Cervical cancer

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Summer B. Dewdney, MD
Rush University
Chicago, IL
38 regimens on this page
54 variants on this page

Contents


Guidelines

ESMO

Older

NCCN

Neoadjuvant chemotherapy

Cisplatin & Paclitaxel

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Regimen

Study Evidence
Park et al. 2004 Phase II

Chemotherapy

Supportive medications

10-day cycle for 3 cycles

Subsequent treatment

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

References

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

No neoadjuvant therapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Herod et al. 2000 Phase III (C) BIP Did not meet primary endpoints of ORR/OS
Eddy et al. 2007 (GOG 141) Phase III (C) Cisplatin & Vincristine Did not meet primary endpoints of PFS/OS
Katsumata et al. 2013 (JCOG 0102) Phase III (C) BOMP Did not meet primary endpoint of OS

No systemic therapy prior to surgery.

Subsequent treatment

References

  1. Herod J, Burton A, Buxton J, Tobias J, Luesley D, Jordan S, Dunn J, Poole CJ. A randomised, prospective, phase III clinical trial of primary bleomycin, ifosfamide and cisplatin (BIP) chemotherapy followed by radiotherapy versus radiotherapy alone in inoperable cancer of the cervix. Ann Oncol. 2000 Sep;11(9):1175-81. link to original article PubMed
  2. GOG 141: Eddy GL, Bundy BN, Creasman WT, Spirtos NM, Mannel RS, Hannigan E, O'Connor D. Treatment of ("bulky") stage IB cervical cancer with or without neoadjuvant vincristine and cisplatin prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy: a phase III trial of the Gynecologic Oncology Group. Gynecol Oncol. 2007 Aug;106(2):362-9. Epub 2007 May 9. link to original article PubMed
  3. JCOG 0102: Katsumata N, Yoshikawa H, Kobayashi H, Saito T, Kuzuya K, Nakanishi T, Yasugi T, Yaegashi N, Yokota H, Kodama S, Mizunoe T, Hiura M, Kasamatsu T, Shibata T, Kamura T; Japan Clinical Oncology Group. Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102). Br J Cancer. 2013 May 28;108(10):1957-63. Epub 2013 May 2. link to original article link to PMC article PubMed

Definitive chemoradiotherapy for locally advanced disease

Carboplatin & RT

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Carboplatin & RT: Carboplatin & Radiation Therapy

Regimen

Study Evidence Comparator Comparative Efficacy
Veerasarn et al. 2006 Phase III (C) Carboplatin, UFT, RT Did not meet primary endpoints of TTP/OS

Chemotherapy

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

Radiotherapy

One course

References

  1. Veerasarn V, Lorvidhaya V, Kamnerdsupaphon P, Suntornpong N, Sangruchi S, Lertsanguansinchai P, Khorprasert C, Sookpreedee L, Udompunturak S. A randomized phase III trial of concurrent chemoradiotherapy in locally advanced cervical cancer: preliminary results. Gynecol Oncol. 2007 Jan;104(1):15-23. Epub 2006 Sep 25. link to original article contains verified protocol PubMed

Cisplatin & RT

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Cisplatin & RT: Cisplatin & Radiation Therapy

Variant #1, 40.8 Gy, no cap

Study Evidence Comparator Comparative Efficacy
Rose et al. 1999 (GOG 120) Phase III (E-esc) 1. Cisplatin, Fluorouracil, Hydroxyurea, RT Did not meet primary endpoints of PFS/OS
2. Hydroxyurea & RT Superior OS

This regimen was intended for stage IIB disease.

Chemotherapy

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

Radiotherapy, part 1

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

Radiotherapy, part 2

Variant #2, 45 Gy, capped cisplatin

Study Evidence Comparator Comparative Efficacy
Keys et al. 1999 (GOG 123) Phase III (E-esc) RT Superior OS
Lanciano et al. 2005 (GOG 165) Phase III (E-switch-ic) Fluorouracil & RT Might have superior ORR

Chemotherapy

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

Radiotherapy, part 1

5-week course, followed by:

Radiotherapy, part 2

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

Subsequent treatment

Variant #3, 45 Gy, uncapped cisplatin

Study Evidence Comparator Comparative Efficacy
DiSilvestro et al. 2014 (GOG 219) Phase III (C) Cisplatin, Tirapazamine, RT Did not meet primary endpoint of PFS

Chemotherapy

Radiotherapy, part 1

  • Concurrent radiation therapy: 1.8 Gy x 23 to 25 fractions, for an initial dose of 41.4 to 45 Gy

5-week course, followed by:

Radiotherapy, part 2

Variant #4, 45 Gy, no cap

Study Evidence Comparator Comparative Efficacy
Pearcey et al. 2002 Phase III (E-esc) RT Did not meet primary endpoint of OS36

Chemotherapy

Radiotherapy

5-week course

Subsequent treatment

  • Brachytherapy; see paper for details

Variant #5, 50 Gy, no cap

Study Evidence Comparator Comparative Efficacy
Lutgens et al. 2016 (RADCHOC) Phase III (C) RT-HT Did not meet primary endpoint of EFS
Shrivastava et al. 2018 (CRACx) Phase III (E-esc) RT Seems to have superior OS

Chemotherapy

Supportive medications

7-day cycle for 5 cycles

Radiotherapy, part 1

5-week course, followed by:

Radiotherapy, part 2

  • See paper for details

Variant #6, 50.4 Gy, no cap

Study Evidence Comparator Comparative Efficacy
Dueñas-González et al. 2011 (B9E-MC-JHQS) Phase III (C) Cisplatin, Gemcitabine, RT Seems to have inferior OS
Sehouli et al. 2012 Phase III (C) Carboplatin & Paclitaxel, then RT Did not meet primary endpoint of PFS

Chemotherapy

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

Radiotherapy, part 1

6-week course, followed by:

Radiotherapy, part 2

  • Brachytherapy with cesium-137, with 30 to 35 Gy delivered to point A

Variant #7, 51 Gy, no cap

Study Evidence Comparator Comparative Efficacy
Rose et al. 1999 (GOG 120) Phase III (E-esc) 1. Cisplatin, Fluorouracil, Hydroxyurea, RT Did not meet primary endpoints of PFS/OS
2. Hydroxyurea & RT Superior OS

This regimen was intended for stage III or IVA disease.

Chemotherapy

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

Radiotherapy, part 1

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

Radiotherapy, part 2

References

  1. GOG 120: Rose PG, Bundy BN, Watkins EB, Thigpen JT, Deppe G, Maiman MA, Clarke-Pearson DL, Insalaco S. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med. 1999 Apr 15;340(15):1144-53. link to original article contains verified protocol PubMed
    1. Update: Rose PG, Ali S, Watkins E, Thigpen JT, Deppe G, Clarke-Pearson DL, Insalaco S; Gynecologic Oncology Group. Long-term follow-up of a randomized trial comparing concurrent single agent cisplatin, cisplatin-based combination chemotherapy, or hydroxyurea during pelvic irradiation for locally advanced cervical cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2007 Jul 1;25(19):2804-10. Epub 2007 May 14. link to original article PubMed
  2. GOG 123: Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL 3rd, Walker JL, Gersell D. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999 Apr 15;340(15):1154-61. link to original article contains verified protocol PubMed
  3. NCIC CTG: Pearcey R, Brundage M, Drouin P, Jeffrey J, Johnston D, Lukka H, MacLean G, Souhami L, Stuart G, Tu D. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol. 2002 Feb 15;20(4):966-72. link to original article contains verified protocol PubMed
  4. GOG 165: Lanciano R, Calkins A, Bundy BN, Parham G, Lucci JA 3rd, Moore DH, Monk BJ, O'Connor DM. Randomized comparison of weekly cisplatin or protracted venous infusion of fluorouracil in combination with pelvic radiation in advanced cervix cancer: a gynecologic oncology group study. J Clin Oncol. 2005 Nov 20;23(33):8289-95. Epub 2005 Oct 17. link to original article contains verified protocol PubMed
  5. B9E-MC-JHQS: Dueñas-González A, Zarbá JJ, Patel F, Alcedo JC, Beslija S, Casanova L, Pattaranutaporn P, Hameed S, Blair JM, Barraclough H, Orlando M. Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol. 2011 May 1;29(13):1678-85. Epub 2011 Mar 28. link to original article contains verified protocol PubMed
  6. 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. A randomized phase III adjuvant study in high-risk cervical cancer: simultaneous radiochemotherapy with cisplatin (S-RC) versus systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R): a NOGGO-AGO Intergroup Study. Ann Oncol. 2012 Sep;23(9):2259-64. Epub 2012 Feb 21. link to original article contains verified protocol PubMed
  7. GOG 219: DiSilvestro PA, Ali S, Craighead PS, Lucci JA, Lee YC, Cohn DE, Spirtos NM, Tewari KS, Muller C, Gajewski WH, Steinhoff MM, Monk BJ. Phase III randomized trial of weekly cisplatin and irradiation versus cisplatin and tirapazamine and irradiation in stages IB2, IIA, IIB, IIIB, and IVA cervical carcinoma limited to the pelvis: a Gynecologic Oncology Group study. J Clin Oncol. 2014 Feb 10;32(5):458-64. Epub 2014 Jan 6. link to original article link to PMC article contains verified protocol PubMed
  8. RADCHOC: Lutgens LC, Koper PC, Jobsen JJ, van der Steen-Banasik EM, Creutzberg CL, van den Berg HA, Ottevanger PB, van Rhoon GC, van Doorn HC, Houben R, van der Zee J. Radiation therapy combined with hyperthermia versus cisplatin for locally advanced cervical cancer: Results of the randomized RADCHOC trial. Radiother Oncol. 2016 Sep;120(3):378-382. Epub 2016 Feb 17. link to original article contains protocol PubMed
  9. CRACx: Shrivastava S, Mahantshetty U, Engineer R, Chopra S, Hawaldar R, Hande V, Kerkar RA, Maheshwari A, Shylasree TS, Ghosh J, Bajpai J, Gurram L, Gulia S, Gupta S; Gynecologic Disease Management Group. Cisplatin chemoradiotherapy vs radiotherapy in FIGO stage IIIB squamous cell carcinoma of the uterine cervix: a randomized clinical trial. JAMA Oncol. 2018 Apr 1;4(4):506-513. link to original article contains verified protocol in supplement PubMed

Cisplatin, Fluorouracil, RT

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CF & RT: Cisplatin, Fluorouracil Radiation Therapy

Variant #1, 70/4000 x 4

Study Evidence Comparator Comparative Efficacy
Whitney et al. 1999 (GOG 85/SWOG 8695) Phase III (E-esc) Hydroxyurea & RT Seems to have superior OS
Peters et al. 2000 (GOG 109/SWOG-8797) Phase III (E-esc) Radiation therapy Superior OS

Chemotherapy

21-day cycle for 4 cycles

Radiotherapy

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

6-week course

Variant #2, 75/4000 x 3

Study Evidence Comparator Comparative Efficacy
Morris et al. 1999 Phase III (E-esc) Radiation therapy Superior OS

Chemotherapy

21-day cycle for 3 cycles

Radiotherapy

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

5-week course

Subsequent treatment

  • Brachytherapy (see paper for details)

References

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

Cisplatin, Fluorouracil, Hydroxyurea, RT

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

Regimen

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

Chemotherapy

28-day cycle for 2 cycles

Radiotherapy, part 1

  • Concurrent radiation therapy as follows:
    • Stage IIB patients received 1.7 Gy x 24 fractions, for an initial dose of 40.8 Gy
    • Stage III or IVA disease received 1.7 Gy x 30 fractions, for an initial dose of 51 Gy

5- to 6-week course, followed by:

Radiotherapy, part 2

References

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

Cisplatin, Gemcitabine, RT

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

Regimen

Study Evidence Comparator Comparative Efficacy
Dueñas-González et al. 2011 (B9E-MC-JHQS) Phase III (E-esc) Cisplatin & RT Seems to have superior OS
Cetina et al. 2013 Non-randomized portion of RCT

Chemotherapy

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

Radiotherapy

6-week course

Subsequent treatment

References

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

Fluorouracil & RT

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

Regimen

Study Evidence Comparator Comparative Efficacy
Lanciano et al. 2005 (GOG 165) Phase III (E-switch-ic) Cisplatin & RT Might have inferior ORR

Chemotherapy

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

7-day cycle for 6 cycles

Radiotherapy, part 1

6-week course, followed by:

Radiotherapy, part 2

  • Parametrial boost of 5.4 to 9 Gy was administered to the involved parametrium after whole pelvic RT was complete

References

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

Fluorouracil, Mitomycin, RT

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Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, Radiation Therapy

Regimen

Study Evidence Comparator Comparative Efficacy
Lorvidhava et al. 2003 Phase III (E-esc) RT Superior DFS

Here for historic reference.

Chemotherapy

Radiotherapy

References

  1. Lorvidhaya V, Chitapanarux I, Sangruchi S, Lertsanguansinchai P, Kongthanarat Y, Tangkaratt S, Visetsiri E. Concurrent mitomycin C, 5-fluorouracil, and radiotherapy in the treatment of locally advanced carcinoma of the cervix: a randomized trial. Int J Radiat Oncol Biol Phys. 2003 Apr 1;55(5):1226-32. link to original article PubMed

Hydroxyurea & RT

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Hydroxyurea & RT: Hydroxyurea & Radiation Therapy

Regimen

Study Evidence Comparator Comparative Efficacy
Hreshchyshyn et al. 1979 (GOG 04) Phase III (E-esc) Radiation therapy Seems to have superior OS
Rose et al. 1999 (GOG 120) Phase III (C) 1. Cisplatin & RT Inferior OS
2. Cisplatin, Fluorouracil, Hydroxyurea, RT Inferior OS
Whitney et al. 1999 (GOG 85/SWOG 8695) Phase III (C) Cisplatin, Fluorouracil, RT Seems to have inferior OS

Chemotherapy

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

Radiotherapy, part 1

  • Concurrent radiation therapy as follows:
    • Stage IIB patients received 1.7 Gy x 24 fractions, for an initial dose of 40.8 Gy
    • Stage III or IVA disease received 1.7 Gy x 30 fractions, for an initial dose of 51 Gy

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

Radiotherapy, part 2

References

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

Radiation therapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Hreshchyshyn et al. 1979 (GOG 04) Phase III (C) Hydroxyurea & RT Seems to have inferior OS
Morris et al. 1999 Phase III (C) Cisplatin & RT Inferior OS
Keys et al. 1999 (GOG 123) Phase III (C) Cisplatin & RT Inferior OS
Peters et al. 2000 (GOG 109/SWOG-8797) Phase III (C) Cisplatin, Fluorouracil, RT Inferior OS
Benedetti-Panici et al. 2002 Phase III (C) NACT, then surgery Inferior OS
Pearcey et al. 2002 Phase III (C) Cisplatin & RT Did not meet primary endpoint of OS36
Srivastava et al. 2013 Phase III (C) Cisplatin & RT Did not meet primary endpoint of LRFS
Sugiyama et al. 2014 (JGOG-DT101) Phase III (C) Z-100 & RT Did not meet primary endpoint of OS
Shrivastava et al. 2018 (CRACx) Phase III (C) Cisplatin & RT Seems to have inferior OS

Demonstrably inferior; here for reference purposes only.

Radiotherapy

Subsequent treatment

References

  1. GOG 04: Hreshchyshyn MM, Aron BS, Boronow RC, Franklin EW 3rd, Shingleton HM, Blessing JA. Hydroxyurea or placebo combined with radiation to treat stages IIIB and IV cervical cancer confined to the pelvis. Int J Radiat Oncol Biol Phys. 1979 Mar;5(3):317-22. link to original article PubMed
  2. Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, Rotman M, Gershenson DM, Mutch DG. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med. 1999 Apr 15;340(15):1137-43. link to original article contains verified protocol PubMed
  3. GOG 123: Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL 3rd, Walker JL, Gersell D. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med. 1999 Apr 15;340(15):1154-61. link to original article contains verified protocol PubMed
  4. GOG 109/SWOG-8797: Peters WA 3rd, Liu PY, Barrett RJ 2nd, Stock RJ, Monk BJ, Berek JS, Souhami L, Grigsby P, Gordon W Jr, Alberts DS. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. 2000 Apr;18(8):1606-13. link to original article contains verified protocol PubMed
  5. Benedetti-Panici P, Greggi S, Colombo A, Amoroso M, Smaniotto D, Giannarelli D, Amunni G, Raspagliesi F, Zola P, Mangioni C, Landoni F. Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. J Clin Oncol. 2002 Jan 1;20(1):179-88. link to original article PubMed
  6. Pearcey R, Brundage M, Drouin P, Jeffrey J, Johnston D, Lukka H, MacLean G, Souhami L, Stuart G, Tu D. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol. 2002 Feb 15;20(4):966-72. link to original article contains verified protocol PubMed
  7. Srivastava K, Paul S, Chufal KS, Shamsundar SD, Lal P, Pant MC, Bhatt M, Singh S, Gupta R. Concurrent chemoradiation versus radiotherapy alone in cervical carcinoma: a randomized phase III trial. Asia Pac J Clin Oncol. 2013 Dec;9(4):349-56. Epub 2013 May 27. link to original article PubMed
  8. JGOG-DT101: Sugiyama T, Fujiwara K, Ohashi Y, Yokota H, Hatae M, Ohno T, Nagai Y, Mitsuhashi N, Ochiai K, Noda K. Phase III placebo-controlled double-blind randomized trial of radiotherapy for stage IIB-IVA cervical cancer with or without immunomodulator Z-100: a JGOG study. Ann Oncol. 2014 May;25(5):1011-7. Epub 2014 Feb 25. link to original article PubMed
  9. CRACx: Shrivastava S, Mahantshetty U, Engineer R, Chopra S, Hawaldar R, Hande V, Kerkar RA, Maheshwari A, Shylasree TS, Ghosh J, Bajpai J, Gurram L, Gulia S, Gupta S; Gynecologic Disease Management Group. Cisplatin chemoradiotherapy vs radiotherapy in FIGO stage IIIB squamous cell carcinoma of the uterine cervix: a randomized clinical trial. JAMA Oncol. 2018 Apr 1;4(4):506-513. link to original article contains verified protocol in supplement PubMed

Adjuvant therapy

Carboplatin & Ifosfamide

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Regimen

Study Evidence Comparator Comparative Efficacy
Blohmer et al. 2011 (NOGGO-AGO) Phase III (C) See link See link

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

Preceding treatment

Chemotherapy

Supportive medications

21-day cycle for 4 cycles

Subsequent treatment

References

  1. 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. Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study. J Clin Oncol. 2011 Oct 1;29(28):3791-7. Epub 2011 Aug 22. link to original article contains verified protocol PubMed

Cisplatin & Gemcitabine

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Regimen

Study Evidence
Dueñas-González et al. 2011 (B9E-MC-JHQS) Non-randomized portion of RCT

Preceding treatment

Chemotherapy

21-day cycle for 2 cycles

References

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

Radiation therapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Blohmer et al. 2011 (NOGGO-AGO) Phase III (C) See link See link

Preceding treatment

Radiotherapy

  • External beam radiotherapy: 1.80 Gy for 28 fractions, for a total dose of 50.4 Gy
  • If resection margins positive, patients received one of the following:

6-week course

References

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

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

Carboplatin monotherapy

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Regimen

Study Evidence
Weiss et al. 1990 Phase II

Chemotherapy

28-day cycles

References

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

Carboplatin & Docetaxel

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Variant #1, 6 cycles

Study Evidence
Takekida et al. 2010 Phase II

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

Variant #2, indefinite

Study Evidence
Nagao et al. 2005 Pilot, <20 pts

Chemotherapy

Supportive medications

21-day cycles

References

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

Carboplatin & Paclitaxel

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TC: Taxol (Paclitaxel) & Carboplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Pectasides et al. 2009a Phase II
Kitagawa et al. 2015 (JCOG0505) Phase III (E-switch-ic) Cisplatin & Paclitaxel Non-inferior OS

Note: Pectasides et al. 2009a allowed the regimen to be given up to 9 cycles.

Chemotherapy

21-day cycle for 6 cycles

References

  1. Pectasides D, Fountzilas G, Papaxoinis G, Pectasides E, Xiros N, Sykiotis C, Koumarianou A, Psyrri A, Panayiotides J, Economopoulos T. Carboplatin and paclitaxel in metastatic or recurrent cervical cancer. Int J Gynecol Cancer. 2009 May;19(4):777-81. link to original article contains protocol PubMed
  2. JCOG0505: Kitagawa R, Katsumata N, Shibata T, Kamura T, Kasamatsu T, Nakanishi T, Nishimura S, Ushijima K, Takano M, Satoh T, Yoshikawa H. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505. J Clin Oncol. 2015 Jul 1;33(19):2129-35. Epub 2015 Mar 2. link to original article contains verified protocol PubMed

Cisplatin monotherapy

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Regimen

Study Evidence Comparator Comparative Efficacy
Thigpen et al. 1979a Phase II
Bonomi et al. 1985 (GOG 43) Phase III (C) 1. Higher-dose cisplatin
2. Higher-dose cisplatin, split doses
Did not meet primary endpoint of ORR
Thigpen et al. 1989 (GOG 64) Phase III (C) CI Cisplatin Did not meet primary efficacy endpoints
Omura et al. 1997 (GOG 110) Phase III (C) Cisplatin & Ifosfamide Inferior PFS
Cisplatin & Mitolactol Did not meet primary endpoint of ORR
Vermorken et al. 2001 Phase III (C) BEMP Did not meet primary endpoint of ORR
Moore et al. 2004 (GOG 169) Phase III (C) Cisplatin & Paclitaxel Inferior PFS
Long et al. 2005 (GOG 179) Phase III (C) 1. Cisplatin & Topotecan Seems to have inferior OS
2. MVAC Not reported
Aoki et al. 2018 (Taiho 10020380) Phase III (C) Cisplatin & S-1 Did not meet primary endpoint of OS

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

Chemotherapy

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

References

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

Cisplatin & Gemcitabine

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GC: Gemcitabine, Cisplatin

Regimen

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

Chemotherapy

21-day cycles

References

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

Cisplatin & Ifosfamide

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Regimen

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

Chemotherapy

References

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

Cisplatin & Mitomycin

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Regimen

Study Evidence Efficacy
Wagenaar et al. 2001 Phase II ORR: 42% (95% CI: 26-61%)

Chemotherapy

Supportive medications

28-day cycle for 9 cycles

References

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

Cisplatin & Paclitaxel

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

Variant #1, 50/135, 3 hr paclitaxel

Study Evidence Comparator Comparative Efficacy
Tewari et al. 2014 (GOG 240) Phase III (C) 1. Cisplatin, Paclitaxel, Bevacizumab Seems to have inferior OS
2. Paclitaxel & Topotecan Did not meet primary endpoint of OS
3. Paclitaxel, Topotecan, Bevacizumab Not reported

Chemotherapy

21-day cycles until CR or indefinitely

Variant #2, 50/135, CI paclitaxel

Study Evidence Comparator Comparative Efficacy
Moore et al. 2004 (GOG 169) Phase III (E-esc) Cisplatin Superior PFS
Monk et al. 2009 (GOG 204) Phase III (C) 1. Cisplatin & Gemcitabine Seems to have superior PFS
2. Cisplatin & Topotecan Did not meet primary endpoint of OS
3. Cisplatin & Vinorelbine Might have superior PFS
Kitagawa et al. 2015 (JCOG0505) Phase III (C) Carboplatin & Paclitaxel Non-inferior OS

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

Chemotherapy

Supportive medications

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

Variant #3, 50/175

Study Evidence Comparator Comparative Efficacy
Tewari et al. 2014 (GOG 240) Phase III (C) 1. Cisplatin, Paclitaxel, Bevacizumab Seems to have inferior OS
2. Paclitaxel & Topotecan Did not meet primary endpoint of OS
3. Paclitaxel, Topotecan, Bevacizumab Not reported

Chemotherapy

21-day cycles until CR or indefinitely

References

  1. GOG 169: Moore DH, Blessing JA, McQuellon RP, Thaler HT, Cella D, Benda J, Miller DS, Olt G, King S, Boggess JF, Rocereto TF. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol. 2004 Aug 1;22(15):3113-9. link to original article contains verified protocol PubMed
  2. GOG 204: Monk BJ, Sill MW, McMeekin DS, Cohn DE, Ramondetta LM, Boardman CH, Benda J, Cella D. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009 Oct 1;27(28):4649-55. Epub 2009 Aug 31. link to original article contains verified protocol link to PMC article PubMed
  3. GOG 240: Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, Monk BJ. Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med. 2014 Feb 20;370(8):734-43. link to original article link to supplementary appendix contains verified protocol link to PMC article PubMed
    1. Update: Tewari KS, Sill MW, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, Michael HE, DiSaia PJ, Copeland LJ, Creasman WT, Stehman FB, Brady MF, Burger RA, Thigpen JT, Birrer MJ, Waggoner SE, Moore DH, Look KY, Koh WJ, Monk BJ. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017 Oct 7;390(10103):1654-1663. Epub 2017 Jul 27. link to original article PubMed
  4. JCOG0505: Kitagawa R, Katsumata N, Shibata T, Kamura T, Kasamatsu T, Nakanishi T, Nishimura S, Ushijima K, Takano M, Satoh T, Yoshikawa H. Paclitaxel plus carboplatin versus paclitaxel plus cisplatin in metastatic or recurrent cervical cancer: the open-label randomized phase III trial JCOG0505. J Clin Oncol. 2015 Jul 1;33(19):2129-35. Epub 2015 Mar 2. link to original article contains verified protocol PubMed

Cisplatin, Paclitaxel, Bevacizumab

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CP+Bev: Cisplatin, Paclitaxel, Bevacizumab

Variant #1, 135 mg/m2 paclitaxel

Study Evidence Comparator Comparative Efficacy
Tewari et al. 2014 (GOG 240) Phase III (E-RT-esc) 1. Cisplatin & Paclitaxel Seems to have superior OS
2. Paclitaxel & Topotecan Did not meet primary endpoint of OS (*)
3. Paclitaxel, Topotecan, Bevacizumab Not reported

Note: efficacy marked with (*) based on 2017 update.

Chemotherapy

21-day cycles until CR or indefinitely

Variant #2, 175 mg/m2 paclitaxel

Study Evidence Comparator Comparative Efficacy
Tewari et al. 2014 (GOG 240) Phase III (E-RT-esc) 1. Cisplatin & Paclitaxel Seems to have superior OS
2. Paclitaxel & Topotecan Did not meet primary endpoint of OS (*)
3. Paclitaxel, Topotecan, Bevacizumab Not reported

Note: efficacy marked with (*) based on 2017 update.

Chemotherapy

21-day cycles until CR or indefinitely

References

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

Cisplatin & Topotecan

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TC: Topotecan, Cisplatin

Regimen

Study Evidence Comparator Comparative Efficacy
Long et al. 2005 (GOG 179) Phase III (E-RT-esc) 1. Cisplatin Seems to have superior OS
2. MVAC Not reported
Monk et al. 2009 (GOG 204) Phase III (E-switch-ic) 1. Cisplatin & Gemcitabine Did not meet primary endpoint of OS
2. Cisplatin & Paclitaxel Did not meet primary endpoint of OS
3. Cisplatin & Vinorelbine Did not meet primary endpoint of OS

Chemotherapy

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

References

  1. GOG 179: Long HJ 3rd, Bundy BN, Grendys EC Jr, Benda JA, McMeekin DS, Sorosky J, Miller DS, Eaton LA, Fiorica JV; Gynecologic Oncology Group study. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group study. J Clin Oncol. 2005 Jul 20;23(21):4626-33. Epub 2005 May 23. link to original article contains verified protocol PubMed
  2. GOG 204: Monk BJ, Sill MW, McMeekin DS, Cohn DE, Ramondetta LM, Boardman CH, Benda J, Cella D. Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol. 2009 Oct 1;27(28):4649-55. Epub 2009 Aug 31. link to original article contains verified protocol link to PMC article PubMed

Cisplatin & Vinorelbine

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VC: Vinorelbine, Cisplatin

Regimen

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

Chemotherapy

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

References

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

Ifosfamide monotherapy

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Regimen

Study Evidence
Coleman et al. 1986 Phase II
Sutton et al. 1993a Phase II
Sutton et al. 1993b Phase II

Chemotherapy

  • Ifosfamide (Ifex) 1500 mg/m2 IV once per day on days 1 to 5
    • Dosage for patients with previous pelvic radiation or other chemotherapy is 1200 mg/m2
    • Dose could be increased by 300 mg/m2 or decreased by 20% depending on toxicity

Supportive medications

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

21-day cycles

References

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

Paclitaxel monotherapy

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Variant #1, 135 mg/m2

Study Evidence
McGuire et al. 1996 Phase II
Curtin et al. 2001 Phase II

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
    • Dose could be changed to 110 or 200 mg/m2 depending on toxicity

Supportive medications

21-day cycles

Variant #2, 170 mg/m2

Study Evidence
McGuire et al. 1996 Phase II
Curtin et al. 2001 Phase II

Chemotherapy

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

Supportive medications

21-day cycles

Variant #3, 250 mg/m2

Study Evidence
Kudelka et al. 1996 Phase II

Chemotherapy

  • Paclitaxel (Taxol) 250 mg/m2 IV over 3 hours on day 1
    • Dose could be changed to 275, 225, or 200 mg/m2 depending on toxicity

Supportive medications

21-day cycles

References

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

Paclitaxel & Topotecan

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TP: Topotecan, Paclitaxel

Regimen

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

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

Chemotherapy

21-day cycles

References

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

Paclitaxel, Topotecan, Bevacizumab

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TP+Bev: Topotecan, Paclitaxel, Bevacizumab

Regimen

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

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. Efficacy marked with (*) is based on the 2017 update.

Chemotherapy

21-day cycles

References

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

Topotecan monotherapy

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Variant #1, q3wk

Study Evidence
Bookman et al. 2000 (GOG 127-F) Phase II

Chemotherapy

21-day cycles

Variant #2, q4wk

Study Evidence
Muderspach et al. 2001 Phase II

Chemotherapy

28-day cycles

References

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

Vinorelbine monotherapy

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Regimen

Study Evidence Efficacy
Morris et al. 1998 Phase II ORR: 18%

Chemotherapy

7-day cycles

References

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

Advanced or metastatic disease, subsequent lines of therapy

Bevacizumab monotherapy

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Regimen

Study Evidence
Monk et al. 2009 (GOG 227-C) Phase II

Chemotherapy

21-day cycles

References

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

Cisplatin & Gemcitabine

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GC: Gemcitabine, Cisplatin

Regimen

Study Evidence
Brewer et al. 2006 Phase II

Chemotherapy

28-day cycles

References

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

Docetaxel monotherapy

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

Study Evidence
Garcia et al. 2008 Phase II

Chemotherapy

Supportive medications

28-day cycles

Variant #2, 100 mg/m2, q3wk

Study Evidence
Garcia et al. 2007 Phase II

Chemotherapy

21-day cycles

References

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

Fluorouracil & Folinic acid

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Variant #1, 1850/200

Study Evidence
Look et al. 1996 Phase II
Look et al. 1997 Phase II

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

Chemotherapy

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

Variant #2, 2125/100

Study Evidence
Look et al. 1992 Phase II

Chemotherapy

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

References

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

Gemcitabine monotherapy

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Regimen

Study Evidence
Schilder et al. 2000 (GOG 127-K) Phase II
Schilder et al. 2005 Phase II

Chemotherapy

28-day cycles

References

  1. Schilder RJ, Blessing JA, Morgan M, Mangan CE, Rader JS. Evaluation of gemcitabine in patients with squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2000 Feb;76(2):204-7. link to original article contains verified protocol PubMed
  2. Schilder RJ, Blessing J, Cohn DE. Evaluation of gemcitabine in previously treated patients with non-squamous cell carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2005 Jan;96(1):103-7. link to original article contains verified protocol PubMed

Irinotecan monotherapy

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Regimen

Study Evidence
Verschraegen et al. 1997 Phase II

Chemotherapy

Supportive medications

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

42-day cycles

References

  1. Verschraegen CF, Levy T, Kudelka AP, Llerena E, Ende K, Freedman RS, Edwards CL, Hord M, Steger M, Kaplan AL, Kieback D, Fishman A, Kavanagh JJ. Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol. 1997 Feb;15(2):625-31. link to original article contains verified protocol PubMed

Pembrolizumab monotherapy

Regimen

FDA-recommended dose
Study Evidence
Chung et al. 2019 (KEYNOTE-158) Phase II (RT)

Immunotherapy

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

References

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

Pemetrexed monotherapy

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Regimen

Study Evidence
Miller et al. 2008 Phase II

Chemotherapy

Supportive medications

21-day cycles

References

  1. Miller DS, Blessing JA, Bodurka DC, Bonebrake AJ, Schorge JO; Gynecologic Oncology Group. Evaluation of pemetrexed (Alimta, LY231514) as second line chemotherapy in persistent or recurrent carcinoma of the cervix: a phase II study of the Gynecologic Oncology Group. Gynecol Oncol. 2008 Jul;110(1):65-70. Epub 2008 May 5. link to original article contains verified protocol PubMed

Vinorelbine monotherapy

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Regimen

Study Evidence Efficacy
Muggia et al. 2004 Phase II ORR: 14% (95% CI 5-27%)
Muggia et al. 2005 Phase II ORR: 7%

Chemotherapy

21-day cycles

References

  1. Muggia FM, Blessing JA, Method M, Miller DS, Johnson GA, Lee RB, Menzin A; Gynecologic Oncology Group study. Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2004 Feb;92(2):639-43. link to original article contains verified protocol PubMed
  2. Muggia FM, Blessing JA, Waggoner S, Berek JS, Monk BJ, Sorosky J, Pearl ML. Evaluation of vinorelbine in persistent or recurrent nonsquamous carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2005 Jan;96(1):108-11. link to original article contains verified protocol PubMed