Head and neck cancer

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Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
*Note: this page contains regimens which are not histology or biomarker-specific, although they may have been studied in patients selected by histology and/or biomarker. The following links will take you to specific subpages: 
*Regimens for HPV positive oropharyngeal cancer are here.
*Regimens for nasopharyngeal carcinoma are here.
Last updated on 2024-12-02:46 regimens on this page
89 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: Yilmaz et al. Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline EuroPMC
*2021: Geiger et al. Management of Salivary Gland Malignancy: ASCO Guideline EuroPMC
*2020: Maghami et al. Diagnosis and Management of Squamous Cell Carcinoma of Unknown Primary in the Head and Neck: ASCO Guideline EuroPMC
*2017: Forastiere et al. Use of larynx-preservation strategies in the treatment of laryngeal cancer: American Society of Clinical Oncology clinical practice guideline update EuroPMC
*2017: Nekhlyudov et al. Head and neck cancer survivorship care guideline: American Society of Clinical Oncology clinical practice guideline endorsement of the American Cancer Society guideline EuroPMC
==EHNS/ESMO/ESTRO==
*2021: Keam et al. Pan-Asian adaptation of the EHNS-ESMO-ESTRO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with squamous cell carcinoma of the head and neck EuroPMC
*2020: Machiels et al. Squamous cell carcinoma of the oral cavity, larynx, oropharynx and hypopharynx: EHNS–ESMO–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Grégoire et al. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
==ESMO==
*2022: van Herpen et al. Salivary gland cancer: ESMO-European Reference Network on Rare Adult Solid Cancers (EURACAN) Clinical Practice Guideline for diagnosis, treatment and follow-up EuroPMC
*2009: Licitra & Felip. Squamous cell carcinoma of the head and neck: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2008: Pivot & Felip. Squamous cell carcinoma of the head and neck: ESMO clinical Recommendations for diagnosis, treatment and follow-up EuroPMC
**2007: Pivot & Villanueva. Squamous cell carcinoma of the head and neck: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2003: Pivot. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of squamous cell carcinoma of the head and neck EuroPMC
==NCCN==
*NCCN Guidelines - Head and Neck Cancers
**2015: Pfister et al. Head and Neck Cancers, Version 1.2015 EuroPMC
**2014: Pfister et al. Head and neck cancers, Version 2.2014. Clinical practice guidelines in oncology EuroPMC
**2011: Pfister et al. Head and neck cancers. EuroPMC
**2008: Forastiere et al. Head and neck cancers. EuroPMC
**2005: Forastiere et al. Head and neck cancers. EuroPMC
==SITC==
*2019: Cohen et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC) link to PMC article EuroPMC
=Locally advanced disease, induction=
Note that these regimens are intended to be followed by definitive radiotherapy or chemoradiotherapy. In some circumstances, treatment may be followed by surgery; if this sequence was pre-planned it would be considered a neoadjuvant approach as opposed to an induction approach.
==Cisplatin & Fluorouracil (CF)==
CF: Cisplatin & Fluorouracil
PF: Platinol (Cisplatin) & Fluorouracil
===Regimen variant #1, 75/3000===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Sun et al. 2020 (DOCET_L_02557)	2009-08-27 to 2014-12-05	Phase 3 (C)	TPF 	Did not meet primary endpoint of PFSMedian PFS: 342 vs 400 d(HR 1.33, 95% CI 0.94-1.89)
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3000 mg/m2)
21-day cycle for 3 to 4 cycles
====Subsequent treatment====
*Definitive RT
===Regimen variant #2, 100/4000===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Posner et al. 2007 (TAX 324)	1999-2003 	Phase 3 (C)	TPF, then Carboplatin & RT	Shorter OS1 (primary endpoint)OS60: 42% vs 52%(HR 1.35, 95% CI 1.06-1.72)
1Reported efficacy is based on the 2011 update.
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV over 30 to 180 minutes once on day 1, given first
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1, given second (total dose per cycle: 4000 mg/m2)
21-day cycle for 3 cycles
====Subsequent treatment====
*Definitive carboplatin & RT, 3 to 8 weeks after the start of cycle 3
===Regimen variant #3, 100/5000, 2 cycles with response adaptation===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Forastiere et al. 2003 (RTOG 91-11)	1992-2000 	Phase 3 (C)	See link 	See link
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m2)
21-day cycle for 2 cycles 
====Subsequent treatment====
*After cycle 2, patients are evaluated by indirect laryngoscopy and CT neck.
**RTOG 91-11, patients with PR/CR: CF continuation x 1 (3 cycles total), then definitive RT
**RTOG 91-11, patients with worse than a PR: Laryngectomy, then adjuvant RT
===Regimen variant #4, 100/5000 x 3===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Wolf et al. 1991 	1985 to not reported	Phase 3 (E-esc) 	Surgery 	Did not meet primary endpoint of OS
Taylor et al. 1994a 	1986-1991 	Phase 3 (C) 	CF & RT 	Lower ORR
Hitt et al. 2005 	1998-2001 	Phase 3 (C) 	PCF, then Cisplatin & RT	Lower CR rate
Pointreau et al. 2009 (GORTEC 2000-01)	2000-2005 	Phase 3 (C) 	TPF, then RT 	Lower ORR
Hitt et al. 2013 (TTCC 2503) 	2002-2007 	Phase 2/3 (E-esc)	1. No induction2. TPF 	Did not meet co-primary endpoints of PFS/TTF
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV over 15 minutes once on day 1
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m2)
====Supportive therapy====
*Per GORTEC: Normal saline (use of mannitol, KCl, and magnesium sulfate per institutional protocol) 1000 mL IV given twice, before and after cisplatin
21-day cycle for 3 cycles
====Subsequent treatment====
*Wolf et al. 1991 & Taylor et al. 1994a: Definitive RT
*Hitt et al. 2005: Patients then undergo ENT evaluation and CT imaging of the primary tumor and neck
**Hitt et al. 2005, patients with CR or PR of greater than 80% in the primary tumor and no evidence of progression in neck lymph nodes: Definitive cisplatin & RT
**Hitt et al. 2005, patients with a PR of less than 80% or stable disease in the neck lymph nodes (especially if N2 or N3 disease) after induction: Neck dissection, if the surgeons were in agreement, before the administration of adjuvant chemoradiotherapy
*GORTEC 2000-01: re-evaluation is performed 
**GORTEC 2000-01, patients who responded to induction chemotherapy: Definitive RT within 3 to 7 weeks of finishing chemotherapy
**GORTEC 2000-01, patients who did not respond to induction chemotherapy: Surgery, then adjuvant RT (see Pointreau et al. 2009 for details)
*TTCC 2503: Definitive cisplatin & RT
===Regimen variant #5, 100/5000 x 4===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lefebvre et al. 2009 (EORTC 24954)	1996-2004 	Phase 3 (E-switch-ic)	See link 	See link
Vermorken et al. 2007 (TAX 323) 	1999-2002 	Phase 3 (C) 	TPF 	Shorter PFS (primary endpoint)Median PFS: 8.2 vs 11 mo(HR 1.39, 95% CI 1.10-1.75)Shorter OS (secondary endpoint)Median OS: 14.5 vs 18.8 mo(HR 1.37, 95% CI 1.06-1.79)
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on day 1, given first
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1, given second (total dose per cycle: 5000 mg/m2)
====Supportive therapy====
*"Adequate antiemetic medications during chemotherapy"
*Prophylactic G-CSF only allowed for patients who had "febrile neutropenia or infection, a delay in recovery of the absolute neutrophil count at day 28, or grade 4 neutropenia persisting for 7 days or more."
21-day cycle for 4 cycles
====Subsequent treatment====
*TAX 323, patients without progressive disease and who had recovery of marrow function, resolution of mucositis, and healed from any dental procedures: Definitive RT within 4 to 7 weeks of finishing chemotherapy
*EORTC 24954: Definitive RT
===References===
# Taylor SG 4th, Murthy AK, Vannetzel JM, Colin P, Dray M, Caldarelli DD, Shott S, Vokes E, Showel JL, Hutchinson JC, Witt TR, Griem KL, Hartsell WF, Kies MS, Mittal B, Rebischung JL, Coupez DJ, Desphieux JL, Bobin S, LePajolec C. Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol. 1994 Feb;12(2):385-95. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# RTOG 91-11: Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, Glisson B, Trotti A, Ridge JA, Chao C, Peters G, Lee DJ, Leaf A, Ensley J, Cooper J. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003 Nov 27;349(22):2091-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002496
## Update: Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, Morrison W, Glisson B, Trotti A, Ridge JA, Thorstad W, Wagner H, Ensley JF, Cooper JS. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013 Mar 1;31(7):845-52. Epub 2012 Nov 26. link to original article contains partial protocol link to PMC article EuroPMC
# Hitt R, López-Pousa A, Martínez-Trufero J, Escrig V, Carles J, Rizo A, Isla D, Vega ME, Martí JL, Lobo F, Pastor P, Valentí V, Belón J, Sánchez MA, Chaib C, Pallarés C, Antón A, Cervantes A, Paz-Ares L, Cortés-Funes H. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol. 2005 Dec 1;23(34):8636-45. Epub 2005 Nov 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# TAX 323: Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, Stewart JS, Jelic S, Betka J, Preiss JH, van den Weyngaert D, Awada A, Cupissol D, Kienzer HR, Rey A, Desaunois I, Bernier J, Lefebvre JL; EORTC; TAX 323 Study Group. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007 Oct 25;357(17):1695-704. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003888
## HRQoL analysis: van Herpen CM, Mauer ME, Mesia R, Degardin M, Jelic S, Coens C, Betka J, Bernier J, Remenar E, Stewart JS, Preiss JH, van den Weyngaert D, Bottomley A, Vermorken JB; EORTC Head and Neck Group. Short-term health-related quality of life and symptom control with docetaxel, cisplatin, 5-fluorouracil and cisplatin (TPF), 5-fluorouracil (PF) for induction in unresectable locoregionally advanced head and neck cancer patients (EORTC 24971/TAX 323). Br J Cancer. 2010 Oct 12;103(8):1173-81. Epub 2010 Sep 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# TAX 324: Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, Tjulandin S, Shin DM, Cullen K, Ervin TJ, Murphy BA, Raez LE, Cohen RB, Spaulding M, Tishler RB, Roth B, Viroglio Rdel C, Venkatesan V, Romanov I, Agarwala S, Harter KW, Dugan M, Cmelak A, Markoe AM, Read PW, Steinbrenner L, Colevas AD, Norris CM Jr, Haddad RI; TAX 324 Study Group. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007 Oct 25;357(17):1705-15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00273546
## Update: Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, Tan M, Fasciano J, Sammartino DE, Posner MR; TAX 324 Study Group. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol. 2011 Feb;12(2):153-9. Epub 2011 Jan 11. link to original article link to PMC article EuroPMC
# EORTC 24954: Lefebvre JL, Rolland F, Tesselaar M, Bardet E, Leemans CR, Geoffrois L, Hupperets P, Barzan L, de Raucourt D, Chevalier D, Licitra L, Lunghi F, Stupp R, Lacombe D, Bogaerts J, Horiot JC, Bernier J, Vermorken JB; EORTC Head and Neck Cancer Cooperative Group; EORTC Radiation Oncology Group. Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst. 2009 Feb 4;101(3):142-52. Epub 2009 Jan 27. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00002839
##HRQoL analysis: Bottomley A, Tridello G, Coens C, Rolland F, Tesselaar ME, Leemans CR, Hupperets P, Licitra L, Vermorken JB, Van Den Weyngaert D, Truc G, Barillot I, Lefebvre JL. An international phase 3 trial in head and neck cancer: quality of life and symptom results: EORTC 24954 on behalf of the EORTC Head and Neck and the EORTC Radiation Oncology Group. Cancer. 2014 Feb 1;120(3):390-8. Epub 2013 Oct 25. link to original article EuroPMC
## Update: Henriques De Figueiredo B, Fortpied C, Menis J, Lefebvre JL, Barzan L, de Raucourt D, Geoffrois L, Giurgea L, Hupperets P, Leemans CR, Licitra L, Rolland F, Tesselaar M, Vermorken JB, Grégoire V; EORTC Head and Neck Cancer Group; EORTC Radiation Oncology Cooperative Group. Long-term update of the 24954 EORTC phase III trial on larynx preservation. Eur J Cancer. 2016 Sep;65:109-12. Epub 2016 Aug 2. link to original article EuroPMC
# GORTEC 2000-01: Pointreau Y, Garaud P, Chapet S, Sire C, Tuchais C, Tortochaux J, Faivre S, Guerrif S, Alfonsi M, Calais G. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst. 2009 Apr 1;101(7):498-506. Epub 2009 Mar 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00169182
## Update: Janoray G, Pointreau Y, Garaud P, Chapet S, Alfonsi M, Sire C, Jadaud E, Calais G. Long-term results of a multicenter randomized phase III trial of induction chemotherapy with cisplatin, 5-fluorouracil, ± docetaxel for larynx preservation. J Natl Cancer Inst. 2015 Dec 16;108(4). link to original article EuroPMC
# TTCC 2503: Hitt R, Grau JJ, López-Pousa A, Berrocal A, García-Girón C, Irigoyen A, Sastre J, Martínez-Trufero J, Brandariz Castelo JA, Verger E, Cruz-Hernández JJ; Spanish Head and Neck Cancer Cooperative Group. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol. 2014 Jan;25(1):216-25. Epub 2013 Nov 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00261703
##Update: Hitt R, Iglesias L, López-Pousa A, Berrocal-Jaime A, Grau JJ, García-Girón C, Martínez-Trufero J, Guix M, Lambea-Sorrosal J, Del Barco-Morillo E, León-Vintró X, Cunquero-Tomas AJ, Baste N, Ocaña A, Cruz-Hernández JJ; the Spanish Head and Neck Cancer Cooperative Group (TTCC). Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial. Clin Transl Oncol. 2021 Apr;23(4):764-772. Epub 2020 Aug 14. link to original article EuroPMC
# DOCET_L_02557: Sun Y, Guo W, Bai Y, Ge M, Hu C, Wu S, Hao J, Gao M, Pan J, Dong P, Wu Y, Liang H, Wei Q, Zhong M, Lu T. Neoadjuvant dose-modified docetaxel in squamous cell carcinoma of the head and neck: A phase 3 study. Oral Dis. 2020 Mar;26(2):285-294. Epub 2020 Jan 6. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00995293
==PCF==
PCF: Paclitaxel, Cisplatin, Fluorouracil
PPF: Paclitaxel, Platinol (Cisplatin), Fluorouracil
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hitt et al. 2002	1996-1998 	Phase 2 	 	
Hitt et al. 2005	1998-2001 	Phase 3 (E-esc)	CF 	Higher CR rate (primary endpoint)
====Chemotherapy====
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
*Cisplatin (Platinol) 100 mg/m2 IV once on day 2
*Fluorouracil (5-FU) 500 mg/m2/day IV continuous infusion over 120 hours, started on day 2 (total dose per cycle: 2500 mg/m2)
====Supportive therapy====
*Dexamethasone (Decadron) 20 mg IV once on day 1; 30 minutes prior to paclitaxel
*Dexamethasone (Decadron) 8 mg PO twice per day on days 2 & 3
*Ondansetron (Zofran) 8 mg IV or PO every 8 hours or every 12 hours on days 1 to 5
*Diphenhydramine (Benadryl) 50 mg IV once on day 1; 30 minutes prior to paclitaxel 
*Cimetidine (Tagamet) 300 mg IV once on day 1; 30 minutes prior to paclitaxel
**Per Hitt et al. 2005, Ranitidine (Zantac) (dose not specified) could be used instead
*Mannitol and IV hydration with cisplatin
21-day cycle for 3 cycles
====Subsequent treatment====
*Hitt et al. 2002: Patients undergo ENT evaluation and CT imaging of the primary tumor and neck during week 3 or 4 of cycle 3.
**Hitt et al. 2002, patients who did not have at least a PR: Surgery, performed 4 weeks after cycle 3 day 1.
**Hitt et al. 2002, patients with bulky nodal disease prior to therapy and/or suboptimal response to induction chemotherapy: Neck dissection, performed 4 weeks after cycle 3 day 1, then adjuvant RT
**Hitt et al. 2002, patients with PR/CR: Definitive paclitaxel & RT or definitive RT alone was used if concomitant treatment was not feasible.
*Hitt et al. 2005: Patients then undergo ENT evaluation and CT imaging of the primary tumor and neck. 
**Hitt et al. 2005, patients with CR or PR of greater than 80% in the primary tumor and no evidence of progression in neck lymph nodes: Definitive cisplatin & RT
**Hitt et al. 2005, patients with a PR of less than 80% or SD in the neck lymph nodes (especially if N2 or N3 disease) after induction CT: Neck dissection, "if the surgeons were in agreement, before the administration of CRT." 
===References===
# Hitt R, Paz-Ares L, Brandáriz A, Castellano D, Peña C, Millán JM, Calvo F, Ortiz de Urbina D, López E, Alvarez-Vicent JJ, Cortés-Funes H. Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: long-term results of a phase II trial. Ann Oncol. 2002 Oct;13(10):1665-73. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Hitt R, López-Pousa A, Martínez-Trufero J, Escrig V, Carles J, Rizo A, Isla D, Vega ME, Martí JL, Lobo F, Pastor P, Valentí V, Belón J, Sánchez MA, Chaib C, Pallarés C, Antón A, Cervantes A, Paz-Ares L, Cortés-Funes H. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol. 2005 Dec 1;23(34):8636-45. Epub 2005 Nov 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==DCF==
DCF: Docetaxel, Cisplatin, Fluorouracil
TPF: Taxotere (Docetaxel), Platinol (Cisplatin), Fluorouracil 
===Regimen variant #1, 75/75/3750 x 2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Zhong et al. 2012 (2007BAI18B03)	2008-2010 	Phase 3 (E-esc)	No induction	Did not meet primary endpoint of OS
Noronha et al. 2024 	2016-09-19 to 2019-09-25	Phase 3 (C) 	TP 	Longer OS (primary endpoint)OS60: 23.9% vs 18.5%(HR 0.78, 95% CI 0.64-0.95)
Note: this was an experimental arm that did not meet its primary endpoint; included here because it was eventually used to establish this regimen as a standard comparator.
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given first
*Cisplatin (Platinol) 75 mg/m2 IV over 60 minutes once on day 1, given second
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1, given third (total dose per cycle: 3750 mg/m2)
21-day cycle for 2 cycles 
====Subsequent treatment====
*Surgery, then adjuvant RT
===Regimen variant #2, 75/75/3750 x 3===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pointreau et al. 2009 (GORTEC 2000-01)	2000-2005 	Phase 3 (E-esc) 	CF 	Higher ORR (secondary endpoint)Seems to have higher 3-year larynx preservation rate (primary endpoint)
Hitt et al. 2013 (TTCC 2503) 	2002-2007 	Phase 2/3 (E-esc) 	1. No induction2. PF	Did not meet co-primary endpoints of PFS/TTF
Lefebvre et al. 2013 (TREMPLIN) 	2006-2008 	Non-randomized part of phase 2 RCT	 	
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 3750 mg/m2)
====Supportive therapy====
*"Hydration was delivered according to institutional protocols."
*Dexamethasone (Decadron) 8 mg PO twice per day the day before, the day of, and day after docetaxel
*Ciprofloxacin (Cipro) 500 mg PO twice per day on days 5 to 15
*Prophylactic granulocyte colony-stimulating factor was not used. 
**G-CSF (type not specified) 150 mcg/m2 SC once per day was used if febrile neutropenia occurred.
*5-HT3 antagonists given twice, before and after cisplatin
21-day cycle for 3 cycles 
====Subsequent treatment====
*GORTEC 2000-01, patients who responded to induction chemotherapy: Definitive RT within 3 to 7 weeks of finishing chemotherapy
*GORTEC 2000-01, patients who did not respond to induction chemotherapy: Surgery, then adjuvant RT (see Pointreau et al. 2009 for details)
*TREMPLIN: Restaging of disease takes place 2 weeks after finishing cycle 3. 
**TREMPLIN, patients with at least 50% regression of their primary tumor volume and who recovered larynx mobility: Definitive cetuximab & RT versus cisplatin & RT
**TREMPLIN, patients who did not have at least 50% regression: Salvage total laryngectomy
*TTCC 2503: Definitive cisplatin & RT
===Regimen variant #3, 75/75/3750 x 4===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Vermorken et al. 2007 (TAX 323)	1999-2002 	Phase 3 (E-RT-esc)	CF 	Longer PFS (primary endpoint)Median PFS: 11 vs 8.2 mo(HR 0.72, 95% CI 0.57-0.91)Longer OS (secondary endpoint)Median OS: 18.8 vs 14.5 mo(HR 0.73, 95% CI 0.56-0.94)
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given first
*Cisplatin (Platinol) 75 mg/m2 IV over 60 minutes once on day 1, given second
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1, given third (total dose per cycle: 3750 mg/m2)
====Supportive therapy====
*Dexamethasone (Decadron) 8 mg PO for 6 doses (exact schedule not specified) starting the night prior to docetaxel 
*Ciprofloxacin (Cipro) 500 mg PO twice per day "or an alternative agent" on days 5 to 15
*"Adequate antiemetic medications during chemotherapy"
*Prophylactic granulocyte colony-stimulating factor only allowed for patients who had "febrile neutropenia or infection, a delay in recovery of the absolute neutrophil count at day 28, or grade 4 neutropenia persisting for 7 days or more."
21-day cycle for 4 cycles
====Subsequent treatment====
*TAX 323, patients without progressive disease and who had recovery of marrow function, resolution of mucositis, and healed from any dental procedures: Definitive RT within 4 to 7 weeks of finishing chemotherapy
===Regimen variant #4, 75/80/3200===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ghi et al. 2017 (GSTTC H&N07)	2008-2012 	Phase 2/3 (E-esc)	No induction	Seems to have longer OS (primary endpoint)Median OS: 54.7 vs 31.7 mo(HR 0.74, 95% CI 0.55-0.98)
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
*Cisplatin (Platinol) 80 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3200 mg/m2)
21-day cycle for 3 cycles
====Subsequent treatment====
*Definitive cetuximab & RT or cisplatin, 5-FU, RT
===Regimen variant #5, 75/100/4000 x 2===
Study 	Dates of enrollment 	Evidence
Adelstein et al. 2010 (SWOG S0216)	2003-03-01 to 2004-08-15	Phase 2
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
*Cisplatin (Platinol) 100 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Supportive therapy====
*Ciprofloxacin (Cipro) prophylaxis for 10 days (dose/route/precise schedule not specified)
*"Standard anti-emetics, hydration and diuresis"
21-day cycle for 2 cycles 
====Subsequent treatment====
*Restaging of disease takes place 3 weeks after finishing cycle 2. 
**SWOG S0216, patients with SD or tumors which responded to therapy: Definitive cisplatin & RT
**SWOG S0216, patients with progressive disease: considered--if possible--for surgery, then adjuvant RT. Patients who could not undergo surgery also received cisplatin & RT
===Regimen variant #6, 75/100/4000 x 3===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Posner et al. 2007 (TAX 324)	1999-2003 	Phase 3 (E-RT-esc)	CF 	Longer OS1 (primary endpoint)OS60: 52% vs 42%(HR 0.74, 95% CI 0.58-0.94)
1Reported efficacy is based on the 2011 update.
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given first
*Cisplatin (Platinol) 100 mg/m2 IV over 30 to 180 minutes once on day 1, given second
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1, given third (total dose per cycle: 4000 mg/m2) 
====Supportive therapy====
*Dexamethasone (Decadron) used (dose, route, schedule not specified) to prevent Docetaxel (Taxotere)-related side effects
*Prophylactic antibiotics (further details not given) on days 5 to 14
*Prophylactic granulocyte colony-stimulating factor not allowed
21-day cycle for 3 cycles
====Subsequent treatment====
*Definitive carboplatin & RT, 3 to 8 weeks after the start of cycle 3
===References===
# TAX 323: Vermorken JB, Remenar E, van Herpen C, Gorlia T, Mesia R, Degardin M, Stewart JS, Jelic S, Betka J, Preiss JH, van den Weyngaert D, Awada A, Cupissol D, Kienzer HR, Rey A, Desaunois I, Bernier J, Lefebvre JL; EORTC; TAX 323 Study Group. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007 Oct 25;357(17):1695-704. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003888
## HRQoL analysis: van Herpen CM, Mauer ME, Mesia R, Degardin M, Jelic S, Coens C, Betka J, Bernier J, Remenar E, Stewart JS, Preiss JH, van den Weyngaert D, Bottomley A, Vermorken JB; EORTC Head and Neck Group. Short-term health-related quality of life and symptom control with docetaxel, cisplatin, 5-fluorouracil and cisplatin (TPF), 5-fluorouracil (PF) for induction in unresectable locoregionally advanced head and neck cancer patients (EORTC 24971/TAX 323). Br J Cancer. 2010 Oct 12;103(8):1173-81. Epub 2010 Sep 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# TAX 324: Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, Tjulandin S, Shin DM, Cullen K, Ervin TJ, Murphy BA, Raez LE, Cohen RB, Spaulding M, Tishler RB, Roth B, Viroglio Rdel C, Venkatesan V, Romanov I, Agarwala S, Harter KW, Dugan M, Cmelak A, Markoe AM, Read PW, Steinbrenner L, Colevas AD, Norris CM Jr, Haddad RI; TAX 324 Study Group. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007 Oct 25;357(17):1705-15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00273546
## Update: Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, Tan M, Fasciano J, Sammartino DE, Posner MR; TAX 324 Study Group. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol. 2011 Feb;12(2):153-9. Epub 2011 Jan 11. link to original article link to PMC article EuroPMC
# GORTEC 2000-01: Pointreau Y, Garaud P, Chapet S, Sire C, Tuchais C, Tortochaux J, Faivre S, Guerrif S, Alfonsi M, Calais G. Randomized trial of induction chemotherapy with cisplatin and 5-fluorouracil with or without docetaxel for larynx preservation. J Natl Cancer Inst. 2009 Apr 1;101(7):498-506. Epub 2009 Mar 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00169182
## Update: Janoray G, Pointreau Y, Garaud P, Chapet S, Alfonsi M, Sire C, Jadaud E, Calais G. Long-term results of a multicenter randomized phase III trial of induction chemotherapy with cisplatin, 5-fluorouracil, ± docetaxel for larynx preservation. J Natl Cancer Inst. 2015 Dec 16;108(4). link to original article EuroPMC content property of HemOnc.org
# SWOG S0216: Adelstein DJ, Moon J, Hanna E, Giri PG, Mills GM, Wolf GT, Urba SG. Docetaxel, cisplatin, and fluorouracil induction chemotherapy followed by accelerated fractionation/concomitant boost radiation and concurrent cisplatin in patients with advanced squamous cell head and neck cancer: A Southwest Oncology Group phase II trial (S0216). Head Neck. 2010 Feb;32(2):221-8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00054054
# TREMPLIN: Lefebvre JL, Pointreau Y, Rolland F, Alfonsi M, Baudoux A, Sire C, de Raucourt D, Malard O, Degardin M, Tuchais C, Blot E, Rives M, Reyt E, Tourani JM, Geoffrois L, Peyrade F, Guichard F, Chevalier D, Babin E, Lang P, Janot F, Calais G, Garaud P, Bardet E. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol. 2013 Mar 1;31(7):853-9. Epub 2013 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00169247
# PARADIGM: Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, Clark J, Sarlis N, Lorch J, Beitler JJ, Limaye S, Riley S, Posner M. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013 Mar;14(3):257-64. Epub 2013 Feb 13. link to original article EuroPMC NCT00095875
# 2007BAI18B03: Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr, Sun J, Zhu HG, Tu WY, Li J, Cai YL, Wang LZ, Fan XD, Wang ZH, Hu YJ, Ji T, Yang WJ, Ye WM, Li J, He Y, Wang YA, Xu LQ, Wang BS, Kies MS, Lee JJ, Myers JN, Zhang ZY. Randomized phase III trial of induction chemotherapy with docetaxel, cisplatin, and fluorouracil followed by surgery versus up-front surgery in locally advanced resectable oral squamous cell carcinoma. J Clin Oncol. 2013 Feb 20;31(6):744-51. Epub 2012 Nov 5. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01542931
## Update: Zhong LP, Zhang CP, Ren GX, Guo W, William WN Jr, Hong CS, Sun J, Zhu HG, Tu WY, Li J, Cai YL, Yin QM, Wang LZ, Wang ZH, Hu YJ, Ji T, Yang WJ, Ye WM, Li J, He Y, Wang YA, Xu LQ, Zhuang Z, Lee JJ, Myers JN, Zhang ZY. Long-term results of a randomized phase III trial of TPF induction chemotherapy followed by surgery and radiation in locally advanced oral squamous cell carcinoma. Oncotarget. 2015 Jul 30;6(21):18707-14. link to original article link to PMC article EuroPMC
# TTCC 2503: Hitt R, Grau JJ, López-Pousa A, Berrocal A, García-Girón C, Irigoyen A, Sastre J, Martínez-Trufero J, Brandariz Castelo JA, Verger E, Cruz-Hernández JJ; Spanish Head and Neck Cancer Cooperative Group. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol. 2014 Jan;25(1):216-25. Epub 2013 Nov 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00261703
##Update: Hitt R, Iglesias L, López-Pousa A, Berrocal-Jaime A, Grau JJ, García-Girón C, Martínez-Trufero J, Guix M, Lambea-Sorrosal J, Del Barco-Morillo E, León-Vintró X, Cunquero-Tomas AJ, Baste N, Ocaña A, Cruz-Hernández JJ; the Spanish Head and Neck Cancer Cooperative Group (TTCC). Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial. Clin Transl Oncol. 2021 Apr;23(4):764-772. Epub 2020 Aug 14. link to original article EuroPMC
# GSTTC H&N07: Ghi MG, Paccagnella A, Ferrari D, Foa P, Alterio D, Codecà C, Nolè F, Verri E, Orecchia R, Morelli F, Parisi S, Mastromauro C, Mione CA, Rossetto C, Polsinelli M, Koussis H, Loreggian L, Bonetti A, Campostrini F, Azzarello G, D'Ambrosio C, Bertoni F, Casanova C, Emiliani E, Guaraldi M, Bunkheila F, Bidoli P, Niespolo RM, Gava A, Massa E, Frattegiani A, Valduga F, Pieri G, Cipani T, Da Corte D, Chiappa F, Rulli E; GSTTC. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer: a phase II-III trial. Ann Oncol. 2017 Sep 1;28(9):2206-2212. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01086826
#Noronha V, Patil V, Chaturvedi P, Mathrudev V, Menon N, Bhattacharjee A, Singh A, Peelay Z, Chakraborty S, Jadhav M, Alone M, Bhagyavant P, Kolkur M, Srinivas S, Das S, Roy S, Mandal T, Dsouza H, Saha S, Rai R, Srikanth A, Shah D, Khan A, Muthuluri H, Kumar A, Agarwal A, Rajpurohit A, Goli VB, Sekar A, Mantri A, Kanteti APK, Majumdar S, Khaddar S, Shenoy R, Elamarthi P, Rathnasamy N, Kashyap L, Abraham G, Booma N, Simha V, Chaukar D, Pai P, Nair S, Laskar S, Nawale K, Naidu P, Salian S, Shelar P, Raulo R, Dhumal SB, Prabhash K. Phase 3 RCT comparing docetaxel-platinum with docetaxel-platinum-5FU as neoadjuvant chemotherapy in borderline resectable oral cancer. Eur J Cancer. 2024 Mar;200:113560. Epub 2024 Jan 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2016/04/006804
=Locally advanced disease, definitive therapy=
==Carboplatin & RT==
Carboplatin & RT: Carboplatin & Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence
Posner et al. 2007 (TAX 324)	1999-2003 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*CF versus TPF induction
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 1.5 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions x 35 to 37 fractions (total dose: 7000 to 7400 cGy), given 5 times per week over 7 to 7.5 weeks 
7- to 7.5-week course 
====Subsequent treatment====
*TAX 324, patients who had an initial nodal stage of N2 and a partial response to induction chemotherapy, N3 disease, or residual disease after chemoradiotherapy: Surgery, 6 to 12 weeks after completion of chemoradiotherapy
===References===
# TAX 324: Posner MR, Hershock DM, Blajman CR, Mickiewicz E, Winquist E, Gorbounova V, Tjulandin S, Shin DM, Cullen K, Ervin TJ, Murphy BA, Raez LE, Cohen RB, Spaulding M, Tishler RB, Roth B, Viroglio Rdel C, Venkatesan V, Romanov I, Agarwala S, Harter KW, Dugan M, Cmelak A, Markoe AM, Read PW, Steinbrenner L, Colevas AD, Norris CM Jr, Haddad RI; TAX 324 Study Group. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med. 2007 Oct 25;357(17):1705-15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00273546
## Update: Lorch JH, Goloubeva O, Haddad RI, Cullen K, Sarlis N, Tishler R, Tan M, Fasciano J, Sammartino DE, Posner MR; TAX 324 Study Group. Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial. Lancet Oncol. 2011 Feb;12(2):153-9. Epub 2011 Jan 11. link to original article link to PMC article EuroPMC
==Carboplatin, Fluorouracil, RT==
Carboplatin, Fluorouracil, RT: Carboplatin, Fluorouracil, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Calais et al. 1999 (GORTEC 94-01) 	1994-1997 	Phase 3 (E-esc)	Radiation therapy 	Seems to have longer OS (primary endpoint)OS36: 51% vs 31%(HR not reported)
Staar et al. 2001 	1995-1999 	Phase 3 (E-esc)	Radiation therapy 	Seems to have higher SLC12 (primary endpoint)
Bourhis et al. 2012 (GORTEC 99-02) 	2000-2007 	Phase 3 (C) 	1. Carboplatin, 5-FU, RT; accelerated concurrent RT	Did not meet primary endpoint of PFS
Bourhis et al. 2012 (GORTEC 99-02) 	2000-2007 	Phase 3 (C) 	2. RT; very accelerated 	Seems to have longer PFS
Geoffrois et al. 2018 (GORTEC 2007-02)	2009-2013 	Phase 3 (C) 	TPF, then Cetuximab & RT 	Did not meet primary endpoint of PFS24
====Chemotherapy====
*Carboplatin (Paraplatin) 70 mg/m2 IV once per day on days 1 to 4, 22 to 26, 43 to 46
*Fluorouracil (5-FU) 600 mg/m2/day IV continuous infusion over 96 hours, started on days 1, 22, 43 (total dose: 7200 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy 200 cGy fractions x 35 fractions (total dose: 7000 cGy), given 5 days per week 
7-week course
===References===
# GORTEC 94-01: Calais G, Alfonsi M, Bardet E, Sire C, Germain T, Bergerot P, Rhein B, Tortochaux J, Oudinot P, Bertrand P. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst. 1999 Dec 15;91(24):2081-6. link to original article EuroPMC
## Update: Denis F, Garaud P, Bardet E, Alfonsi M, Sire C, Germain T, Bergerot P, Rhein B, Tortochaux J, Calais G. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol. 2004 Jan 1;22(1):69-76. Epub 2003 Dec 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Staar S, Rudat V, Stuetzer H, Dietz A, Volling P, Schroeder M, Flentje M, Eckel HE, Mueller RP. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1161-71. Erratum in: Int J Radiat Oncol Biol Phys 2001 Oct 1;51(2):569. link to original article EuroPMC
# GORTEC 99-02: Bourhis J, Sire C, Graff P, Grégoire V, Maingon P, Calais G, Gery B, Martin L, Alfonsi M, Desprez P, Pignon T, Bardet E, Rives M, Geoffrois L, Daly-Schveitzer N, Sen S, Tuchais C, Dupuis O, Guerif S, Lapeyre M, Favrel V, Hamoir M, Lusinchi A, Temam S, Pinna A, Tao YG, Blanchard P, Aupérin A. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol. 2012 Feb;13(2):145-53. Epub 2012 Jan 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00158652
# GORTEC 2007-02: Geoffrois L, Martin L, De Raucourt D, Sun XS, Tao Y, Maingon P, Buffet J, Pointreau Y, Sire C, Tuchais C, Babin E, Coutte A, Rolland F, Kaminsky MC, Alfonsi M, Lapeyre M, Saliou M, Lafond C, Jadaud E, Gery B, Zawadi A, Tourani JM, Khoury C, Henry AR, Hasbini A, Guichard F, Borel C, Meert N, Guillet P, Calais MH, Garaud P, Bourhis J. Induction chemotherapy followed by cetuximab radiotherapy is not superior to concurrent chemoradiotherapy for head and neck carcinomas: results of the GORTEC 2007-02 phase III randomized trial. J Clin Oncol. 2018 Nov 1;36(31):3077-83. Epub 2018 Jul 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01233843
==Carboplatin, Fluorouracil, Cetuximab, RT==
Carboplatin, Fluorouracil, Cetuximab, RT: Carboplatin, Fluorouracil, Cetuximab, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tao et al. 2018 (GORTEC 2007-01)	2008-01 to 2014-03 	Phase 3 (E-esc)	Cetuximab & RT	Longer PFS (primary endpoint)Median PFS: 37.9 vs 22.4 mo(HR 0.73, 95% CI 0.57-0.94)
====Chemotherapy====
*Carboplatin (Paraplatin) 70 mg/m2 IV once per day on days 1 to 4, 22 to 26, 43 to 47
*Fluorouracil (5-FU) 600 mg/m2/day IV continuous infusion over 96 hours, started on days 1, 22, 43 (total dose: 7200 mg/m2)
====Targeted therapy====
*Cetuximab (Erbitux) 400 mg/m2 IV once on day 7, then 250 mg/m2 IV once per day on days 14, 21, 28, 35, 42, 49
====Radiotherapy====
*Concurrent radiation therapy 200 cGy fractions x 35 fractions (total dose: 7000 cGy), given 5 days per week 
7-week course
===References===
# GORTEC 2007-01: Tao Y, Auperin A, Sire C, Martin L, Khoury C, Maingon P, Bardet E, Kaminsky MC, Lapeyre M, Chatellier T, Alfonsi M, Pointreau Y, Jadaud E, Géry B, Zawadi A, Tourani JM, Laguerre B, Coutte A, Racadot S, Hasbini A, Malaurie E, Borel C, Meert N, Cornely A, Ollivier N, Casiraghi O, Sun XS, Bourhis J. Improved outcome by adding concurrent chemotherapy to cetuximab and radiotherapy for locally advanced head and neck carcinomas: results of the GORTEC 2007-01 phase III randomized trial. J Clin Oncol. 2018 Nov 1;36(31):3084-90. Epub 2018 Jun 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00609284
==Carboplatin & Paclitaxel (CP) & RT==
CP & RT: Carboplatin, Paclitaxel, Radiation Therapy
===Regimen variant #1, accelerated hyperfractionated RT===
Study 	Dates of enrollment	Evidence
Carter et al. 2008	2000-02 to 2001-05 	Phase 2
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 1 IV once per day on days 1, 8, 15, 22, 29, 36
*Paclitaxel (Taxol) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
====Radiotherapy====
*Concurrent radiation therapy, 120 cGy twice per day fractions (total dose: 6960 cGy)
6-week course
===Regimen variant #2, standard RT===
Study 	Dates of enrollment 	Evidence
Conley et al. 1997 	Not reported in abstract	Pilot, fewer than 20 patients
Suntharalingam et al. 2000	1993-08 to 1998-11 	Phase 2
Note: According to the abstract of Conley et al. 1997, the initial paclitaxel dose was 45 mg/m2, but 40 mg/m2 was subsequently used. The full manuscript was not available for review.
====Chemotherapy====
*Carboplatin (Paraplatin) 100 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36, 43, 50, given prior to radiation therapy
*Paclitaxel (Taxol) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36, 43, 50, given prior to radiation therapy
====Supportive therapy====
*Dexamethasone (Decadron) 20 mg (route not specified) given twice per day once per day on days 1, 8, 15, 22, 29, 36, 43, 50, given 12 and 6 hours prior to chemotherapy
*Diphenhydramine (Benadryl) 50 mg IV once per day on days 1, 8, 15, 22, 29, 36, 43, 50, given prior to chemotherapy
*Ranitidine (Zantac) 50 mg IV once per day on days 1, 8, 15, 22, 29, 36, 43, 50, given prior to chemotherapy
*Granisetron 1 mg IV once per day on days 1, 8, 15, 22, 29, 36, 43, 50, given prior to chemotherapy
====Radiotherapy====
*Concurrent radiation therapy, 180 cGy fractions x 39 fractions (total dose: 7020 cGy), given 5 times per week (i.e., days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40, 43 to 47, 50 to 53)
7.5-week course
===References===
# Conley B, Jacobs M, Suntharalingam M, Zacharski D, Ord RA, Gray W, Aisner J. A pilot trial of paclitaxel, carboplatin, and concurrent radiotherapy for unresectable squamous cell carcinoma of the head and neck. Semin Oncol. 1997 Feb;24(1 Suppl 2):S2-78-S2-80. dosing details in abstract have been reviewed by our editors EuroPMC
# Suntharalingam M, Haas ML, Conley BA, Egorin MJ, Levy S, Sivasailam S, Herman JM, Jacobs MC, Gray WC, Ord RA, Aisner JA, Van Echo DA. The use of carboplatin and paclitaxel with daily radiotherapy in patients with locally advanced squamous cell carcinomas of the head and neck. Int J Radiat Oncol Biol Phys. 2000 Apr 1;47(1):49-56. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Carter DL, Asmar L, Barrera D, Caracandas J, Dakhil JS, McCracken D, O'Rourke MA, Rosenberg RK, Boehm KA, Ilegbodu D, Reid RL. Favorable survival observed after carboplatin, paclitaxel, and concurrent accelerated hyperfractionated radiotherapy for treatment of locally advanced head and neck carcinoma. Invest New Drugs. 2008 Oct;26(5):473-81. Epub 2008 May 13. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
==Cisplatin & Fluorouracil (CF) & RT==
CF & RT: Cisplatin, Fluorouracil, Radiation Therapy
===Regimen variant #1, 60/3000 x 2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Brizel et al. 1998	1990-1995 	Phase 3 (E-esc)	RT 	Might have longer OS (secondary endpoint)OS36: 55% vs 34%(HR not reported)
====Chemotherapy====
*Cisplatin (Platinol) 12 mg/m2 IV once per day on days 1 to 5, 36 to 40
*Fluorouracil (5-FU) 600 mg/m2/day IV continuous infusion over 120 hours, started on days 1 & 36 (total dose: 6000 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy 120 cGy fractions given twice per day, 5 times per week (total dose: 7500 cGy)
6-week course
===Regimen variant #2, 60/4000 x 7===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Taylor et al. 1994a	1986-1991 	Phase 3 (E-switch-ic)	CF, then RT	Higher ORR
====Chemotherapy====
*Cisplatin (Platinol) 60 mg/m2 IV over 15 minutes once on day 1
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions x 35 fractions (total dose: 7000 cGy), given 5 times per week on weeks 1, 3, 5, 7, 9, 11, 13
14-day cycle for 7 cycles
===Regimen variant #3, 75/4000 x 4===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Adelstein et al. 2003 (Head and Neck Intergroup)	1992-1999 	Phase 3 (E-esc)	1. Cisplatin & RT	Did not meet primary endpoint of OS
Adelstein et al. 2003 (Head and Neck Intergroup)	1992-1999 	Phase 3 (E-esc)	2. RT 	Did not meet primary endpoint of OS
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy as follows:
**Cycle 1: 200 cGy fractions once per day on days 1 to 5, 8 to 12, 15 to 19
**Cycle 3: 200 cGy fractions once per day on days 15 to 19, 22 to 26
**Cycle 4: 200 cGy fractions once per day on days 1 to 5
**Total fractions: 35
**Total dose: 6000 to 7000 cGy
28-day cycle for 4 cycles
===Regimen variant #4, 80/3200 x 2===
Study 	Dates of enrollment	Evidence
Ghi et al. 2017 (GSTTC H&N07)	2008-2012 	Non-randomized part of phase 2/3 RCT
====Preceding treatment====
*No induction versus TPF induction x 3
====Chemotherapy====
*Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 4, 36 to 40
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 96 hours, started on days 1 & 36 (total dose: 6400 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions once per day, 5 times per week (total dose: 7000 cGy)
7-week course
===Regimen variant #5, 80/4000 x 2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Adelstein et al. 1997 	1990-1995 	Phase 3 (E-esc) 	RT 	Seems to have longer RFSRFS36: 67% vs 52%(HR not reported)
Soo et al. 2005 (NMRC-SHN01)	1996-2002 	Phase 3 (E-switch-ooc)	Surgery, then RT	Did not meet primary endpoint of DFS36
====Chemotherapy====
*Cisplatin (Platinol) 20 mg/m2/day IV continuous infusion over 96 hours, started on days 1 & 22 (total dose: 160 mg/m2)
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on days 1 & 22 (total dose: 8000 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy, 6800 to 7200 cGy at 180 to 200 cGy per day
===Regimen variant #6, 100/1000 x 4, alternating with RT===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Merlano et al. 1992 	1987-1990 	Phase 3 (E-esc) 	RT 	Longer OS1Median OS: 17 vs 11 mo(HR 0.59, 95% CI 0.41-0.85)
Lefebvre et al. 2009 (EORTC 24954)	1996-2004 	Phase 3 (E-switch-ic)	Cisplatin & 5-FU, then RT	Did not meet primary endpoint of survival with a functional larynx
1Reported efficacy in Merlano et al. 1992 is based on the 1995 update.
====Chemotherapy====
*Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 5
*Fluorouracil (5-FU) 200 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 1000 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy during cycles 1 to 3: 200 cGy fractions x 30 fractions (total dose: 6000 cGy), given 5 times per week on days 8 to 12, 15 to 19
21-day cycle for 4 cycles
===Regimen variant #7, 100/3000 x 2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Fietkau et al. 2020 (PacCis)	2010-2015 	Phase 3 (C)	Cisplatin, Paclitaxel, RT	Did not meet primary endpoint of DFS36
====Chemotherapy====
*Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 5, 29 to 33
*Fluorouracil (5-FU) 600 mg/m2/day IV continuous infusion over 120 hours, started on days 1 & 29 (total dose: 6000 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy, 7060 cGy total
8-week course
===Regimen variant #8, 100/3750 x 1, then 100/2150 x 2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Bensadoun et al. 2006 (FNCLCC 96003)	1997-2002 	Phase 3 (E-esc)	RT 	Seems to have longer OSMedian OS: 16 vs 10 mo(HR not reported)
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1, 22, 43
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 120 hours, started on day 1, then 430 mg/m2/day IV continuous infusion over 120 hours, started on days 22 & 43 (total dose: 8050 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy, 120 cGy fractions given twice per day, 5 times per week (total dose: 8040 cGy for oropharynx; 7560 cGy for hypopharynx)
7-week course
===Regimen variant #9, 100/4000 x 1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy	Comparative Toxicity
Garden et al. 2004 (RTOG 97-03)	1997-1999 	Randomized Phase 2 (E-switch-ic)	1. Cisplatin, Paclitaxel, RT	 	Similar tolerance
Garden et al. 2004 (RTOG 97-03)	1997-1999 	Randomized Phase 2 (E-switch-ic)	2. 5-FU, Hydroxyurea, RT 	 	Similar tolerance
Note: this regimen is best described in the trial protocol, which is available directly from RTOG as a PDF. Treatment is assumed to start on a Monday.
====Chemotherapy====
*Cisplatin (Platinol) 10 mg/m2 IV over 60 minutes once per day on days 26 to 35
*Fluorouracil (5-FU) 400 mg/m2/day IV continuous infusion over 120 hours, started on days 36 & 42 (total dose: 4000 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions x 35 fractions (total dose: 7000 cGy) 
7-week course
===References===
# Merlano M, Vitale V, Rosso R, Benasso M, Corvò R, Cavallari M, Sanguineti G, Bacigalupo A, Badellino F, Margarino G, Brema F, Pastorino G, Marziano C, Grimaldi A, Scasso F, Sperati G, Pallestrini E, Garaventa G, Accomando E, Cordone G, Comella G, Daponte A, Rubagotti A, Bruzzi P, Santi L. Treatment of advanced squamous-cell carcinoma of the head and neck with alternating chemotherapy and radiotherapy. N Engl J Med. 1992 Oct 15;327(16):1115-21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Merlano M, Benasso M, Corvò R, Rosso R, Vitale V, Blengio F, Numico G, Margarino G, Bonelli L, Santi L. Five-year update of a randomized trial of alternating radiotherapy and chemotherapy compared with radiotherapy alone in treatment of unresectable squamous cell carcinoma of the head and neck. J Natl Cancer Inst. 1996 May 1;88(9):583-9. link to original article EuroPMC
# Taylor SG 4th, Murthy AK, Vannetzel JM, Colin P, Dray M, Caldarelli DD, Shott S, Vokes E, Showel JL, Hutchinson JC, Witt TR, Griem KL, Hartsell WF, Kies MS, Mittal B, Rebischung JL, Coupez DJ, Desphieux JL, Bobin S, LePajolec C. Randomized comparison of neoadjuvant cisplatin and fluorouracil infusion followed by radiation versus concomitant treatment in advanced head and neck cancer. J Clin Oncol. 1994 Feb;12(2):385-95. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Adelstein DJ, Saxton JP, Lavertu P, Tuason L, Wood BG, Wanamaker JR, Eliachar I, Strome M, Van Kirk MA. A phase III randomized trial comparing concurrent chemotherapy and radiotherapy with radiotherapy alone in resectable stage III and IV squamous cell head and neck cancer: preliminary results. Head Neck. 1997 Oct;19(7):567-75. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
## Update: Adelstein DJ, Lavertu P, Saxton JP, Secic M, Wood BG, Wanamaker JR, Eliachar I, Strome M, Larto MA. Mature results of a phase III randomized trial comparing concurrent chemoradiotherapy with radiation therapy alone in patients with stage III and IV squamous cell carcinoma of the head and neck. Cancer. 2000 Feb 15;88(4):876-83. link to original article EuroPMC
# Brizel DM, Albers ME, Fisher SR, Scher RL, Richtsmeier WJ, Hars V, George SL, Huang AT, Prosnitz LR. Hyperfractionated irradiation with or without concurrent chemotherapy for locally advanced head and neck cancer. N Engl J Med. 1998 Jun 18;338(25):1798-804. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Head and Neck Intergroup: Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, Schuller DE, Forastiere AA. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003 Jan 1;21(1):92-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# RTOG 97-03: Garden AS, Harris J, Vokes EE, Forastiere AA, Ridge JA, Jones C, Horwitz EM, Glisson BS, Nabell L, Cooper JS, Demas W, Gore E. Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized phase ii trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. J Clin Oncol. 2004 Jul 15;22(14):2856-64. link to original article link to protocol dosing details in supplement have been reviewed by our editors EuroPMC
# NMRC-SHN01: Soo KC, Tan EH, Wee J, Lim D, Tai BC, Khoo ML, Goh C, Leong SS, Tan T, Fong KW, Lu P, See A, Machin D. Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison. Br J Cancer. 2005 Aug 8;93(3):279-86. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT00003576
# FNCLCC 96003: Bensadoun RJ, Bénézery K, Dassonville O, Magné N, Poissonnet G, Ramaïoli A, Lemanski C, Bourdin S, Tortochaux J, Peyrade F, Marcy PY, Chamorey E, Vallicioni J, Seng H, Alzieu C, Géry B, Chauvel P, Schneider M, Santini J, Demard F, Calais G. French multicenter phase III randomized study testing concurrent twice-a-day radiotherapy and cisplatin/5-fluorouracil chemotherapy (BiRCF) in unresectable pharyngeal carcinoma: Results at 2 years (FNCLCC-GORTEC). Int J Radiat Oncol Biol Phys. 2006 Mar 15;64(4):983-94. Epub 2006 Jan 10. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00003627
# EORTC 24954: Lefebvre JL, Rolland F, Tesselaar M, Bardet E, Leemans CR, Geoffrois L, Hupperets P, Barzan L, de Raucourt D, Chevalier D, Licitra L, Lunghi F, Stupp R, Lacombe D, Bogaerts J, Horiot JC, Bernier J, Vermorken JB; EORTC Head and Neck Cancer Cooperative Group; EORTC Radiation Oncology Group. Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst. 2009 Feb 4;101(3):142-52. Epub 2009 Jan 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002839
##HRQoL analysis: Bottomley A, Tridello G, Coens C, Rolland F, Tesselaar ME, Leemans CR, Hupperets P, Licitra L, Vermorken JB, Van Den Weyngaert D, Truc G, Barillot I, Lefebvre JL. An international phase 3 trial in head and neck cancer: quality of life and symptom results: EORTC 24954 on behalf of the EORTC Head and Neck and the EORTC Radiation Oncology Group. Cancer. 2014 Feb 1;120(3):390-8. Epub 2013 Oct 25. link to original article EuroPMC
## Update: Henriques De Figueiredo B, Fortpied C, Menis J, Lefebvre JL, Barzan L, de Raucourt D, Geoffrois L, Giurgea L, Hupperets P, Leemans CR, Licitra L, Rolland F, Tesselaar M, Vermorken JB, Grégoire V; EORTC Head and Neck Cancer Cooperative Group; EORTC Radiation Oncology Group. Long-term update of the 24954 EORTC phase III trial on larynx preservation. Eur J Cancer. 2016 Sep;65:109-12. Epub 2016 Aug 2. link to original article EuroPMC
# GSTTC H&N07: Ghi MG, Paccagnella A, Ferrari D, Foa P, Alterio D, Codecà C, Nolè F, Verri E, Orecchia R, Morelli F, Parisi S, Mastromauro C, Mione CA, Rossetto C, Polsinelli M, Koussis H, Loreggian L, Bonetti A, Campostrini F, Azzarello G, D'Ambrosio C, Bertoni F, Casanova C, Emiliani E, Guaraldi M, Bunkheila F, Bidoli P, Niespolo RM, Gava A, Massa E, Frattegiani A, Valduga F, Pieri G, Cipani T, Da Corte D, Chiappa F, Rulli E; GSTTC. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer: a phase II-III trial. Ann Oncol. 2017 Sep 1;28(9):2206-2212. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01086826
# PacCis: Fietkau R, Hecht M, Hofner B, Lubgan D, Iro H, Gefeller O, Rödel C, Hautmann MG, Kölbl O, Salay A, Rübe C, Melchior P, Breinl P, Krings W, Gripp S, Wollenberg B, Keerl R, Schreck U, Siekmeyer B, Grabenbauer GG, Balermpas P; PacCis-Study Group. Randomized phase-III-trial of concurrent chemoradiation for locally advanced head and neck cancer comparing dose reduced radiotherapy with paclitaxel/cisplatin to standard radiotherapy with fluorouracil/cisplatin: The PacCis-trial. Radiother Oncol. 2020 Mar;144:209-217. Epub 2020 Feb 7. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01126216
==Cisplatin & RT==
Cisplatin & RT: Cisplatin & Radiation Therapy
===Regimen variant #1, 6 mg/m2 daily dosing===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Jeremic et al. 2000	1991-1993 	Phase 3 (E-esc)	RT 	Longer OS (primary endpoint)OS60: 46% vs 25%(HR not reported)
====Chemotherapy====
*Cisplatin (Platinol) 6 mg/m2 IV once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40, 43 to 47
====Radiotherapy====
*Concurrent radiation therapy, 110 cGy twice per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40, 43 to 47 (70 fractions, total dose: 7700 cGy)
7-week course
===Regimen variant #2, 20 mg/m2 weekly dosing===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Quon et al. 2011 (ECOG E2382)	1982-1987 	Phase 3 (E-esc)	RT 	Might have longer FFSMedian FFS: 7.2 vs 6.5 mo(HR not reported)
====Chemotherapy====
*Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36, 43
====Radiotherapy====
*Concurrent radiation therapy, 180 cGy fractions given 5 times per week (total dose: 7000 cGy)
7-week course
===Regimen variant #3, 30 mg/m2 weekly dosing===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ghosh-Laskar et al. 2014	2000-2007 	Phase 3 (E-esc)	1. RT; accelerated2. RT; standard	Seems to have higher LRC (primary endpoint)
Patil et al. 2019a 	2012-2018 	Phase 3 (C) 	Cisplatin, Nimotuzumab, RT 	Shorter PFSPFS24: 50.1% vs 61.8%(HR 1.45, 95% CI 1.12-1.89)
====Chemotherapy====
*Cisplatin (Platinol) 30 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36, 43
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions given 5 times per week (total dose: 6600 to 7000 cGy)
7-week course
===Regimen variant #4, 40 mg/m2 weekly dosing===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gebre-Medhin et al. 2020 (ARTSCAN III)	2013-2018 	Phase 3 (C)	Cetuximab & RT	Did not meet primary endpoint of OSOS36: 88% vs 78%(HR 0.61, 95% CI 0.35-1.08)
====Chemotherapy====
*Cisplatin (Platinol) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36, 43
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions to primary tumor and lymph node metastases (total dose: 6800 cGy) and 160 cGy fractions to elective neck volumes (total dose: 5440 cGy), given 5 times per week
7-week course
===Regimen variant #5, 100 mg/m2 q3wk x 2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Adelstein et al. 2010 (SWOG S0216)	2003-03-01 to 2004-08-15	Phase 2 	 	
Haddad et al. 2013 (PARADIGM) 	2004-2008 	Phase 3 (C)	TPF x 3, then Carboplatin & RT or Docetaxel & RT	Did not meet primary endpoint of OS
Ang et al. 2014 (RTOG 0522) 	2005-2009 	Phase 3 (C)	Cetuximab, Cisplatin, RT 	Did not meet primary endpoint of PFSPFS36: 61.2% vs 58.9%
====Preceding treatment====
*SWOG S0216: TPF induction
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1 & 22
====Radiotherapy====
*Concurrent radiation therapy by one of the following study-specific criteria:
**SWOG S0216: 180 cGy fractions x 30 fractions, given 5 times per week (total dose: 5400 cGy)
***The last 12 treatments involved a boost volume, 150 cGy fractions x 12 fractions (dose to boost volume: 1800 cGy)
**RTOG 0522, IMRT: 200 cGy fractions x 35 fractions (total dose: 7000 cGy), given 6 times per week over 6 weeks
**RTOG 0522 & PARADIGM: 42 fractions (total dose: 7200 cGy), given twice per day for 12 days then once per day for 6 weeks
6- to 7-week course
====Subsequent treatment====
*SWOG S0216: surgical resection was considered after concomitant chemoradiotherapy for those patients with histologically confirmed residual or recurrent disease at the primary site.
===Regimen variant #6, 100 mg/m2 q3wk x 3===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Adelstein et al. 2003 (Head and Neck Intergroup)	1992-1999 	Phase 3 (C) 	1. CF & RT 	Did not meet primary endpoint of OS
Adelstein et al. 2003 (Head and Neck Intergroup)	1992-1999 	Phase 3 (C) 	2. RT 	Seems to have longer OS
Forastiere et al. 2003 (RTOG 91-11) 	1992-2000 	Phase 3 (E-de-esc) 	See link 	See link
Fountzilas et al. 2004a 	1995-1999 	Phase 3 (E-esc) 	1. RT 	Longer OS (primary endpoint)Median OS: 48.6 vs 12.2 mo(aHR 0.25, 95% CI 0.13-0.48)
Fountzilas et al. 2004a 	1995-1999 	Phase 3 (E-esc) 	2. Carboplatin & RT 	Not reported
Hitt et al. 2005 	1998-2001 	Non-randomized part of phase 3 RCT 	 	
Rasch et al. 2010 	2000-2004 	Phase 3 (C) 	Cisplatin & RT; IA 	Did not meet primary endpoint of LRC
Rischin et al. 2010 (HeadSTART) 	2002-2005 	Phase 3 (C) 	Cisplatin, Tirapazamine, RT 	Did not meet primary endpoint of OS24
Nguyen-Tan et al. 2014 (RTOG 0129) 	2002-2005 	Phase 3 (C) 	Cisplatin & RT; hyperfractionated	Did not meet primary endpoint of OS
Hitt et al. 2013 (TTCC 2503) 	2002-2007 	Non-randomized part of phase 2/3 RCT	 	
Tao et al. 2020 (GORTEC 2004-01) 	2005-2015 	Phase 3 (C) 	Cisplatin & RT; dose-escalated 	Did not meet primary endpoint of LRP
Lefebvre et al. 2013 (TREMPLIN) 	2006-2008 	Randomized Phase 2 (C) 	Cetuximab & RT 	Did not meet primary endpoint of LP at 3 months
Siu et al. 2016 (CCTG HN.6) 	2008-2011 	Phase 3 (C) 	Panitumumab & RT 	Did not meet primary endpoint of PFSPFS24: 73% vs 76%
Hitt et al. 2013 (TTCC-2007-01) 	2008-07-15 to 2013-07-05	Phase 3 (C) 	Cetuximab & RT 	Inconclusive whether non-inferior OSMedian OS: 63.6 vs 42.9 mo(HR 0.90, 90% CI 0.72-1.12)
Merlano et al. 2020 (INTERCEPTOR) 	2009-2016 	Phase 3 (C) 	TPF, then Cetuximab & RT 	Did not meet primary endpoint of OS
Noronha et al. 2017 	2013-2017 	Phase 3 (C) 	Cisplatin & RT; weekly 	Seems to have higher LRC
Lee et al. 2021 (JAVELIN HEAD AND NECK 100) 	2016-2019 	Phase 3 (C) 	Cisplatin, Avelumab, RT 	Did not meet primary endpoint of PFS
Machiels et al. 2024 (KEYNOTE-412) 	2017-04-19 to 2019-05-02	Phase 3 (C) 	Cisplatin, Pembrolizumab, RT 	Might have shorter EFS (primary endpoint)Median EFS: 46.6 vs NYR mo(HR 1.20, 95% CI 0.97-1.47)
====Preceding treatment====
*Hitt et al. 2005: CF versus PCF induction
*TTCC 2503: CF versus TPF versus no induction
*TREMPLIN & TTCC-2007-01: TPF induction
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1, 22, 43
====Supportive therapy====
*Best described by Al-Sarraf et al. 1998
*Forced hydration: 5% dextrose in 1/2 normal saline with 40 mEq KCl, 2000 mL IV continuous infusion over 24 hours given twice, before each dose of cisplatin and after the second mannitol infusion
*Mannitol 12.5 g IV bolus once on day 1, prior to cisplatin
*5% dextrose in 1/2 normal saline with 30 mEq KCl and mannitol 25 g, 1000 mL IV over 4 hours on day 1, immediately after cisplatin
*Antiemetic such as:
**Prochlorperazine (Compazine) 25 mg rectal suppository once on day 1; 30 minutes prior to cisplatin
**Prochlorperazine (Compazine) 10 mg IM every 4 hours as needed for nausea after cisplatin
====Radiotherapy====
*Concurrent radiation therapy: 200 cGy fractions x 35 fractions (total dose: 7000 cGy), given 5 days per week
**Hitt et al. 2005: Nodal areas not involved by tumor received 5000 cGy.
7-week course
===References===
# Jeremic B, Shibamoto Y, Milicic B, Nikolic N, Dagovic A, Aleksandrovic J, Vaskovic Z, Tadic L. Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J Clin Oncol. 2000 Apr;18(7):1458-64. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Head and Neck Intergroup: Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, Schuller DE, Forastiere AA. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003 Jan 1;21(1):92-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# RTOG 91-11: Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, Glisson B, Trotti A, Ridge JA, Chao C, Peters G, Lee DJ, Leaf A, Ensley J, Cooper J. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003 Nov 27;349(22):2091-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002496
## Update: Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, Morrison W, Glisson B, Trotti A, Ridge JA, Thorstad W, Wagner H, Ensley JF, Cooper JS. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013 Mar 1;31(7):845-52. Epub 2012 Nov 26. link to original article contains partial protocol link to PMC article EuroPMC
# Fountzilas G, Ciuleanu E, Dafni U, Plataniotis G, Kalogera-Fountzila A, Samantas E, Athanassiou E, Tzitzikas J, Ciuleanu T, Nikolaou A, Pantelakos P, Zaraboukas T, Zamboglou N, Daniilidis J, Ghilezan N; Hellenic Cooperative Oncology Group. Concomitant radiochemotherapy vs radiotherapy alone in patients with head and neck cancer: a Hellenic Cooperative Oncology Group Phase III Study. Med Oncol. 2004;21(2):95-107. link to original article EuroPMC
# Hitt R, López-Pousa A, Martínez-Trufero J, Escrig V, Carles J, Rizo A, Isla D, Vega ME, Martí JL, Lobo F, Pastor P, Valentí V, Belón J, Sánchez MA, Chaib C, Pallarés C, Antón A, Cervantes A, Paz-Ares L, Cortés-Funes H. Phase III study comparing cisplatin plus fluorouracil to paclitaxel, cisplatin, and fluorouracil induction chemotherapy followed by chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol. 2005 Dec 1;23(34):8636-45. Epub 2005 Nov 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# SWOG S0216: Adelstein DJ, Moon J, Hanna E, Giri PG, Mills GM, Wolf GT, Urba SG. Docetaxel, cisplatin, and fluorouracil induction chemotherapy followed by accelerated fractionation/concomitant boost radiation and concurrent cisplatin in patients with advanced squamous cell head and neck cancer: A Southwest Oncology Group phase II trial (S0216). Head Neck. 2010 Feb;32(2):221-8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00054054
# Rasch CR, Hauptmann M, Schornagel J, Wijers O, Buter J, Gregor T, Wiggenraad R, de Boer JP, Ackerstaff AH, Kroger R, Hoebers FJ, Balm AJ, Hilgers FJ. Intra-arterial versus intravenous chemoradiation for advanced head and neck cancer: Results of a randomized phase 3 trial. Cancer. 2010 May 1;116(9):2159-65. Erratum in: Cancer. 2010 Aug 1;116(15):3750. Hilgers, Frans J [added]. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# HeadSTART: Rischin D, Peters LJ, O'Sullivan B, Giralt J, Fisher R, Yuen K, Trotti A, Bernier J, Bourhis J, Ringash J, Henke M, Kenny L; Trans-Tasman Radiation Oncology Group. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): a phase III trial of the Trans-Tasman Radiation Oncology Group. J Clin Oncol. 2010 Jun 20;28(18):2989-95. Epub 2010 May 17. Erratum in: J Clin Oncol. 2014 May 1;32(13):1386. link to original article EuroPMC NCT00094081
# ECOG E2382: Quon H, Leong T, Haselow R, Leipzig B, Cooper J, Forastiere A. Phase III study of radiation therapy with or without cis-platinum in patients with unresectable squamous or undifferentiated carcinoma of the head and neck: an intergroup trial of the Eastern Cooperative Oncology Group (E2382). Int J Radiat Oncol Biol Phys. 2011 Nov 1;81(3):719-25. Epub 2010 Oct 1. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
# TREMPLIN: Lefebvre JL, Pointreau Y, Rolland F, Alfonsi M, Baudoux A, Sire C, de Raucourt D, Malard O, Degardin M, Tuchais C, Blot E, Rives M, Reyt E, Tourani JM, Geoffrois L, Peyrade F, Guichard F, Chevalier D, Babin E, Lang P, Janot F, Calais G, Garaud P, Bardet E. Induction chemotherapy followed by either chemoradiotherapy or bioradiotherapy for larynx preservation: the TREMPLIN randomized phase II study. J Clin Oncol. 2013 Mar 1;31(7):853-9. Epub 2013 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00169247
# PARADIGM: Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, Clark J, Sarlis N, Lorch J, Beitler JJ, Limaye S, Riley S, Posner M. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013 Mar;14(3):257-64. Epub 2013 Feb 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00095875
# TTCC 2503: Hitt R, Grau JJ, López-Pousa A, Berrocal A, García-Girón C, Irigoyen A, Sastre J, Martínez-Trufero J, Brandariz Castelo JA, Verger E, Cruz-Hernández JJ; TTCC. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol. 2014 Jan;25(1):216-25. Epub 2013 Nov 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00261703
##Update: Hitt R, Iglesias L, López-Pousa A, Berrocal-Jaime A, Grau JJ, García-Girón C, Martínez-Trufero J, Guix M, Lambea-Sorrosal J, Del Barco-Morillo E, León-Vintró X, Cunquero-Tomas AJ, Baste N, Ocaña A, Cruz-Hernández JJ; the Spanish Head and Neck Cancer Cooperative Group (TTCC). Long-term outcomes of induction chemotherapy followed by chemoradiotherapy vs chemoradiotherapy alone as treatment of unresectable head and neck cancer: follow-up of the Spanish Head and Neck Cancer Group (TTCC) 2503 Trial. Clin Transl Oncol. 2021 Apr;23(4):764-772. Epub 2020 Aug 14. link to original article EuroPMC
# RTOG 0522: Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, Galvin JM, Bonner JA, Harris J, El-Naggar AK, Gillison ML, Jordan RC, Konski AA, Thorstad WL, Trotti A, Beitler JJ, Garden AS, Spanos WJ, Yom SS, Axelrod RS. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol. 2014 Sep 20;32(27):2940-50. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00265941
##Update: Caudell JJ, Torres-Saavedra PA, Rosenthal DI, Axelrod RS, Nguyen-Tan PF, Sherman EJ, Weber RS, Galvin JM, El-Naggar AK, Konski AA, Echevarria MI, Dunlap NE, Shenouda G, Singh AK, Beitler JJ, Garsa A, Bonner JA, Garden AS, Algan O, Harris J, Le QT. Long-Term Update of NRG/RTOG 0522: A Randomized Phase 3 Trial of Concurrent Radiation and Cisplatin With or Without Cetuximab in Locoregionally Advanced Head and Neck Cancer. Int J Radiat Oncol Biol Phys. 2023 Jul 1;116(3):533-543. Epub 2022 Dec 19. link to original article link to PMC article EuroPMC
# RTOG 0129: Nguyen-Tan PF, Zhang Q, Ang KK, Weber RS, Rosenthal DI, Soulieres D, Kim H, Silverman C, Raben A, Galloway TJ, Fortin A, Gore E, Westra WH, Chung CH, Jordan RC, Gillison ML, List M, Le QT. Randomized phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas in the Radiation Therapy Oncology Group 0129 trial: long-term report of efficacy and toxicity. J Clin Oncol. 2014 Dec 1;32(34):3858-66. Epub 2014 Nov 3. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00047008
# Ghosh-Laskar S, Kalyani N, Gupta T, Budrukkar A, Murthy V, Sengar M, Chaukar D, Pai P, Chaturvedi P, D'Cruz A, Agarwal J. Conventional radiotherapy versus concurrent chemoradiotherapy versus accelerated radiotherapy in locoregionally advanced carcinoma of head and neck: results of a prospective randomized trial. Head Neck. 2016 Feb;38(2):202-7. Epub 2014 Sep 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# CCTG HN.6: Siu LL, Waldron JN, Chen BE, Winquist E, Wright JR, Nabid A, Hay JH, Ringash J, Liu G, Johnson A, Shenouda G, Chasen M, Pearce A, Butler JB, Breen S, Chen EX, FitzGerald TJ, Childs TJ, Montenegro A, O'Sullivan B, Parulekar WR. Effect of standard radiotherapy with cisplatin vs accelerated radiotherapy with panitumumab in locoregionally advanced squamous cell head and neck carcinoma: a randomized clinical trial. JAMA Oncol. 2017 Feb;3(2):220-6. Epub 2016 Dec 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00820248
# Noronha V, Joshi A, Patil VM, Agarwal J, Ghosh-Laskar S, Budrukkar A, Murthy V, Gupta T, D'Cruz AK, Banavali S, Pai PS, Chaturvedi P, Chaukar D, Pande N, Chandrasekharan A, Talreja V, Vallathol DH, Mathrudev V, Manjrekar A, Maske K, Bhelekar AS, Nawale K, Kannan S, Gota V, Bhattacharjee A, Kane S, Juvekar SL, Prabhash K. Once-a-week versus once-every-3-weeks cisplatin chemoradiation for locally advanced head and neck cancer: a phase III randomized noninferiority trial. J Clin Oncol. 2018 Apr 10;36(11):1064-1072. Epub 2017 Dec 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2012/10/003062
##Update: Noronha V, Patil V, Menon N, Singh A, Shah M, Shetake A, Peelay Z, Mathrudev V, Nawale K, Shah S, Prabhash K. Long-Term Update of a Phase 3 Randomized Study Comparing Once-a-Week Versus Once-Every-3-Weeks Cisplatin Along With Radiation in Head and Neck Cancer. Int J Radiat Oncol Biol Phys. 2025 Jan 1;121(1):128-136. Epub 2024 Jul 27. link to original article EuroPMC
# Patil VM, Noronha V, Joshi A, Agarwal J, Ghosh-Laskar S, Budrukkar A, Murthy V, Gupta T, Mahimkar M, Juvekar S, Arya S, Mahajan A, Agarwal A, Purandare N, Rangarajan V, Balaji A, Chaudhari SV, Banavali S, Kannan S, Bhattacharjee A, D'Cruz AK, Chaturvedi P, Pai PS, Chaukar D, Pantvaidya G, Nair D, Nair S, Deshmukh A, Thiagarajan S, Mathrudev V, Manjrekar A, Dhumal S, Maske K, Bhelekar AS, Nawale K, Chandrasekharan A, Pande N, Goel A, Talreja V, Simha V, Srinivas S, Swami R, Vallathol DH, Dsouza H, Shrirangwar S, Turkar S, Abraham G, Thanky AH, Patel U, Pandey MK, Prabhash K. A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer. Cancer. 2019 Sep 15;125(18):3184-3197. Epub 2019 May 31. link to original article dosing details in abstract have been reviewed by our editors EuroPMC CTRI/2014/09/004980
##HRQoL analysis: Menon N, Patil V, Noronha V, Joshi A, Bhattacharjee A, Satam BJ, Mathrudev V, Ghosh Laskar S, Prabhash K. Quality of life in patients with locally advanced head and neck cancer treated with concurrent chemoradiation with cisplatin and nimotuzumab versus cisplatin alone - Additional data from a phase 3 trial. Oral Oncol. 2021 Nov;122:105517. Epub 2021 Sep 21. link to original article EuroPMC
# GORTEC 2004-01: Tao Y, Auperin A, Blanchard P, Alfonsi M, Sun XS, Rives M, Pointreau Y, Castelli J, Graff P, Wong Hee Kam S, Thariat J, Veresezan O, Heymann S, Renard-Oldrini S, Lafond C, Cornely A, Casiraghi O, Boisselier P, Lapeyre M, Biau J, Bourhis J. Concurrent cisplatin and dose escalation with intensity-modulated radiotherapy (IMRT) versus conventional radiotherapy for locally advanced head and neck squamous cell carcinomas (HNSCC): GORTEC 2004-01 randomized phase III trial. Radiother Oncol. 2020 Sep;150:18-25. Epub 2020 May 15. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00158678
# INTERCEPTOR: Merlano MC, Denaro N, Vecchio S, Licitra L, Curcio P, Benasso M, Bagicalupo A, Numico G, Russi E, Corvo' R, Bruzzi P; INTERCEPTOR trialists. Phase III Randomized Study of Induction Chemotherapy Followed by Definitive Radiotherapy + Cetuximab Versus Chemoradiotherapy in Squamous Cell Carcinoma of Head and Neck: The INTERCEPTOR-GONO Study. Oncology. 2020;98(11):763-770. Epub 2020 Jul 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00999700
# ARTSCAN III: Gebre-Medhin M, Brun E, Engström P, Haugen Cange H, Hammarstedt-Nordenvall L, Reizenstein J, Nyman J, Abel E, Friesland S, Sjödin H, Carlsson H, Söderkvist K, Thomasson M, Zackrisson B, Nilsson P. ARTSCAN III: A Randomized Phase III Study Comparing Chemoradiotherapy With Cisplatin Versus Cetuximab in Patients With Locoregionally Advanced Head and Neck Squamous Cell Cancer. J Clin Oncol. 2021 Jan 1;39(1):38-47. Epub 2020 Oct 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01969877
# JAVELIN HEAD AND NECK 100: Lee NY, Ferris RL, Psyrri A, Haddad RI, Tahara M, Bourhis J, Harrington K, Chang PM, Lin JC, Razaq MA, Teixeira MM, Lövey J, Chamois J, Rueda A, Hu C, Dunn LA, Dvorkin MV, De Beukelaer S, Pavlov D, Thurm H, Cohen E. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck: a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Oncol. 2021 Apr;22(4):450-462. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT02952586
# TTCC-2007-01: Hitt R, Mesía R, Lozano A, Iglesias Docampo L, Grau JJ, Taberna M, Rubió-Casadevall J, Martínez-Trufero J, Morillo EDB, García Girón C, Vázquez Estévez S, Cirauqui B, Cruz-Hernández JJ. Randomized phase 3 noninferiority trial of radiotherapy and cisplatin vs radiotherapy and cetuximab after docetaxel-cisplatin-fluorouracil induction chemotherapy in patients with locally advanced unresectable head and neck cancer. Oral Oncol. 2022 Nov;134:106087. Epub 2022 Sep 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00716391
# KEYNOTE-412: Machiels JP, Tao Y, Licitra L, Burtness B, Tahara M, Rischin D, Alves G, Lima IPF, Hughes BGM, Pointreau Y, Aksoy S, Laban S, Greil R, Burian M, Hetnał M, Delord JP, Mesía R, Taberna M, Waldron JN, Simon C, Grégoire V, Harrington KJ, Swaby RF, Zhang Y, Gumuscu B, Bidadi B, Siu LL; KEYNOTE-412 Investigators. Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2024 May;25(5):572-587. Epub 2024 Mar 29. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT03040999
# GORTEC 2017-01: NCT02999087
# OCAT: NCT00193843
==Cisplatin, Nimotuzumab, RT==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Patil et al. 2019a	2012-2018 	Phase 3 (E-esc)	Cisplatin & RT	Longer PFS (primary endpoint)PFS24: 61.8% vs 50.1%(HR 0.69, 95% CI 0.53-0.89)
====Chemotherapy====
*Cisplatin (Platinol) 30 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36, 43
====Targeted therapy====
*Nimotuzumab (Theraloc) 200 mg IV once per day on days 1, 8, 15, 22, 29, 36, 43
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions given 5 times per week (total dose: 6600 to 7000 cGy)
7-week course
===References===
# Patil VM, Noronha V, Joshi A, Agarwal J, Ghosh-Laskar S, Budrukkar A, Murthy V, Gupta T, Mahimkar M, Juvekar S, Arya S, Mahajan A, Agarwal A, Purandare N, Rangarajan V, Balaji A, Chaudhari SV, Banavali S, Kannan S, Bhattacharjee A, D'Cruz AK, Chaturvedi P, Pai PS, Chaukar D, Pantvaidya G, Nair D, Nair S, Deshmukh A, Thiagarajan S, Mathrudev V, Manjrekar A, Dhumal S, Maske K, Bhelekar AS, Nawale K, Chandrasekharan A, Pande N, Goel A, Talreja V, Simha V, Srinivas S, Swami R, Vallathol DH, Dsouza H, Shrirangwar S, Turkar S, Abraham G, Thanky AH, Patel U, Pandey MK, Prabhash K. A randomized phase 3 trial comparing nimotuzumab plus cisplatin chemoradiotherapy versus cisplatin chemoradiotherapy alone in locally advanced head and neck cancer. Cancer. 2019 Sep 15;125(18):3184-3197. Epub 2019 May 31. link to original article dosing details in abstract have been reviewed by our editors EuroPMC CTRI/2014/09/004980
##HRQoL analysis: Menon N, Patil V, Noronha V, Joshi A, Bhattacharjee A, Satam BJ, Mathrudev V, Ghosh Laskar S, Prabhash K. Quality of life in patients with locally advanced head and neck cancer treated with concurrent chemoradiation with cisplatin and nimotuzumab versus cisplatin alone - Additional data from a phase 3 trial. Oral Oncol. 2021 Nov;122:105517. Epub 2021 Sep 21. link to original article EuroPMC
==Cisplatin & Paclitaxel (TP) & RT==
CP & RT: Cisplatin, Paclitaxel, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy	Comparative Toxicity
Garden et al. 2004 (RTOG 97-03)	1997-1999 	Randomized Phase 2 (E-switch-ic)	1. CF & RT 	 	Similar tolerance
Garden et al. 2004 (RTOG 97-03)	1997-1999 	Randomized Phase 2 (E-switch-ic)	2. 5-FU, Hydroxyurea, RT	 	Similar tolerance
====Chemotherapy====
*Cisplatin (Platinol) 20 mg/m2 IV once per day on days 2, 9, 16, 23, 30, 37, 44, given prior to radiation
*Paclitaxel (Taxol) 30 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36, 43, given prior to radiation
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions x 35 fractions (total dose: 7000 cGy), given 5 days per week
7-week course
===References===
# RTOG 97-03: Garden AS, Harris J, Vokes EE, Forastiere AA, Ridge JA, Jones C, Horwitz EM, Glisson BS, Nabell L, Cooper JS, Demas W, Gore E. Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized phase ii trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. J Clin Oncol. 2004 Jul 15;22(14):2856-64. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Docetaxel, Fluorouracil, Hydroxyurea, RT==
DFHX: Docetaxel, Fluorouracil, Hydroxyurea, XRT (Radiation therapy)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Brockstein et al. 2000 	1995-1997 	Phase 1/2 	 	
Cohen et al. 2014 (DeCIDE)	2004-2009 	Phase 3 (C)	TPF, then DFHX	Did not meet primary endpoint of OS
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm. Regimen details are from ClinicalTrials.gov
====Chemotherapy====
*Docetaxel (Taxotere) 25 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2/day IV continuous infusion over 120 hours, started on day 0 (total dose per cycle: 3000 mg/m2)
*Hydroxyurea (Hydrea) 500 mg PO twice per day on days 1 to 6 (11 doses per cycle)
====Radiotherapy====
*Concurrent radiation therapy 150 cGy twice per day on days 1 to 5
14-day cycle for 5 cycles
===References===
# Brockstein B, Haraf DJ, Stenson K, Sulzen L, Witt ME, Weichselbaum RW, Vokes EE. A phase I-II study of concomitant chemoradiotherapy with paclitaxel (one-hour infusion), 5-fluorouracil and hydroxyurea with granulocyte colony stimulating factor support for patients with poor prognosis head and neck cancer. Ann Oncol. 2000 Jun;11(6):721-8. link to original article EuroPMC
# DeCIDE: Cohen EE, Karrison TG, Kocherginsky M, Mueller J, Egan R, Huang CH, Brockstein BE, Agulnik MB, Mittal BB, Yunus F, Samant S, Raez LE, Mehra R, Kumar P, Ondrey F, Marchand P, Braegas B, Seiwert TY, Villaflor VM, Haraf DJ, Vokes EE. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol. 2014 Sep 1;32(25):2735-43. Epub 2014 Jul 21. link to original article link to PMC article does not contain dosing details EuroPMC NCT00117572
==Docetaxel & RT==
Docetaxel & RT: Docetaxel & Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Patil et al. 2023a	2017-07 to 2021-05 	Phase 2/3 (E-esc)	RT 	Seems to have longer OS (secondary endpoint)Median OS: 25.5 vs 15.3 mo(HR 0.75, 95% CI 0.57-0.98)Higher DFS24 (primary endpoint)DFS24: 42% vs 30.3%(HR 0.67, 95% CI 0.52-0.87)
====Eligibility criteria====
*Cisplatin-ineligible
====Chemotherapy====
*Docetaxel (Taxotere) 15 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
====Radiotherapy====
*Concurrent radiation therapy 200 cGy once per day on days 1 to 5, 8 to 12, 15 to 19, 22 to 26, 29 to 33, 36 to 40, 43 to 47 (7000 cGy total in 35 fractions)
7-week course
===References===
# Patil VM, Noronha V, Menon N, Singh A, Ghosh-Laskar S, Budrukkar A, Bhattacharjee A, Swain M, Mathrudev V, Nawale K, Balaji A, Peelay Z, Alone M, Pathak S, Mahajan A, Kumar S, Purandare N, Agarwal A, Puranik A, Pendse S, Reddy Yallala M, Sahu H, Kapu V, Dey S, Choudhary J, Krishna MR, Shetty A, Karuvandan N, Ravind R, Rai R, Jobanputra K, Chaturvedi P, Pai PS, Chaukar D, Nair S, Thiagarajan S, Prabhash K. Results of Phase III Randomized Trial for Use of Docetaxel as a Radiosensitizer in Patients With Head and Neck Cancer, Unsuitable for Cisplatin-Based Chemoradiation. J Clin Oncol. 2023 May 1;41(13):2350-2361. Epub 2023 Jan 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2017/05/008700
==Fluorouracil, Hydroxyurea, RT==
Fluorouracil, Hydroxyurea, RT: Fluorouracil, Hydroxyurea, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy	Comparative Toxicity
Garden et al. 2004 (RTOG 97-03)	1997-1999 	Randomized Phase 2 (E-switch-ic)	1. CF & RT 	 	Similar tolerance
Garden et al. 2004 (RTOG 97-03)	1997-1999 	Randomized Phase 2 (E-switch-ic)	2. Cisplatin, Paclitaxel, RT	 	Similar tolerance
Note: treatment was intended to start on a Monday.
====Chemotherapy====
*Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
**Garden et al. 2004 was not clear about the exact schedule nor duration of the continuous infusion
*Hydroxyurea (Hydrea) 1000 mg PO every 12 hours on days 1 to 6 (total of 11 doses per cycle)
**Garden et al. 2004 did not clearly specify when the doses of hydroxyurea were to be taken in relation to radiation treatments
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions x 35 fractions (total dose: 7000 cGy), given 5 times per week on weeks 1, 3, 5, 7, 9, 11, 13
14-day cycle for 7 cycles
===References===
# RTOG 97-03: Garden AS, Harris J, Vokes EE, Forastiere AA, Ridge JA, Jones C, Horwitz EM, Glisson BS, Nabell L, Cooper JS, Demas W, Gore E. Preliminary results of Radiation Therapy Oncology Group 97-03: a randomized phase ii trial of concurrent radiation and chemotherapy for advanced squamous cell carcinomas of the head and neck. J Clin Oncol. 2004 Jul 15;22(14):2856-64. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Fluorouracil, Mitomycin, RT==
Fluorouracil, Mitomycin, RT: Fluorouracil, Mitomycin, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Budach et al. 2005 (ARO 95-06)	1995-1999 	Phase 3 (E-esc)	RT 	Seems to have longer OS (secondary endpoint)Median OS: 23 vs 16 mo(HR 0.71, 95% CI 0.52-0.96)Longer LRC (primary endpoint)Median LRC: 48 vs 15 mo(HR 0.48, 95% CI 0.33-0.71)
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose: 3000 mg/m2)
*Mitomycin (Mutamycin) 10 mg/m2 IV once per day on days 5 & 36
====Radiotherapy====
*Concurrent radiation therapy, hyperfractionated to total dose 7060 cGy
6-week course
===References===
# ARO 95-06: Budach V, Stuschke M, Budach W, Baumann M, Geismar D, Grabenbauer G, Lammert I, Jahnke K, Stueben G, Herrmann T, Bamberg M, Wust P, Hinkelbein W, Wernecke KD. Hyperfractionated accelerated chemoradiation with concurrent fluorouracil-mitomycin is more effective than dose-escalated hyperfractionated accelerated radiation therapy alone in locally advanced head and neck cancer: final results of the radiotherapy cooperative clinical trials group of the German Cancer Society 95-06 prospective randomized trial. J Clin Oncol. 2005 Feb 20;23(6):1125-35. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Budach V, Stromberger C, Poettgen C, Baumann M, Budach W, Grabenbauer G, Marnitz S, Olze H, Wernecke KD, Ghadjar P. Hyperfractionated accelerated radiation therapy (HART) of 7060 cGy with concurrent 5-FU/Mitomycin C is superior to HART of 7760 cGy alone in locally advanced head and neck cancer: long-term results of the ARO 95-06 randomized phase III trial. Int J Radiat Oncol Biol Phys. 2015 Apr 1;91(5):916-24. Epub 2015 Feb 7. link to original article EuroPMC
==Fluorouracil & RT==
5-FU & RT: 5-FluoroUracil & Radiation Therapy
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Gollin et al. 1972 	1961 to not reported	Phase 3 (E-esc)	RT 	Seems to have longer OS1
Sanchíz et al. 1990	1978-1988 	Phase 3 (E-esc)	1. RT; conventional	Longer OS
Sanchíz et al. 1990	1978-1988 	Phase 3 (E-esc)	2. RT; twice-daily 	Did not meet co-primary endpoints of RFI/OS
Browman et al. 1994	1987-1991 	Phase 3 (E-esc)	RT 	Might have longer OSMedian OS: 33 vs 25 mo(HR not reported)
1Reported efficacy for Gollin et al. 1972 is based on the 1976 update, for oral lesions only.
====Chemotherapy====
*Fluorouracil (5-FU) 1200 mg/m2/day IV continuous infusion over 72 hours, started on days 1 & 15 (total dose: 7200 mg/m2)
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy x 33 fractions, given 5 days per week (total dose: 6600 cGy)
6.5-week course
===References===
# Gollin FF, Ansfield FJ, Brandenburg JH, Ramirez G, Vermund H. Combined therapy in advanced head and neck cancer: a randomized study. Am J Roentgenol Radium Ther Nucl Med. 1972 Jan;114(1):83-8. link to original article EuroPMC
## Update: Lo TC, Wiley AL Jr, Ansfield FJ, Brandenburg JH, Davis HL Jr, Gollin FF, Johnson RO, Ramirez G, Vermund H. Combined radiation therapy and 5-fluorouracil for advanced squamous cell carcinoma of the oral cavity and oropharynx: a randomized study. AJR Am J Roentgenol. 1976 Feb;126(2):229-35. link to original article EuroPMC
# Sanchíz F, Millá A, Torner J, Bonet F, Artola N, Carreño L, Moya LM, Riera D, Ripol S, Cirera L. Single fraction per day versus two fractions per day versus radiochemotherapy in the treatment of head and neck cancer. Int J Radiat Oncol Biol Phys. 1990 Dec;19(6):1347-50. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Browman GP, Cripps C, Hodson DI, Eapen L, Sathya J, Levine MN. Placebo-controlled randomized trial of infusional fluorouracil during standard radiotherapy in locally advanced head and neck cancer. J Clin Oncol. 1994 Dec;12(12):2648-53. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Paclitaxel & RT==
Paclitaxel & RT: Paclitaxel & Radiation Therapy
===Regimen===
Study 	Evidence
Hitt et al. 2002	Phase 2
Chemoradiotherapy starts 4 to 6 weeks after cycle 3 day 1 or as soon as patients recover from surgery (if any).
====Preceding treatment====
*Depending on response, PCF induction or surgery
====Chemotherapy====
*Paclitaxel (Taxol) 25 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, 42
====Supportive therapy====
*"Usual pre-medication was given before each paclitaxel infusion" (presumably the same ones used during PCF induction).
====Radiotherapy====
*Concurrent radiation therapy to primary unresected tumors, 1.8 to 200 cGy fractions (total dose: 65 to 7000 cGy). Post-operative areas received 6000 cGy. Nodal areas not involved by tumor received at least 4500 cGy.
7-week course
===References===
# Hitt R, Paz-Ares L, Brandáriz A, Castellano D, Peña C, Millán JM, Calvo F, Ortiz de Urbina D, López E, Alvarez-Vicent JJ, Cortés-Funes H. Induction chemotherapy with paclitaxel, cisplatin and 5-fluorouracil for squamous cell carcinoma of the head and neck: long-term results of a phase II trial. Ann Oncol. 2002 Oct;13(10):1665-73. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Adjuvant therapy=
==Cisplatin, Cetuximab, RT==
Cisplatin, Cetuximab, RT: Cisplatin, Cetuximab, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Harari et al. 2014 (RTOG-0234)	2004-2006 	Randomized Phase 2 (E-esc)	Cisplatin & RT (see note)	Did not meet primary endpoint of DFSDFS24: 57.3% vs 54.8%(HR 0.76, 95% CI 0.54-1.06)
Note: the control in this trial was the historical control arm of RTOG 9501 that received chemoradiotherapy.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cisplatin (Platinol) 30 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
====Targeted therapy====
*Cetuximab (Erbitux) as follows:
**5 to 9 days prior to RT: 400 mg/m2 IV once
**During RT: 250 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
====Supportive therapy====
*Diphenhydramine (Benadryl) 50 mg IV once on day 1; 30 to 60 minutes prior to the first dose of cetuximab
*Dolasetron (Anzemet) 100 mg IV once per day on days 1, 8, 15, 22, 29, 36; 30 minutes prior to cisplatin
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions (total dose: 58 to 6600 cGy), given 5 days per week
5.5- to 6.5-week course
===References===
# RTOG-0234: Harari PM, Harris J, Kies MS, Myers JN, Jordan RC, Gillison ML, Foote RL, Machtay M, Rotman M, Khuntia D, Straube W, Zhang Q, Ang K. Postoperative chemoradiotherapy and cetuximab for high-risk squamous cell carcinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. J Clin Oncol. 2014 Aug 10;32(23):2486-95. Epub 2014 Jul 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00084318
==Cisplatin & RT==
Cisplatin & RT: Cisplatin & Radiation Therapy
===Regimen variant #1, 40 mg/m2 weekly===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kiyota et al. 2022 (JCOG1008)	2012-2018 	Phase 2/3 (E-switch-ic)	Cisplatin & RT; q3wk	Non-inferior OS (primary endpoint)OS36: 71.6% vs 59.1%(HR 0.69, 99.1% CI 0.37-1.27)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cisplatin (Platinol) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36, 43
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions for 33 fractions (total dose: 6600 cGy)
6.5-week course
===Regimen variant #2, 50 mg/m2 weekly===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bachaud et al. 1991	1984-1988 	Phase 3 (E-esc)	Radiation therapy	Longer OS1OS60: 36% vs 13%(HR not reported)
1Reported efficacy is based on the 1996 update.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV bolus once per day on days 1, 8, 15, 22, 29, 36, 43, (50), (57)
====Supportive therapy====
*"Forced hydration" with cisplatin
====Radiotherapy====
*Concurrent radiation therapy, 170 cGy fractions x ~32 fractions (total dose: 5400 cGy), given 5 times per week, with boost to "primary site and/or cervical lymph nodes" with 1.8 to 200 cGy fractions for an additional boost dose of 11 to 1600 cGy to close (<5 mm) or positive margin areas of (overall dose to these sites: 65 to 7000 cGy). A boost of 11 to 2000 cGy was given to metastatic nodal sites (overall dose to these sites: 65 to 7400 cGy); see Bachaud et al. 1996 for details.
7- to 9-week course, depending on duration of radiation therapy
===Regimen variant #3, 100 mg/m2 x 3, 5400 cGy===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bernier et al. 2004 (EORTC 22931)	1994-2000 	Phase 3 (E-esc)	Radiation therapy	Longer OS (secondary endpoint)Median OS: 72 vs 32 mo(HR 0.70, 95% CI 0.52-0.95)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1, 22, 43
====Supportive therapy====
*"Prophylactic hydration and antiemetic agents"
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions x 27 fractions (total dose: 5400 cGy), given 5 times per week, with boost to areas at "high risk for malignant dissemination or that had inadequate resection margins" of 200 cGy fractions x 6 fractions (boost dose: 1200 cGy)
5.5-week course
===Regimen variant #4, 100 mg/m2 x 3, 6000 cGy===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cooper et al. 2004 (RTOG 9501)	1995-2000 	Phase 3 (E-esc)	Radiation therapy 	Seems to have longer DFS (secondary endpoint)Median DFS: 29 vs 19 mo(HR 0.78, 95% CI 0.61-0.99)
Noronha et al. 2017 	2013-2017 	Phase 3 (C) 	Cisplatin & RT; weekly cisplatin	Seems to have higher LRC
====Preceding treatment====
*RTOG 9501: Patients "had undergone macroscopically complete resection of disease" and at least one high-risk characteristic: "histologic evidence of invasion of two or more regional lymph nodes, extracapsular extension of nodal disease, and microscopically involved mucosal margins of resection."
*Noronha et al. 2017: Surgery
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1, 22, 43
====Supportive therapy====
*Hydration before and after treatment
*Antiemetics per physician choice
*Optional use of feeding tubes
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions x 30 fractions (total dose: 6000 cGy), given 5 times per week
**RTOG 9501: Optional boost of 200 cGy fractions x 3 fractions (boost dose: 600 cGy) to high-risk sites
6.5-week course
===Regimen variant #5, 100 mg/m2 x 3, 6600 cGy===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Harrington et al. 2015 (EGF102988)	2006-2013 	Phase 3 (C) 	Cisplatin, Lapatinib, RT	Did not meet primary endpoint of DFSMedian DFS: NYR vs 53.6 mo(HR 0.91, 95% CI 0.70-1.18)
Kiyota et al. 2022 (JCOG1008) 	2012-2018 	Phase 2/3 (C)	Cisplatin & RT; weekly 	Non-inferior OSOS36: 59.1% vs 71.6%(HR 1.45, 99.1% CI 0.79-2.70)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1, 22, 43
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions x 33 fractions (total dose: 6600 cGy), given 5 times per week
6.5-week course
===References===
# Bachaud JM, David JM, Boussin G, Daly N. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced squamous cell carcinoma of the head and neck: preliminary report of a randomized trial. Int J Radiat Oncol Biol Phys. 1991 Feb;20(2):243-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 
## Update: Bachaud JM, Cohen-Jonathan E, Alzieu C, David JM, Serrano E, Daly-Schveitzer N. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys. 1996 Dec 1;36(5):999-1004. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# RTOG 9501: Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Machtay M, Ensley JF, Chao KS, Schultz CJ, Lee N, Fu KK; RTOG; EORTC. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004 May 6;350(19):1937-44. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002670
## Post-hoc analysis: Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, Lefèbvre JL. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005 Oct;27(10):843-50. link to original article EuroPMC
## Update: Cooper JS, Zhang Q, Pajak TF, Forastiere AA, Jacobs J, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Lustig R, Ensley JF, Thorstad W, Schultz CJ, Yom SS, Ang KK. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2012 Dec 1;84(5):1198-205. Epub 2012 Jun 30. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# EORTC 22931: Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, Cognetti F, Bourhis J, Kirkpatrick A, van Glabbeke M; EORTC Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004 May 6;350(19):1945-52. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002555
## Post-hoc analysis: Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, Lefèbvre JL. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005 Oct;27(10):843-50. link to original article EuroPMC
# EGF102988: Harrington K, Temam S, Mehanna H, D'Cruz A, Jain M, D'Onofrio I, Manikhas G, Horvath Z, Sun Y, Dietzsch S, Dubinsky P, Holeckova P, El-Hariry I, Franklin N, Biswas-Baldwin N, Legenne P, Wissel P, Netherway T, Farrell J, Ellis C, Wang-Silvanto J, Amonkar M, Ahmed N, Santillana S, Bourhis J. Postoperative adjuvant lapatinib and concurrent chemoradiotherapy followed by maintenance lapatinib monotherapy in high-risk patients with resected squamous cell carcinoma of the head and neck: a phase III, randomized, double-blind, placebo-controlled study. J Clin Oncol. 2015 Dec 10;33(35):4202-9. Epub 2015 Nov 2. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00424255
# Noronha V, Joshi A, Patil VM, Agarwal J, Ghosh-Laskar S, Budrukkar A, Murthy V, Gupta T, D'Cruz AK, Banavali S, Pai PS, Chaturvedi P, Chaukar D, Pande N, Chandrasekharan A, Talreja V, Vallathol DH, Mathrudev V, Manjrekar A, Maske K, Bhelekar AS, Nawale K, Kannan S, Gota V, Bhattacharjee A, Kane S, Juvekar SL, Prabhash K. Once-a-week versus once-every-3-weeks cisplatin chemoradiation for locally advanced head and neck cancer: a phase III randomized noninferiority trial. J Clin Oncol. 2018 Apr 10;36(11):1064-1072. Epub 2017 Dec 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2012/10/003062
##Update: Noronha V, Patil V, Menon N, Singh A, Shah M, Shetake A, Peelay Z, Mathrudev V, Nawale K, Shah S, Prabhash K. Long-Term Update of a Phase 3 Randomized Study Comparing Once-a-Week Versus Once-Every-3-Weeks Cisplatin Along With Radiation in Head and Neck Cancer. Int J Radiat Oncol Biol Phys. 2025 Jan 1;121(1):128-136. Epub 2024 Jul 27. link to original article EuroPMC
#JCOG1008: Kiyota N, Tahara M, Mizusawa J, Kodaira T, Fujii H, Yamazaki T, Mitani H, Iwae S, Fujimoto Y, Onozawa Y, Hanai N, Ogawa T, Hara H, Monden N, Shimura E, Minami S, Fujii T, Tanaka K, Homma A, Yoshimoto S, Oridate N, Omori K, Ueda T, Okami K, Ota I, Shiga K, Sugasawa M, Asakage T, Saito Y, Murono S, Nishimura Y, Nakamura K, Hayashi R; Head and Neck Cancer Study Group of the Japan Clinical Oncology Group (JCOG-HNCSG). Weekly Cisplatin Plus Radiation for Postoperative Head and Neck Cancer (JCOG1008): A Multicenter, Noninferiority, Phase II/III Randomized Controlled Trial. J Clin Oncol. 2022 Jun 20;40(18):1980-1990. Epub 2022 Mar 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC jRCTs031180135
# IMSTAR-HN: NCT03700905
==Docetaxel, Cetuximab, RT==
Docetaxel, Cetuximab, RT: Docetaxel, Cetuximab, Radiation Therapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Harari et al. 2014 (RTOG-0234)	2004-2006 	Randomized Phase 2 (E-esc)	Cisplatin & RT (see note)	Seems to have longer DFS (primary endpoint)DFS24: 65.9% vs 54.8%(HR 0.69, 95% CI 0.50-0.96)
Note: the control in this trial was the historical control arm of RTOG 9501 that received chemoradiotherapy.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Docetaxel (Taxotere) 15 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
====Targeted therapy====
*Cetuximab (Erbitux) as follows:
**5 to 9 days prior to RT: 400 mg/m2 IV once
**During RT: 250 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
====Supportive therapy====
*Diphenhydramine (Benadryl) 50 mg IV once on day 1; 30 to 60 minutes prior to the first dose of cetuximab
*Dexamethasone (Decadron) 20 mg IV once per day on days 1, 8, 15, 22, 29, 36, prior to docetaxel
====Radiotherapy====
*Concurrent radiation therapy, 200 cGy fractions (total dose: 58 to 6600 cGy), given 5 times per week
5.5- to 6.5-week course
===References===
# RTOG-0234: Harari PM, Harris J, Kies MS, Myers JN, Jordan RC, Gillison ML, Foote RL, Machtay M, Rotman M, Khuntia D, Straube W, Zhang Q, Ang K. Postoperative chemoradiotherapy and cetuximab for high-risk squamous cell carcinoma of the head and neck: Radiation Therapy Oncology Group RTOG-0234. J Clin Oncol. 2014 Aug 10;32(23):2486-95. Epub 2014 Jul 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00084318
==Radiation therapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Bachaud et al. 1991 	1984-1988 	Phase 3 (C) 	Cisplatin & RT 	Shorter OS1OS60: 13% vs 36%(HR not reported)
Wolf et al. 1991 	1985 to not reported	Non-randomized part of phase 3 RCT	 	
Bernier et al. 2004 (EORTC 22931)	1994-2000 	Phase 3 (C) 	Cisplatin & RT 	Seems to have shorter OSMedian OS: 32 vs 72 mo(HR 1.43, 95% CI 1.05-1.92)
Cooper et al. 2004 (RTOG 9501) 	1995-2000 	Phase 3 (C) 	Cisplatin & RT 	Seems to have shorter DFSMedian DFS: 19 vs 29 mo(HR 1.28, 95% CI 1.01-1.64)
Porceddu et al. 2018 (TROG 05.01)	2005-2014 	Phase 3 (C) 	Carboplatin & RT	Did not meet primary endpoint of FFLRR
1Reported efficacy for Bachaud et al. 1991 is based on the 1996 update.
====Preceding treatment====
*Surgery
====Radiotherapy====
*External beam radiotherapy of varying doses
===References===
# Bachaud JM, David JM, Boussin G, Daly N. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced squamous cell carcinoma of the head and neck: preliminary report of a randomized trial. Int J Radiat Oncol Biol Phys. 1991 Feb;20(2):243-6. link to original article EuroPMC 
## Update: Bachaud JM, Cohen-Jonathan E, Alzieu C, David JM, Serrano E, Daly-Schveitzer N. Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced head and neck carcinoma: final report of a randomized trial. Int J Radiat Oncol Biol Phys. 1996 Dec 1;36(5):999-1004. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Wolf GT, Fisher SG, Hong WK, Hillman R, Spaulding M, Laramore GE, Endicott JW, McClatchey K, Henderson WG; Department of Veterans Affairs Laryngeal Cancer Study Group. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. N Engl J Med. 1991 Jun 13;324(24):1685-90. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# RTOG 9501: Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Machtay M, Ensley JF, Chao KS, Schultz CJ, Lee N, Fu KK; RTOG; EORTC. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004 May 6;350(19):1937-44. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002670
## Post-hoc analysis: Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, Lefèbvre JL. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005 Oct;27(10):843-50. link to original article EuroPMC
## Update: Cooper JS, Zhang Q, Pajak TF, Forastiere AA, Jacobs J, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Lustig R, Ensley JF, Thorstad W, Schultz CJ, Yom SS, Ang KK. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2012 Dec 1;84(5):1198-205. Epub 2012 Jun 30. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# EORTC 22931: Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, Cognetti F, Bourhis J, Kirkpatrick A, van Glabbeke M; EORTC Trial 22931. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004 May 6;350(19):1945-52. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002555
## Post-hoc analysis: Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, Lefèbvre JL. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck. 2005 Oct;27(10):843-50. link to original article EuroPMC
# TROG 05.01: Porceddu SV, Bressel M, Poulsen MG, Stoneley A, Veness MJ, Kenny LM, Wratten C, Corry J, Cooper S, Fogarty GB, Collins M, Collins MK, Macann AMJ, Milross CG, Penniment MG, Liu HY, King MT, Panizza BJ, Rischin D. Postoperative concurrent chemoradiotherapy versus postoperative radiotherapy in high-risk cutaneous squamous cell carcinoma of the head and neck: the randomized phase III TROG 05.01 trial. J Clin Oncol. 2018 May 1;36(13):1275-1283. Epub 2018 Mar 14. link to original article EuroPMC NCT00193895
==UFT monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Tsukahara et al. 2015 (ACTS-HNC)	2006-2008 	Phase 3 (C)	S-1 	Did not meet primary endpoint of DFS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Tegafur and uracil (UFT) 300 mg PO once per day
1-year course
===References===
# ACTS-HNC: Tsukahara K, Kubota A, Hasegawa Y, Takemura H, Terada T, Taguchi T, Nagahara K, Nakatani H, Yoshino K, Higaki Y, Iwae S, Beppu T, Hanamure Y, Tomita K, Kohno N, Kawabata K, Fukushima M, Teramukai S, Fujii M; ACTS-HNC group. Randomized phase III trial of adjuvant chemotherapy with S-1 after curative treatment in patients with squamous-cell carcinoma of the head and neck (ACTS-HNC). PLoS One. 2015 Feb 11;10(2):e0116965. eCollection 2015. link to original article link to PMC article dosing details in abstract have been reviewed by our editors EuroPMC NCT00336947
=Recurrent or metastatic disease, first-line therapy=
==Carboplatin & Docetaxel (DCb)==
===Regimen variant #1, 6/65===
Study 	Dates of enrollment 	Evidence
Samlowski et al. 2007	1999-11-15 to 2000-01-02	Phase 2
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV once on day 1
*Docetaxel (Taxotere) 65 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2, 6/75===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Argiris et al. 2019 (ECOG E1305)	2008-2015 	Phase 3 (C)	1a. Carboplatin, 5-FU, Bevacizumab1b. CF & Bevacizumab1c. DCb & Bevacizumab1d. DC & Bevacizumab	Did not meet primary endpoint of OSMedian OS: 11 vs 12.6 mo(HR 1.15, 95% CI 0.92-1.43)
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given second
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given first
21-day cycles
===References===
# Samlowski WE, Moon J, Kuebler JP, Nichols CR, Gandara DR, Ozer H, Williamson SK, Atkins JN, Schuller DE, Ensley JF; Southwest Oncology Group. Evaluation of the combination of docetaxel/carboplatin in patients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN): a Southwest Oncology Group Phase II study. Cancer Invest. 2007 Apr-May;25(3):182-8. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# ECOG E1305: Argiris A, Li S, Savvides P, Ohr JP, Gilbert J, Levine MA, Chakravarti A, Haigentz M Jr, Saba NF, Ikpeazu CV, Schneider CJ, Pinto HA, Forastiere AA, Burtness B. Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer. J Clin Oncol. 2019 Dec 1;37(34):3266-3274. Epub 2019 Oct 16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00588770
==Carboplatin & Fluorouracil==
===Regimen variant #1, 6/4000===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Argiris et al. 2019 (ECOG E1305)	2008-2015 	Phase 3 (C)	1a. Carboplatin, 5-FU, Bevacizumab1b. CF & Bevacizumab1c. DCb & Bevacizumab1d. DC & Bevacizumab	Did not meet primary endpoint of OSMedian OS: 11 vs 12.6 mo(HR 1.15, 95% CI 0.92-1.43)
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 6 IV over 30 minutes once on day 1, given first
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1, given second (total dose per cycle: 4000 mg/m2)
21-day cycles
===Regimen variant #2, 300/4000===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Forastiere et al. 1992 (SWOG-8514)	1986-1989 	Phase 3 (E-switch-ic)	1. CF 	Not reported
Forastiere et al. 1992 (SWOG-8514)	1986-1989 	Phase 3 (E-switch-ic)	2. MTX 	Seems to have higher ORR
Vermorken et al. 2008 (EXTREME) 	2004-12-21 to 2005-12-30	Phase 3 (C) 	1a. Carboplatin, Fluorouracil, Cetuximab1b. CF & Cetuximab	Seems to have shorter OSMedian OS: 7.4 vs 10.1 mo(HR 1.25, 95% CI 1.01-1.56)
====Chemotherapy====
*Carboplatin (Paraplatin) 300 mg/m2 IV over 5 to 10 minutes once on day 1
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, start day not specified (total dose per cycle: 4000 mg/m2)
====Supportive therapy====
*"Standard antiemetic regimens"
28-day cycles
===References===
# SWOG-8514: Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK, Von Hoff DD. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol. 1992 Aug;10(8):1245-51. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# EXTREME: Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008 Sep 11;359(11):1116-27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00122460
##HRQoL analysis: Mesía R, Rivera F, Kawecki A, Rottey S, Hitt R, Kienzer H, Cupissol D, De Raucourt D, Benasso M, Koralewski P, Delord JP, Bokemeyer C, Curran D, Gross A, Vermorken JB. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2010 Oct;21(10):1967-1973. Epub 2010 Mar 24. link to original article link to PMC article EuroPMC
# ECOG E1305: Argiris A, Li S, Savvides P, Ohr JP, Gilbert J, Levine MA, Chakravarti A, Haigentz M Jr, Saba NF, Ikpeazu CV, Schneider CJ, Pinto HA, Forastiere AA, Burtness B. Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer. J Clin Oncol. 2019 Dec 1;37(34):3266-3274. Epub 2019 Oct 16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00588770
==Carboplatin, Fluorouracil, Cetuximab==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Vermorken et al. 2008 (EXTREME) 	2004-12-21 to 2005-12-30	Phase 3 (E-RT-esc)	1a. Carboplatin & Fluorouracil1b. CF 	Seems to have longer OS (primary endpoint)Median OS: 10.1 vs 7.4 mo(HR 0.80, 95% CI 0.64-0.99)
Burtness et al. 2019 (KEYNOTE-048)	2015-2017 	Phase 3 (C) 	1a. Carboplatin, 5-FU, Pembrolizumab1b. CF & Pembrolizumab	Shorter OS1 (co-primary endpoint)Median OS: 10.7 vs 13 mo(HR 1.30, 95% CI 1.08-1.59)Did not meet co-primary endpoint of PFS
Burtness et al. 2019 (KEYNOTE-048)	2015-2017 	Phase 3 (C) 	2. Pembrolizumab 	Non-inferior OS1
Psyrri et al. 2022 (KESTREL) 	2015-2017 	Phase 3 (C) 	1. Durvalumab2. Durvalumab & Tremelimumab 	Did not meet primary endpoint of OS
Haddad et al. 2022 (CheckMate 651)	Not reported 	Phase 3 (C) 	Ipilimumab & Nivolumab 	Did not meet primary endpoint of OSMedian OS: 13.5 vs 13.9 mo(HR 1.05, 97.9% CI 0.88-1.25)
Cho et al. 2024 (ECHO-304) 	2017-12-01 to 2018-05-02	Phase 3 (C) 	1. Pembrolizumab2. Epacadostat & Pembrolizumab 	Did not meet primary endpoint of ORR
1Reported efficacy is for the total population; see paper for details of other populations stratified by CPS.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 6: AUC 5 IV over 60 minutes once on day 1
*Fluorouracil (5-FU) as follows:
**Cycles 1 to 6: 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Targeted therapy====
*Cetuximab (Erbitux) as follows:
**Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, given first before chemotherapy and ending at least 1 hour before chemotherapy starts, then 250 mg/m2 IV over 60 minutes once per day on days 8 & 15
**Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, given first before chemotherapy and ending at least 1 hour before chemotherapy starts
21-day cycles
===References===
# EXTREME: Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008 Sep 11;359(11):1116-27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00122460
##HRQoL analysis: Mesía R, Rivera F, Kawecki A, Rottey S, Hitt R, Kienzer H, Cupissol D, De Raucourt D, Benasso M, Koralewski P, Delord JP, Bokemeyer C, Curran D, Gross A, Vermorken JB. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2010 Oct;21(10):1967-1973. Epub 2010 Mar 24. link to original article link to PMC article EuroPMC
# KEYNOTE-048: Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Basté N, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesía R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, González Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. Epub 2019 Oct 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02358031
##HRQoL analysis: Rischin D, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Braña I, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesía R, Ngamphaiboon N, Rordorf T, Ishak WZW, Hong RL, Mendoza RG, Jia L, Chirovsky D, Norquist J, Jin F, Burtness B. Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048. Oral Oncol. 2022 May;128:105815. Epub 2022 Apr 2. link to original article EuroPMC
##Update: Harrington KJ, Burtness B, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Basté N, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Lin J, Gumuscu B, Swaby RF, Rischin D. Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol. 2023 Feb 1;41(4):790-802. Epub 2022 Oct 11. link to original article link to PMC article EuroPMC
#KESTREL: Psyrri A, Fayette J, Harrington K, Gillison M, Ahn MJ, Takahashi S, Weiss J, Machiels JP, Baxi S, Vasilyev A, Karpenko A, Dvorkin M, Hsieh CY, Thungappa SC, Segura PP, Vynnychenko I, Haddad R, Kasper S, Mauz PS, Baker V, He P, Evans B, Wildsmith S, Olsson RF, Yovine A, Kurland JF, Morsli N, Seiwert TY; KESTREL Investigators. Durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study. Ann Oncol. 2023 Mar;34(3):262-274. Epub 2022 Dec 16. link to original article EuroPMC NCT02551159
# CheckMate 651: Haddad RI, Harrington K, Tahara M, Ferris RL, Gillison M, Fayette J, Daste A, Koralewski P, Zurawski B, Taberna M, Saba NF, Mak M, Kawecki A, Girotto G, Alvarez Avitia MA, Even C, Toledo JGR, Guminski A, Müller-Richter U, Kiyota N, Roberts M, Khan TA, Miller-Moslin K, Wei L, Argiris A. Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651. J Clin Oncol. 2023 Apr 20;41(12):2166-2180. Epub 2022 Dec 6. link to original article link to PMC article does not contain dosing details in manuscript EuroPMC NCT02741570
#ECHO-304: Cho BC, Braña I, Cirauqui B, Aksoy S, Couture F, Hong RL, Miller WH Jr, Chaves-Conde M, Teixeira M, Leopold L, Munteanu M, Ge JY, Swaby RF, Hughes BGM. Pembrolizumab plus epacadostat in patients with recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-669/ECHO-304): a phase 3, randomized, open-label study. BMC Cancer. 2024 Jul 25;23(Suppl 1):1254. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03358472
==Carboplatin, Fluorouracil, Pembrolizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Burtness et al. 2019 (KEYNOTE-048)	2015-2017 	Phase 3 (E-switch-ooc)	1a. Carboplatin, 5-FU, Cetuximab1b. CF & Cetuximab	Longer OS1 (co-primary endpoint)Median OS: 13 vs 10.7 mo(HR 0.77, 95% CI 0.63-0.93)Did not meet co-primary endpoint of PFS
Burtness et al. 2019 (KEYNOTE-048)	2015-2017 	Phase 3 (E-switch-ooc)	2. Pembrolizumab 	Not reported
1Reported efficacy is for the total population; see paper for details of other populations stratified by CPS.
====Chemotherapy====
*Carboplatin (Paraplatin) as follows:
**Cycles 1 to 6: AUC 5 IV once on day 1
*Fluorouracil (5-FU) as follows:
**Cycles 1 to 6: 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles
===References===
# KEYNOTE-048: Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Basté N, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesía R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, González Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. Epub 2019 Oct 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02358031
##HRQoL analysis: Rischin D, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Braña I, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesía R, Ngamphaiboon N, Rordorf T, Ishak WZW, Hong RL, Mendoza RG, Jia L, Chirovsky D, Norquist J, Jin F, Burtness B. Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048. Oral Oncol. 2022 May;128:105815. Epub 2022 Apr 2. link to original article EuroPMC
##Update: Harrington KJ, Burtness B, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Basté N, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Lin J, Gumuscu B, Swaby RF, Rischin D. Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol. 2023 Feb 1;41(4):790-802. Epub 2022 Oct 11. link to original article link to PMC article EuroPMC
==Celecoxib & Methotrexate==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Patil et al. 2020	2016-05-16 to 2020-01-17	Phase 3 (E-de-esc)	Cisplatin 	Non-inferior OS (primary endpoint)Median OS: 7.5 vs 6.1 mo(HR 0.77, 95% CI 0.615-0.97)
====Chemotherapy====
*Methotrexate (MTX) 15 mg/m2 PO once on day 1
====Targeted therapy====
*Celecoxib (Celebrex) 200 mg PO twice per day on days 1 to 7
7-day cycles
===References===
#Patil V, Noronha V, Dhumal SB, Joshi A, Menon N, Bhattacharjee A, Kulkarni S, Ankathi SK, Mahajan A, Sable N, Nawale K, Bhelekar A, Mukadam S, Chandrasekharan A, Das S, Vallathol D, D'Souza H, Kumar A, Agrawal A, Khaddar S, Rathnasamy N, Shenoy R, Kashyap L, Rai RK, Abraham G, Saha S, Majumdar S, Karuvandan N, Simha V, Babu V, Elamarthi P, Rajpurohit A, Kumar KAP, Srikanth A, Ravind R, Banavali S, Prabhash K. Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial. Lancet Glob Health. 2020 Sep;8(9):e1213-e1222. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2015/11/006388
==Celecoxib, Erlotinib, Methotrexate==
TMC: Triple Metronomic Chemotherapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Patil et al. 2023b	2021-01 to 2021-09 	Phase 3 (C)	TMC & Nivolumab	Lower OS12OS12: 16.3% vs 43.4%(HR 1.83, 95% CI 1.22-2.78)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT, prior to becoming a standard comparator arm.
====Chemotherapy====
*Methotrexate (MTX) 9 mg/m2 PO once on day 1
====Targeted therapy====
*Celecoxib (Celebrex) 200 mg PO twice per day on days 1 to 7
*Erlotinib (Tarceva) 150 mg PO once per day on days 1 to 7
7-day cycles
===References===
#Patil VM, Noronha V, Menon N, Rai R, Bhattacharjee A, Singh A, Nawale K, Jogdhankar S, Tambe R, Dhumal S, Sawant R, Alone M, Karla D, Peelay Z, Pathak S, Balaji A, Kumar S, Purandare N, Agarwal A, Puranik A, Mahajan A, Janu A, Kumar Singh G, Mittal N, Yadav S, Banavali S, Prabhash K. Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study. J Clin Oncol. 2023 Jan 10;41(2):222-232. Epub 2022 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2020/11/028953
==Celecoxib, Erlotinib, Methotrexate, Nivolumab==
TMC-I: Triple Metronomic Chemotherapy, Immunotherapy
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Patil et al. 2023b	2021-01 to 2021-09 	Phase 3 (E-esc)	TMC 	Higher OS12 (primary endpoint)OS12: 43.4% vs 16.3%(HR 0.545, 95% CI 0.36-0.82)
====Chemotherapy====
*Methotrexate (MTX) 9 mg/m2 PO once per day on days 1, 8, 15
====Targeted therapy====
*Celecoxib (Celebrex) 200 mg PO twice per day on days 1 to 21
*Erlotinib (Tarceva) 150 mg PO once per day on days 1 to 21
====Immunotherapy====
*Nivolumab (Opdivo) 20 mg IV over 60 minutes once on day 1
21-day cycles
===References===
#Patil VM, Noronha V, Menon N, Rai R, Bhattacharjee A, Singh A, Nawale K, Jogdhankar S, Tambe R, Dhumal S, Sawant R, Alone M, Karla D, Peelay Z, Pathak S, Balaji A, Kumar S, Purandare N, Agarwal A, Puranik A, Mahajan A, Janu A, Kumar Singh G, Mittal N, Yadav S, Banavali S, Prabhash K. Low-Dose Immunotherapy in Head and Neck Cancer: A Randomized Study. J Clin Oncol. 2023 Jan 10;41(2):222-232. Epub 2022 Oct 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2020/11/028953
==Cisplatin monotherapy==
===Regimen variant #1, 50 mg/m2, 2 out of 4 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hong et al. 1983 	1979-1981 	Phase 3 (E-switch-ic)	Methotrexate	Did not meet efficacy endpoints
Clavel et al. 1994	1984-1987 	Phase 3 (C) 	1. CABO2. CF	Lower ORR
====Chemotherapy====
*Cisplatin (Platinol) 50 mg/m2 IV over 6 hours once per day on days 1 & 8
28-day cycles 
===Regimen variant #2, 75 mg/m2 q3wk x 6===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Urba et al. 2012 (JMHR)	2006-2010 	Phase 3 (C)	Cisplatin & Pemetrexed 	Might have shorter OS (primary endpoint)Median OS: 6.3 vs 7.3 mo(HR 1.15, 95% CI 0.98-1.33)
Patil et al. 2020 	2016-05-16 to 2020-01-17	Phase 3 (C)	Celecoxib & Methotrexate	Non-inferior OSMedian OS: 6.1 vs 7.5 mo(HR 1.30, 95% CI 1.03-1.63)
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
21-day cycle for 6 cycles
===Regimen variant #3, 80 mg/m2 q3wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Jacobs et al. 1983	1979-1981 	Phase 3 (C)	Cisplatin & Methotrexate	Did not meet efficacy endpoints
====Chemotherapy====
*Cisplatin (Platinol) 80 mg/m2 IV continuous infusion over 24 hours, started on day 1
21-day cycles
===Regimen variant #4, 100 mg/m2 q3wk===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Jacobs et al. 1992	1985-1989 	Phase 3 (C)	1. CF 	Seems to have lower ORR
Jacobs et al. 1992	1985-1989 	Phase 3 (C)	2. 5-FU 	Not reported
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV over 15 to 20 minutes once on day 1
21-day cycles
===Regimen variant #5, 100 mg/m2 q4wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Burtness et al. 2005 (ECOG E5397)	1999-2001 	Phase 3 (C)	Cisplatin & Cetuximab	Did not meet primary endpoint of PFS
Note: Per physician discretion, patients with complete response (CR) could have treatment discontinued 2 cycles past the point at which CR was attained. Patients with partial response (PR) continued on treatment until there was evidence of CR or progression disease. Patients with stable disease (SD) could discontinue treatment after 6 cycles. Patients with progressive disease discontinued therapy.
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once on day 1
28-day cycles (see note)
===References===
# Hong WK, Schaefer S, Issell B, Cummings C, Luedke D, Bromer R, Fofonoff S, D'Aoust J, Shapshay S, Welch J, Levin E, Vincent M, Vaughan C, Strong S. A prospective randomized trial of methotrexate versus cisplatin in the treatment of recurrent squamous cell carcinoma of the head and neck. Cancer. 1983 Jul 15;52(2):206-10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Jacobs C, Meyers F, Hendrickson C, Kohler M, Carter S; Northern California Oncology Group. A randomized phase III study of cisplatin with or without methotrexate for recurrent squamous cell carcinoma of the head and neck: a Northern California Oncology Group study. Cancer. 1983 Nov 1;52(9):1563-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Jacobs C, Lyman G, Velez-García E, Sridhar KS, Knight W, Hochster H, Goodnough LT, Mortimer JE, Einhorn LH, Schacter L, Cherng N, Dalton T, Burroughs J, Rozencweig M. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992 Feb;10(2):257-63. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Clavel M, Vermorken JB, Cognetti F, Cappelaere P, de Mulder PH, Schornagel JH, Tueni EA, Verweij J, Wildiers J, Clerico M, Dalesio O, Kirkpatrick A, Snow GB; EORTC Head and Neck Cancer Cooperative Group. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck: a phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol. 1994 Jul;5(6):521-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# ECOG E5397: Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA; ECOG. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2005 Dec 1;23(34):8646-54. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003809
# JMHR: Urba S, van Herpen CM, Sahoo TP, Shin DM, Licitra L, Mezei K, Reuter C, Hitt R, Russo F, Chang SC, Hossain AM, Frimodt-Moller B, Koustenis A, Hong RL. Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with recurrent or metastatic head and neck cancer: final results of a randomized, double-blind, placebo-controlled, phase 3 study. Cancer. 2012 Oct 1;118(19):4694-705. Epub 2012 Mar 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00415194
#Patil V, Noronha V, Dhumal SB, Joshi A, Menon N, Bhattacharjee A, Kulkarni S, Ankathi SK, Mahajan A, Sable N, Nawale K, Bhelekar A, Mukadam S, Chandrasekharan A, Das S, Vallathol D, D'Souza H, Kumar A, Agrawal A, Khaddar S, Rathnasamy N, Shenoy R, Kashyap L, Rai RK, Abraham G, Saha S, Majumdar S, Karuvandan N, Simha V, Babu V, Elamarthi P, Rajpurohit A, Kumar KAP, Srikanth A, Ravind R, Banavali S, Prabhash K. Low-cost oral metronomic chemotherapy versus intravenous cisplatin in patients with recurrent, metastatic, inoperable head and neck carcinoma: an open-label, parallel-group, non-inferiority, randomised, phase 3 trial. Lancet Glob Health. 2020 Sep;8(9):e1213-e1222. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2015/11/006388
==Cisplatin & Docetaxel (DC)==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Glisson et al. 2002 	Not reported 	Phase 2 	 	
Argiris et al. 2019 (ECOG E1305)	2008-2015 	Phase 3 (C)	1a. Carboplatin, 5-FU, Bevacizumab1b. CF & Bevacizumab1c. DCb & Bevacizumab1d. DC & Bevacizumab	Did not meet primary endpoint of OSMedian OS: 11 vs 12.6 mo(HR 1.15, 95% CI 0.92-1.43)
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV over 60 to 120 minutes once on day 1, given second
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given first
21-day cycles
===References===
# Glisson BS, Murphy BA, Frenette G, Khuri FR, Forastiere AA. Phase II Trial of docetaxel and cisplatin combination chemotherapy in patients with squamous cell carcinoma of the head and neck. J Clin Oncol. 2002 Mar 15;20(6):1593-9. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# ECOG E1305: Argiris A, Li S, Savvides P, Ohr JP, Gilbert J, Levine MA, Chakravarti A, Haigentz M Jr, Saba NF, Ikpeazu CV, Schneider CJ, Pinto HA, Forastiere AA, Burtness B. Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer. J Clin Oncol. 2019 Dec 1;37(34):3266-3274. Epub 2019 Oct 16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00588770
==Cisplatin & Fluorouracil (CF)==
CF: Cisplatin and Fluorouracil
C5F: Cisplatin and 5-Fluorouracil
===Regimen variant #1, 75/3000===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Shi et al. 2024 (SCT-I10A-B301)	2019-12-31 to 2022-03-16	Phase 3 (C)	CF & Finotonlimab	Shorter OS (primary endpoint)Median OS: 10.5 vs 14.1 mo(HR 1.37, 95% CI 1.05-1.75)
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3000 mg/m2)
21-day cycle for 6 cycles
===Regimen variant #2, 100/4000===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Jacobs et al. 1992 	1985-1989 	Phase 3 (E-esc) 	1. Cisplatin2. 5-FU 	Seems to have higher ORR
Forastiere et al. 1992 (SWOG-8514)	1986-1989 	Phase 3 (E-switch-ic)	1. Carboplatin & Fluorouracil 	Not reported
Forastiere et al. 1992 (SWOG-8514)	1986-1989 	Phase 3 (E-switch-ic)	2. MTX 	Higher ORR
Schrijvers et al. 1998 	1992-1994 	Phase 3 (C) 	CF & IFN alfa 	Did not meet primary endpoint of OS
Gibson et al. 2005 (ECOG E1395) 	1997-2000 	Phase 3 (C) 	CP 	Did not meet primary endpoint of OS
Vermorken et al. 2008 (EXTREME) 	2004-12-21 to 2005-12-30	Phase 3 (C) 	1a. Carboplatin, Fluorouracil, Cetuximab1b. CF & Cetuximab 	Seems to have shorter OSMedian OS: 7.4 vs 10.1 mo(HR 1.25, 95% CI 1.01-1.56)
Vermorken et al. 2013 (SPECTRUM) 	2007-2009 	Phase 3 (C) 	CF & Panitumumab 	Might have shorter OSMedian OS: 9 vs 11.1 mo(HR 1.15, 95% CI 0.95-1.37)
Argiris et al. 2019 (ECOG E1305) 	2008-2015 	Phase 3 (C) 	1a. Carboplatin, 5-FU, Bevacizumab1b. CF & Bevacizumab1c. DCb & Bevacizumab1d. DC & Bevacizumab	Did not meet primary endpoint of OSMedian OS: 11 vs 12.6 mo(HR 1.15, 95% CI 0.92-1.43)
Note: In ECOG E1395, patients with complete response (CR) received at least 6 cycles or 2 cycles past the point at which CR was documented, whichever came later; patients with partial response (PR) continued on treatment until there was evidence of CR or progression disease; patients with stable disease (SD) could discontinue treatment after six cycles.
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV over 60 to 120 minutes once on day 1, given first
**ECOG E1395: Carboplatin AUC 6 IV once on day 1 could be substituted in patients who developed at least grade 2 neuropathy or renal impairment (CrCl less than 50 mL/min/1.73m2; note: later in Gibson et al. 2005, it says that carboplatin was used for patients who had CrCl less than or equal to 50 mL/min/1.73m2)
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1, given second (total dose per cycle: 4000 mg/m2)
====Supportive therapy====
*Details vary per reference
*Pretreatment and posttreatment hydration and mannitol diuresis with cisplatin
*"Standard antiemetic regimens"
21-day cycle for varying durations: 6 cycles (Schrijvers et al. 1998, SPECTRUM); at least 6 cycles (ECOG E1395); indefinitely (ECOG E1305, EXTREME, Jacobs et al. 1992, SWOG-8514)
===Regimen variant #3, 100/4000 x3, with cisplatin maintenance===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Clavel et al. 1994	1984-1987 	Phase 3 (E-esc)	1. CABO 	Seems to have lower ORR
Clavel et al. 1994	1984-1987 	Phase 3 (E-esc)	2. Cisplatin	Higher ORR
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once on day 1
*Fluorouracil (5-FU) as follows:
**Cycles 1 to 3: 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
21-day cycles
===References===
# Jacobs C, Lyman G, Velez-García E, Sridhar KS, Knight W, Hochster H, Goodnough LT, Mortimer JE, Einhorn LH, Schacter L, Cherng N, Dalton T, Burroughs J, Rozencweig M. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992 Feb;10(2):257-63. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# SWOG-8514: Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK, Von Hoff DD. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol. 1992 Aug;10(8):1245-51. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Clavel M, Vermorken JB, Cognetti F, Cappelaere P, de Mulder PH, Schornagel JH, Tueni EA, Verweij J, Wildiers J, Clerico M, Dalesio O, Kirkpatrick A, Snow GB; EORTC Head and Neck Cancer Cooperative Group. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck: a phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann Oncol. 1994 Jul;5(6):521-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Schrijvers D, Johnson J, Jiminez U, Gore M, Kosmidis P, Szpirglas H, Robbins K, Oliveira J, Lewensohn R, Schüller J, Riviere A, Arvay C, Langecker P, Jacob H, Cvitkovic E, Vokes E; Head and Neck Interferon Cooperative Study Group. Phase III trial of modulation of cisplatin/fluorouracil chemotherapy by interferon alfa-2b in patients with recurrent or metastatic head and neck cancer. J Clin Oncol. 1998 Mar;16(3):1054-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# ECOG E1395: Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J, Forastiere AA; ECOG. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2005 May 20;23(15):3562-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002888
# EXTREME: Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008 Sep 11;359(11):1116-27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00122460
##HRQoL analysis: Mesía R, Rivera F, Kawecki A, Rottey S, Hitt R, Kienzer H, Cupissol D, De Raucourt D, Benasso M, Koralewski P, Delord JP, Bokemeyer C, Curran D, Gross A, Vermorken JB. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2010 Oct;21(10):1967-1973. Epub 2010 Mar 24. link to original article link to PMC article EuroPMC
# SPECTRUM: Vermorken JB, Stöhlmacher-Williams J, Davidenko I, Licitra L, Winquist E, Villanueva C, Foa P, Rottey S, Skladowski K, Tahara M, Pai VR, Faivre S, Blajman CR, Forastiere AA, Stein BN, Oliner KS, Pan Z, Bach BA; SPECTRUM investigators. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol. 2013 Jul;14(8):697-710. Epub 2013 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00460265
# ECOG E1305: Argiris A, Li S, Savvides P, Ohr JP, Gilbert J, Levine MA, Chakravarti A, Haigentz M Jr, Saba NF, Ikpeazu CV, Schneider CJ, Pinto HA, Forastiere AA, Burtness B. Phase III Randomized Trial of Chemotherapy With or Without Bevacizumab in Patients With Recurrent or Metastatic Head and Neck Cancer. J Clin Oncol. 2019 Dec 1;37(34):3266-3274. Epub 2019 Oct 16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00588770
#SCT-I10A-B301: Shi Y, Guo W, Wang W, Wu Y, Fang M, Huang X, Han P, Zhang Q, Dong P, Zhou X, Peng H, Hu C, Chen X, Zhang S, Chang Z, Li X, Ding Y, Qu S, Jing S, Zhang S, Gui L, Sun Y, Wang L, Liu Y, Wu H, Li G, Fu Z, Shi J, Jiang H, Bai Y, Cui J, Zheng Y, Cui W, Jia X, Zhai L, Cai Q, Xiong D, Wu Y, Cao J, Wu R, Hu G, Peng L, Xie L, Gai W, Wang Y, Su Y. Finotonlimab with chemotherapy in recurrent or metastatic head and neck cancer: a randomized phase 3 trial. Nat Med. 2024 Sep;30(9):2568-2575. Epub 2024 Jun 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04146402
==Cisplatin & Fluorouracil (CF) & Cetuximab==
===Regimen variant #1, 75/3000===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Guo et al. 2021 (CHANGE-2)	2015-2017 	Phase 3 (E-esc)	CF 	Longer PFS (primary endpoint)Median PFS: 5.5 vs 4.2 mo(HR 0.57, 95% CI 0.40-0.80)Longer OS (secondary endpoint)Median OS: 11.1 vs 8.9 mo(HR 0.69, 95% CI 0.50-0.93)
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 75 mg/m2 IV once on day 1
*Fluorouracil (5-FU) as follows:
**Cycles 1 to 6: 750 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 3000 mg/m2)
====Targeted therapy====
*Cetuximab (Erbitux) as follows:
**Cycle 1: 400 mg/m2 IV once on day 1, then 250 mg/m2 IV once per day on days 8 & 15
**Cycle 2 onwards: 250 mg/m2 IV once per day on days 1, 8, 15
21-day cycles
===Regimen variant #2, 100/4000 x 6 with cetuximab maintenance===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Vermorken et al. 2008 (EXTREME) 	2004-12-21 to 2005-12-30	Phase 3 (E-RT-esc)	1a. Carboplatin & Fluorouracil1b. CF 	Seems to have longer OS (primary endpoint)Median OS: 10.1 vs 7.4 mo(HR 0.80, 95% CI 0.64-0.99)
Burtness et al. 2019 (KEYNOTE-048)	2015-2017 	Phase 3 (C) 	1a. Carboplatin, 5-FU, Pembrolizumab1b. CF & Pembrolizumab	Shorter OS1 (co-primary endpoint)Median OS: 10.7 vs 13 mo(HR 1.30, 95% CI 1.08-1.59)Did not meet co-primary endpoint of PFS
Burtness et al. 2019 (KEYNOTE-048)	2015-2017 	Phase 3 (C) 	2. Pembrolizumab 	Non-inferior OS1
Psyrri et al. 2022 (KESTREL) 	2015-2017 	Phase 3 (C) 	1. Durvalumab2. Durvalumab & Tremelimumab 	Did not meet primary endpoint of OS
Haddad et al. 2022 (CheckMate 651)	Not reported 	Phase 3 (C) 	Ipilimumab & Nivolumab 	Did not meet primary endpoint of OSMedian OS: 13.5 vs 13.9 mo(HR 1.05, 97.9% CI 0.88-1.25)
Cho et al. 2024 (ECHO-304) 	2017-12-01 to 2018-05-02	Phase 3 (C) 	1. Pembrolizumab2. Epacadostat & Pembrolizumab 	Did not meet primary endpoint of ORR
1Reported efficacy is for the total population; see paper for details of other populations stratified by CPS.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 100 mg/m2 IV over 60 minutes once on day 1
*Fluorouracil (5-FU) as follows:
**Cycles 1 to 6: 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Targeted therapy====
*Cetuximab (Erbitux) as follows:
**Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, given first before chemotherapy and ending at least 1 hour before chemotherapy starts, then 250 mg/m2 IV over 60 minutes once per day on days 8 & 15
**Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, given first before chemotherapy and ending at least 1 hour before chemotherapy starts
21-day cycles
===Regimen variant #3, 100/4000 x 6===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Prabhash et al. 2024	Not reported 	Phase 3 (C)	CF & ENZ-124 (cetuximab biosimilar)	Non-inferior DCR/ORR (co-primary endpoints)
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on day 1
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Targeted therapy====
*Cetuximab (Erbitux) as follows:
**Cycle 1: 400 mg/m2 IV once on day 1, then 250 mg/m2 IV once per day on days 8 & 15
**Cycle 2 onwards: 250 mg/m2 IV once per day on days 1, 8, 15
21-day cycle for 6 cycles
===References===
# EXTREME: Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Benasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008 Sep 11;359(11):1116-27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00122460
##HRQoL analysis: Mesía R, Rivera F, Kawecki A, Rottey S, Hitt R, Kienzer H, Cupissol D, De Raucourt D, Benasso M, Koralewski P, Delord JP, Bokemeyer C, Curran D, Gross A, Vermorken JB. Quality of life of patients receiving platinum-based chemotherapy plus cetuximab first line for recurrent and/or metastatic squamous cell carcinoma of the head and neck. Ann Oncol. 2010 Oct;21(10):1967-1973. Epub 2010 Mar 24. link to original article link to PMC article EuroPMC
# KEYNOTE-048: Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Basté N, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesía R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, González Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. Epub 2019 Oct 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02358031
##HRQoL analysis: Rischin D, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Braña I, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesía R, Ngamphaiboon N, Rordorf T, Ishak WZW, Hong RL, Mendoza RG, Jia L, Chirovsky D, Norquist J, Jin F, Burtness B. Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048. Oral Oncol. 2022 May;128:105815. Epub 2022 Apr 2. link to original article EuroPMC
##Update: Harrington KJ, Burtness B, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Basté N, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Lin J, Gumuscu B, Swaby RF, Rischin D. Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol. 2023 Feb 1;41(4):790-802. Epub 2022 Oct 11. link to original article link to PMC article EuroPMC
# CHANGE-2: Guo Y, Luo Y, Zhang Q, Huang X, Li Z, Shen L, Feng J, Sun Y, Yang K, Ge M, Zhu X, Wang L, Liu Y, He X, Bai C, Xue K, Zeng Y, Chang X, Chen W, Lin T. First-line treatment with chemotherapy plus cetuximab in Chinese patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Efficacy and safety results of the randomised, phase III CHANGE-2 trial. Eur J Cancer. 2021 Oct;156:35-45. Epub 2021 Aug 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02383966
#KESTREL: Psyrri A, Fayette J, Harrington K, Gillison M, Ahn MJ, Takahashi S, Weiss J, Machiels JP, Baxi S, Vasilyev A, Karpenko A, Dvorkin M, Hsieh CY, Thungappa SC, Segura PP, Vynnychenko I, Haddad R, Kasper S, Mauz PS, Baker V, He P, Evans B, Wildsmith S, Olsson RF, Yovine A, Kurland JF, Morsli N, Seiwert TY; KESTREL Investigators. Durvalumab with or without tremelimumab versus the EXTREME regimen as first-line treatment for recurrent or metastatic squamous cell carcinoma of the head and neck: KESTREL, a randomized, open-label, phase III study. Ann Oncol. 2023 Mar;34(3):262-274. Epub 2022 Dec 16. link to original article EuroPMC NCT02551159
# CheckMate 651: Haddad RI, Harrington K, Tahara M, Ferris RL, Gillison M, Fayette J, Daste A, Koralewski P, Zurawski B, Taberna M, Saba NF, Mak M, Kawecki A, Girotto G, Alvarez Avitia MA, Even C, Toledo JGR, Guminski A, Müller-Richter U, Kiyota N, Roberts M, Khan TA, Miller-Moslin K, Wei L, Argiris A. Nivolumab Plus Ipilimumab Versus EXTREME Regimen as First-Line Treatment for Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck: The Final Results of CheckMate 651. J Clin Oncol. 2023 Apr 20;41(12):2166-2180. Epub 2022 Dec 6. link to original article link to PMC article does not contains dosing details in manuscript EuroPMC NCT02741570
#ECHO-304: Cho BC, Braña I, Cirauqui B, Aksoy S, Couture F, Hong RL, Miller WH Jr, Chaves-Conde M, Teixeira M, Leopold L, Munteanu M, Ge JY, Swaby RF, Hughes BGM. Pembrolizumab plus epacadostat in patients with recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-669/ECHO-304): a phase 3, randomized, open-label study. BMC Cancer. 2024 Jul 25;23(Suppl 1):1254. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03358472
#Prabhash K, Deshmukh C, Malhotra H, Sharma A, Jain M, Dhamne N, Nagarakar R, Ganesan P, Mahobia VK, Das CK, Kumar R, Shivanna PS, Avaronnan MP, Chaithanya PK, Chaudhary V, Singh K, Aagre S, Ravishankar B, Mehta D, Shilpa K, Maniar V, Chatterjee K, Majumdar SD, Dana R, Noronha V, Menon N, Sharma A, Pawar R, Shahavi V, Yadav R, Aiwale A. Efficacy and Safety of Biosimilar Cetuximab Versus Innovator Cetuximab in Indian Patients With Head and Neck Cancer: A Multicenter, Randomized, Double-Blind, Phase III Trial. JCO Glob Oncol. 2024 Nov;10:e2400059. Epub 2024 Nov 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC CTRI/2019/09/021256
==Cisplatin & Fluorouracil (CF) & Panitumumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Vermorken et al. 2013 (SPECTRUM)	2007-2009 	Phase 3 (E-esc)	CF 	Might have longer OS (primary endpoint)Median OS: 11.1 vs 9 mo(HR 0.87, 95% CI 0.73-1.05)
====Chemotherapy====
*Cisplatin (Platinol) 100 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Targeted therapy====
*Panitumumab (Vectibix) 9 mg/kg IV once on day 1, given first
21-day cycle for up to 6 cycles 
====Subsequent treatment====
*Patients could choose to continue panitumumab maintenance
===References===
# SPECTRUM: Vermorken JB, Stöhlmacher-Williams J, Davidenko I, Licitra L, Winquist E, Villanueva C, Foa P, Rottey S, Skladowski K, Tahara M, Pai VR, Faivre S, Blajman CR, Forastiere AA, Stein BN, Oliner KS, Pan Z, Bach BA; SPECTRUM investigators. Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. Lancet Oncol. 2013 Jul;14(8):697-710. Epub 2013 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00460265
==Cisplatin & Fluorouracil (CF) & Pembrolizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Burtness et al. 2019 (KEYNOTE-048)	2015-2017 	Phase 3 (E-switch-ooc)	1a. Carboplatin, 5-FU, Cetuximab1b. CF & Cetuximab	Longer OS1 (co-primary endpoint)Median OS: 13 vs 10.7 mo(HR 0.77, 95% CI 0.63-0.93)Did not meet co-primary endpoint of PFS
Burtness et al. 2019 (KEYNOTE-048)	2015-2017 	Phase 3 (E-switch-ooc)	2. Pembrolizumab 	Not reported
1Reported efficacy is for the total population; see paper for details of other populations stratified by CPS.
====Chemotherapy====
*Cisplatin (Platinol) as follows:
**Cycles 1 to 6: 100 mg/m2 IV once on day 1
*Fluorouracil (5-FU) as follows:
**Cycles 1 to 6: 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles
===References===
# KEYNOTE-048: Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Basté N, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesía R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, González Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. Epub 2019 Oct 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02358031
##HRQoL analysis: Rischin D, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Braña I, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesía R, Ngamphaiboon N, Rordorf T, Ishak WZW, Hong RL, Mendoza RG, Jia L, Chirovsky D, Norquist J, Jin F, Burtness B. Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048. Oral Oncol. 2022 May;128:105815. Epub 2022 Apr 2. link to original article EuroPMC
##Update: Harrington KJ, Burtness B, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Basté N, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Lin J, Gumuscu B, Swaby RF, Rischin D. Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol. 2023 Feb 1;41(4):790-802. Epub 2022 Oct 11. link to original article link to PMC article EuroPMC
==Cisplatin & Paclitaxel (TP)==
CP: Cisplatin and Paclitaxel
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Gibson et al. 2005 (ECOG E1395)	1997-2000 	Phase 3 (E-switch-ic)	CF 	Did not meet primary endpoint of OS
Note: Patients with complete response (CR) received at least 6 cycles or 2 cycles past the point at which CR was documented, whichever came later. Patients with partial response (PR) continued on treatment until there was evidence of CR or progression disease. "Patients with stable disease (SD) could discontinue treatment after six cycles."
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
**Carboplatin AUC 6 IV once on day 1 could be used in patients who developed at least grade 2 neuropathy or renal impairment (CrCl less than 50 mL/min/1.73m2; note: later in Gibson et al. 2005, it says that carboplatin was used for patients who had CrCl less than or equal to 50 mL/min/1.73m2)
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
====Supportive therapy====
*Hydration and forced diuresis (no further details given) with cisplatin
*Dexamethasone (Decadron) 20 mg PO given twice on day 1; 12 and 6 hours prior to paclitaxel
*Diphenhydramine (Benadryl) (no dose specified) IV once on day 1, within 60 minutes prior to paclitaxel 
*H2 receptor antagonist (no further details given) IV once on day 1, within 60 minutes prior to paclitaxel 
21-day cycles for at least 6 cycles (see note) 
===References===
# ECOG E1395: Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J, Forastiere AA; ECOG. Randomized phase III evaluation of cisplatin plus fluorouracil versus cisplatin plus paclitaxel in advanced head and neck cancer (E1395): an intergroup trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2005 May 20;23(15):3562-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002888
==Fluorouracil monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Jacobs et al. 1992	1985-1989 	Phase 3 (C)	1. CF 	Seems to have lower ORR
Jacobs et al. 1992	1985-1989 	Phase 3 (C)	2. Cisplatin	Not reported
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====
*Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 4000 mg/m2)
21-day cycles
===References===
# Jacobs C, Lyman G, Velez-García E, Sridhar KS, Knight W, Hochster H, Goodnough LT, Mortimer JE, Einhorn LH, Schacter L, Cherng N, Dalton T, Burroughs J, Rozencweig M. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J Clin Oncol. 1992 Feb;10(2):257-63. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Methotrexate monotherapy==
===Regimen variant #1, 40 mg/m2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Forastiere et al. 1992 (SWOG-8514)	1986-1989 	Phase 3 (C)	1. Carboplatin & Fluorouracil	Seems to have lower ORR
Forastiere et al. 1992 (SWOG-8514)	1986-1989 	Phase 3 (C)	2. CF 	Lower ORR
Schornagel et al. 1995 	1988-1992 	Phase 3 (C)	Edatrexate 	Did not meet primary endpoint of ORR
Stewart et al. 2009 	2003-2006 	Phase 3 (C)	Gefitinib 	Did not meet primary endpoint of OS
Guigay et al. 2024 (ELAN UNFIT) 	2013-11-07 to 2018-04-23	Phase 3 (C)	Cetuximab 	Did not meet primary endpoint of FFS
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====
*Methotrexate (MTX) 40 mg/m2 IV once on day 1
====Supportive therapy====
*"Standard antiemetic regimens"
7-day cycles
===Regimen variant #2, 60 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lane et al. 1968 	Not reported 	Non-randomized	 	
Leone et al. 1968	Not reported 	Phase 2 	 	
Hong et al. 1983 	1979-1981 	Phase 3 (C) 	Cisplatin 	Did not meet efficacy endpoints
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====
*Methotrexate (MTX) as follows:
**Cycles 1 & 2: 40 mg/m2 IV bolus once on day 1
**Cycles 3 & 4: 50 mg/m2 IV bolus once on day 1
**Cycle 5 onwards: 60 mg/m2 IV bolus once on day 1
7-day cycles
===References===
# Lane M, Moore JE 3rd, Levin H, Smith FE. Methotrexate therapy for squamous cell carcinomas of the head and neck: intermittent intravenous dose program. JAMA. 1968 May 13;204(7):561-4. link to original article EuroPMC
# Leone LA, Albala MM, Rege VB. Treatment of carcinoma of the head and neck with intravenous methotrexate. Cancer. 1968 May;21(5):828-37. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Hong WK, Schaefer S, Issell B, Cummings C, Luedke D, Bromer R, Fofonoff S, D'Aoust J, Shapshay S, Welch J, Levin E, Vincent M, Vaughan C, Strong S. A prospective randomized trial of methotrexate versus cisplatin in the treatment of recurrent squamous cell carcinoma of the head and neck. Cancer. 1983 Jul 15;52(2):206-10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# SWOG-8514: Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK, Von Hoff DD. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol. 1992 Aug;10(8):1245-51. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Schornagel JH, Verweij J, de Mulder PH, Cognetti F, Vermorken JB, Cappelaere P, Armand JP, Wildiers J, de Graeff A, Clavel M, Sahmoud T, Kirkpatrick A, Lefebvre JL; EORTC Head and Neck Cancer Cooperative Group. Randomized phase III trial of edatrexate versus methotrexate in patients with metastatic and/or recurrent squamous cell carcinoma of the head and neck: a European Organisation for Research and Treatment of Cancer Head and Neck Cancer Cooperative Group study. J Clin Oncol. 1995 Jul;13(7):1649-55. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# Stewart JS, Cohen EE, Licitra L, Van Herpen CM, Khorprasert C, Soulieres D, Vodvarka P, Rischin D, Garin AM, Hirsch FR, Varella-Garcia M, Ghiorghiu S, Hargreaves L, Armour A, Speake G, Swaisland A, Vokes EE. Phase III study of gefitinib compared with intravenous methotrexate for recurrent squamous cell carcinoma of the head and neck [corrected]. J Clin Oncol. 2009 Apr 10;27(11):1864-71. Epub 2009 Mar 16. Erratum in: J Clin Oncol. 2009 Jul 10;27(20):3410. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#ELAN UNFIT: Guigay J, Ortholan C, Vansteene D, Cupissol D, Even C, Kaminsky MC, Sire C, Blot E, Debourdeau P, Bozec L, Saada-Bouzid E, Fayette J, Dalloz P, Pointreau Y, Caer HL, Falandry C, Digue L, Braccini A, Lopez S, Guillet P, Michel C, Cheurfa N, Schwob D, Bourhis J, Mertens C, Aupérin A; ELAN Group including Gustave Roussy, Unicancer GERICO and H&N groups and the GORTEC. Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial. Lancet Healthy Longev. 2024 Mar;5(3):e182-e193. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01884623
#ECOG E7397: NCT00003592
==Pembrolizumab monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Burtness et al. 2019 (KEYNOTE-048)	2015-2017 	Phase 3 (E-RT-switch-ooc)	1a. Carboplatin, 5-FU, Cetuximab1b. CF & Cetuximab 	Non-inferior OS1 (co-primary endpoint)Median OS: 11.6 vs 10.7 mo(HR 0.85, 95% CI 0.71-1.03)
Burtness et al. 2019 (KEYNOTE-048)	2015-2017 	Phase 3 (E-RT-switch-ooc)	2a. Carboplatin, 5-FU, Pembrolizumab2b. CF & Pembrolizumab 	Not reported
Cho et al. 2024 (ECHO-304) 	2017-12-01 to 2018-05-02	Phase 3 (C) 	1a. Carboplatin, 5-FU, Cetuximab1b. CF & Cetuximab2. Epacadostat & Pembrolizumab	Did not meet primary endpoint of ORR
1Reported efficacy is for the total population; see paper for details of other populations stratified by CPS.
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles
===References===
# KEYNOTE-048: Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Basté N, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesía R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Hong RL, González Mendoza R, Roy A, Zhang Y, Gumuscu B, Cheng JD, Jin F, Rischin D; KEYNOTE-048 Investigators. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019 Nov 23;394(10212):1915-1928. Epub 2019 Oct 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02358031
##HRQoL analysis: Rischin D, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Braña I, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesía R, Ngamphaiboon N, Rordorf T, Ishak WZW, Hong RL, Mendoza RG, Jia L, Chirovsky D, Norquist J, Jin F, Burtness B. Pembrolizumab alone or with chemotherapy for recurrent or metastatic head and neck squamous cell carcinoma: Health-related quality-of-life results from KEYNOTE-048. Oral Oncol. 2022 May;128:105815. Epub 2022 Apr 2. link to original article EuroPMC
##Update: Harrington KJ, Burtness B, Greil R, Soulières D, Tahara M, de Castro G Jr, Psyrri A, Brana I, Basté N, Neupane P, Bratland Å, Fuereder T, Hughes BGM, Mesia R, Ngamphaiboon N, Rordorf T, Wan Ishak WZ, Lin J, Gumuscu B, Swaby RF, Rischin D. Pembrolizumab With or Without Chemotherapy in Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma: Updated Results of the Phase III KEYNOTE-048 Study. J Clin Oncol. 2023 Feb 1;41(4):790-802. Epub 2022 Oct 11. link to original article link to PMC article EuroPMC
#ECHO-304: Cho BC, Braña I, Cirauqui B, Aksoy S, Couture F, Hong RL, Miller WH Jr, Chaves-Conde M, Teixeira M, Leopold L, Munteanu M, Ge JY, Swaby RF, Hughes BGM. Pembrolizumab plus epacadostat in patients with recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-669/ECHO-304): a phase 3, randomized, open-label study. BMC Cancer. 2024 Jul 25;23(Suppl 1):1254. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03358472
=Recurrent or metastatic disease, subsequent lines of therapy=
==Afatinib monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Machiels et al. 2015 (LUX-Head & Neck 1)	2012-01-10 to 2013-12-12	Phase 3 (E-switch-ooc)	Methotrexate	Seems to have longer PFS (primary endpoint)Median PFS: 2.6 vs 1.7 mo(HR 0.80, 95% CI 0.65-0.98)
Guo et al. 2019 (LUX-Head & Neck 3) 	2013-2018 	Phase 3 (E-switch-ooc)	Methotrexate	Longer PFS (primary endpoint)Median PFS: 2.9 vs 2.6 mo(HR 0.63, 95% CI 0.48-0.82)
====Targeted therapy====
*Afatinib (Gilotrif) 40 mg PO once per day
Continued indefinitely
====Dose and schedule modifications====
*LUX-Head & Neck 1: Dose could be increased to 50 mg PO once per day after 4 weeks, if side effects were minimal
===References===
# LUX-Head & Neck 1: Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, Clement PM, Gauler T, Cupissol D, Grau JJ, Guigay J, Caponigro F, de Castro G Jr, de Souza Viana L, Keilholz U, Del Campo JM, Cong XJ, Ehrnrooth E, Cohen EE; LUX-H&N 1 investigators. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol. 2015 May;16(5):583-94. Epub 2015 Apr 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01345682
# LUX-Head & Neck 3: Guo Y, Ahn MJ, Chan A, Wang CH, Kang JH, Kim SB, Bello M, Arora RS, Zhang Q, He X, Li P, Dechaphunkul A, Kumar V, Kamble K, Li W, Kandil A, Cohen EEW, Geng Y, Zografos E, Tang PZ. Afatinib versus methotrexate as second-line treatment in Asian patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 3): an open-label, randomised phase III trial. Ann Oncol. 2019 Nov 1;30(11):1831-1839. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01856478
==Cetuximab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Vermorken et al. 2007 (EMR 62202-016)	2001-06 to 2002-12 	Phase 2 (RT)	 	
Ferris et al. 2016 (CheckMate 141) 	2014-06 to 2015-08 	Phase 3 (C) 	Nivolumab 	Shorter OS1Median OS: 5.1 vs 7.7 mo(HR 1.47, 95% CI 1.16-1.85)
Cohen et al. 2018 (KEYNOTE-040) 	2014-2016 	Phase 3 (C) 	Pembrolizumab	Seems to have shorter OSMedian OS: 6.9 vs 8.4 mo(HR 1.25, 95% CI 1.02-1.54)
1Reported efficacy for CheckMate 141 is based on the 2018 update.
Note: EMR 62202-016 gave a 20 mg test dose as part of the initial dose; this was not specified in CheckMate 141. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
====Targeted therapy====
*Cetuximab (Erbitux) as follows:
**Cycle 1: 400 mg/m2 IV over 2 hours once on day 1
**Cycle 2 onwards: 250 mg/m2 IV over 60 minutes once on day 1
7-day cycles
===References===
# EMR 62202-016: Vermorken JB, Trigo J, Hitt R, Koralewski P, Diaz-Rubio E, Rolland F, Knecht R, Amellal N, Schueler A, Baselga J. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol. 2007 Jun 1;25(16):2171-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# CheckMate 141: Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016 Nov;375(19):1856-67. Epub 2016 Oct 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02105636
##HRQoL analysis: Harrington KJ, Ferris RL, Blumenschein G Jr, Colevas AD, Fayette J, Licitra L, Kasper S, Even C, Vokes EE, Worden F, Saba NF, Kiyota N, Haddad R, Tahara M, Grünwald V, Shaw JW, Monga M, Lynch M, Taylor F, DeRosa M, Morrissey L, Cocks K, Gillison ML, Guigay J. Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1104-1115. Epub 2017 Jun 23. link to original article link to PMC article EuroPMC
##Update: Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington KJ, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Docampo LCI, Haddad R, Rordorf T, Kiyota N, Tahara M, Lynch M, Jayaprakash V, Li L, Gillison ML. Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol. 2018 Jun;81:45-51. Epub 2018 Apr 17. link to original article link to PMC article EuroPMC
# KEYNOTE-040: Cohen EEW, Soulières D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, Soria A, Machiels JP, Mach N, Mehra R, Burtness B, Zhang P, Cheng J, Swaby RF, Harrington KJ; KEYNOTE-040 investigators. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019 Jan 12;393(10167):156-167. Epub 2018 Nov 30. link to original article dosing details on CT.gov have been reviewed by our editors EuroPMC NCT02252042
##HRQoL analysis: Harrington KJ, Soulières D, Le Tourneau C, Dinis J, Licitra LF, Ahn MJ, Soria A, Machiels JH, Mach N, Mehra R, Burtness B, Ellison MC, Cheng JD, Chirovsky DR, Swaby RF, Cohen EEW. Quality of Life With Pembrolizumab for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: KEYNOTE-040. J Natl Cancer Inst. 2021 Feb 1;113(2):171-181. link to original article link to PMC article EuroPMC
==Docetaxel monotherapy==
===Regimen variant #1, 30 mg/m2 weekly===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ferris et al. 2016 (CheckMate 141)	2014-06 to 2015-08 	Phase 3 (C)	Nivolumab 	Shorter OS1Median OS: 5.1 vs 7.7 mo(HR 1.47, 95% CI 1.16-1.85)
1Reported efficacy is based on the 2018 update.
Note: this was the lower bound of the dose range provided in CheckMate 141.
====Chemotherapy====
*Docetaxel (Taxotere) 30 mg/m2 IV once on day 1
7-day cycles
===Regimen variant #2, 35 mg/m2, 3 weeks out of 4===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Argiris et al. 2013 (ECOG E1302)	2004-2008 	Phase 3 (C)	Docetaxel & Gefitinib	Did not meet primary endpoint of OS50%Median OS: 6 vs 7.3 mo(HR 1.08, 95% CI 0.83-1.39)
====Chemotherapy====
*Docetaxel (Taxotere) 35 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===Regimen variant #3, 40 mg/m2 weekly===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Guardiola et al. 2004 	2000-2003 	Randomized Phase 2 (E-switch-ic)	Methotrexate	Higher ORR
Ferris et al. 2016 (CheckMate 141)	2014-06 to 2015-08 	Phase 3 (C) 	Nivolumab 	Shorter OS1Median OS: 5.1 vs 7.7 mo(HR 1.47, 95% CI 1.16-1.85)
1Reported efficacy for CheckMate 141 is based on the 2018 update.
Note: this was the upper bound of the dose range provided in CheckMate 141.
====Chemotherapy====
*Docetaxel (Taxotere) 40 mg/m2 IV once on day 1
7-day cycles
===Regimen variant #4, 75 mg/m2 q3wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cohen et al. 2018 (KEYNOTE-040)	2014-2016 	Phase 3 (C)	Pembrolizumab	Seems to have shorter OSMedian OS: 6.9 vs 8.4 mo(HR 1.25, 95% CI 1.02-1.54)
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycles
===References===
# Guardiola E, Peyrade F, Chaigneau L, Cupissol D, Tchiknavorian X, Bompas E, Madroszyk A, Ronchin P, Schneider M, Bleuze JP, Blay JY, Pivot X. Results of a randomised phase II study comparing docetaxel with methotrexate in patients with recurrent head and neck cancer. Eur J Cancer. 2004 Sep;40(14):2071-6. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# ECOG E1302: Argiris A, Ghebremichael M, Gilbert J, Lee JW, Sachidanandam K, Kolesar JM, Burtness B, Forastiere AA. Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2013 Apr 10;31(11):1405-14. Epub 2013 Mar 4. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00088907
# CheckMate 141: Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016 Nov;375(19):1856-67. Epub 2016 Oct 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02105636
##HRQoL analysis: Harrington KJ, Ferris RL, Blumenschein G Jr, Colevas AD, Fayette J, Licitra L, Kasper S, Even C, Vokes EE, Worden F, Saba NF, Kiyota N, Haddad R, Tahara M, Grünwald V, Shaw JW, Monga M, Lynch M, Taylor F, DeRosa M, Morrissey L, Cocks K, Gillison ML, Guigay J. Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1104-1115. Epub 2017 Jun 23. link to original article link to PMC article EuroPMC
##Update: Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington KJ, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Docampo LCI, Haddad R, Rordorf T, Kiyota N, Tahara M, Lynch M, Jayaprakash V, Li L, Gillison ML. Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol. 2018 Jun;81:45-51. Epub 2018 Apr 17. link to original article link to PMC article EuroPMC
# KEYNOTE-040: Cohen EEW, Soulières D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, Soria A, Machiels JP, Mach N, Mehra R, Burtness B, Zhang P, Cheng J, Swaby RF, Harrington KJ; KEYNOTE-040 investigators. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019 Jan 12;393(10167):156-167. Epub 2018 Nov 30. link to original article dosing details on CT.gov have been reviewed by our editors EuroPMC NCT02252042
##HRQoL analysis: Harrington KJ, Soulières D, Le Tourneau C, Dinis J, Licitra LF, Ahn MJ, Soria A, Machiels JH, Mach N, Mehra R, Burtness B, Ellison MC, Cheng JD, Chirovsky DR, Swaby RF, Cohen EEW. Quality of Life With Pembrolizumab for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: KEYNOTE-040. J Natl Cancer Inst. 2021 Feb 1;113(2):171-181. link to original article link to PMC article EuroPMC
==Methotrexate monotherapy==
===Regimen variant #1, 40 mg/m2 weekly===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Machiels et al. 2015 (LUX-Head & Neck 1)	2012-01-10 to 2013-12-12	Phase 3 (C)	Afatinib 	Seems to have shorter PFSMedian PFS: 1.7 vs 2.6 mo(HR 1.25, 95% CI 1.02-1.54)
Guo et al. 2019 (LUX-Head & Neck 3) 	2013-2018 	Phase 3 (C)	Afatinib 	Shorter PFSMedian PFS: 2.6 vs 2.9 mo(HR 1.59, 95% CI 1.22-2.08)
Ferris et al. 2016 (CheckMate 141) 	2014-06 to 2015-08 	Phase 3 (C)	Nivolumab 	Shorter OS1Median OS: 5.1 vs 7.7 mo(HR 1.47, 95% CI 1.16-1.85)
Cohen et al. 2018 (KEYNOTE-040) 	2014-2016 	Phase 3 (C)	Pembrolizumab 	Seems to have shorter OSMedian OS: 6.9 vs 8.4 mo(HR 1.25, 95% CI 1.02-1.54)
Ferris et al. 2020 (EAGLE) 	2015-2017 	Phase 3 (C)	1. Durvalumab 	Did not meet primary endpoint of OS
Ferris et al. 2020 (EAGLE) 	2015-2017 	Phase 3 (C)	2. Durvalumab & Tremelimumab	Did not meet primary endpoint of OS
1Reported efficacy for CheckMate 141 is based on the 2018 update.
Note: this was the lower bound of the dose range provided in CheckMate 141. This was a standard-of-care arm in EAGLE; dosing was not specified in the manuscript.
====Chemotherapy====
*Methotrexate (MTX) 40 mg/m2 IV bolus once on day 1
====Supportive therapy====
*"Standard antiemetic regimens"
7-day cycles
====Dose and schedule modifications====
*LUX-Head & Neck 1, no TRAEs: dose could be increased to 50 mg/m2 from cycle 3 onwards
===Regimen variant #2, 60 mg/m2 weekly===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ferris et al. 2016 (CheckMate 141)	2014-06 to 2015-08 	Phase 3 (C)	Nivolumab 	Shorter OS1Median OS: 5.1 vs 7.7 mo(HR 1.47, 95% CI 1.16-1.85)
Cohen et al. 2018 (KEYNOTE-040) 	2014-2016 	Phase 3 (C)	Pembrolizumab	Seems to have shorter OSMedian OS: 6.9 vs 8.4 mo(HR 1.25, 95% CI 1.02-1.54)
1Reported efficacy for CheckMate 141 is based on the 2018 update.
Note: this was the upper bound of the dose range provided in CheckMate 141, and was an optional escalation in KEYNOTE-040.
====Chemotherapy====
*Methotrexate (MTX) 60 mg/m2 IV once on day 1
7-day cycles
===References===
# LUX-Head & Neck 1: Machiels JP, Haddad RI, Fayette J, Licitra LF, Tahara M, Vermorken JB, Clement PM, Gauler T, Cupissol D, Grau JJ, Guigay J, Caponigro F, de Castro G Jr, de Souza Viana L, Keilholz U, Del Campo JM, Cong XJ, Ehrnrooth E, Cohen EE; LUX-H&N 1 investigators. Afatinib versus methotrexate as second-line treatment in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 1): an open-label, randomised phase 3 trial. Lancet Oncol. 2015 May;16(5):583-94. Epub 2015 Apr 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01345682
# CheckMate 141: Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016 Nov;375(19):1856-67. Epub 2016 Oct 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02105636
##HRQoL analysis: Harrington KJ, Ferris RL, Blumenschein G Jr, Colevas AD, Fayette J, Licitra L, Kasper S, Even C, Vokes EE, Worden F, Saba NF, Kiyota N, Haddad R, Tahara M, Grünwald V, Shaw JW, Monga M, Lynch M, Taylor F, DeRosa M, Morrissey L, Cocks K, Gillison ML, Guigay J. Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1104-1115. Epub 2017 Jun 23. link to original article link to PMC article EuroPMC
##Update: Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington KJ, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Docampo LCI, Haddad R, Rordorf T, Kiyota N, Tahara M, Lynch M, Jayaprakash V, Li L, Gillison ML. Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol. 2018 Jun;81:45-51. Epub 2018 Apr 17. link to original article link to PMC article EuroPMC
# KEYNOTE-040: Cohen EEW, Soulières D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, Soria A, Machiels JP, Mach N, Mehra R, Burtness B, Zhang P, Cheng J, Swaby RF, Harrington KJ; KEYNOTE-040 investigators. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019 Jan 12;393(10167):156-167. Epub 2018 Nov 30. link to original article dosing details on CT.gov have been reviewed by our editors EuroPMC NCT02252042
##HRQoL analysis: Harrington KJ, Soulières D, Le Tourneau C, Dinis J, Licitra LF, Ahn MJ, Soria A, Machiels JH, Mach N, Mehra R, Burtness B, Ellison MC, Cheng JD, Chirovsky DR, Swaby RF, Cohen EEW. Quality of Life With Pembrolizumab for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: KEYNOTE-040. J Natl Cancer Inst. 2021 Feb 1;113(2):171-181. link to original article link to PMC article EuroPMC
# LUX-Head & Neck 3: Guo Y, Ahn MJ, Chan A, Wang CH, Kang JH, Kim SB, Bello M, Arora RS, Zhang Q, He X, Li P, Dechaphunkul A, Kumar V, Kamble K, Li W, Kandil A, Cohen EEW, Geng Y, Zografos E, Tang PZ. Afatinib versus methotrexate as second-line treatment in Asian patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 3): an open-label, randomised phase III trial. Ann Oncol. 2019 Nov 1;30(11):1831-1839. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01856478
# EAGLE: Ferris RL, Haddad R, Even C, Tahara M, Dvorkin M, Ciuleanu TE, Clement PM, Mesia R, Kutukova S, Zholudeva L, Daste A, Caballero-Daroqui J, Keam B, Vynnychenko I, Lafond C, Shetty J, Mann H, Fan J, Wildsmith S, Morsli N, Fayette J, Licitra L. Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study. Ann Oncol. 2020 Jul;31(7):942-950. Epub 2020 Apr 12. link to original article does not contain dosing details EuroPMC NCT02369874
==Nivolumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ferris et al. 2016 (CheckMate 141)	2014-06 to 2015-08 	Phase 3 (E-RT-switch-ooc)	Investigator's choice of:1a. Methotrexate1b. Docetaxel1c. Cetuximab	Longer OS1 (primary endpoint)Median OS: 7.7 vs 5.1 mo (HR 0.68, 95% CI 0.54-0.86)
1Reported efficacy is based on the 2018 update.
====Immunotherapy====
*Nivolumab (Opdivo) 3 mg/kg IV over 60 minutes once on day 1
14-day cycles
===References===
# CheckMate 141: Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016 Nov;375(19):1856-67. Epub 2016 Oct 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02105636
##HRQoL analysis: Harrington KJ, Ferris RL, Blumenschein G Jr, Colevas AD, Fayette J, Licitra L, Kasper S, Even C, Vokes EE, Worden F, Saba NF, Kiyota N, Haddad R, Tahara M, Grünwald V, Shaw JW, Monga M, Lynch M, Taylor F, DeRosa M, Morrissey L, Cocks K, Gillison ML, Guigay J. Nivolumab versus standard, single-agent therapy of investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck (CheckMate 141): health-related quality-of-life results from a randomised, phase 3 trial. Lancet Oncol. 2017 Aug;18(8):1104-1115. Epub 2017 Jun 23. link to original article link to PMC article EuroPMC
##Update: Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington KJ, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Docampo LCI, Haddad R, Rordorf T, Kiyota N, Tahara M, Lynch M, Jayaprakash V, Li L, Gillison ML. Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression. Oral Oncol. 2018 Jun;81:45-51. Epub 2018 Apr 17. link to original article link to PMC article EuroPMC
==Paclitaxel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Soulières et al. 2017 (BERIL-1)	2013-2015 	Randomized Phase 2 (C)	Buparlisib & Paclitaxel	Seems to have shorter PFSMedian PFS: 3.5 vs 4.6 mo(HR 1.54, 95% CI 1.05-2.22)
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
7-day cycles
===References===
# BERIL-1: Soulières D, Faivre S, Mesía R, Remenár É, Li SH, Karpenko A, Dechaphunkul A, Ochsenreither S, Kiss LA, Lin JC, Nagarkar R, Tamás L, Kim SB, Erfán J, Alyasova A, Kasper S, Barone C, Turri S, Chakravartty A, Chol M, Aimone P, Hirawat S, Licitra L. Buparlisib and paclitaxel in patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck (BERIL-1): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Oncol. 2017 Mar;18(3):323-335. Epub 2017 Jan 26. link to original article EuroPMC NCT01852292
==Pembrolizumab monotherapy==
===Regimen variant #1, 10 mg/kg===
Study 	Dates of enrollment	Evidence
Seiwert et al. 2016 (KEYNOTE-012)	2013 	Phase 1b, >20 pts (RT)
Note: a small number (N=7) of patients received this treatment as their first-line therapy for recurrent or metastatic disease.
====Immunotherapy====
*Pembrolizumab (Keytruda) 10 mg/kg IV once on day 1
14-day cycle for up to 52 cycles (2 years)
===Regimen variant #2, 200 mg===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Cohen et al. 2018 (KEYNOTE-040)	2014-2016 	Phase 3 (E-switch-ooc)	Investigator's choice of:1a. Docetaxel1b. MTX1c. Cetuximab	Seems to have longer OS (primary endpoint)Median OS: 8.4 vs 6.9 mo(HR 0.80, 95% CI 0.65-0.98)
====Immunotherapy====
*Pembrolizumab (Keytruda) 200 mg IV once on day 1
21-day cycle for up to 35 cycles (2 years)
===References===
# KEYNOTE-012: Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, Cheng JD, Chow LQ. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016 Jul;17(7):956-65. Epub 2016 May 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01848834
##Update: Chow LQM, Haddad R, Gupta S, Mahipal A, Mehra R, Tahara M, Berger R, Eder JP, Burtness B, Lee SH, Keam B, Kang H, Muro K, Weiss J, Geva R, Lin CC, Chung HC, Meister A, Dolled-Filhart M, Pathiraja K, Cheng JD, Seiwert TY. Antitumor Activity of Pembrolizumab in Biomarker-Unselected Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: Results From the Phase Ib KEYNOTE-012 Expansion Cohort. J Clin Oncol. 2016 Nov 10;34(32):3838-3845. Epub 2016 Sep 30. link to original article link to PMC article EuroPMC
# KEYNOTE-040: Cohen EEW, Soulières D, Le Tourneau C, Dinis J, Licitra L, Ahn MJ, Soria A, Machiels JP, Mach N, Mehra R, Burtness B, Zhang P, Cheng J, Swaby RF, Harrington KJ; KEYNOTE-040 investigators. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet. 2019 Jan 12;393(10167):156-167. Epub 2018 Nov 30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02252042
##HRQoL analysis: Harrington KJ, Soulières D, Le Tourneau C, Dinis J, Licitra LF, Ahn MJ, Soria A, Machiels JH, Mach N, Mehra R, Burtness B, Ellison MC, Cheng JD, Chirovsky DR, Swaby RF, Cohen EEW. Quality of Life With Pembrolizumab for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: KEYNOTE-040. J Natl Cancer Inst. 2021 Feb 1;113(2):171-181. link to original article link to PMC article EuroPMC
Category:Head and neck cancer regimens
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Category:Head and neck cancers