Head and neck cancer

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 Jennifer H. Choe, MD, PhD
Vanderbilt University
Nashville, TN, USA
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 C. Beau Hilton, MD
Vanderbilt University
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Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!

45 regimens on this page
85 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

EHNS/ESMO/ESTRO

ESMO

NCCN

SITC

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 PFS
Median PFS: 342 vs 400 d
(HR 1.33, 95% CI 0.94-1.89)

Chemotherapy

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 Inferior OS1

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


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

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-NR Phase 3 (E-esc) Surgery Did not meet primary endpoint of OS
Taylor et al. 1994a 1986-1991 Phase 3 (C) CF & RT Inferior ORR
Hitt et al. 2005 1998-2001 Phase 3 (C) PCF, then Cisplatin & RT Inferior CR rate
Pointreau et al. 2009 (GORTEC 2000-01) 2000-2005 Phase 3 (C) TPF, then RT Inferior ORR
Hitt et al. 2013 (TTCC XRP6976F/2503) 2002-2007 Phase 2/3 (E-esc) 1. No induction
2. TPF 		Did not meet co-primary endpoints of PFS/TTF

Chemotherapy

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 XRP6976F/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 Seems to have inferior OS

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

  1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed NCT00002496
    1. 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 PubMed
  3. 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 contains dosing details in manuscript PubMed
  4. 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 contains dosing details in manuscript PubMed NCT00003888
    1. 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 contains dosing details in manuscript link to PMC article PubMed
  5. 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 contains dosing details in manuscript PubMed NCT00273546
    1. 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 PubMed
  6. 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 contains dosing details in manuscript link to PMC article PubMed NCT00002839
    1. 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 PubMed
  7. 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 contains dosing details in manuscript PubMed NCT00169182
    1. 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 PubMed
  8. TTCC XRP6976F/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 contains dosing details in manuscript PubMed NCT00261703
  9. 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 contains dosing details in abstract PubMed 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 Superior CR rate (primary endpoint)

Chemotherapy

Supportive therapy

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

  1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed

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

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Chemotherapy

21-day cycle for 2 cycles

Subsequent treatment


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 Superior ORR (secondary endpoint)

Seems to have superior 3-year larynx preservation rate (primary endpoint)
Hitt et al. 2013 (TTCC XRP6976F/2503) 2002-2007 Phase 2/3 (E-esc) 1. No induction
2. 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

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 XRP6976F/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 Superior PFS (primary endpoint)
Median PFS: 11 vs 8.2 mo
(HR 0.72, 95% CI 0.57-0.91)

Superior OS (secondary endpoint)
Median OS: 18.8 vs 14.5 mo
(HR 0.73, 95% CI 0.56-0.94)

Chemotherapy

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 superior OS (primary endpoint)
Median OS: 54.7 vs 31.7 mo
(HR 0.74, 95% CI 0.55-0.98)

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment


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

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 Superior 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

References

  1. 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 contains dosing details in manuscript PubMed NCT00003888
    1. 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 contains dosing details in manuscript link to PMC article PubMed
  2. 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 contains dosing details in manuscript PubMed NCT00273546
    1. 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 PubMed
  3. 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 contains dosing details in manuscript PubMed NCT00169182
    1. 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 PubMed content property of HemOnc.org
  4. 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 contains dosing details in manuscript link to PMC article PubMed NCT00054054
  5. 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 contains dosing details in manuscript PubMed NCT00169247
  6. 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 PubMed NCT00095875
  7. 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 contains dosing details in manuscript PubMed NCT01542931
    1. 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 PubMed
  8. TTCC XRP6976F/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 contains dosing details in manuscript PubMed NCT00261703
  9. 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 contains dosing details in manuscript PubMed NCT01086826

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

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 200 cGy fractions x 35 to 37 fractions (total dose: 70 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

  1. 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 contains dosing details in manuscript PubMed NCT00273546
    1. 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 PubMed

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 superior OS (primary endpoint)
Staar et al. 2001 1995-1999 Phase 3 (E-esc) Radiation therapy Seems to have superior 1-year SLC (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
2. RT; very accelerated Seems to have superior 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

Radiotherapy

  • Concurrent radiation therapy 200 cGy fractions x 35 fractions (total dose: 7000 cGy), given 5 days per week

7-week course

References

  1. 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 PubMed
    1. 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 contains dosing details in manuscript PubMed
  2. 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 PubMed
  3. 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 contains dosing details in manuscript PubMed NCT00158652
  4. 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 contains dosing details in manuscript PubMed 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 Superior PFS (primary endpoint)
Median PFS: 37.9 vs 22.4 mo
(HR 0.73, 95% CI 0.57-0.94)

Chemotherapy

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

  1. 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 contains dosing details in manuscript PubMed NCT00609284

Carboplatin & Paclitaxel (CP) & RT

Carboplatin, Paclitaxel, RT: Carboplatin, Paclitaxel, Radiation Therapy

Regimen variant #1, accelerated hyperfractionated RT

Study Evidence
Carter et al. 2008 Phase 2

Chemotherapy

Radiotherapy

6-week course


Regimen variant #2, standard RT

Study Evidence
Conley et al. 1997 Pilot, fewer than 20 patients
Suntharalingam et al. 2000 Phase 2

Note: According to Conley et al. 1997, the initial paclitaxel dose was 45 mg/m2, but 40 mg/m2 was subsequently used.

Chemotherapy

Supportive therapy

Radiotherapy

  • Concurrent radiation therapy, 180 cGy fractions x 39 fractions (total dose: 7020 cGy), given 5 times per week

7.5-week course

References

  1. 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. contains dosing details in abstract PubMed
  2. 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 contains dosing details in manuscript PubMed
  3. 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 contains dosing details in abstract PubMed

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 superior OS (secondary endpoint)

Chemotherapy

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 Superior ORR

Chemotherapy

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
2. RT Did not meet primary endpoint of OS

Chemotherapy

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: 60 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

Chemotherapy

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 superior RFS
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


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 Superior OS1
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

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

Radiotherapy


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 superior OS

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
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

  1. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
  2. 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 contains dosing details in manuscript PubMed
  3. 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 contains dosing details in abstract PubMed
    1. 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 PubMed
  4. 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 contains dosing details in manuscript PubMed
  5. 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 contains dosing details in manuscript PubMed
  6. 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 contains dosing details in supplement PubMed
  7. 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 contains dosing details in abstract link to PMC article PubMed NCT00003576
  8. 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 contains dosing details in abstract PubMed NCT00003627
  9. 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 contains dosing details in manuscript PubMed NCT00002839
    1. 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 PubMed
  10. 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 contains dosing details in manuscript PubMed NCT01086826
  11. 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 contains dosing details in abstract PubMed 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 Superior OS

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 superior FFS

Chemotherapy

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; accelerated
2. RT; standard 		Seems to have superior LRC (primary endpoint)
Patil et al. 2019a 2012-2018 Phase 3 (C) Cisplatin, Nimotuzumab, RT Inferior PFS

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 200 cGy fractions given 5 times per week (total dose: 66 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 Might have superior OS

Chemotherapy

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 PFS

Preceding treatment

  • SWOG S0216: TPF induction

Chemotherapy

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
2. RT Seems to have superior 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) RT Superior OS (primary endpoint)
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 XRP6976F/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 PFS
Hitt et al. 2013 (TTCC-2007-01) 2008-07-15 to 2013-07-05 Phase 3 (C) Cetuximab & RT Inconclusive whether non-inferior OS
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 superior 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

Preceding treatment

  • Hitt et al. 2005: CF versus PCF induction
  • TTCC XRP6976F/2503: CF versus TPF versus no induction
  • TREMPLIN: TPF induction

Chemotherapy

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:

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

  1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed
  3. 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 contains dosing details in manuscript PubMed NCT00002496
    1. 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 PubMed
  4. 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 PubMed
  5. 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 contains dosing details in manuscript PubMed
  6. 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 contains dosing details in manuscript link to PMC article PubMed NCT00054054
  7. 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 contains dosing details in abstract PubMed
  8. 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 PubMed NCT00094081
  9. 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 contains dosing details in manuscript PubMed
  10. 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 contains dosing details in manuscript PubMed NCT00169247
  11. 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 contains dosing details in manuscript PubMed NCT00095875
  12. TTCC XRP6976F/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 contains dosing details in manuscript PubMed NCT00261703
  13. 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 contains dosing details in manuscript link to PMC article PubMed NCT00265941
    1. 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 PubMed
  14. 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 contains dosing details in manuscript PubMed NCT00047008
  15. 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 contains dosing details in manuscript PubMed
  16. 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 contains dosing details in manuscript PubMed NCT00820248
  17. 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 contains dosing details in manuscript PubMed CTRI/2012/10/003062
  18. 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 contains dosing details in abstract PubMed CTRI/2014/09/004980
  19. 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 contains dosing details in abstract PubMed NCT00158678
  20. 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 contains dosing details in manuscript PubMed NCT00999700
  21. 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 contains dosing details in manuscript link to PMC article PubMed NCT01969877
  22. 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 contains dosing details in abstract PubMed NCT02952586
  23. 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 PubMed NCT00716391
  24. GORTEC 2017-01: NCT02999087
  25. KEYNOTE-412: NCT03040999
  26. OCAT: NCT00193843

Cisplatin, Paclitaxel, 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
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

  1. 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 contains dosing details in manuscript PubMed

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

Radiotherapy

14-day cycle for 5 cycles

References

  1. 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 PubMed
  2. 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 PubMed 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 superior OS (secondary endpoint)
Median OS: 25.5 vs 15.3 mo
(HR 0.75, 95% CI 0.57-0.98)

Superior DFS24 (primary endpoint)
DFS24: 42% vs 30.3%
(HR 0.67, 95% CI 0.52-0.87)

Eligibility criteria

  • Cisplatin-ineligible

Chemotherapy

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

  1. 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 contains dosing details in manuscript PubMed 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
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

  1. 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 contains dosing details in manuscript PubMed

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 superior OS (secondary endpoint)

Chemotherapy

Radiotherapy

6-week course

References

  1. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed

Fluorouracil & RT

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gollin et al. 1972 1961-NR Phase 3 (E-esc) RT Seems to have superior OS1
Sanchíz et al. 1990 1978-1988 Phase 3 (E-esc) 1. RT; conventional Superior OS
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 superior OS

1Reported efficacy for Gollin et al. 1972 is based on the 1976 update, for oral lesions only.

Chemotherapy

Radiotherapy

References

  1. 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 PubMed
    1. 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 PubMed
  2. 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 contains dosing details in abstract PubMed
  3. 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 contains dosing details in abstract PubMed

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

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

  1. 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 contains dosing details in manuscript PubMed

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 Seems to have superior DFS (primary endpoint)

Note: the control in this trial was the historical control arm of RTOG 9501 that received chemoradiotherapy.

Preceding treatment

Chemotherapy

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

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

  1. 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 contains dosing details in manuscript link to PMC article PubMed 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

Chemotherapy

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 Superior OS

Preceding treatment

Chemotherapy

Supportive therapy

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 Superior OS (secondary endpoint)
Median OS: 72 vs 32 mo
(HR 0.70, 95% CI 0.52-0.95)

Preceding treatment

Chemotherapy

Supportive therapy

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 superior 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 superior 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

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 DFS
Kiyota et al. 2022 (JCOG1008) 2012-2018 Phase 2/3 (C) Cisplatin & RT; weekly Non-inferior OS

Preceding treatment

Chemotherapy

Radiotherapy

  • Concurrent radiation therapy, 200 cGy fractions x 33 fractions (total dose: 6600 cGy), given 5 times per week

6.5-week course

References

  1. 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 PubMed
    1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed NCT00002670
    1. 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 PubMed
    2. 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 contains dosing details in manuscript link to PMC article PubMed
  3. 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 contains dosing details in manuscript PubMed NCT00002555
    1. 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 PubMed
  4. 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 contains dosing details in abstract PubMed NCT00424255
  5. 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 contains dosing details in manuscript PubMed CTRI/2012/10/003062
  6. 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 contains dosing details in manuscript link to PMC article PubMed jRCTs031180135
  7. 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 Superior DFS (primary endpoint)

Note: the control in this trial was the historical control arm of RTOG 9501 that received chemoradiotherapy.

Preceding treatment

Chemotherapy

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

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

  1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00084318

Radiation therapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bachaud et al. 1991 1984-1988 Phase 3 (C) Cisplatin & RT Inferior OS
Wolf et al. 1991 1985-NR Non-randomized part of phase 3 RCT
Bernier et al. 2004 (EORTC 22931) 1994-2000 Phase 3 (C) Cisplatin & RT Seems to have inferior OS
Cooper et al. 2004 (RTOG 9501) 1995-2000 Phase 3 (C) Cisplatin & RT Seems to have inferior DFS
Porceddu et al. 2018 (TROG 05.01) 2005-2014 Phase 3 (C) Carboplatin & RT Did not meet primary endpoint of FFLRR

Preceding treatment

Radiotherapy

References

  1. 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 PubMed
    1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed
  3. 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 contains dosing details in manuscript PubMed NCT00002670
    1. 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 PubMed
    2. 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 contains dosing details in manuscript link to PMC article PubMed
  4. 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 contains dosing details in manuscript PubMed NCT00002555
    1. 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 PubMed
  5. 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 PubMed 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

Chemotherapy

1-year course

References

  1. 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 contains dosing details in abstract PubMed NCT00336947

Recurrent or metastatic disease, first-line therapy

Carboplatin & Docetaxel

Regimen variant #1, 6/65

Study Evidence
Samlowski et al. 2007 Phase 2

Chemotherapy

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, Bevacizumab
1b. CF & Bevacizumab
1c. DCb & Bevacizumab
1d. DC & Bevacizumab 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

References

  1. 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 contains dosing details in abstract PubMed
  2. 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 contains dosing details in manuscript link to PMC article PubMed 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, Bevacizumab
1b. CF & Bevacizumab
1c. DCb & Bevacizumab
1d. DC & Bevacizumab 		Did not meet primary endpoint of OS

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
2. MTX Seems to have superior ORR
Vermorken et al. 2008 (EXTREME) 2004-12-21 to 2005-12-30 Phase 3 (C) 1a. Carboplatin, Fluorouracil, Cetuximab
1b. CF & Cetuximab 		Seems to have inferior OS

Chemotherapy

Supportive therapy

  • "Standard antiemetic regimens"

28-day cycles

References

  1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript PubMed NCT00122460
    1. 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 PubMed
  3. 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 contains dosing details in manuscript link to PMC article PubMed 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 & Fluorouracil
1b. CF 		Seems to have superior 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, Pembrolizumab
1b. CF & Pembrolizumab 		Inferior OS
2. Pembrolizumab Non-inferior OS1
Psyrri et al. 2022 (KESTREL) 2015-2017 Phase 3 (C) 1. Durvalumab
2. Durvalumab & Tremelimumab 		Did not meet primary endpoint of OS
Haddad et al. 2022 (CheckMate 651) NR Phase 3 (C) Ipilimumab & Nivolumab Did not meet primary endpoint of OS

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) given first before chemotherapy and ending at least 1 hour before chemotherapy starts, as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, 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

21-day cycles

References

  1. 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 contains dosing details in manuscript PubMed NCT00122460
    1. 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 PubMed
  2. 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 contains dosing details in manuscript PubMed NCT02358031
    1. 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 PubMed
  3. 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 PubMed NCT02551159
  4. 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 refers to Vermorken et al. 2008 for dosing PubMed NCT02741570

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, Cetuximab
1b. CF & Cetuximab 		Superior 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
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

21-day cycle for up to 35 cycles

References

  1. 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 contains dosing details in manuscript PubMed NCT02358031
    1. 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 PubMed

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

Targeted therapy

7-day cycles

References

  1. 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 contains dosing details in abstract PubMed 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 Inferior OS12

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

Chemotherapy

Targeted therapy

7-day cycles

References

  1. 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 contains dosing details in abstract PubMed 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 Superior OS12 (primary endpoint)
OS12: 43.4% vs 16.3%
(HR 0.545, 95% CI 0.36-0.82)

Chemotherapy

Targeted therapy

Immunotherapy

21-day cycles

References

  1. 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 contains dosing details in abstract PubMed 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. CABO
2. CF 		Inferior ORR

Chemotherapy

28-day cycles


Regimen variant #2, 75 mg/m2 q3wk x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Patil et al. 2020 2016-05-16 to 2020-01-17 Phase 3 (C) Celecoxib & Methotrexate Non-inferior OS

Chemotherapy

21-day cycles


Regimen variant #3, 75 mg/m2 q3wk, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Urba et al. 2012 (JMHR) 2006-2010 Phase 3 (C) Cisplatin & Pemetrexed Might have inferior OS

Chemotherapy

21-day cycles


Regimen variant #4, 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

21-day cycles


Regimen variant #5, 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 inferior ORR
2. 5-FU Not reported

Chemotherapy

21-day cycles


Regimen variant #6, 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

28-day cycles (see note)

References

  1. 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 contains dosing details in abstract PubMed
  2. 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 contains dosing details in abstract PubMed
  3. 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 contains dosing details in abstract PubMed
  4. 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 contains dosing details in abstract PubMed
  5. 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 contains dosing details in manuscript PubMed NCT00003809
  6. 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 contains dosing details in abstract PubMed NCT00415194
  7. 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 contains dosing details in abstract PubMed CTRI/2015/11/006388

Cisplatin & Docetaxel (DC)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Glisson et al. 2002 NR Phase 2
Argiris et al. 2019 (ECOG E1305) 2008-2015 Phase 3 (C) 1a. Carboplatin, 5-FU, Bevacizumab
1b. CF & Bevacizumab
1c. DCb & Bevacizumab
1d. DC & Bevacizumab 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycles

References

  1. 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 contains dosing details in abstract PubMed
  2. 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 contains dosing details in manuscript link to PMC article PubMed NCT00588770

Cisplatin & Fluorouracil (CF)

CF: Cisplatin and Fluorouracil

Regimen variant #1, 3 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Clavel et al. 1994 1984-1987 Phase 3 (E-esc) 1. CABO Seems to have inferior ORR
2. Cisplatin Superior ORR

Chemotherapy

Supportive therapy

  • Details vary per reference
  • Pretreatment and posttreatment hydration and mannitol diuresis with cisplatin
  • "Standard antiemetic regimens"

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #2, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gibson et al. 2005 (ECOG E1395) 1997-2000 Phase 3 (C) CP Did not meet primary endpoint of OS
Vermorken et al. 2013 (SPECTRUM) 2007-2009 Phase 3 (C) CF & Panitumumab Inferior PFS

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 once on day 1
    • 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 (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 6 cycles (see note)


Regimen variant #3, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jacobs et al. 1992 1985-1989 Phase 3 (E-esc) 1. Cisplatin
2. 5-FU 		Seems to have superior ORR
Forastiere et al. 1992 (SWOG-8514) 1986-1989 Phase 3 (E-switch-ic) 1. Carboplatin & Fluorouracil Not reported
2. MTX Superior ORR
Schrijvers et al. 1998 1992-1994 Phase 3 (C) CF & IFN alfa 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, Cetuximab
1b. CF & Cetuximab 		Seems to have inferior OS
Argiris et al. 2019 (ECOG E1305) 2008-2015 Phase 3 (C) 1a. Carboplatin, 5-FU, Bevacizumab
1b. CF & Bevacizumab
1c. DCb & Bevacizumab
1d. DC & Bevacizumab 		Did not meet primary endpoint of OS

Chemotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV over 60 to 120 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)

Supportive therapy

  • Details vary per reference
  • Pretreatment and posttreatment hydration and mannitol diuresis with cisplatin
  • "Standard antiemetic regimens"

21-day cycles

References

  1. 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 contains dosing details in abstract PubMed
  2. 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 contains dosing details in manuscript PubMed
  3. 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 contains dosing details in abstract PubMed
  4. 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 PubMed
  5. 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 contains dosing details in manuscript PubMed NCT00002888
  6. 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 contains dosing details in manuscript PubMed NCT00122460
    1. 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 PubMed
  7. 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 contains dosing details in abstract PubMed NCT00460265
  8. 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 contains dosing details in manuscript link to PMC article PubMed NCT00588770

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 Superior PFS (primary endpoint)
Median PFS: 5.5 vs 4.2 mo
(HR 0.57, 95% CI 0.40-0.80)

Superior 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

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 & Fluorouracil
1b. CF 		Seems to have superior 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, Pembrolizumab
1b. CF & Pembrolizumab 		Inferior OS
2. Pembrolizumab Non-inferior OS1
Psyrri et al. 2022 (KESTREL) 2015-2017 Phase 3 (C) 1. Durvalumab
2. Durvalumab & Tremelimumab 		Did not meet primary endpoint of OS
Haddad et al. 2022 (CheckMate 651) NR Phase 3 (C) Ipilimumab & Nivolumab Did not meet primary endpoint of OS

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) given first before chemotherapy and ending at least 1 hour before chemotherapy starts, as follows:
    • Cycle 1: 400 mg/m2 IV over 2 hours once on day 1, 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

21-day cycles

References

  1. 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 contains dosing details in manuscript PubMed NCT00122460
    1. 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 PubMed
  2. 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 contains dosing details in manuscript PubMed NCT02358031
    1. 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 PubMed
  3. 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 contains dosing details in manuscript PubMed NCT02383966
  4. 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 PubMed NCT02551159
  5. 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 refers to Vermorken et al. 2008 for dosing PubMed NCT02741570

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 superior OS (primary endpoint)
Median OS: 11.1 vs 9 mo
(HR 0.87, 95% CI 0.73-1.05)

Chemotherapy

Targeted therapy

21-day cycle for up to 6 cycles

Subsequent treatment

  • Patients could choose to continue panitumumab maintenance

References

  1. 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 contains dosing details in abstract PubMed 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, Cetuximab
1b. CF & Cetuximab 		Superior 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
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

21-day cycle for up to 35 cycles

References

  1. 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 contains dosing details in manuscript PubMed NCT02358031
    1. 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 PubMed

Cisplatin & Paclitaxel

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

  1. 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 contains dosing details in manuscript PubMed 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 inferior ORR
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

  1. 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 contains dosing details in manuscript PubMed

Methotrexate monotherapy

Regimen variant #1, 40 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hong et al. 1983 1979-1981 Phase 3 (C) Cisplatin Did not meet efficacy endpoints
Forastiere et al. 1992 (SWOG-8514) 1986-1989 Phase 3 (C) 1. Carboplatin & Fluorouracil Seems to have inferior ORR
2. CF Inferior 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

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 NR Non-randomized
Leone et al. 1968 NR 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

7-day cycles

References

  1. 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 PubMed
  2. 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 contains dosing details in abstract PubMed
  3. 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 contains dosing details in abstract PubMed
  4. 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 contains dosing details in manuscript PubMed
  5. 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 contains dosing details in abstract PubMed
  6. 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 contains dosing details in manuscript PubMed
  7. 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 contains dosing details in abstract PubMed NCT01884623
  8. 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, Cetuximab
1b. 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)
2a. Carboplatin, 5-FU, Pembrolizumab
2b. CF & Pembrolizumab 		Not reported

1Reported efficacy is for the total population; see paper for details of other populations stratified by CPS.

Immunotherapy

21-day cycle for up to 35 cycles

References

  1. 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 contains dosing details in manuscript PubMed NCT02358031
    1. 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 PubMed

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 superior 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 Superior PFS (primary endpoint)
Median PFS: 2.9 vs 2.6 mo
(HR 0.63, 95% CI 0.48-0.82)

Targeted therapy

Continued indefinitely

References

  1. 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 contains dosing details in abstract PubMed NCT01345682
  2. 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 contains dosing details in abstract link to PMC article PubMed 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 Inferior OS

Note: EMR 62202-016 gave a 20 mg test dose as part of the initial dose; this is 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

  1. 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 contains dosing details in manuscript PubMed
  2. 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 contains dosing details in manuscript link to PMC article PubMed NCT02105636
    1. 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 PubMed
    2. 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 PubMed
  3. 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 PubMed NCT02252042
    1. 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 PubMed

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 Inferior OS

Note: this was the lower bound of the dose range provided in CheckMate 141.

Chemotherapy

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%

Chemotherapy

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 Superior ORR
Ferris et al. 2016 (CheckMate 141) 2014-06 to 2015-08 Phase 3 (C) Nivolumab Inferior OS

Note: this was the upper bound of the dose range provided in CheckMate 141.

Chemotherapy

7-day cycles

References

  1. 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 contains dosing details in abstract PubMed
  2. 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 contains dosing details in manuscript link to PMC article PubMed NCT00088907
  3. 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 contains dosing details in manuscript link to PMC article PubMed NCT02105636
    1. 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 PubMed
    2. 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 PubMed
  4. 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 PubMed NCT02252042
    1. 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 PubMed

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 inferior PFS
Guo et al. 2019 (LUX-Head & Neck 3) 2013-2018 Phase 3 (C) Afatinib Inferior PFS
Ferris et al. 2016 (CheckMate 141) 2014-06 to 2015-08 Phase 3 (C) Nivolumab Inferior OS
Ferris et al. 2020 (EAGLE) 2015-2017 Phase 3 (C) 1. Durvalumab Did not meet primary endpoint of OS
2. Durvalumab & Tremelimumab Did not meet primary endpoint of OS

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

Supportive therapy

  • "Standard antiemetic regimens"

7-day cycles


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 Inferior OS

Note: this was the upper bound of the dose range provided in CheckMate 141.

Chemotherapy

7-day cycles

References

  1. 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 contains dosing details in abstract PubMed NCT01345682
  2. 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 contains dosing details in manuscript link to PMC article PubMed NCT02105636
    1. 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 PubMed
    2. 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 PubMed
  3. 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 PubMed NCT02252042
    1. 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 PubMed
  4. 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 contains dosing details in abstract link to PMC article PubMed NCT01856478
  5. 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 PubMed 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. Methotrexate
1b. Docetaxel
1c. Cetuximab 		Superior OS1 (primary endpoint)
Median OS: 7.7 vs 5.1 mo
(HR 0.68, 95% CI 0.54-0.86)

1Reported efficacy based on the 2018 update.

Immunotherapy

14-day cycles

References

  1. 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 contains dosing details in manuscript link to PMC article PubMed NCT02105636
    1. 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 PubMed
    2. 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 PubMed

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 inferior PFS

Chemotherapy

7-day cycles

References

  1. 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 PubMed 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

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. Docetaxel
1b. MTX
1c. Cetuximab 		Seems to have superior OS (primary endpoint)
Median OS: 8.4 vs 6.9 mo
(HR 0.80, 95% CI 0.65-0.98)

Immunotherapy

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

References

  1. 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 contains dosing details in manuscript PubMed NCT01848834
    1. 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 PubMed
  2. 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 contains dosing details in manuscript PubMed NCT02252042
    1. 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 PubMed
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