maintenance===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Vermorken et al. 2001	1986-1991 	Phase 3 (C)	BEMP 	Did not meet primary endpoint of ORR
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 cycle for 4 cycles, then 28-day cycles
===References===
# 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. EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003945
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00770874
==Cisplatin & Gemcitabine (GC)==
GC: Gemcitabine, Cisplatin
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Monk et al. 2009 (GOG 204)	2003-2007 	Phase 3 (E-switch-ic)	1. Cisplatin & Paclitaxel 	Seems to have shorter PFS (secondary endpoint)
Monk et al. 2009 (GOG 204)	2003-2007 	Phase 3 (E-switch-ic)	2. Cisplatin & Topotecan 	Did not meet primary endpoint of OS
Monk et al. 2009 (GOG 204)	2003-2007 	Phase 3 (E-switch-ic)	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===
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00064077
==Cisplatin & Ifosfamide==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Omura et al. 1997 (GOG 110)	1990-1994 	Phase 3 (E-esc)	1. Cisplatin 	Longer PFS (secondary endpoint)
Omura et al. 1997 (GOG 110)	1990-1994 	Phase 3 (E-esc)	2. Cisplatin & Mitolactol	Not reported
Bloss et al. 2002 (GOG 149)	1994-1997 	Phase 3 (C) 	CIB 	Did not meet primary endpoint of ORR
====Chemotherapy====
*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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
==Cisplatin & Mitomycin==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Wagenaar et al. 2001	Not reported 	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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Cisplatin & Paclitaxel (TP)==
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. TP & Bevacizumab 	Shorter OS1
Tewari et al. 2014 (GOG 240)	2009-2012 	Phase 3 (C)	2. Paclitaxel & Topotecan 	Did not meet primary endpoint of OS
Tewari et al. 2014 (GOG 240)	2009-2012 	Phase 3 (C)	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 	Longer PFS (secondary endpoint)Higher ORR (primary endpoint)
Monk et al. 2009 (GOG 204) 	2003-2007 	Phase 3 (C) 	1. Cisplatin & Gemcitabine	Seems to have longer PFS (secondary endpoint)
Monk et al. 2009 (GOG 204) 	2003-2007 	Phase 3 (C) 	2. Cisplatin & Topotecan 	Did not meet primary endpoint of OS
Monk et al. 2009 (GOG 204) 	2003-2007 	Phase 3 (C) 	3. Cisplatin & Vinorelbine	Might have longer PFS (secondary endpoint)
Kitagawa et al. 2015 (JCOG0505)	2006-2009 	Phase 3 (C) 	Carboplatin & Paclitaxel 	Non-inferior OSMedian OS: 18.3 vs 17.5 mo(HR 1.01, 90% CI 0.80-1.27)
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. TP & Bevacizumab 	Shorter OS1
Tewari et al. 2014 (GOG 240) 	2009-2012 	Phase 3 (C)	2. Paclitaxel & Topotecan 	Did not meet primary endpoint of OS
Tewari et al. 2014 (GOG 240) 	2009-2012 	Phase 3 (C)	3. Paclitaxel, Topotecan, Bevacizumab 	Not reported
Colombo et al. 2021 (KEYNOTE-826)	2018-2020 	Phase 3 (C)	1a. CP & Pembrolizumab1b. CP, Bevacizumab, Pembrolizumab1c. TP & Pembrolizumab1d. TP, Bevacizumab, Pembrolizumab	Shorter OS2Median OS: 16.8 vs 26.4 mo(HR 1.59, 95% CI 1.30-1.92)
1Reported efficacy for GOG 240 is based on the 2017 update.
2Reported efficacy for KEYNOTE-826 is based on the 2023 update for all patients.
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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00064077
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00803062
##PRO analysis: Penson RT, Huang HQ, Wenzel LB, Monk BJ, Stockman S, Long HJ 3rd, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Method M, Michael H, Tewari KS. Bevacizumab for advanced cervical cancer: patient-reported outcomes of a randomised, phase 3 trial (NRG Oncology-Gynecologic Oncology Group protocol 240). Lancet Oncol. 2015 Mar;16(3):301-11. Epub 2015 Jan 29. Erratum in: Lancet Oncol. 2016 Jan;17(1):e6. link to original article link to PMC article EuroPMC
## 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 EuroPMC
## 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 link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00295789
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03635567
##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 EuroPMC
##Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article EuroPMC
==Cisplatin & Paclitaxel (TP) & Bevacizumab==
CP+Bev: Cisplatin, Paclitaxel, Bevacizumab
TP & Bevacizumab: Taxol (Paclitaxel), Platinol (Cisplatin), Bevacizumab
ESMO-preferred (I-A, 2017)
===Regimen variant #1, 135 mg/m2 paclitaxel===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tewari et al. 2014 (GOG 240)	2009-2012 	Phase 3 (E-RT-esc)	1. Cisplatin & Paclitaxel 	Longer OS1 (primary endpoint)Median OS: 16.8 vs 13.3 mo(HR 0.77, 95% CI 0.62-0.95)
Tewari et al. 2014 (GOG 240)	2009-2012 	Phase 3 (E-RT-esc)	2. Paclitaxel & Topotecan 	Did not meet primary endpoint of OS1
Tewari et al. 2014 (GOG 240)	2009-2012 	Phase 3 (E-RT-esc)	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) 	2009-2012 	Phase 3 (E-RT-esc)	1. Cisplatin & Paclitaxel 	Longer OS1 (primary endpoint)Median OS: 16.8 vs 13.3 mo(HR 0.77, 95% CI 0.62-0.95)
Tewari et al. 2014 (GOG 240) 	2009-2012 	Phase 3 (E-RT-esc)	2. Paclitaxel & Topotecan 	Did not meet primary endpoint of OS1
Tewari et al. 2014 (GOG 240) 	2009-2012 	Phase 3 (E-RT-esc)	3. Paclitaxel, Topotecan, Bevacizumab 	Not reported
Colombo et al. 2021 (KEYNOTE-826)	2018-2020 	Phase 3 (C) 	1a. CP & Pembrolizumab1b. CP, Bevacizumab, Pembrolizumab1c. TP & Pembrolizumab1d. TP, Bevacizumab, Pembrolizumab	Shorter OS2Median OS: 16.8 vs 26.4 mo(HR 1.59, 95% CI 1.30-1.92)
Oaknin et al. 2023 (BEATcc) 	2018-10-08 to 2021-08-20	Phase 3 (C) 	1a. ABCP1b. TP, Atezolizumab, Bevacizumab 	Shorter OSMedian OS: 22.8 vs 32.1 mo(HR 1.47, 95% CI 1.14-1.92)Shorter PFSMedian PFS: 10.4 vs 13.7 mo(HR 1.61, 95% CI 1.28-2.04)
1Reported efficacy for this comparison in GOG 240 is based on the 2017 update.
2Reported efficacy for KEYNOTE-826 is based on the 2023 update for all patients.
Note: Treatment in GOG 240 was given until CR or indefinitely. Patients in KEYNOTE-826 were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects. Patients in BEATcc with a complete response after at least six cycles could discontinue chemotherapy and continue bevacizumab maintenance. The decision to give bevacizumab in KEYNOTE-826 was at the discretion of the treating institution and was not a randomization.
====Chemotherapy====
*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===
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00803062
##PRO analysis: Penson RT, Huang HQ, Wenzel LB, Monk BJ, Stockman S, Long HJ 3rd, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Method M, Michael H, Tewari KS. Bevacizumab for advanced cervical cancer: patient-reported outcomes of a randomised, phase 3 trial (NRG Oncology-Gynecologic Oncology Group protocol 240). Lancet Oncol. 2015 Mar;16(3):301-11. Epub 2015 Jan 29. Erratum in: Lancet Oncol. 2016 Jan;17(1):e6. link to original article link to PMC article EuroPMC
## 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 EuroPMC
## 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 link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03635567
##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 EuroPMC
##Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article EuroPMC
#BEATcc: Oaknin A, Gladieff L, Martínez-García J, Villacampa G, Takekuma M, De Giorgi U, Lindemann K, Woelber L, Colombo N, Duska L, Leary A, Godoy-Ortiz A, Nishio S, Angelergues A, Rubio MJ, Fariñas-Madrid L, Yamaguchi S, Lorusso D, Ray-Coquard I, Manso L, Joly F, Alarcón J, Follana P, Romero I, Lebreton C, Pérez-Fidalgo JA, Yunokawa M, Dahlstrand H, D'Hondt V, Randall LM; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2024 Jan 6;403(10421):31-43. Epub 2023 Dec 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03556839
==Cisplatin & Paclitaxel (TP), Atezolizumab, Bevacizumab==
TP, Atezolizumab, Bevacizumab: Taxol (Paclitaxel), Platinol (Cisplatin), Atezolizumab, Bevacizumab
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Oaknin et al. 2023 (BEATcc)	2018-10-08 to 2021-08-20	Phase 3 (E-esc)	1a. CP & Bevacizumab1b. TP & Bevacizumab	Longer OS (co-primary endpoint)Median OS: 32.1 vs 22.8 mo(HR 0.68, 95% CI 0.52-0.88)Longer PFS (co-primary endpoint)Median PFS: 13.7 vs 10.4 mo(HR 0.62, 95% CI 0.49-0.78)
Note: Patients with a complete response after at least six cycles could discontinue chemotherapy and continue atezolizumab & bevacizumab maintenance.
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
====Immunotherapy====
*Atezolizumab (Tecentriq) 1200 mg IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
#BEATcc: Oaknin A, Gladieff L, Martínez-García J, Villacampa G, Takekuma M, De Giorgi U, Lindemann K, Woelber L, Colombo N, Duska L, Leary A, Godoy-Ortiz A, Nishio S, Angelergues A, Rubio MJ, Fariñas-Madrid L, Yamaguchi S, Lorusso D, Ray-Coquard I, Manso L, Joly F, Alarcón J, Follana P, Romero I, Lebreton C, Pérez-Fidalgo JA, Yunokawa M, Dahlstrand H, D'Hondt V, Randall LM; ENGOT-Cx10–GEICO 68-C–JGOG1084–GOG-3030 Investigators. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet. 2024 Jan 6;403(10421):31-43. Epub 2023 Dec 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03556839
==Cisplatin & Paclitaxel (TP), Bevacizumab, Pembrolizumab==
TP, Bevacizumab, Pembrolizumab: Taxol (Paclitaxel), Platinol (Cisplatin), Bevacizumab, Pembrolizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826)	2018-2020 	Phase 3 (E-RT-esc)	1a. CP1b. CP & Bevacizumab1c. Cisplatin & Paclitaxel1d. TP & Bevacizumab	Longer OS1 (co-primary endpoint)Median OS: 26.4 vs 16.8 mo(HR 0.63, 95% CI 0.52-0.77)
1Reported efficacy is based on the 2023 update for all patients.
Note: The decision to give bevacizumab was at the discretion of the treating institution and was not a randomization. Patients were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects.
====Chemotherapy====
*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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03635567
##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 EuroPMC
##Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article EuroPMC
==Cisplatin & Paclitaxel (TP) & Pembrolizumab==
TP & Pembrolizumab: Taxol (Paclitaxel), Platinol (Cisplatin), Pembrolizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Colombo et al. 2021 (KEYNOTE-826)	2018-2020 	Phase 3 (E-RT-esc)	1a. CP1b. CP & Bevacizumab1c. Cisplatin & Paclitaxel1d. TP & Bevacizumab	Longer OS1 (co-primary endpoint)Median OS: 26.4 vs 16.8 mo(HR 0.63, 95% CI 0.52-0.77)
1Reported efficacy is based on the 2023 update for all patients.
Note: Patients were permitted to receive more than 6 cycles of chemotherapy if they had ongoing clinical benefit and did not have unacceptable side effects.
====Chemotherapy====
*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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03635567
##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 EuroPMC
##Update: Monk BJ, Colombo N, Tewari KS, Dubot C, Caceres MV, Hasegawa K, Shapira-Frommer R, Salman P, Yañez E, Gümüş M, Olivera Hurtado de Mendoza M, Samouëlian V, Castonguay V, Arkhipov A, Tekin C, Li K, Keefe SM, Lorusso D; KEYNOTE-826 Investigators. First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023 Dec 20;41(36):5505-5511. Epub 2023 Nov 1. link to original article EuroPMC
==Cisplatin & Topotecan==
TC: Topotecan & Cisplatin
CT: Cisplatin & Topotecan
===Regimen variant #1, 6 cycles===
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 longer OS (primary endpoint)Median OS: 9.4 vs 6.5 mo(RR 0.76, 95% CI 0.59-0.98)
Long et al. 2005 (GOG 179) 	1999-2002 	Phase 3 (E-RT-esc) 	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
Monk et al. 2009 (GOG 204) 	2003-2007 	Phase 3 (E-switch-ic)	2. Cisplatin & Paclitaxel 	Did not meet primary endpoint of OS
Monk et al. 2009 (GOG 204) 	2003-2007 	Phase 3 (E-switch-ic)	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 shorter PFSMedian PFS: 6 vs 10 mo(HR not reported)
====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
===Regimen variant #2, 6 to 9 cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Gass et al. 2024 (AGO-Zervix-1)	2007-01 to 2012-06 	Phase 3 (C)	TP 	Did not meet primary endpoint of OSMedian OS: 12 vs 9.6 mo
====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 6 up to 9 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003945
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00064077
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00532818
#AGO-Zervix-1: Gass P, Thiel FC, Häberle L, Ackermann S, Theuser AK, Hummel N, Boehm S, Kimmig R, Reinthaller A, Becker S, Hilpert F, Janni W, Vergote I, Harter P, Emons J, Hein A, Beckmann MW, Fasching PA, Pöschke P; AGO Uterus Commission. Primary results of the AGO-Zervix-1 Study: A prospective, randomized phase III study to compare the effects of paclitaxel and topotecan with those of cisplatin and topotecan in the treatment of patients with recurrent and persistent cervical cancer. Gynecol Oncol. 2024 Apr;183:25-32. Epub 2024 Mar 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01405235
==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
Monk et al. 2009 (GOG 204)	2003-2007 	Phase 3 (E-switch-ic)	2. Cisplatin & Paclitaxel 	Might have shorter PFS (primary endpoint)
Monk et al. 2009 (GOG 204)	2003-2007 	Phase 3 (E-switch-ic)	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===
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00064077
==Ifosfamide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Coleman et al. 1986	Not reported 	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 on days 1 to 5, given at 0, 4, and 8 hours after each dose of ifosfamide
21-day cycles
====Dose and schedule modifications====
*Ifosfamide (Ifex) dose could be increased by 300 mg/m2 or decreased by 20% depending on toxicity
===References===
# 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 EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 and schedule 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 and schedule 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	Not reported 	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, continued until day 19 or until ANC greater or equal to 10,000/μL
21-day cycles
====Dose and schedule modifications====
*Paclitaxel (Taxol) dose could be changed to 275, 225, or 200 mg/m2 depending on toxicity
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC content property of HemOnc.org
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Paclitaxel, Topotecan, Bevacizumab==
TP+Bev: Topotecan, Paclitaxel, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tewari et al. 2014 (GOG 240)	2009-2012 	Phase 3 (E-RT-esc)	1. Cisplatin & Paclitaxel	Not reported
Tewari et al. 2014 (GOG 240)	2009-2012 	Phase 3 (E-RT-esc)	2. TP & Bevacizumab 	Not reported
Tewari et al. 2014 (GOG 240)	2009-2012 	Phase 3 (E-RT-esc)	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===
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00803062
##PRO analysis: Penson RT, Huang HQ, Wenzel LB, Monk BJ, Stockman S, Long HJ 3rd, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Method M, Michael H, Tewari KS. Bevacizumab for advanced cervical cancer: patient-reported outcomes of a randomised, phase 3 trial (NRG Oncology-Gynecologic Oncology Group protocol 240). Lancet Oncol. 2015 Mar;16(3):301-11. Epub 2015 Jan 29. Erratum in: Lancet Oncol. 2016 Jan;17(1):e6. link to original article link to PMC article EuroPMC
## 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 EuroPMC
## 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 link to PMC article EuroPMC
==Topotecan monotherapy==
===Regimen variant #1, q3wk===
Study 	Dates of enrollment 	Evidence
Bookman et al. 2000 (GOG 127-F)	1994-12 to not reported	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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
=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===
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Cemiplimab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tewari et al. 2022 (EMPOWER-Cervical 1)	2017-2020 	Phase 3 (E-switch-ooc)	1a. Pemetrexed1b. Topotecan1c. Irinotecan1d. Gemcitabine1e. Vinorelbine	Longer OS1 (primary endpoint)Median OS: 11.7 vs 8.5 mo(HR 0.67, 95% CI 0.56-0.80)
1Reported efficacy is based on the 2025 update.
====Immunotherapy====
*Cemiplimab (Libtayo) 350 mg IV once on day 1
21-day cycle for up to 32 cycles (96 weeks)
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03257267
##PRO analysis: Oaknin A, Monk BJ, Vergote I, Cristina de Melo A, Kim YM, Lisyanskaya AS, Samouëlian V, Kim HS, Gotovkin EA, Damian F, Chang CL, Takahashi S, Li J, Mathias M, Fury MG, Ivanescu C, Reaney M, LaFontaine PR, Lowy I, Harnett J, Chen CI, Tewari KS. EMPOWER CERVICAL-1: Effects of cemiplimab versus chemotherapy on patient-reported quality of life, functioning and symptoms among women with recurrent cervical cancer. Eur J Cancer. 2022 Oct;174:299-309. Epub 2022 Jul 31. link to original article EuroPMC
##Update: Oaknin A, Monk BJ, de Melo AC, Kim HS, Kim YM, Lisyanskaya AS, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin E, Takahashi S, Ramone D, Maćkowiak-Matejczyk B, Polastro L, Alia EMG, Colombo N, Makarova Y, Goh JC, Hasegawa K, Mora P, Pikiel J, Srivastav R, Rischin D, Rubio MJ, Perez J, Yoo SY, Gao B, Jamil S, Seebach F, Lowy I, Mathias M, Fury MG, Tewari KS. Cemiplimab in recurrent cervical cancer: Final analysis of overall survival in the phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial. Eur J Cancer. 2025 Jan;216:115146. link to original article link to EuroPMC
==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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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
====Supportive therapy====
*Dexamethasone (Decadron) 8 mg PO twice per day
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==FULV==
FULV: 5-FU & LeucoVorin
===Regimen variant #1, 1850/200===
Study 	Dates of enrollment	Evidence
Look et al. 1996	1990-1992 	Phase 2
Look et al. 1997	1993-1995 	Phase 2
Note: it is not entirely clear from these publications whether leucovorin is given on day 1 only, versus on days 1 to 5.
====Chemotherapy====
*Fluorouracil (5-FU) 370 mg/m2 IV over 5 minutes once per day on days 1 to 5, given second
*Leucovorin (Folinic acid) 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
*Leucovorin (Folinic acid) 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===
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Gemcitabine monotherapy==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Schilder et al. 2000 (GOG 127-K)	Not reported 	Phase 2
Schilder et al. 2005 	Not reported 	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 	Phase 3 (C)	Cemiplimab 	Shorter OS1 (primary endpoint)Median OS: 8.5 vs 11.7 mo(HR 1.49, 95% CI 1.25-1.79)
Vergote et al. 2024 (innovaTV 301) 	2021-2023 	Phase 3 (C)	Tisotumab vedotin	Shorter OSMedian OS: 9.5 vs 11.5 mo(HR 1.43, 95% CI 1.12-1.85)
1Reported efficacy for EMPOWER-Cervical 1 is based on the 2025 update.
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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03257267
##PRO analysis: Oaknin A, Monk BJ, Vergote I, Cristina de Melo A, Kim YM, Lisyanskaya AS, Samouëlian V, Kim HS, Gotovkin EA, Damian F, Chang CL, Takahashi S, Li J, Mathias M, Fury MG, Ivanescu C, Reaney M, LaFontaine PR, Lowy I, Harnett J, Chen CI, Tewari KS. EMPOWER CERVICAL-1: Effects of cemiplimab versus chemotherapy on patient-reported quality of life, functioning and symptoms among women with recurrent cervical cancer. Eur J Cancer. 2022 Oct;174:299-309. Epub 2022 Jul 31. link to original article EuroPMC
##Update: Oaknin A, Monk BJ, de Melo AC, Kim HS, Kim YM, Lisyanskaya AS, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin E, Takahashi S, Ramone D, Maćkowiak-Matejczyk B, Polastro L, Alia EMG, Colombo N, Makarova Y, Goh JC, Hasegawa K, Mora P, Pikiel J, Srivastav R, Rischin D, Rubio MJ, Perez J, Yoo SY, Gao B, Jamil S, Seebach F, Lowy I, Mathias M, Fury MG, Tewari KS. Cemiplimab in recurrent cervical cancer: Final analysis of overall survival in the phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial. Eur J Cancer. 2025 Jan;216:115146. link to original article link to EuroPMC
#innovaTV 301: Vergote I, González-Martín A, Fujiwara K, Kalbacher E, Bagaméri A, Ghamande S, Lee JY, Banerjee S, Maluf FC, Lorusso D, Yonemori K, Van Nieuwenhuysen E, Manso L, Woelber L, Westermann A, Covens A, Hasegawa K, Kim BG, Raimondo M, Bjurberg M, Cruz FM, Angelergues A, Cibula D, Barraclough L, Oaknin A, Gennigens C, Nicacio L, Teng MSL, Whalley E, Soumaoro I, Slomovitz BM; innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. N Engl J Med. 2024 Jul 4;391(1):44-55. link to original article EuroPMC NCT04697628
==Irinotecan monotherapy==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tewari et al. 2022 (EMPOWER-Cervical 1)	2017-2020 	Phase 3 (C)	Cemiplimab 	Shorter OS1 (primary endpoint)Median OS: 8.5 vs 11.7 mo(HR 1.49, 95% CI 1.25-1.79)
Vergote et al. 2024 (innovaTV 301) 	2021-2023 	Phase 3 (C)	Tisotumab vedotin	Shorter OSMedian OS: 9.5 vs 11.5 mo(HR 1.43, 95% CI 1.12-1.85)
1Reported efficacy for EMPOWER-Cervical 1 is based on the 2025 update.
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 	 	
Vergote et al. 2024 (innovaTV 301)	2021-2023 	Phase 3 (C)	Tisotumab vedotin	Shorter OSMedian OS: 9.5 vs 11.5 mo(HR 1.43, 95% CI 1.12-1.85)
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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03257267
##PRO analysis: Oaknin A, Monk BJ, Vergote I, Cristina de Melo A, Kim YM, Lisyanskaya AS, Samouëlian V, Kim HS, Gotovkin EA, Damian F, Chang CL, Takahashi S, Li J, Mathias M, Fury MG, Ivanescu C, Reaney M, LaFontaine PR, Lowy I, Harnett J, Chen CI, Tewari KS. EMPOWER CERVICAL-1: Effects of cemiplimab versus chemotherapy on patient-reported quality of life, functioning and symptoms among women with recurrent cervical cancer. Eur J Cancer. 2022 Oct;174:299-309. Epub 2022 Jul 31. link to original article EuroPMC
##Update: Oaknin A, Monk BJ, de Melo AC, Kim HS, Kim YM, Lisyanskaya AS, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin E, Takahashi S, Ramone D, Maćkowiak-Matejczyk B, Polastro L, Alia EMG, Colombo N, Makarova Y, Goh JC, Hasegawa K, Mora P, Pikiel J, Srivastav R, Rischin D, Rubio MJ, Perez J, Yoo SY, Gao B, Jamil S, Seebach F, Lowy I, Mathias M, Fury MG, Tewari KS. Cemiplimab in recurrent cervical cancer: Final analysis of overall survival in the phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial. Eur J Cancer. 2025 Jan;216:115146. link to original article link to EuroPMC
#innovaTV 301: Vergote I, González-Martín A, Fujiwara K, Kalbacher E, Bagaméri A, Ghamande S, Lee JY, Banerjee S, Maluf FC, Lorusso D, Yonemori K, Van Nieuwenhuysen E, Manso L, Woelber L, Westermann A, Covens A, Hasegawa K, Kim BG, Raimondo M, Bjurberg M, Cruz FM, Angelergues A, Cibula D, Barraclough L, Oaknin A, Gennigens C, Nicacio L, Teng MSL, Whalley E, Soumaoro I, Slomovitz BM; innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. N Engl J Med. 2024 Jul 4;391(1):44-55. link to original article EuroPMC NCT04697628
==Pembrolizumab monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence
Chung et al. 2019 (KEYNOTE-158cervical)	2016-01-27 to 2016-08-18	Phase 2 (RT)
Note: KEYNOTE-158 was a basket study with multiple arms of different enrollment periods.
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV over 30 minutes once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
# KEYNOTE-158cervical: Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-Frommer R, Manzuk L, Piha-Paul SA, Xu L, Zeigenfuss S, Pruitt SK, Leary A. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019 Jun 10;37(17):1470-1478. Epub 2019 Apr 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02628067
==Pemetrexed monotherapy==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tewari et al. 2022 (EMPOWER-Cervical 1)	2017-2020 	Phase 3 (C)	Cemiplimab 	Shorter OS1 (primary endpoint)Median OS: 8.5 vs 11.7 mo(HR 1.49, 95% CI 1.25-1.79)
Vergote et al. 2024 (innovaTV 301) 	2021-2023 	Phase 3 (C)	Tisotumab vedotin	Shorter OSMedian OS: 9.5 vs 11.5 mo(HR 1.43, 95% CI 1.12-1.85)
1Reported efficacy for EMPOWER-Cervical 1 is based on the 2025 update.
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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03257267
##PRO analysis: Oaknin A, Monk BJ, Vergote I, Cristina de Melo A, Kim YM, Lisyanskaya AS, Samouëlian V, Kim HS, Gotovkin EA, Damian F, Chang CL, Takahashi S, Li J, Mathias M, Fury MG, Ivanescu C, Reaney M, LaFontaine PR, Lowy I, Harnett J, Chen CI, Tewari KS. EMPOWER CERVICAL-1: Effects of cemiplimab versus chemotherapy on patient-reported quality of life, functioning and symptoms among women with recurrent cervical cancer. Eur J Cancer. 2022 Oct;174:299-309. Epub 2022 Jul 31. link to original article EuroPMC
##Update: Oaknin A, Monk BJ, de Melo AC, Kim HS, Kim YM, Lisyanskaya AS, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin E, Takahashi S, Ramone D, Maćkowiak-Matejczyk B, Polastro L, Alia EMG, Colombo N, Makarova Y, Goh JC, Hasegawa K, Mora P, Pikiel J, Srivastav R, Rischin D, Rubio MJ, Perez J, Yoo SY, Gao B, Jamil S, Seebach F, Lowy I, Mathias M, Fury MG, Tewari KS. Cemiplimab in recurrent cervical cancer: Final analysis of overall survival in the phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial. Eur J Cancer. 2025 Jan;216:115146. link to original article link to EuroPMC
#innovaTV 301: Vergote I, González-Martín A, Fujiwara K, Kalbacher E, Bagaméri A, Ghamande S, Lee JY, Banerjee S, Maluf FC, Lorusso D, Yonemori K, Van Nieuwenhuysen E, Manso L, Woelber L, Westermann A, Covens A, Hasegawa K, Kim BG, Raimondo M, Bjurberg M, Cruz FM, Angelergues A, Cibula D, Barraclough L, Oaknin A, Gennigens C, Nicacio L, Teng MSL, Whalley E, Soumaoro I, Slomovitz BM; innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. N Engl J Med. 2024 Jul 4;391(1):44-55. link to original article EuroPMC NCT04697628
==Tisotumab vedotin monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Coleman et al. 2021 (innovaTV 204)	2018-06-12 to 2019-04-11	Phase 2 (RT) 	 	
Vergote et al. 2024 (innovaTV 301)	2021-2023 	Phase 3 (E-RT-switch-ooc)	1a. Pemetrexed1b. Topotecan1c. Irinotecan1d. Gemcitabine1e. Vinorelbine	Longer OS (primary endpoint)Median OS: 11.5 vs 9.5 mo(HR 0.70, 95% CI 0.54-0.89)
====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
====Dose and schedule modifications====
*innovaTV 204: Dose reductions to 1.3 mg/kg and 0.9 mg/kg were allowed
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03438396
#innovaTV 301: Vergote I, González-Martín A, Fujiwara K, Kalbacher E, Bagaméri A, Ghamande S, Lee JY, Banerjee S, Maluf FC, Lorusso D, Yonemori K, Van Nieuwenhuysen E, Manso L, Woelber L, Westermann A, Covens A, Hasegawa K, Kim BG, Raimondo M, Bjurberg M, Cruz FM, Angelergues A, Cibula D, Barraclough L, Oaknin A, Gennigens C, Nicacio L, Teng MSL, Whalley E, Soumaoro I, Slomovitz BM; innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. N Engl J Med. 2024 Jul 4;391(1):44-55. link to original article EuroPMC NCT04697628
==Topotecan monotherapy==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tewari et al. 2022 (EMPOWER-Cervical 1)	2017-2020 	Phase 3 (C)	Cemiplimab 	Shorter OS1 (primary endpoint)Median OS: 8.5 vs 11.7 mo(HR 1.49, 95% CI 1.25-1.79)
Vergote et al. 2024 (innovaTV 301) 	2021-2023 	Phase 3 (C)	Tisotumab vedotin	Shorter OSMedian OS: 9.5 vs 11.5 mo(HR 1.43, 95% CI 1.12-1.85)
1Reported efficacy for EMPOWER-Cervical 1 is based on the 2025 update.
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
Vergote et al. 2024 (innovaTV 301)	2021-2023 	Phase 3 (C)	Tisotumab vedotin	Shorter OSMedian OS: 9.5 vs 11.5 mo(HR 1.43, 95% CI 1.12-1.85)
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===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03257267
##PRO analysis: Oaknin A, Monk BJ, Vergote I, Cristina de Melo A, Kim YM, Lisyanskaya AS, Samouëlian V, Kim HS, Gotovkin EA, Damian F, Chang CL, Takahashi S, Li J, Mathias M, Fury MG, Ivanescu C, Reaney M, LaFontaine PR, Lowy I, Harnett J, Chen CI, Tewari KS. EMPOWER CERVICAL-1: Effects of cemiplimab versus chemotherapy on patient-reported quality of life, functioning and symptoms among women with recurrent cervical cancer. Eur J Cancer. 2022 Oct;174:299-309. Epub 2022 Jul 31. link to original article EuroPMC
##Update: Oaknin A, Monk BJ, de Melo AC, Kim HS, Kim YM, Lisyanskaya AS, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin E, Takahashi S, Ramone D, Maćkowiak-Matejczyk B, Polastro L, Alia EMG, Colombo N, Makarova Y, Goh JC, Hasegawa K, Mora P, Pikiel J, Srivastav R, Rischin D, Rubio MJ, Perez J, Yoo SY, Gao B, Jamil S, Seebach F, Lowy I, Mathias M, Fury MG, Tewari KS. Cemiplimab in recurrent cervical cancer: Final analysis of overall survival in the phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial. Eur J Cancer. 2025 Jan;216:115146. link to original article link to EuroPMC
#innovaTV 301: Vergote I, González-Martín A, Fujiwara K, Kalbacher E, Bagaméri A, Ghamande S, Lee JY, Banerjee S, Maluf FC, Lorusso D, Yonemori K, Van Nieuwenhuysen E, Manso L, Woelber L, Westermann A, Covens A, Hasegawa K, Kim BG, Raimondo M, Bjurberg M, Cruz FM, Angelergues A, Cibula D, Barraclough L, Oaknin A, Gennigens C, Nicacio L, Teng MSL, Whalley E, Soumaoro I, Slomovitz BM; innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. N Engl J Med. 2024 Jul 4;391(1):44-55. link to original article EuroPMC NCT04697628
==Vinorelbine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Muggia et al. 2004 	1997-1999 	Phase 2 	 	ORR: 14% (95% CI 5-27%)
Muggia et al. 2005 	1997-1999 	Phase 2 	 	ORR: 7%
Tewari et al. 2022 (EMPOWER-Cervical 1)	2017-2020 	Phase 3 (C)	Cemiplimab 	Shorter OS1 (primary endpoint)Median OS: 8.5 vs 11.7 mo(HR 1.49, 95% CI 1.25-1.79)
Vergote et al. 2024 (innovaTV 301) 	2021-2023 	Phase 3 (C)	Tisotumab vedotin	Shorter OSMedian OS: 9.5 vs 11.5 mo(HR 1.43, 95% CI 1.12-1.85)
1Reported efficacy for EMPOWER-Cervical 1 is based on the 2025 update.
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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT03257267
##PRO analysis: Oaknin A, Monk BJ, Vergote I, Cristina de Melo A, Kim YM, Lisyanskaya AS, Samouëlian V, Kim HS, Gotovkin EA, Damian F, Chang CL, Takahashi S, Li J, Mathias M, Fury MG, Ivanescu C, Reaney M, LaFontaine PR, Lowy I, Harnett J, Chen CI, Tewari KS. EMPOWER CERVICAL-1: Effects of cemiplimab versus chemotherapy on patient-reported quality of life, functioning and symptoms among women with recurrent cervical cancer. Eur J Cancer. 2022 Oct;174:299-309. Epub 2022 Jul 31. link to original article EuroPMC
##Update: Oaknin A, Monk BJ, de Melo AC, Kim HS, Kim YM, Lisyanskaya AS, Samouëlian V, Lorusso D, Damian F, Chang CL, Gotovkin E, Takahashi S, Ramone D, Maćkowiak-Matejczyk B, Polastro L, Alia EMG, Colombo N, Makarova Y, Goh JC, Hasegawa K, Mora P, Pikiel J, Srivastav R, Rischin D, Rubio MJ, Perez J, Yoo SY, Gao B, Jamil S, Seebach F, Lowy I, Mathias M, Fury MG, Tewari KS. Cemiplimab in recurrent cervical cancer: Final analysis of overall survival in the phase III EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 trial. Eur J Cancer. 2025 Jan;216:115146. link to original article link to EuroPMC
#innovaTV 301: Vergote I, González-Martín A, Fujiwara K, Kalbacher E, Bagaméri A, Ghamande S, Lee JY, Banerjee S, Maluf FC, Lorusso D, Yonemori K, Van Nieuwenhuysen E, Manso L, Woelber L, Westermann A, Covens A, Hasegawa K, Kim BG, Raimondo M, Bjurberg M, Cruz FM, Angelergues A, Cibula D, Barraclough L, Oaknin A, Gennigens C, Nicacio L, Teng MSL, Whalley E, Soumaoro I, Slomovitz BM; innovaTV 301/ENGOT-cx12/GOG-3057 Collaborators. Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. N Engl J Med. 2024 Jul 4;391(1):44-55. link to original article EuroPMC NCT04697628
Category:Cervical cancer regimens
Category:Disease-specific pages
Category:Gynecologic cancers