Head and neck cancer

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Michael Gibson, MD, PhD
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Note: Regimens for nasopharyngeal carcinoma have been moved to a dedicated page.

37 regimens on this page
63 variants on this page

Contents


Guidelines

ASCO

EHNS/ESMO/ESTRO

NCCN

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

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CF: Cisplatin & Fluorouracil
PF: Platinol (Cisplatin) & Fluorouracil

Variant #1, 100/4000

Study Evidence Comparator Efficacy
Posner et al. 2007 (TAX 324) Phase III (C) TPF, then Carboplatin & RT Seems to have inferior OS (*)

Reported 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 on days 1 to 4 (total dose per cycle: 4000 mg/m2)

21-day cycle for 3 cycles

Subsequent treatment

Variant #2, 100/5000, 2 cycles with response adaptation

Study Evidence Comparator Efficacy
Forastiere et al. 2003 (RTOG 91-11) Phase III (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.
    • Patients with PR/CR receive a third cycle, then definitive RT
    • Patients with worse than a PR: Laryngectomy, then adjuvant RT

Variant #3, 100/5000 x 3

Study Evidence Comparator Efficacy
Wolf et al. 1991 Phase III (E) Surgery Seems not superior
Taylor et al. 1994 Phase III (C) CF & RT Inferior ORR
Hitt et al. 2005 Phase III (C) PCF, then Cisplatin & RT Inferior CR rate
Pointreau et al. 2009 (GORTEC 2000-01) Phase III (C) TPF, then RT Inferior ORR
Hitt et al. 2013 (TTCC XRP6976F/2503) Phase III (E) No induction Seems not superior

Chemotherapy

Supportive medications

  • Per GORTEC: Normal saline (use of mannitol, KCl, and magnesium sulfate per institutional protocol) 1000 mL IV given twice, before and after Cisplatin (Platinol)

21-day cycle for 3 cycles

Subsequent treatment

  • Wolf et al. 1991 & Taylor et al. 1994: Definitive RT
  • Hitt et al. 2005: Patients then undergo ENT evaluation and CT imaging of the primary tumor and neck
    • 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
    • Patients with a PR of less than 80% or stable disease in the neck lymph nodes (especially if N2 or N3 disease) after induction: Surgery for neck dissection, if the surgeons were in agreement, before the administration of adjuvant chemoradiotherapy
    • Patients with no response or progression of disease were taken off study
  • GORTEC 2000-01: re-evaluation is performed
    • Patients who responded to induction chemotherapy: Definitive RT within 3 to 7 weeks of finishing chemotherapy
    • 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

Variant #4, 100/5000 x 4

Study Evidence Comparator Efficacy
Vermorken et al. 2007 (EORTC 24971/TAX 323) Phase III (C) TPF Seems to have inferior OS
Lefebvre et al. 2009 (EORTC 24954) Phase III (E) See link See link

Chemotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on day 1, given first before fluorouracil
  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 5 days on days 1 to 5 (total dose per cycle: 5000 mg/m2)

Supportive medications

  • "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

  • EORTC 24971/TAX 323: Patients without progressive disease and who had recovery of marrow function, resolution of mucositis, and healed from any dental procedures started 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 verified protocol 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 verified protocol PubMed
    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 verified protocol PubMed
  4. EORTC 24971/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 24971/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 verified protocol PubMed
    1. QoL 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 verified protocol 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 verified protocol PubMed
    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 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 verified protocol link to PMC article PubMed
    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 and Radiation Oncology Cooperative Groups. 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. PubMed
  7. 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 verified protocol 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 (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 verified protocol PubMed

No induction

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Regimen

Study Evidence Comparator Efficacy
Zhong et al. 2012 Phase III (C) TPF Seems not superior
Hitt et al. 2013 (TTCC XRP6976F/2503) Phase II/III (C) 1. PF
2. TPF
Seems not superior
Ghi et al. 2017 (GSTTC H&N07) Phase II/III (C) TPF Seems to have inferior OS

No treatment given prior to definitive therapy.

Subsequent treatment

References

  1. 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 does not contain protocol in abstract PubMed
  2. 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 PubMed
  3. 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 (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 verified protocol PubMed
  4. 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 (Gruppo di Studio Tumori della Testa e del Collo) Italian Study Group. 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 verified protocol PubMed

PCF

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PCF: Paclitaxel, Cisplatin, Fluorouracil
PPF: Paclitaxel, Platinol (Cisplatin), Fluorouracil

Regimen

Study Evidence Comparator Efficacy
Hitt et al. 2002 Phase II
Hitt et al. 2005 Phase III (E) CF Superior CR rate

Chemotherapy

Supportive medications

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.
    • Patients who did not have at least a PR were recommended for surgery, performed 4 weeks after cycle 3 day 1.
    • Patients with bulky nodal disease prior to therapy "and/or suboptimal response to induction chemotherapy" were recommended for neck dissection, performed 4 weeks after cycle 3 day 1, then adjuvant RT
    • Patients with PR/CR: Definitive paclitaxel & RT; 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.
    • 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
    • Patients with a PR of less than 80% or SD in the neck lymph nodes (especially if N2 or N3 disease) after induction CT: Surgery for neck dissection, "if the surgeons were in agreement, before the administration of CRT."
    • Patients with no response or progression of disease were taken off study

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 verified protocol 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 verified protocol PubMed

DCF

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DCF: Docetaxel, Cisplatin, Fluorouracil
TPF: Taxotere (Docetaxel), Platinol (Cisplatin), Fluorouracil

Variant #1, 75/75/3750 x 2

Study Evidence Comparator Efficacy
Zhong et al. 2012 Phase III (E) No induction Seems not superior

Note: this is 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

  • Surgery, then adjuvant RT

Variant #2, 75/75/3750 x 3

Study Evidence Comparator Efficacy
Pointreau et al. 2009 (GORTEC 2000-01) Phase III (E) CF Superior ORR
Lefebvre et al. 2013 (TREMPLIN) Non-randomized portion of RCT
Hitt et al. 2013 (TTCC XRP6976F/2503) Phase III (E) No induction Seems not superior

Chemotherapy

Supportive medications

21-day cycle for 3 cycles

Subsequent treatment

  • GORTEC, as follows:
    • Patients who responded to induction chemotherapy: Definitive RT within 3 to 7 weeks of finishing chemotherapy
    • 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.
    • Patients who had "at least 50% regression of their primary tumor volume and who recovered larynx mobility": Definitive cetuximab & RT versus cisplatin & RT
    • Patients who did not have at least 50% regression: Salvage total laryngectomy
  • TTCC XRP6976F/2503: Definitive cisplatin & RT

Variant #3, 75/75/3750 x 4

Study Evidence Comparator Efficacy
Vermorken et al. 2007 (EORTC 24971/TAX 323) Phase III (E) CF Seems to have superior OS

Chemotherapy

  • Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given first before cisplatin
  • Cisplatin (Platinol) 75 mg/m2 IV over 60 minutes once on day 1, given second after docetaxel
  • Fluorouracil (5-FU) 750 mg/m2/day IV continuous infusion over 5 days on days 1 to 5 (total dose per cycle: 3750 mg/m2)

Supportive medications

21-day cycle for 4 cycles

Subsequent treatment

  • Patients without progressive disease and who had recovery of marrow function, resolution of mucositis, and healed from any dental procedures started definitive RT within 4 to 7 weeks of finishing chemotherapy

Variant #4, 75/80/3200

Study Evidence Comparator Efficacy
Ghi et al. 2017 (GSTTC H&N07) Phase III (E) No induction Seems to have superior OS

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment

Variant #5, 75/100/4000 x 2

Study Evidence
Adelstein et al. 2010 (SWOG S0216) Phase II

Chemotherapy

Supportive medications

  • 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.
    • Patients with SD or tumors which responded to therapy: Definitive cisplatin & RT
    • Patients with progressive disease are considered--if possible--for surgical resection and adjuvant RT. Patients who could not undergo surgery also received cisplatin & RT

Variant #6, 75/100/4000 x 3

Study Evidence Comparator Efficacy
Posner et al. 2007 (TAX 324) Phase III (E) CF Seems to have superior OS (*)

Reported efficacy is based on the 2011 update.

Chemotherapy

  • Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given first before cisplatin
  • Cisplatin (Platinol) 100 mg/m2 IV over 30 to 180 minutes once on day 1, given second after docetaxel
  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4, given third (total dose per cycle: 4000 mg/m2)

Supportive medications

  • 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. EORTC 24971/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 24971/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 verified protocol PubMed
    1. QoL 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 verified protocol 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 verified protocol PubMed
    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 PMC article PubMed
  3. 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 verified protocol 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. contains verified protocol link to PMC article PubMed
  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 verified protocol PubMed
  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 does not contain protocol in abstract PubMed
  7. 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 verified protocol 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 (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 verified protocol PubMed
  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 (Gruppo di Studio Tumori della Testa e del Collo) Italian Study Group. 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 verified protocol PubMed

Locally advanced disease, definitive therapy

Carboplatin & RT

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RT: Radiation Therapy

Regimen

Study Evidence
Posner et al. 2007 (TAX 324) Non-randomized portion of RCT

Reported efficacy is based on the 2011 update.

Preceding treatment

Chemoradiotherapy

  • Carboplatin (Paraplatin) AUC 1.5 IV over 60 minutes once per day on days 1, 8, 15, 22, 29, 36, 43
  • Concurrent radiation therapy, 2 Gy fractions x 35 to 37 fractions (total dose: 70 to 74 Gy), given 5 times per week over 7 to 7.5 weeks

7 to 7.5-week course

Surgery "performed 6 to 12 weeks after completion of chemoradiotherapy for patients who had an initial nodal stage of N2 and a partial response to induction chemotherapy, N3 disease, or residual disease after 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 verified protocol PubMed
    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 PMC article PubMed

Carboplatin, Fluorouracil, RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Calais et al. 1999 (GORTEC 94-01) Phase III (E) Radiation therapy Seems to have superior OS
Bourhis et al. 2012 (GORTEC 99-02) Phase III (C) 1. Carboplatin, Fluorouracil, accelerated concurrent RT Seems not superior
2. Very accelerated RT Seems to have superior PFS

Chemoradiotherapy

  • Carboplatin (Paraplatin) 70 mg/m2 IV once per day on days 1 to 4, 22 to 25, 43 to 46
  • Fluorouracil (5-FU) 600 mg/m2/day IV continuous infusion on days 1 to 4, 22 to 25, 43 to 46 (total dose for each 4-day continuous infusion: 2400 mg/m2)
  • Concurrent radiation therapy, 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 5 times per week over 7 weeks

7-week course of therapy

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 verified protocol PubMed
  2. 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 verified protocol PubMed

Carboplatin, Paclitaxel, RT

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RT: Radiation Therapy

Variant #1, accelerated hyperfractionated RT

Study Evidence
Carter et al. 2008 Phase II

Chemoradiotherapy

6-week course of therapy

Variant #2, standard RT

Study Evidence
Conley et al. 1997 Pilot, <20 patients
Suntharalingam et al. 2000 Phase II

Chemoradiotherapy

  • Carboplatin (Paraplatin) 100 mg/m2 IV once per week, given prior to radiation therapy
  • Paclitaxel (Taxol) 40 mg/m2 IV once per week, given prior to radiation therapy
    • According to Conley et al. 1997, the initial dose was 45 mg/m2, but 40 mg/m2 was subsequently used
  • Concurrent radiation therapy, 1.8 Gy fractions x 39 fractions (total dose: 70.2 Gy), given 5 times per week

Supportive medications

7.5-week course of therapy

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 protocol 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 verified protocol 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 protocol PubMed

Cetuximab & RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Bonner et al. 2006 (IMCL-9815) Phase III (E) Radiation therapy Seems to have superior OS
Lefebvre et al. 2013 (TREMPLIN) Randomized Phase II (E) Cisplatin & RT Seems not superior
Ghi et al. 2017 (GSTTC H&N07) Non-randomized portion of RCT

Note: all patients in TREMPLIN received conventional RT.

Preceding treatment

Chemoradiotherapy

  • Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours once 1 week before radiation therapy begins; then 250 mg/m2 IV over 60 minutes once per week during course of radiation therapy
    • A test dose of 20 mg IV over 10 minutes, followed by 30 minutes of observation, was given prior to the first full dose
  • Concurrent radiation therapy with one of the following regimens:
    • "Coventional" regimen: 2 Gy fractions x 35 fractions (total dose: 70 Gy), given once per day 5 times per week over 7 weeks
    • "Twice per day" regimen: 1.2 Gy fractions x 60 to 64 fractions (total dose: 72 to 76.8 Gy), given twice per day for a total of 10 times per week over 6 to 6.5 weeks
    • "Concomitant boost" regimen: 1.8 Gy fractions x 18 fractions (total dose: 32.4 Gy), given once per day 5 times per week for 3.6 weeks; and twice per day fractions:
      • Morning dose: 1.8 Gy fractions x 12 fractions (total dose: 21.6 Gy), given 5 days per week over 2.4 weeks
      • Afternoon dose: 1.5 Gy fractions x 12 fractions (total dose: 18 Gy), given 5 days per week over 2.4 weeks
      • Total dose for concomitant boost regimen: 72 Gy

Supportive medications

One course

References

  1. IMCL-9815: Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006 Feb 9;354(6):567-78. link to original article contains verified protocol PubMed
    1. QoL Analysis: Curran D, Giralt J, Harari PM, Ang KK, Cohen RB, Kies MS, Jassem J, Baselga J, Rowinsky EK, Amellal N, Comte S, Bonner JA. Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol. 2007 Jun 1;25(16):2191-7. link to original article contains partial protocol PubMed
    2. Update: Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010 Jan;11(1):21-8. Epub 2009 Nov 10. link to original article contains partial protocol PubMed
    3. Retrospective subgroup analysis: Rosenthal DI, Harari PM, Giralt J, Bell D, Raben D, Liu J, Schulten J, Ang KK, Bonner JA. Association of Human Papillomavirus and p16 Status With Outcomes in the IMCL-9815 Phase III Registration Trial for Patients With Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma of the Head and Neck Treated With Radiotherapy With or Without Cetuximab. J Clin Oncol. 2016 Apr 20;34(12):1300-8. Epub 2015 Dec 28. link to original article link to PMC article PubMed
  2. 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 verified protocol PubMed
  3. 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 (Gruppo di Studio Tumori della Testa e del Collo) Italian Study Group. 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 verified protocol PubMed

Cisplatin, Fluorouracil, RT

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CF & RT: Cisplatin and Fluorouracil with concurrent Radiation Therapy

Variant #1, 60/3000 x 2

Study Evidence Comparator Efficacy
Brizel et al. 1998 Phase III (E) RT Might have superior OS

Chemoradiotherapy

  • Cisplatin (Platinol) 12 mg/m2 IV once per day on days 1 to 5, 36 to 40
  • Fluorouracil (5-FU) 600 mg/m2/day IV continuous infusion over 120 hours on days 1 to 5, 36 to 40 (total dose per infusion: 3000 mg/m2)
  • Concurrent radiation therapy, 1.2 Gy fractions given twice per day, 5 times per week (total dose: 75 Gy)

6-week course

Variant #2, 60/4000 x 7

Study Evidence Comparator Efficacy
Taylor et al. 1994 Phase III (E) CF, then RT Superior ORR

Chemoradiotherapy

  • Cisplatin (Platinol) 60 mg/m2 IV over 15 minutes once on day 1
  • Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 120 hours on days 1 to 5 (total dose per cycle: 4000 mg/m2)
  • Concurrent radiation therapy, 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 5 times per week on weeks 1, 3, 5, 7, 9, 11, 13

14-day cycle for 7 cycles

Variant #3, 75/4000 x 4

Study Evidence Comparator Efficacy
Adelstein et al. 2003 (Head and Neck Intergroup) Phase III (E) 1. Cisplatin & RT Seems not superior
2. RT Seems not superior

Chemoradiotherapy

  • Cisplatin (Platinol) 75 mg/m2 IV once on day 1
  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 4000 mg/m2)
  • Concurrent radiation therapy, 2 Gy fractions x 35 fractions (total dose: 60 to 70 Gy), given 5 times per week on weeks 1 to 3, 7 to 9

28-day cycle for 4 cycles

Variant #4, 80/3200 x 2

Study Evidence
Ghi et al. 2017 (GSTTC H&N07) Non-randomized portion of RCT

Preceding treatment

Chemoradiotherapy

  • Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 4, 36 to 39
  • Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4, 36 to 39 (total dose per infusion: 3200 mg/m2)
  • Concurrent radiation therapy, 2.0 Gy fractions given once per day, 5 times per week (total dose: 70 Gy)

6-week course

Variant #5, 100/1000 x 4, alternating with RT

Study Evidence Comparator Efficacy
Merlano et al. 1992 Phase III (E) RT Superior OS (*)
Lefebvre et al. 2009 (EORTC 24954) Phase III (E) Cisplatin & 5-FU, then RT Seems not superior

Efficacy in Merlano et al. 1992 is based on the 1995 update.

Chemoradiotherapy

  • Cisplatin (Platinol) 20 mg/m2 IV once per day on days 1 to 5
  • Fluorouracil (5-FU) 200 mg/m2/day IV continuous infusion over 120 hours on days 1 to 5 (total dose per cycle: 1000 mg/m2)
  • Concurrent radiation therapy, 2 Gy fractions x 30 fractions (total dose: 60 Gy), given 5 times per week on weeks 2, 3, 5, 6, 8, 9

21-day cycle for 4 cycles

Variant #6, 100/3750 x 1, then 100/2150 x 2

Study Evidence Comparator Efficacy
Bensadoun et al. 2006 Phase III (E) RT Seems to have superior OS

Chemoradiotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV once on day 1
  • Fluorouracil (5-FU) as follows:
    • Cycle 1: 750 mg/m2/day IV continuous infusion over 120 hours on days 1 to 5 (total dose: 3750 mg/m2)
    • Cycles 2 & 3: 430 mg/m2/day IV continuous infusion over 120 hours on days 1 to 5 (total dose per cycle: 2150 mg/m2)
  • Concurrent radiation therapy, 1.2 Gy fractions given twice per day, 5 times per week (total dose: 80.4 Gy for oropharynx; 75.6 Gy for hypopharynx)

21-day cycle for 3 cycles

Variant #7, 100/4000 x 1

Study Evidence Comparator Efficacy
Garden et al. 2004 (RTOG 97-03) Randomized Phase II (E) 1. Cisplatin, Paclitaxel, RT Seems not superior
2. 5-FU, Hydroxyurea, RT Seems not superior

Note: this regimen is best described in the trial protocol, which is available directly from RTOG as a PDF.

Chemoradiotherapy

  • Cisplatin (Platinol) 10 mg/m2 IV over 60 minutes once per day on days 26 to 35 of radiation (10 doses total)
  • Fluorouracil (5-FU) 400 mg/m2/day IV continuous infusion over 120 hours of the sixth and seventh week of radiation (total dose: 4000 mg/m2)
  • Concurrent radiation therapy, 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 5 times per week over 7 weeks

7-week course of therapy

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 verified protocol 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. 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 verified protocol PubMed
  3. 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 verified protocol PubMed
  4. 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 verified protocol PubMed
  5. 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 verified protocol in supplement PubMed
  6. 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 protocol PubMed
  7. 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 verified protocol PubMed
    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 and Radiation Oncology Cooperative Groups. 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. PubMed
  8. 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 (Gruppo di Studio Tumori della Testa e del Collo) Italian Study Group. 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 verified protocol PubMed

Cisplatin & RT

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RT: Radiation Therapy

Variant #1, 6 mg/m2 daily dosing

Study Evidence Comparator Efficacy
Jeremic et al. 2000 Phase III (E) Radiation therapy Superior OS

Chemoradiotherapy

7-week course

Variant #2, 20 mg/m2 weekly dosing

Study Evidence Comparator Efficacy
Quon et al. 2011 (ECOG E2382) Phase III (E) RT Might have superior FFS

Chemoradiotherapy

7-week course

Variant #3, 30 mg/m2 weekly dosing

Study Evidence Comparator Efficacy
Ghosh-Laskar et al. 2014 Phase III (E) 1. Accelerated RT
2. Standard RT
Seems to have superior locoregional control

Chemoradiotherapy

7-week course

Variant #4, 100 mg/m2 q3wk x 2

Study Evidence Comparator Efficacy
Adelstein et al. 2010 (SWOG S0216) Phase II
Ang et al. 2014 (RTOG 0522) Phase III (C) Cetuximab, Cisplatin, RT Seems not superior

Preceding treatment

Chemoradiotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1 & 22
  • Concurrent radiation therapy by one of the following:
    • SWOG S0216: 1.8 Gy fractions x 30 fractions, given 5 times per week (total dose: 54 Gy)
      • The last 12 treatments involved a boost volume, 1.5 Gy fractions x 12 fractions (dose to boost volume: 18 Gy)
    • RTOG 0522: IMRT: 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 6 times per week over 6 weeks
    • RTOG 0522: Accelerated radiotherapy: 42 fractions (total dose: 72 Gy), given twice per day for 12 days then once per day over 6 weeks

One 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.

Variant #5, 100 mg/m2 q3wk x 3

Study Evidence Comparator Efficacy
Adelstein et al. 2003 (Head and Neck Intergroup) Phase III (C) 1. CF & RT Seems not superior
2. RT Seems to have superior OS
Forastiere et al. 2003 (RTOG 91-11) Phase III (C) See link See link
Hitt et al. 2005 Non-randomized portion of RCT
Hitt et al. 2013 (TTCC XRP6976F/2503) Non-randomized portion of RCT
Lefebvre et al. 2013 (TREMPLIN) Randomized Phase II (C) Cetuximab & RT Seems not superior
Nguyen-Tan et al. 2014 (RTOG 0129) Phase III (C) Cisplatin & Hyperfractionated RT Seems not superior
Siu et al. 2016 (CCTG HN.6) Phase III (C) Panitumumab & RT Seems not superior
Noronha et al. 2017 Phase III (C) Weekly cisplatin & RT Seems to have superior LRC

Preceding treatment

Chemoradiotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1, 22, 43
  • Concurrent radiation therapy: 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 5 times per week over 7 weeks
    • Hitt et al. 2005: Nodal areas not involved by tumor received 50 Gy.

Supportive medications

One 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 verified protocol 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 verified protocol 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 verified protocol PubMed
    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. 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 verified protocol PubMed
  5. 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. contains verified protocol link to PMC article PubMed
  6. 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 PMC article contains verified protocol PubMed
  7. 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 verified protocol PubMed
  8. 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 does not contain protocol in abstract PubMed
  9. 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 (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 verified protocol PubMed
  10. 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 verified protocol link to PMC article PubMed
  11. 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 verified protocol PubMed
  12. 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 verified protocol PubMed
  13. 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 verified protocol PubMed
  14. 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 verified protocol PubMed

Cisplatin, Paclitaxel, RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Garden et al. 2004 (RTOG 97-03) Randomized Phase II (E) 1. CF & RT Seems not superior
2. 5-FU, Hydroxyurea, RT Seems not superior

Chemoradiotherapy

  • Cisplatin (Platinol) 20 mg/m2 IV once each Tuesday on weeks 1 to 7, given prior to radiation
  • Paclitaxel (Taxol) 30 mg/m2 IV once each Monday on weeks 1 to 7, given prior to radiation
  • Concurrent radiation therapy, 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 5 times per week over 7 weeks

7-week course of therapy

References

  1. 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 verified protocol PubMed

Docetaxel, Fluorouracil, Hydroxyurea, RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Cohen et al. 2014 Phase III (C) TPF, then Docetaxel, Fluorouracil, Hydroxyurea, RT Seems not superior

To be completed

Chemoradiotherapy

References

  1. 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 PubMed

Fluorouracil, Hydroxyurea, RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Garden et al. 2004 (RTOG 97-03) Randomized Phase II (E) 1. CF & RT Seems not superior
2. Cisplatin, Paclitaxel, RT Seems not superior

Chemoradiotherapy

  • Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion given 5 days per week on weeks 1, 3, 5, 7, 9, 11, 13 (total dose per week: 4000 mg/m2)
    • Note: Garden et al. 2004 was not clear about the exact schedule nor duration of the continuous infusion, such as whether each continuous infusion was over 24 hours or not
  • Hydroxyurea (Hydrea) 1000 mg PO every 12 hours x 11 doses per week on weeks 1, 3, 5, 7, 9, 11, 13 (total dose per week: 11,000 mg)
    • Note: Garden et al. 2004 did not clearly specify when the doses of hydroxyurea were to be taken in relation to radiation treatments
  • Concurrent radiation therapy, 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 5 times per week on weeks 1, 3, 5, 7, 9, 11, 13

13-week course of therapy

References

  1. 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 verified protocol PubMed

Fluorouracil, Mitomycin, RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Budach et al. 2005 (ARO 95-06) Phase III (E) Radiation therapy Seems to have superior OS

Chemoradiotherapy

6-week course of therapy

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 verified protocol 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 70.6 Gy with concurrent 5-FU/Mitomycin C is superior to HART of 77.6 Gy 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

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

Regimen

Study Evidence Comparator Efficacy
Gollin et al. 1972 Phase III (E) RT Seems to have superior OS (*)
Sanchíz et al. 1990 Phase III (E) 1. Conventional RT Superior OS
2. Twice-daily RT Seems not superior
Browman et al. 1994 Phase III (E) RT Might have superior OS

Of historic interest. Efficacy for Gollin et al. 1972 is based on the 1976 update, for oral lesions only.

Chemoradiotherapy

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 protocol 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 protocol PubMed

Paclitaxel & RT

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RT: Radiation Therapy

Regimen

Study Evidence
Hitt et al. 2002 Phase II

Chemoradiotherapy starts 4 to 6 weeks after cycle 3 day 1 or as soon as patients recover from surgery (if any).

Preceding treatment

Chemoradiotherapy

  • Paclitaxel (Taxol) 25 mg/m2 IV over 60 minutes once per week during radiation therapy, starting on day 1
  • Concurrent radiation therapy to primary unresected tumors, 1.8 to 2 Gy fractions (total dose: 65 to 70 Gy). Post-operative areas received 60 Gy. Nodal areas not involved by tumor received at least 45 Gy.

Supportive medications

  • "Usual pre-medication was given before each paclitaxel infusion" (presumably the same ones used during PCF induction).

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 verified protocol PubMed

Radiation therapy

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Regimen

Study Evidence Comparator Efficacy
Gollin et al. 1972 Phase III (C) 5-FU & RT Seems to have inferior OS (*)
Sanchíz et al. 1990 Phase III (E) 1. 5-FU & RT Inferior OS
2. Twice-daily RT Inferior OS
Wolf et al. 1991 Non-randomized portion of RCT
Merlano et al. 1992 Phase III (C) CF & RT Inferior OS (*)
Taylor et al. 1994 Non-randomized portion of RCT
Browman et al. 1994 Phase III (C) 5-FU & RT Might have inferior OS
Wendt et al. 1998 Phase III (C) Cisplatin, 5-FU, LV, RT Inferior OS
Brizel et al. 1998 Phase III (C) CF & RT Might have inferior OS
Calais et al. 1999 (GORTEC 94-01) Phase III (C) Carboplatin, 5-FU, RT Seems to have inferior OS
Jeremic et al. 2000 Phase III (C) Cisplatin & RT Inferior OS
Adelstein et al. 2003 (Head and Neck Intergroup) Phase III (C) 1. CF & RT Seems not superior
2. Cisplatin & RT Seems to have inferior OS
Forastiere et al. 2003 (RTOG 91-11) Phase III (C) See link See link
Budach et al. 2005 (ARO 95-06) Phase III (C) 5-FU, Mitomycin, RT Seems to have inferior OS
Bensadoun et al. 2006 Phase III (C) CF & RT Seems to have inferior OS
Bonner et al. 2006 (IMCL-9815) Phase III (C) Cetuximab & RT Seems to have inferior OS
Vermorken et al. 2007 (EORTC 24971/TAX 323) Non-randomized portion of RCT
Lefebvre et al. 2009 (EORTC 24954) Phase III (E) See link See link
Pointreau et al. 2009 (GORTEC 2000-01) Non-randomized portion of RCT
Bourhis et al. 2012 (GORTEC 99-02) Phase III (C) 1. Carboplatin, 5-FU, RT Seems to have inferior PFS
2. Carboplatin, 5-FU, accelerated concurrent RT Might have inferior PFS
Ghosh-Laskar et al. 2014 Phase III (C) Cisplatin & RT Seems to have inferior locoregional control

This is included for historical context and is unlikely to be further completed. Efficacy for Gollin et al. 1972 is based on the 1976 update, for oral lesions only. Efficacy in Merlano et al. 1992 is based on the 1995 update.

Preceding treatment

  • RTOG 91-11: CF x 3 versus no induction
  • Taylor et al. 1994: CF x 7
  • GORTEC: CF x 3 versus TPF x 3
  • Wolf et al. 1991: CF x 3
  • EORTC 24971/TAX 323: CF x 4 versus TPF x 4
  • EORTC 24954: CF x 4

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 PubMed
  3. 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 protocol PubMed
  4. 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 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. PubMed
  5. 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 verified protocol PubMed
  6. 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 PubMed
  7. Wendt TG, Grabenbauer GG, Rödel CM, Thiel HJ, Aydin H, Rohloff R, Wustrow TP, Iro H, Popella C, Schalhorn A. Simultaneous radiochemotherapy versus radiotherapy alone in advanced head and neck cancer: a randomized multicenter study. J Clin Oncol. 1998 Apr;16(4):1318-24. link to original article PubMed
  8. 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 PubMed
  9. 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 verified protocol PubMed
  10. 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 PubMed
  11. 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 verified protocol PubMed
  12. 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 verified protocol PubMed
    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
  13. 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 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 70.6 Gy with concurrent 5-FU/Mitomycin C is superior to HART of 77.6 Gy 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
  14. 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 PubMed
  15. IMCL-9815: Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006 Feb 9;354(6):567-78. link to original article contains verified protocol PubMed
    1. Update: Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2010 Jan;11(1):21-8. Epub 2009 Nov 10. link to original article contains partial protocol PubMed
    2. QoL Analysis: Curran D, Giralt J, Harari PM, Ang KK, Cohen RB, Kies MS, Jassem J, Baselga J, Rowinsky EK, Amellal N, Comte S, Bonner JA. Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol. 2007 Jun 1;25(16):2191-7. link to original article contains partial protocol PubMed
    3. Retrospective subgroup analysis: Rosenthal DI, Harari PM, Giralt J, Bell D, Raben D, Liu J, Schulten J, Ang KK, Bonner JA. Association of Human Papillomavirus and p16 Status With Outcomes in the IMCL-9815 Phase III Registration Trial for Patients With Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma of the Head and Neck Treated With Radiotherapy With or Without Cetuximab. J Clin Oncol. 2016 Apr 20;34(12):1300-8. Epub 2015 Dec 28. link to original article link to PMC article PubMed
  16. EORTC 24971/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 24971/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 verified protocol PubMed
    1. QoL 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 verified protocol link to PMC article PubMed
  17. 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 PubMed
    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 and Radiation Oncology Cooperative Groups. 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. PubMed
  18. 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 verified protocol PubMed
  19. 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 verified protocol PubMed
  20. 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 PubMed

Surgery

Regimen

Study Evidence Comparator Efficacy
Wolf et al. 1991 Phase III (C) CF Seems not superior

Of historic interest as a control comparator, only.

Treatment

  • Surgery

Subsequent treatment

References

  1. 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 protocol PubMed

Adjuvant therapy

Cisplatin, Cetuximab, RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Harari et al. 2014 (RTOG-0234) Randomized Phase II (E) Cisplatin & RT Seems to have superior DFS

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

Chemoradiotherapy

  • Cisplatin (Platinol) 30 mg/m2 IV once per week for 6 weeks
  • Cetuximab (Erbitux) as follows:
    • 5 to 9 days prior to RT: 400 mg/m2 IV once
    • During RT: 250 mg/m2 IV once per week for 6 weeks
  • Concurrent radiation therapy, 2 Gy fractions (total dose: 58 to 66 Gy), given 5 times per week over 5.5 to 6.5 weeks

Supportive medications

References

  1. 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 verified protocol link to PMC article PubMed

Cisplatin & RT

back to top

RT: Radiation Therapy

Variant #1, 50 mg/m2 weekly

Study Evidence Comparator Efficacy
Bachaud et al. 1991 Phase III (E) Radiation therapy Superior OS

Chemoradiotherapy

  • Cisplatin (Platinol) 50 mg/m2 IV bolus once per week on the first day of radiation
  • Concurrent radiation therapy, 1.7 Gy fractions x ~32 fractions (total dose: 54 Gy), given 5 times per week, with boost to "primary site and/or cervical lymph nodes" with 1.8 to 2 Gy fractions for an additional boost dose of 11 to 16 Gy to close (<5 mm) or positive margin areas of (overall dose to these sites: 65 to 70 Gy). A boost of 11 to 20 Gy was given to metastatic nodal sites (overall dose to these sites: 65 to 74 Gy); see Bachaud et al. 1996 for details.

Supportive medications

7 to 9-week course, depending on duration of radiation therapy

Variant #2, 100 mg/m2 x 3, 54 Gy

Study Evidence Comparator Efficacy
Bernier et al. 2004 (EORTC 22931) Phase III (E) Radiation therapy Seems to have superior OS

Chemoradiotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1, 22, 43
  • Concurrent radiation therapy, 2 Gy fractions x 27 fractions (total dose: 54 Gy), given 5 times per week over 5.5 weeks, with boost to areas at "high risk for malignant dissemination or that had inadequate resection margins" of 2 Gy fractions x 6 fractions (boost dose: 12 Gy)

Supportive medications

7-week course

Variant #3, 100 mg/m2 x 3, 60 Gy

Study Evidence Comparator Efficacy
Cooper et al. 2004 (RTOG 9501) Phase III (E) Radiation therapy Seems to have superior DFS
Noronha et al. 2017 Phase III (C) Weekly cisplatin & RT 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

Chemoradiotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV once per day on days 1, 22, 43
  • Concurrent radiation therapy, 2 Gy fractions x 30 fractions (total dose: 60 Gy), given 5 times per week over 6 weeks,
    • RTOG 9501: Optional boost of 2 Gy fractions x 3 fractions (boost dose: 6 Gy) to high-risk sites

Supportive medications

  • Hydration before and after treatment
  • Antiemetics per physician choice
  • Optional use of feeding tubes

7-week course

Variant #4, 100 mg/m2 x 3, 66 Gy

Study Evidence Comparator Efficacy
Harrington et al. 2015 Phase III (C) Cisplatin, Lapatinib, RT Seems not superior

Preceding treatment

  • Surgery

Chemoradiotherapy

One 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 verified protocol 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; Radiation Therapy Oncology Group 9501/Intergroup. 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 verified protocol PubMed
    1. Posthoc 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 verified protocol 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; European Organization for Research and Treatment of Cancer 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 verified protocol PubMed
    1. Posthoc 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. 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 protocol PubMed
  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 verified protocol PubMed

Docetaxel, Cetuximab, RT

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RT: Radiation Therapy

Regimen

Study Evidence Comparator Efficacy
Harari et al. 2014 (RTOG-0234) Randomized Phase II (E) Cisplatin & RT Superior DFS

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

Chemoradiotherapy

  • Docetaxel (Taxotere) 15 mg/m2 IV once per week for 6 weeks
  • Cetuximab (Erbitux) as follows:
    • 5 to 9 days prior to RT: 400 mg/m2 IV once
    • During RT: 250 mg/m2 IV once per week for 6 weeks
  • Concurrent radiation therapy, 2 Gy fractions (total dose: 58 to 66 Gy), given 5 times per week over 5.5 to 6.5 weeks

Supportive medications

References

  1. 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 verified protocol link to PMC article PubMed

Radiation therapy

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Regimen

Study Evidence Comparator Efficacy
Wolf et al. 1991 Non-randomized portion of RCT
Bachaud et al. 1991 Phase III (C) Cisplatin & RT Inferior OS
Cooper et al. 2004 (RTOG 9501, ECOG R9501, SWOG 9515) Phase III (C) Cisplatin & RT Seems to have inferior DFS
Bernier et al. 2004 (EORTC 22931) Phase III (C) Cisplatin & RT Seems to have inferior OS

For reference only.

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 verified protocol 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 verified protocol 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; Radiation Therapy Oncology Group 9501/Intergroup. 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 verified protocol PubMed
    1. Posthoc 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 verified protocol 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; European Organization for Research and Treatment of Cancer 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 verified protocol PubMed
    1. Posthoc 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

Recurrent or metastatic disease, first-line therapy

Carboplatin & Docetaxel

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Regimen

Study Evidence
Samlowski et al. 2007 Phase II

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. 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 protocol PubMed

Carboplatin & Fluorouracil

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Regimen

Study Evidence Comparator Efficacy
Forastiere et al. 1992 (SWOG-8514) Phase III (E) 1. CF Not reported
2. MTX Seems to have superior ORR
Vermorken et al. 2008 (EXTREME) Phase III (C) Carboplatin, Fluorouracil, Cetuximab Seems to have inferior OS

Chemotherapy

Supportive medications

  • "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 verified protocol 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 verified protocol PubMed

Carboplatin, Fluorouracil, Cetuximab

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Regimen

Study Evidence Comparator Efficacy
Vermorken et al. 2008 (EXTREME) Phase III (E) Carboplatin & Fluorouracil Seems to have superior OS

Chemotherapy

  • Carboplatin (Paraplatin) AUC 5 IV over 60 minutes once on day 1
  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 4000 mg/m2)
  • 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 cycle for up to 6 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 verified protocol PubMed

Cisplatin & Fluorouracil

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CF: Cisplatin and Fluorouracil

Regimen

Study Evidence Comparator Efficacy
Jacobs et al. 1992 Phase III (E) 1. Cisplatin
2. 5-FU
Seems to have superior ORR
Forastiere et al. 1992 (SWOG-8514) Phase III (E) 1. Carboplatin & Fluorouracil Not reported
2. MTX Superior ORR
Clavel et al. 1994 Phase III (E) 1. CABO Seems to have inferior ORR
2. Cisplatin Superior ORR
Gibson et al. 2005 (ECOG E1395) Phase III (C) CP Seems not superior
Vermorken et al. 2008 (EXTREME) Phase III (C) CF & Cetuximab Seems to have inferior OS
Vermorken et al. 2013 (SPECTRUM) Phase III (C) CF & Panitumumab Inferior PFS

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 on days 1 to 4 (total dose per cycle: 4000 mg/m2)

Supportive medications

  • Details vary per reference
  • Pretreatment and posttreatment hydration and mannitol diuresis with Cisplatin (Platinol)
  • "Standard antiemetic regimens"

21-day cycle for up to 3 cycles (Clavel et al. 1994), 6 cycles (SPECTRUM) or indefinitely, see note below

In Clavel et al. 1994, patients proceeded to cisplatin monotherapy after 3 cycles. 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.

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 protocol 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 verified protocol 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. 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 protocol PubMed
  4. ECOG E1395: Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J, Forastiere AA; Eastern Cooperative Oncology Group. 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 verified protocol PubMed
  5. 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 verified protocol PubMed
  6. 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 protocol PubMed

Cisplatin monotherapy

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Variant #1, 50 mg/m2, 2 out of 4 weeks

Study Evidence Comparator Efficacy
Clavel et al. 1994 Phase III (C) 1. CABO
2. CF
Inferior ORR

Chemotherapy

28-day cycles

Variant #2, 100 mg/m2 q3wk

Study Evidence Comparator Efficacy
Jacobs et al. 1992 Phase III (C) 1. CF Seems to have inferior ORR
2. 5-FU Not reported

Chemotherapy

21-day cycles

Variant #3, 100 mg/m2 q4wk

Study Evidence Comparator Efficacy
Burtness et al. 2005 Phase III (C) Cisplatin & Cetuximab Seems not superior

Chemotherapy

28-day cycles

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.

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 protocol PubMed
  2. 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. 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 protocol PubMed
  3. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA; Eastern Cooperative Oncology Group. 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 verified protocol PubMed

Cisplatin & Cetuximab

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Regimen

Study Evidence Comparator Efficacy
Burtness et al. 2005 Phase III (E) Cisplatin Seems not superior

Chemotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV once on day 1
  • Cetuximab (Erbitux) as follows:
    • Cycle 1: 200 mg/m2 IV over 2 hours once on day 1, then 125 mg/m2 IV over 60 minutes once per day on days 8, 15, 22
    • Subsequent cycles: 125 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22

28-day cycles

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.

References

  1. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA; Eastern Cooperative Oncology Group. 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 verified protocol PubMed

Cisplatin, Fluorouracil, Cetuximab

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Regimen

Study Evidence Comparator Efficacy
Vermorken et al. 2008 (EXTREME) Phase III (E) CF Seems to have superior OS

Chemotherapy

  • Cisplatin (Platinol) 100 mg/m2 IV over 60 minutes once on day 1
  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 4000 mg/m2)
  • 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 cycle for up to 6 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 verified protocol PubMed

Cisplatin, Fluorouracil, Panitumumab

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Regimen

Study Evidence Comparator Efficacy
Vermorken et al. 2013 (SPECTRUM) Phase III (E) CF Superior PFS

Chemotherapy

21-day cycle for up to 6 cycles

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 protocol PubMed

Cisplatin & Paclitaxel

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CP: Cisplatin and Paclitaxel

Regimen

Study Evidence Comparator Efficacy
Gibson et al. 2005 (ECOG E1395) Phase III (E) CF Seems not superior

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 medications

21-day cycles

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."

References

  1. ECOG E1395: Gibson MK, Li Y, Murphy B, Hussain MH, DeConti RC, Ensley J, Forastiere AA; Eastern Cooperative Oncology Group. 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 verified protocol PubMed

Fluorouracil monotherapy

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Regimen

Study Evidence Comparator Efficacy
Jacobs et al. 1992 Phase III (C) 1. CF Seems to have inferior ORR
2. Cisplatin Not reported

Chemotherapy

  • Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion on days 1 to 4 (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 verified protocol PubMed

Methotrexate monotherapy

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Regimen

Study Evidence Comparator Efficacy
Forastiere et al. 1992 (SWOG-8514) Phase III (C) 1. Carboplatin & Fluorouracil Seems to have inferior ORR
2. CF Inferior ORR
Stewart et al. 2009 Phase III (C) Gefitinib Seems not superior

Chemotherapy

Supportive medications

  • "Standard antiemetic regimens"

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 verified protocol PubMed
  2. 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 verified protocol PubMed

Recurrent or metastatic disease, subsequent lines of therapy

Afatinib monotherapy

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Regimen

Study Evidence Comparator Efficacy
Machiels et al. 2015 (LUX-Head & Neck 1) Phase III (E) Methotrexate Seems to have superior PFS

Chemotherapy

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 protocol PubMed

Cetuximab monotherapy

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Regimen

Study Evidence Comparator Efficacy
Vermorken et al. 2007 Phase II
Ferris et al. 2016 (CheckMate 141) Phase III (C) Nivolumab Inferior OS

Note: Vermorken et al. 2007 gave a 20 mg test dose as part of the initial dose; this is not specified in CheckMate 141.

Chemotherapy

  • Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours once on day 1, then 250 mg/m2 IV over 60 minutes once per week

References

  1. 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 verified protocol 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 verified protocol' PubMed

Docetaxel monotherapy

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Variant #1, 30 mg/m2 weekly

Study Evidence Comparator Efficacy
Ferris et al. 2016 (CheckMate 141) Phase III (C) Nivolumab Inferior OS

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

Chemotherapy

Continued until progression

Variant #2, 35 mg/m2, 3 weeks out of 4

Study Evidence Comparator Efficacy
Argiris et al. 2013 (ECOG E1302) Phase III (C) Docetaxel & Gefitinib Seems not superior

Chemotherapy

28-day cycles

Variant #3, 40 mg/m2 weekly

Study Evidence Comparator Efficacy
Ferris et al. 2016 (CheckMate 141) Phase III (C) Nivolumab Inferior OS

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

Chemotherapy

Continued until progression

References

  1. 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 verified protocol link to PMC article 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 verified protocol PubMed

Methotrexate monotherapy

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Variant #1, 40 mg/m2

Study Evidence Comparator Efficacy
Machiels et al. 2015 (LUX-Head & Neck 1) Phase III (C) Afatinib Seems to have inferior PFS
Ferris et al. 2016 (CheckMate 141) Phase III (C) Nivolumab Inferior OS

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

Chemotherapy

Supportive medications

  • "Standard antiemetic regimens"

Continued until progression

Variant #2, 60 mg/m2

Study Evidence Comparator Efficacy
Ferris et al. 2016 (CheckMate 141) Phase III (C) Nivolumab Inferior OS

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

Chemotherapy

Continued until progression

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 protocol 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 verified protocol PubMed

Nivolumab monotherapy

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Regimen

Study Evidence Comparator Efficacy ORR Comparator ORR
Ferris et al. 2016 (CheckMate 141) Phase III (E) Investigators' choice of:
1. Methotrexate
2. Docetaxel
3. Cetuximab
Superior OS 13% (95% CI 9-18) 6% (95% CI 2-12)

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 verified protocol PubMed

Pembrolizumab monotherapy

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Regimen

Study Evidence
Seiwert et al. 2016 (KEYNOTE-012) Phase Ib, >20 pts

Note: a small number (N=7) of patients received this treatment as their first-line therapy for recurrent or metastatic disease.

Immunotherapy

14-day cycles until progression, intolerance, or maximum of 24 months

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 verified protocol PubMed