Head and neck cancer

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45 regimens on this page 86 variants on this page

Guidelines

ASCO

• 2017: Head and Neck Cancer Survivorship Care Guideline: American Society of Clinical Oncology Clinical Practice Guideline Endorsement of the American Cancer Society Guideline PubMed

EHNS/ESMO/ESTRO

• 2012: Nasopharyngeal cancer: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
• 2010: Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed

NCCN

• NCCN Guidelines - Head and Neck Cancers

Locally advanced disease, induction

Cisplatin & Fluorouracil

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CF: Cisplatin & Fluorouracil

Regimen #1

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

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV over 1 hour 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 granulocyte colony-stimulating factor only allowed for patients who had "febrile neutropenia or infection, a delay in recovery of the absolute neutrophil count at day 28, or grade 4 neutropenia persisting for 7 days or more."

21-day cycle for 4 cycles

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

Regimen #2

Study	Evidence	Comparator	Efficacy
Posner et al. 2007 (TAX 324)	Phase III	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

Patients proceed to carboplatin & RT 3 to 8 weeks after the start of cycle 3.

Regimen #3

Study	Evidence	Comparator	Efficacy
Taylor et al. 1994	Phase III	CF & RT	Inferior ORR
Hitt et al. 2005	Phase III	PCF, then Cisplatin & RT	Inferior CR rate
Pointreau et al. 2009 (GORTEC 2000-01)	Phase III	TPF, then RT	Inferior ORR

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV over 15 minutes once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 5 days on days 1 to 5 (total dose per cycle: 5000 mg/m²)

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

Taylor et al. 1994: Patients then proceeded to radiation therapy. Hitt et al. 2005: Patients then undergo ENT evaluation and CT imaging of the primary tumor and neck. Patients with complete response (CR) or partial response of greater than 80% in the primary tumor and no evidence of progression in neck lymph nodes proceeded to 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 CT were referred to 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. GORTEC: Patients who responded to induction chemotherapy proceeded to radiation therapy within 3 to 7 weeks of finishing chemotherapy. Patients who did not respond to induction chemotherapy proceeded to surgery and postoperative radiotherapy (see Pointreau et al. 2009 for details).

Regimen #4, response-adapted

Study	Evidence	Comparator	Efficacy
Forastiere et al. 2003 (RTOG 91-11)	Phase III	Cisplatin & RT (no induction)	Not reported
		No induction	Seems to have superior DFS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 120 hours on days 1 to 5 (total dose per cycle: 5000 mg/m²)

21-day cycle for 2 cycles

After cycle 2, patients are evaluated by indirect laryngoscopy and CT neck. Patients with complete or partial response receive a third cycle of induction chemotherapy as described above, followed by radiation therapy. Patients with worse than a partial response underwent laryngectomy and adjuvant radiation therapy.

References

1. Department of Veterans Affairs Laryngeal Cancer Study Group, Wolf GT, Fisher SG, Hong WK, Hillman R, Spaulding M, Laramore GE, Endicott JW, McClatchey K, Henderson WG. 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 PubMed
2. Taylor SG 4th, Murthy AK, Vannetzel JM, Colin P, Dray M, Caldarelli DD, Shott S, Vokes E, Showel JL, Hutchinson JC et al. 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. 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. 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
6. 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
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 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. 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
9. 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 PubMed
10. Cao SM, Yang Q, Guo L, Mai HQ, Mo HY, Cao KJ, Qian CN, Zhao C, Xiang YQ, Zhang XP, Lin ZX, Li WX, Liu Q, Qiu F, Sun R, Chen QY, Huang PY, Luo DH, Hua YJ, Wu YS, Lv X, Wang L, Xia WX, Tang LQ, Ye YF, Chen MY, Guo X, Hong MH. Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: A phase III multicentre randomised controlled trial. Eur J Cancer. 2017 Apr;75:14-23. Epub 2017 Feb 16. link to original article PubMed

No induction

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Regimen

Study	Evidence	Comparator	Efficacy
Sun et al. 2016	Phase III	TPF	Seems to have inferior FFS

No therapy given prior to definitive chemoradiotherapy. Sun et al. 2016: Followed by cisplatin & RT.

References

1. 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
2. Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, Clark J, Sarlis N, Lorch J, Beitler JJ, Limaye S, Riley S, Posner M. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013 Mar;14(3):257-64. Epub 2013 Feb 13. link to original article PubMed
3. 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. Sun Y, Li WF, Chen NY, Zhang N, Hu GQ, Xie FY, Sun Y, Chen XZ, Li JG, Zhu XD, Hu CS, Xu XY, Chen YY, Hu WH, Guo L, Mo HY, Chen L, Mao YP, Sun R, Ai P, Liang SB, Long GX, Zheng BM, Feng XL, Gong XC, Li L, Shen CY, Xu JY, Guo Y, Chen YM, Zhang F, Lin L, Tang LL, Liu MZ, Ma J. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 2016 Nov;17(11):1509-1520. Epub 2016 Sep 26. 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	CF	Superior CR rate

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1
• Cisplatin (Platinol) 100 mg/m² IV once on day 2
• Fluorouracil (5-FU) 500 mg/m²/day IV continuous infusion over 5 days on days 2 to 6 (total dose per cycle: 2500 mg/m²)

Supportive medications

• Dexamethasone (Decadron) 20 mg IV once 30 minutes prior to Paclitaxel (Taxol)
• Dexamethasone (Decadron) 8 mg PO BID on days 2 & 3
• Ondansetron (Zofran) 8 mg IV/PO Q8H or Q12H on days 1 to 5
• Diphenhydramine (Benadryl) 50 mg IV once 30 minutes prior to Paclitaxel (Taxol)
• Cimetidine (Tagamet) 300 mg IV once 30 minutes prior to Paclitaxel (Taxol)
  • Per Hitt et al. 2005, Ranitidine (Zantac) (dose not specified) could be used instead
• Mannitol and IV hydration with Cisplatin (Platinol)

21-day cycle for 3 cycles

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 partial response were recommended for surgery. Patients with bulky nodal disease prior to therapy "and/or suboptimal response to induction chemotherapy" were recommended for neck dissection before radiation therapy. Surgery was performed 4 weeks after cycle 3 day 1. Patients with complete response (CR) or partial response proceeded to paclitaxel & RT; radiation therapy 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 complete response (CR) or partial response of greater than 80% in the primary tumor and no evidence of progression in neck lymph nodes proceeded to 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 CT were referred to 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

TPF (Taxotere)

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

Regimen #1, 60/60/600

Study	Evidence	Comparator	Efficacy
Sun et al. 2016	Phase III	No induction	Seems to have superior FFS

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1
• Cisplatin (Platinol) 60 mg/m² IV once on day 1
• Fluorouracil (5-FU) 600 mg/m²/day IV continuous infusion over 120 hours on days 1 to 5 (total dose per cycle: 3000 mg/m²)

21-day cycle for 3 cycles

Treatment followed by cisplatin & RT.

Regimen #2, 75/75/750 (3 cycles)

Study	Evidence	Comparator	Efficacy
Pointreau et al. 2009 (GORTEC 2000-01)	Phase III	CF	Superior ORR
Lefebvre et al. 2013 (TREMPLIN)	Non-randomized portion of RCT

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Cisplatin (Platinol) 75 mg/m² IV once on day 1
• Fluorouracil (5-FU) 750 mg/m² IV once per day on days 1 to 5 (total dose per cycle: 3750 mg/m²)

Supportive medications

• "Hydration was delivered according to institutional protocols."
• Dexamethasone (Decadron) 8 mg PO BID the day before, the day of, and day after Docetaxel (Taxotere)
• Ciprofloxacin (Cipro) 500 mg PO BID on days 5 to 15
• Prophylactic granulocyte colony-stimulating factor was not used.
  • G-CSF 150 mcg/m² SC once per day was used if febrile neutropenia occurred.
• 5-HT3 antagonists given twice, before and after Cisplatin (Platinol)

21-day cycle for 3 cycles

GORTEC: Patients who responded to induction chemotherapy proceeded to radiation therapy within 3 to 7 weeks of finishing chemotherapy. Patients who did not respond to induction chemotherapy proceeded to surgery and postoperative radiotherapy (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" were treated with cetuximab & RT versus cisplatin & RT. Patients who did not have at least 50% regression had salvage total laryngectomy.

Regimen #3, 75/100/1000 (3 cycles)

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

Reported efficacy is based on the 2011 update.

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 1 hour 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

Patients proceed to carboplatin & RT 3 to 8 weeks after the start of cycle 3.

Regimen #4, 75/75/750 (4 cycles)

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

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV over 1 hour once on day 1, given first before cisplatin
• Cisplatin (Platinol) 75 mg/m² IV over 1 hour 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

• Dexamethasone (Decadron) 8 mg PO for 6 doses (exact schedule not specified) starting the night before Docetaxel (Taxotere)
• Ciprofloxacin (Cipro) 500 mg PO BID "or an alternative agent" on days 5 to 15 as prophylaxis
• "Adequate antiemetic medications during chemotherapy"
• Prophylactic granulocyte colony-stimulating factor only allowed for patients who had "febrile neutropenia or infection, a delay in recovery of the absolute neutrophil count at day 28, or grade 4 neutropenia persisting for 7 days or more."

21-day cycle for 4 cycles

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

Regimen #5, 75/100/1000 (2 cycles)

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

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 4 days on days 1 to 4 (total dose per cycle: 4000 mg/m²)

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

Restaging of disease takes place 3 weeks after finishing cycle 2. Patients with stable disease or tumors which responded to therapy proceed to cisplatin & RT. Patients with progressive disease are considered--if possible--for surgical resection and post-operative radiation. Patients who could not undergo surgery also received cisplatin & RT.

Regimen #6, 70/75/1000

Study	Evidence
Bae et al. 2010	Phase II

This study only involved patients with locoregionally advanced nasopharyngeal cancer.

Chemotherapy

• Docetaxel (Taxotere) 70 mg/m² in 300 mL normal saline IV over 1 hour once on day 1, given first
• Cisplatin (Platinol) 75 mg/m² IV over 3 hours once on day 1, given second
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 4 days on days 1 to 4, started after completion of cisplatin (total dose per cycle: 4000 mg/m²)

Supportive medications

• Dexamethasone (Decadron) 20 mg IV once 30 minutes prior to Docetaxel (Taxotere)
• Ranitidine (Zantac) 50 mg IV once 30 minutes prior to Docetaxel (Taxotere)
• Chlorpheniramine (Chlor-Trimeton) 5 mg IV once 30 minutes prior to Docetaxel (Taxotere)
• Posthydration after Cisplatin (Platinol) with normal saline (volume/rate not specified)
• Ondansetron (Zofran) 8 mg IV "was routinely given"
• Levofloxacin (Levaquin) 500 mg PO once per day on days 5 to 10 as prophylaxis
• Prophylactic G-CSF per physician's discretion

21-day cycle for 3 cycles

Treatment followed by cisplatin & RT.

References

1. 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. 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. Bae WK, Hwang JE, Shim HJ, Cho SH, Lee JK, Lim SC, Chung WK, Chung IJ. Phase II study of docetaxel, cisplatin, and 5-FU induction chemotherapy followed by chemoradiotherapy in locoregionally advanced nasopharyngeal cancer. Cancer Chemother Pharmacol. 2010 Feb;65(3):589-95. link to original article contains verified protocol PubMed
5. 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. 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
7. Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, Clark J, Sarlis N, Lorch J, Beitler JJ, Limaye S, Riley S, Posner M. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013 Mar;14(3):257-64. Epub 2013 Feb 13. link to original article PubMed
8. 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 PubMed
9. Sun Y, Li WF, Chen NY, Zhang N, Hu GQ, Xie FY, Sun Y, Chen XZ, Li JG, Zhu XD, Hu CS, Xu XY, Chen YY, Hu WH, Guo L, Mo HY, Chen L, Mao YP, Sun R, Ai P, Liang SB, Long GX, Zheng BM, Feng XL, Gong XC, Li L, Shen CY, Xu JY, Guo Y, Chen YM, Zhang F, Lin L, Tang LL, Liu MZ, Ma J. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 2016 Nov;17(11):1509-1520. Epub 2016 Sep 26. link to original article contains verified protocol PubMed

Locally advanced disease, definitive chemoradiotherapy

Carboplatin & RT

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Chitapanarux et al. 2007	Phase III	Cisplatin & RT, then CF	Seems not superior

This study only involved patients with locally advanced nasopharyngeal cancer.

Chemoradiotherapy

• Carboplatin (Paraplatin) 100 mg/m² IV over 1 hour once per day on days 1, 8, 15, 22, 29, 36
• Concurrent radiation therapy to the primary tumor, 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 5 times per week over 7 weeks

7-week course

Treatment followed in 4 weeks by carboplatin & fluorouracil consolidation.

Regimen #2

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

Reported efficacy is based on the 2011 update.

Preceding treatment

• CF versus TPF induction

Chemoradiotherapy

• Carboplatin (Paraplatin) AUC 1.5 IV over 1 hour 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. Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, Sumitsawan Y, Tharavichitkul E, Sukthomya V, Ford J. Chemoradiotherapy comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiority, open trial. Eur J Cancer. 2007 Jun;43(9):1399-406. Epub 2007 Apr 27. link to original article contains verified protocol PubMed
2. 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	Radiation therapy	Seems to have superior OS
Bourhis et al. 2012 (GORTEC 99-02)	Phase III	Carboplatin, Fluorouracil, accelerated concurrent RT	Seems not superior
		Very accelerated radiation therapy	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. 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. 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. 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

Regimen #1, accelerated hyperfractionated RT

Study	Evidence
Carter et al. 2008	Phase II

Chemoradiotherapy

• Carboplatin (Paraplatin) AUC 1 IV once per week
• Paclitaxel (Taxol) 40 mg/m² IV once per week
• Concurrent radiation therapy, 1.2 Gy BID fractions (total dose: 69.6 Gy)

6-week course of therapy

Regimen #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

• Dexamethasone (Decadron) 20 mg (route not specified) given twice, 12 and 6 hours prior to chemotherapy
• Diphenhydramine (Benadryl) 50 mg IV once prior to chemotherapy
• Ranitidine (Zantac) 50 mg IV once prior to chemotherapy
• Granisetron (Kytril) 1 mg IV once prior to chemotherapy

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	Radiation therapy	Seems to have superior OS

Chemoradiotherapy

• Cetuximab (Erbitux) 400 mg/m² IV over 2 hours once 1 week before radiation therapy begins; then 250 mg/m² IV over 1 hour 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:
  • "Once per day" regimen: Concurrent radiation therapy, 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: Concurrent radiation therapy, 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: Concurrent radiation therapy, 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

• Diphenhydramine (Benadryl) 50 mg (route not specified) "or an equivalent histamine H1–receptor antagonist" prior to Cetuximab (Erbitux)

References

1. 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. 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 PubMed

Cisplatin, Fluorouracil, RT

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CF & RT: Cisplatin and Fluorouracil with concurrent Radiation Therapy

Regimen #1

Study	Evidence	Comparator	Efficacy
Bensadoun et al. 2006	Phase III	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
  • Cycles 2 & 3: 430 mg/m²/day IV continuous infusion over 120 hours on days 1 to 5
• 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

Regimen #2

Study	Evidence	Comparator	Efficacy
Brizel et al. 1998	Phase III	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
• Concurrent radiation therapy, 1.2 Gy fractions given twice per day, 5 times per week (total dose: 75 Gy)

6-week course

Regimen #3

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

Note: Garden et al. 2004 described this regimen in an unclear way, and it is not clear exactly how many doses or when each chemotherapy is given. Specifically, it's confusing how people would "receive their treatments every week for 7 consecutive weeks," yet fluorouracil (and maybe also cisplatin) would be given "daily for the final 10 days of radiation treatment."

Chemoradiotherapy

• Cisplatin (Platinol) 10 mg/m² IV once per day (unable to discern what days this is given on based on the paper)
• Fluorouracil (5-FU) 400 mg/m²/day IV continuous infusion over 10 days on the last 10 days of radiation treatments
• 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

Regimen #4

Study	Evidence	Comparator	Efficacy
Taylor et al. 1994	Phase III	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

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 PubMed
   1. Update: Merlano M, Benasso M, Corvò R, Rosso R, Vitale V, Blengio F, Numico G,vMargarino 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 et al. 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. 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 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 contains verified protocol--see comment above 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 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

Cisplatin & RT

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RT: Radiation Therapy

Regimen #1, 100 mg/m² on days 1, 22, 43

Study	Evidence	Comparator	Efficacy
Al-Sarraf et al. 1998 (Intergroup 0099)	Phase III	Radiation therapy	Superior OS
Adelstein et al. 2003	Phase III	CF & RT	Seems not superior
		Radiation therapy	Seems to have superior OS
Forastiere et al. 2003 (RTOG 91-11)	Phase III	CF, then RT	Not reported
		Radiation therapy	Superior DFS
Hitt et al. 2005	Non-randomized portion of RCT
Chitapanarux et al. 2007	Phase III	Carboplatin & RT, then Carboplatin & 5-FU	Seems not superior
Lee et al. 2010 (NPC-9901)	Phase III	Radiation therapy	Seems to have superior OS (*)
Hitt et al. 2013	Non-randomized portion of RCT
Lefebvre et al. 2013 (TREMPLIN)	Randomized Phase II	Cetuximab & RT	Seems not superior
Sun et al. 2016	Non-randomized portion of RCT
Siu et al. 2016 (CCTG HN.6)	Phase III	Panitumumab & RT	Seems not superior

Intergroup 0099 involved patients with stage III and IV nasopharynx cancers without evidence of metastases. Efficacy for NPC-9901 is based on the 2016 update.

Preceding treatment

• Hitt et al. 2005: CF versus PCF induction
• Hitt et al. 2013: CF versus TPF versus no induction
• TREMPLIN: TPF induction

Chemoradiotherapy

• Cisplatin (Platinol) 100 mg/m² IV once per day on days 1, 22, 43
• Concurrent radiation therapy with one of the following:
  • Intergroup 0099: 1.8 to 2 Gy fractions x 35 to 39 fractions to the primary tumor (total dose: 70 Gy), given 5 times per week. Minimum total dose to neck nodes is 50 Gy for N0 disease; 66 Gy for nodes less than or equal to 2 cm in size; 70 Gy for nodes greater than 2 cm.
  • Adelstein et al. 2003, Chitapanarux et al. 2007, RTOG 91-11, and CCTG HN.6: 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 5 times per week over 7 weeks
  • Hitt et al. 2005: 2 Gy fractions x 35 fractions to the primary tumor (total dose: 70 Gy), given 5 times per week over 7 weeks. Nodal areas not involved by tumor received 50 Gy.
  • Sun et al. 2016: see paper for details

Supportive medications

• Best described by Al-Sarraf et al. 1998
• Forced hydration: 5% dextrose in 1/2 normal saline with 40 mEq KCl, 2000 mL IV continuous infusion over 24 hours given twice, before each dose of Cisplatin (Platinol) and after the second mannitol infusion
• Mannitol 12.5 g IV bolus prior to Cisplatin (Platinol)
• 5% dextrose in 1/2 normal saline with 30 mEq KCl and mannitol 25 g, 1000 mL IV over 4 hours immediately after Cisplatin (Platinol)
• Antiemetic such as Prochlorperazine (Compazine) 25 mg rectal suppository given 30 minutes prior to Cisplatin (Platinol); Prochlorperazine (Compazine) 10 mg IM every 4 hours as needed for nausea after Cisplatin (Platinol)

One course

In Intergroup 0099, Chitapanarux et al. 2007, and NPC-9901, treatment followed 4 weeks after the last dose of cisplatin by adjuvant CF.

Regimen #2, 100 mg/m² on days 1 & 22

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

Preceding treatment

• SWOG S0216: TPF induction

Chemoradiotherapy

• Cisplatin (Platinol) 100 mg/m² IV once per day on days 1 & 22
• Concurrent radiation therapy by one of the following:
  • Bae et al. 2010: 1.8 to 2 Gy fractions (total dose: 68.4 Gy), given 5 times per week
  • 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

In SWOG S0216, surgical resection was considered after concomitant chemoradiotherapy for those patients with histologically confirmed residual or recurrent disease at the primary site.

Regimen #3, 40 mg/m² weekly dosing

Study	Evidence	Comparator	Efficacy
Chan et al. 2005	Phase III	Radiation therapy	Might have superior OS

This study only involved patients with locoregionally advanced nasopharyngeal carcinoma.

Chemoradiotherapy

• Cisplatin (Platinol) 40 mg/m² in 1 liter normal saline IV over 2 hours once per day on days 1, 8, 15, 22, 29, 36, 43
• Concurrent radiation therapy, 2 Gy fractions x 33 fractions (total dose: 66 Gy), given 5 times per week over 6.5 weeks. See Chan et al. 2005 for additional information about boost doses.

One course

Regimen #4, 6 mg/m² daily dosing

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

Chemoradiotherapy

• Cisplatin (Platinol) 6 mg/m² IV once per day on treatment days
• Concurrent radiation therapy, 1.1 Gy fractions x 70 fractions, given twice per day, 5 times per week (total dose: 77 Gy)

One 7-week course

References

1. Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, Forastiere AA, Adams G, Sakr WA, Schuller DE, Ensley JF. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 1998 Apr;16(4):1310-7. link to original article contains verified protocol PubMed
2. 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
3. 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
4. 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
5. Chan AT, Leung SF, Ngan RK, Teo PM, Lau WH, Kwan WH, Hui EP, Yiu HY, Yeo W, Cheung FY, Yu KH, Chiu KW, Chan DT, Mok TS, Yau S, Yuen KT, Mo FK, Lai MM, Ma BB, Kam MK, Leung TW, Johnson PJ, Choi PH, Zee BC. Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst. 2005 Apr 6;97(7):536-9. link to original article contains verified protocol PubMed
6. 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
7. Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, Sumitsawan Y, Tharavichitkul E, Sukthomya V, Ford J. Chemoradiotherapy comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiority, open trial. Eur J Cancer. 2007 Jun;43(9):1399-406. Epub 2007 Apr 27. link to original article contains verified protocol PubMed
8. Bae WK, Hwang JE, Shim HJ, Cho SH, Lee JK, Lim SC, Chung WK, Chung IJ. Phase II study of docetaxel, cisplatin, and 5-FU induction chemotherapy followed by chemoradiotherapy in locoregionally advanced nasopharyngeal cancer. Cancer Chemother Pharmacol. 2010 Feb;65(3):589-95. link to original article contains verified protocol PubMed
9. 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
10. Lee AW, Tung SY, Chua DT, Ngan RK, Chappell R, Tung R, Siu L, Ng WT, Sze WK, Au GK, Law SC, O'Sullivan B, Yau TK, Leung TW, Au JS, Sze WM, Choi CW, Fung KK, Lau JT, Lau WH. Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst. 2010 Aug 4;102(15):1188-98. Epub 2010 Jul 15. link to original article contains partial protocol PubMed
    1. Update: Lee AWM, Tung SY, Ng WT, Lee V, Ngan RKC, Choi HCW, Chan LLK, Siu LL, Ng AWY, Leung TW, Yiu HHY, O'Sullivan B, Chappell R. A multicenter, phase 3, randomized trial of concurrent chemoradiotherapy plus adjuvant chemotherapy versus radiotherapy alone in patients with regionally advanced nasopharyngeal carcinoma: 10-year outcomes for efficacy and toxicity. Cancer. 2017 Nov 1;123(21):4147-4157. Epub 2017 Jun 29. link to original article PubMed
11. Chen L, Hu CS, Chen XZ, Hu GQ, Cheng ZB, Sun Y, Li WX, Chen YY, Xie FY, Liang SB, Chen Y, Xu TT, Li B, Long GX, Wang SY, Zheng BM, Guo Y, Sun Y, Mao YP, Tang LL, Chen YM, Liu MZ, Ma J. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2012 Feb;13(2):163-71. Epub 2011 Dec 7. link to original article PubMed
    1. Update: Chen L, Hu CS, Chen XZ, Hu GQ, Cheng ZB, Sun Y, Li WX, Chen YY, Xie FY, Liang SB, Chen Y, Xu TT, Li B, Long GX, Wang SY, Zheng BM, Guo Y, Sun Y, Mao YP, Tang LL, Chen YM, Liu MZ, Ma J. Adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: Long-term results of a phase 3 multicentre randomised controlled trial. Eur J Cancer. 2017 Apr;75:150-158. Epub 2017 Feb 22. link to original article PubMed
12. 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
13. Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, Clark J, Sarlis N, Lorch J, Beitler JJ, Limaye S, Riley S, Posner M. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherapy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomised phase 3 trial. Lancet Oncol. 2013 Mar;14(3):257-64. Epub 2013 Feb 13. link to original article PubMed
14. 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
15. 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
16. 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 PubMed
17. 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. link to original article PubMed
18. Sun Y, Li WF, Chen NY, Zhang N, Hu GQ, Xie FY, Sun Y, Chen XZ, Li JG, Zhu XD, Hu CS, Xu XY, Chen YY, Hu WH, Guo L, Mo HY, Chen L, Mao YP, Sun R, Ai P, Liang SB, Long GX, Zheng BM, Feng XL, Gong XC, Li L, Shen CY, Xu JY, Guo Y, Chen YM, Zhang F, Lin L, Tang LL, Liu MZ, Ma J. Induction chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: a phase 3, multicentre, randomised controlled trial. Lancet Oncol. 2016 Nov;17(11):1509-1520. Epub 2016 Sep 26. link to original article contains verified protocol PubMed
19. 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
20. Cao SM, Yang Q, Guo L, Mai HQ, Mo HY, Cao KJ, Qian CN, Zhao C, Xiang YQ, Zhang XP, Lin ZX, Li WX, Liu Q, Qiu F, Sun R, Chen QY, Huang PY, Luo DH, Hua YJ, Wu YS, Lv X, Wang L, Xia WX, Tang LQ, Ye YF, Chen MY, Guo X, Hong MH. Neoadjuvant chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in locoregionally advanced nasopharyngeal carcinoma: A phase III multicentre randomised controlled trial. Eur J Cancer. 2017 Apr;75:14-23. Epub 2017 Feb 16. link to original article 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	CF & RT	Seems not superior
		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	TPF, then Docetaxel, Fluorouracil, Hydroxyurea, RT	Seems not superior

To be completed

Chemoradiotherapy

• Docetaxel (Taxotere)
• Fluorouracil (5-FU)
• Hydroxyurea (Hydrea)
• Concurrent radiation therapy

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	CF & RT	Seems not superior
		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
(ARO 95-06)	Phase III	Radiation therapy	Seems to have superior OS

Chemoradiotherapy

• Fluorouracil (5-FU) 600 mg/m²/day IV continuous infusion on days 1 to 5 (total dose: 3000 mg/m²)
• Mitomycin (Mutamycin) 10 mg/m²/day IV once per day on days 5 & 36
• Concurrent radiation therapy, hyperfractionated to total dose 70.6 Gy

6-week course of therapy

References

1. 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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RT: Radiation Therapy

Regimen

Of historic interest.

Chemoradiotherapy

• Fluorouracil (5-FU)
• Concurrent radiation therapy

References

1. 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. 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

Oxaliplatin & RT

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Zhang et al. 2005	Phase III	RT	Seems to have superior OS (*)

Note: this regimen is intended for locoregionally advanced nasopharyngeal carcinoma. Reported efficacy is based on the 2013 update.

Chemoradiotherapy

• Oxaliplatin (Eloxatin) 70 mg/m² IV once per week (6 doses)
• Concurrent radiation therapy to primary tumor (70 to 74 Gy).

6-week course

References

1. Zhang L, Zhao C, Peng PJ, Lu LX, Huang PY, Han F, Wu SX. Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol. 2005 Nov 20;23(33):8461-8. Epub 2005 Oct 17. link to original article contains verified protocol PubMed
   1. Update: Wu X, Huang PY, Peng PJ, Lu LX, Han F, Wu SX, Hou X, Zhao HY, Huang Y, Fang WF, Zhao YY, Xue C, Hu ZH, Zhang J, Zhang JW, Ma YX, Liang WH, Zhao C, Zhang L. Long-term follow-up of a phase III study comparing radiotherapy with or without weekly oxaliplatin for locoregionally advanced nasopharyngeal carcinoma. Ann Oncol. 2013 Aug;24(8):2131-6. Epub 2013 May 9. link to original article 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

• Depending on response, PCF induction or surgery

Chemoradiotherapy

• Paclitaxel (Taxol) 25 mg/m² IV over 1 hour 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
Taylor et al. 1994	Non-randomized portion of RCT
Al-Sarraf et al. 1998 (Intergroup 0099)	Phase III	Cisplatin & RT, then CF	Inferior OS
Adelstein et al. 2003	Phase III	CF & RT	Seems not superior
		Cisplatin & RT	Seems to have inferior OS
Forastiere et al. 2003 (RTOG 91-11)	Phase III	CF, then RT	Seems to have inferior DFS
		Cisplatin & RT	Inferior DFS
Calais et al. 1999 (GORTEC 94-01)	Phase III	Carboplatin, 5-FU, RT	Seems to have inferior OS
Chan et al. 2005	Phase III	Cisplatin & RT	Might have inferior OS
Bonner et al. 2006 (IMCL-9815)	Phase III	Cetuximab & RT	Seems to have inferior OS
Vermorken et al. 2007 (EORTC 24971/TAX 323)	Non-randomized portion of RCT
Pointreau et al. 2009 (GORTEC 2000-01)	Non-randomized portion of RCT
Lee et al. 2010 (NPC-9901)	Phase III	Cisplatin & RT	Seems to have inferior OS (*)
Bourhis et al. 2012 (GORTEC 99-02)	Phase III	Carboplatin, 5-FU, RT	Seems to have inferior PFS
		Carboplatin, 5-FU, accelerated concurrent RT	Might have inferior PFS

Efficacy for NPC-9901 is based on the 2016 update.

Preceding treatment

• RTOG 91-11: CF x 3 versus no induction

Radiotherapy

• Radiation therapy, 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 5 times per week over 7 weeks

Preceding treatment

• Taylor et al. 1994: CF x 7

Radiotherapy

• Radiation therapy, 1.8 to 2 Gy fractions to a total dose of 70 Gy, given 5 times per week over 7 to 8 weeks

Preceding treatment

• GORTEC: CF x 3 versus TPF x 3

Radiotherapy

• Radiation therapy to the primary tumor and involved lymph nodes, 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 5 times per week over 7 weeks. Prophylactic radiation to the volume at risk for microscopic disease, 2 Gy fractions x 25 to 27 fractions (total dose: 50 to 54 Gy), given 5 times per week.
• "Chemotherapy (cisplatin, carboplatin, and 5-fluorouracil or a combination of two drugs) during radiotherapy was allowed for all patients who were treated at the same institute, according to its practice." No further details available.

Preceding treatment

• EORTC 24971/TAX 323: CF x 4 versus TPF x 4

Radiotherapy

• Radiation therapy over 7 weeks with one of the following (further details not provided):
  • Conventional fractionation, total dose 66 to 70 Gy
  • Accelerated fractionation, total dose 70 Gy
  • Hyperfractionated, total dose 74 Gy

References

1. 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. Department of Veterans Affairs Laryngeal Cancer Study Group, Wolf GT, Fisher SG, Hong WK, Hillman R, Spaulding M, Laramore GE, Endicott JW, McClatchey K, Henderson WG. 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 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,vMargarino 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 et al. 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. Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, Forastiere AA, Adams G, Sakr WA, Schuller DE, Ensley JF. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 1998 Apr;16(4):1310-7. link to original article contains verified protocol PubMed
8. 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
9. 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
10. 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. 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
11. 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
12. 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
13. 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
14. 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
15. Chan AT, Leung SF, Ngan RK, Teo PM, Lau WH, Kwan WH, Hui EP, Yiu HY, Yeo W, Cheung FY, Yu KH, Chiu KW, Chan DT, Mok TS, Yau S, Yuen KT, Mo FK, Lai MM, Ma BB, Kam MK, Leung TW, Johnson PJ, Choi PH, Zee BC. Overall survival after concurrent cisplatin-radiotherapy compared with radiotherapy alone in locoregionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst. 2005 Apr 6;97(7):536-9. link to original article contains verified protocol PubMed
16. Wee J, Tan EH, Tai BC, Wong HB, Leong SS, Tan T, Chua ET, Yang E, Lee KM, Fong KW, Tan HS, Lee KS, Loong S, Sethi V, Chua EJ, Machin D. Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol. 2005 Sep 20;23(27):6730-8. link to original article PubMed
17. Zhang L, Zhao C, Peng PJ, Lu LX, Huang PY, Han F, Wu SX. Phase III study comparing standard radiotherapy with or without weekly oxaliplatin in treatment of locoregionally advanced nasopharyngeal carcinoma: preliminary results. J Clin Oncol. 2005 Nov 20;23(33):8461-8. Epub 2005 Oct 17. link to original article contains verified protocol PubMed
    1. Update: Wu X, Huang PY, Peng PJ, Lu LX, Han F, Wu SX, Hou X, Zhao HY, Huang Y, Fang WF, Zhao YY, Xue C, Hu ZH, Zhang J, Zhang JW, Ma YX, Liang WH, Zhao C, Zhang L. Long-term follow-up of a phase III study comparing radiotherapy with or without weekly oxaliplatin for locoregionally advanced nasopharyngeal carcinoma. Ann Oncol. 2013 Aug;24(8):2131-6. Epub 2013 May 9. link to original article PubMed
18. 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
19. 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
20. 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
21. 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
22. 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
23. Lee AW, Tung SY, Chua DT, Ngan RK, Chappell R, Tung R, Siu L, Ng WT, Sze WK, Au GK, Law SC, O'Sullivan B, Yau TK, Leung TW, Au JS, Sze WM, Choi CW, Fung KK, Lau JT, Lau WH. Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst. 2010 Aug 4;102(15):1188-98. Epub 2010 Jul 15. link to original article contains partial protocol PubMed
    1. Update: Lee AWM, Tung SY, Ng WT, Lee V, Ngan RKC, Choi HCW, Chan LLK, Siu LL, Ng AWY, Leung TW, Yiu HHY, O'Sullivan B, Chappell R. A multicenter, phase 3, randomized trial of concurrent chemoradiotherapy plus adjuvant chemotherapy versus radiotherapy alone in patients with regionally advanced nasopharyngeal carcinoma: 10-year outcomes for efficacy and toxicity. Cancer. 2017 Nov 1;123(21):4147-4157. Epub 2017 Jun 29. link to original article PubMed
24. 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
25. 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. link to original article PubMed

Adjuvant therapy

Cisplatin & Fluorouracil

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Cisplatin and Fluorouracil

Regimen #1

Study	Evidence	Comparator	Efficacy
Al-Sarraf et al. 1998 (Intergroup 0099)	Non-randomized portion of RCT
Chitapanarux et al. 2007	Phase III	Carboplatin & RT, then Carboplatin & 5-FU	Seems not superior
Lee et al. 2010 (NPC-9901))	Non-randomized portion of RCT

Preceding treatment

• Cisplatin & RT

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV over 15 to 20 minutes 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)

28-day cycle for 3 cycles

References

1. Al-Sarraf M, LeBlanc M, Giri PG, Fu KK, Cooper J, Vuong T, Forastiere AA, Adams G, Sakr WA, Schuller DE, Ensley JF. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099. J Clin Oncol. 1998 Apr;16(4):1310-7. link to original article contains verified protocol PubMed
2. Wee J, Tan EH, Tai BC, Wong HB, Leong SS, Tan T, Chua ET, Yang E, Lee KM, Fong KW, Tan HS, Lee KS, Loong S, Sethi V, Chua EJ, Machin D. Randomized trial of radiotherapy versus concurrent chemoradiotherapy followed by adjuvant chemotherapy in patients with American Joint Committee on Cancer/International Union against cancer stage III and IV nasopharyngeal cancer of the endemic variety. J Clin Oncol. 2005 Sep 20;23(27):6730-8. link to original article PubMed
3. Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, Sumitsawan Y, Tharavichitkul E, Sukthomya V, Ford J. Chemoradiotherapy comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiority, open trial. Eur J Cancer. 2007 Jun;43(9):1399-406. Epub 2007 Apr 27. link to original article contains verified protocol PubMed
4. Lee AW, Tung SY, Chua DT, Ngan RK, Chappell R, Tung R, Siu L, Ng WT, Sze WK, Au GK, Law SC, O'Sullivan B, Yau TK, Leung TW, Au JS, Sze WM, Choi CW, Fung KK, Lau JT, Lau WH. Randomized trial of radiotherapy plus concurrent-adjuvant chemotherapy vs radiotherapy alone for regionally advanced nasopharyngeal carcinoma. J Natl Cancer Inst. 2010 Aug 4;102(15):1188-98. Epub 2010 Jul 15. link to original article contains partial protocol PubMed
   1. Update: Lee AWM, Tung SY, Ng WT, Lee V, Ngan RKC, Choi HCW, Chan LLK, Siu LL, Ng AWY, Leung TW, Yiu HHY, O'Sullivan B, Chappell R. A multicenter, phase 3, randomized trial of concurrent chemoradiotherapy plus adjuvant chemotherapy versus radiotherapy alone in patients with regionally advanced nasopharyngeal carcinoma: 10-year outcomes for efficacy and toxicity. Cancer. 2017 Nov 1;123(21):4147-4157. Epub 2017 Jun 29. link to original article PubMed
5. Chen L, Hu CS, Chen XZ, Hu GQ, Cheng ZB, Sun Y, Li WX, Chen YY, Xie FY, Liang SB, Chen Y, Xu TT, Li B, Long GX, Wang SY, Zheng BM, Guo Y, Sun Y, Mao YP, Tang LL, Chen YM, Liu MZ, Ma J. Concurrent chemoradiotherapy plus adjuvant chemotherapy versus concurrent chemoradiotherapy alone in patients with locoregionally advanced nasopharyngeal carcinoma: a phase 3 multicentre randomised controlled trial. Lancet Oncol. 2012 Feb;13(2):163-71. Epub 2011 Dec 7. link to original article PubMed
   1. Update: Chen L, Hu CS, Chen XZ, Hu GQ, Cheng ZB, Sun Y, Li WX, Chen YY, Xie FY, Liang SB, Chen Y, Xu TT, Li B, Long GX, Wang SY, Zheng BM, Guo Y, Sun Y, Mao YP, Tang LL, Chen YM, Liu MZ, Ma J. Adjuvant chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma: Long-term results of a phase 3 multicentre randomised controlled trial. Eur J Cancer. 2017 Apr;75:150-158. Epub 2017 Feb 22. link to original article PubMed

Cisplatin, Cetuximab, RT

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Harari et al. 2014 (RTOG-0234)	Randomized Phase II	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

• Diphenhydramine (Benadryl) 50 mg IV once 30 to 60 minutes prior to the first dose of Cetuximab (Erbitux)
• Dolasetron (Anzemet) 100 mg IV once 30 minutes prior to Cisplatin (Platinol)

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

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RT: Radiation Therapy

Regimen #1

Study	Evidence	Comparator	Efficacy
Cooper et al. 2004 (RTOG 9501, ECOG R9501, SWOG 9515)	Phase III	Radiation therapy	Seems to have superior DFS

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."

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, with 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

Regimen #2

Study	Evidence	Comparator	Efficacy
Bernier et al. 2004 (EORTC 22931)	Phase III	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

• "Prophylactic hydration and antiemetic agents"

7-week course

Regimen #3

Study	Evidence	Comparator	Efficacy
Bachaud et al. 1991	Phase III	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

• "Forced hydration" with Cisplatin (Platinol)

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

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. 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. 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. 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
4. 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

Docetaxel, Cetuximab, RT

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RT: Radiation Therapy

Regimen

Study	Evidence	Comparator	Efficacy
Harari et al. 2014 (RTOG-0234)	Randomized Phase II	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

• Diphenhydramine (Benadryl) 50 mg IV once 30 to 60 minutes prior to the first dose of Cetuximab (Erbitux)
• Dexamethasone (Decadron) 20 mg IV once prior to Docetaxel (Taxotere)

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
Bachaud et al. 1991	Phase III	Cisplatin & RT	Inferior OS
Cooper et al. 2004 (RTOG 9501, ECOG R9501, SWOG 9515)	Phase III	Cisplatin & RT	Seems to have inferior DFS
Bernier et al. 2004 (EORTC 22931)	Phase III	Cisplatin & RT	Seems to have inferior OS

Reference only.

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. 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. 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. 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
4. 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

Carboplatin & Fluorouracil

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Regimen

Study	Evidence
Chitapanarux et al. 2007	Non-randomized portion of RCT

This study only involved patients with locally advanced nasopharyngeal cancer.

Preceding treatment

• Carboplatin & RT

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 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)

28-day cycle for 3 cycles

References

1. Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, Sumitsawan Y, Tharavichitkul E, Sukthomya V, Ford J. Chemoradiotherapy comparing cisplatin versus carboplatin in locally advanced nasopharyngeal cancer: randomised, non-inferiority, open trial. Eur J Cancer. 2007 Jun;43(9):1399-406. Epub 2007 Apr 27. link to original article contains verified protocol PubMed

Recurrent or metastatic disease

Afatinib monotherapy

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Regimen

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

Chemotherapy

• Afatinib (Gilotrif) 40 mg PO once per day

References

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

Carboplatin & Docetaxel

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Regimen

Study	Evidence
Samlowski et al. 2007	Phase II

Chemotherapy

• Carboplatin (Paraplatin) AUC 6 IV once on day 1
• Docetaxel (Taxotere) 65 mg/m² IV once on day 1

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	Phase III	CF	Not reported
		MTX	Seems to have superior ORR
Vermorken et al. 2008	Phase III	Carboplatin, Fluorouracil, Cetuximab	Seems to have inferior OS

Chemotherapy

• Carboplatin (Paraplatin) 300 mg/m² IV over 5 to 10 minutes once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion over 96 hours, start day not specified (total dose per cycle: 4000 mg/m²)

Supportive medications

• "Standard antiemetic regimens"

28-day cycles

References

1. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK et al. 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. 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	Phase III	Carboplatin & Fluorouracil	Seems to have superior OS

Chemotherapy

• Carboplatin (Paraplatin) AUC 5 IV over 1 hour 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 1 hour once per day on days 8 & 15
  • Cycle 2 onwards: 250 mg/m² IV over 1 hour once per day on days 1, 8, 15

21-day cycle for up to 6 cycles

References

1. 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

Cetuximab monotherapy

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Regimen

Study	Evidence
Vermorken et al. 2007	Phase II

Chemotherapy

• Cetuximab (Erbitux) 400 mg/m² (includes 20 mg IV once as a test dose) IV over 120 minutes once on day 1; then starting 1 week later, 250 mg/m² IV over 1 hour 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. 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 PubMed

Cisplatin & Fluorouracil

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CF: Cisplatin and Fluorouracil

Regimen #1

Study	Evidence	Comparator	Efficacy
Zhang et al. 2016	Phase III	Cisplatin & Gemcitabine	Inferior PFS

Note: this regimen was intended for recurrent or metastatic nasopharyngeal carcinoma.

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion on days 1 to 4 (total dose per cycle: 4000 mg/m²)

21-day cycle for up to 6 cycles

Regimen #2

Study	Evidence	Comparator	Efficacy
Forastiere et al. 1992	Phase III	Carboplatin & Fluorouracil	Not reported
		MTX	Superior ORR
Gibson et al. 2005 (ECOG E1395)	Phase III	CP	Seems not superior
Vermorken et al. 2008	Phase III	Cisplatin, Fluorouracil, Cetuximab	Seems to have inferior OS
Vermorken et al. 2013 (SPECTRUM)	Phase III	Cisplatin, Fluorouracil, Panitumumab	Inferior PFS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
  • ECOG E1395: Carboplatin (Paraplatin) 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 6 cycles (SPECTRUM) or indefinitely, see note below

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 PubMed
2. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK et al. 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, et al. 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. PubMed
4. 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. 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. 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
7. Zhang L, Huang Y, Hong S, Yang Y, Yu G, Jia J, Peng P, Wu X, Lin Q, Xi X, Peng J, Xu M, Chen D, Lu X, Wang R, Cao X, Chen X, Lin Z, Xiong J, Lin Q, Xie C, Li Z, Pan J, Li J, Wu S, Lian Y, Yang Q, Zhao C. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma:a multicentre, randomised, open-label, phase 3 trial. Lancet. 2016 Oct 15;388(10054):1883-1892. Epub 2016 Aug 23. link to original article contains protocol PubMed

Cisplatin monotherapy

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Regimen

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

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1

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 PubMed
2. Clavel M, Vermorken JB, Cognetti F, Cappelaere P, de Mulder PH, Schornagel JH, Tueni EA, Verweij J, Wildiers J, Clerico M, et al. 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. 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	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 120 minutes 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	Phase III	CF	Seems to have superior OS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV over 1 hour 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 1 hour once per day on days 8 & 15
  • Cycle 2 onwards: 250 mg/m² IV over 1 hour once per day on days 1, 8, 15

21-day cycle for up to 6 cycles

References

1. 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	CF	Superior PFS

Chemotherapy

• Cisplatin (Platinol) 100 mg/m² IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m²/day IV continuous infusion on days 1 to 4 (total dose per cycle: 4000 mg/m²)
• Panitumumab (Vectibix) 9 mg/kg IV once on day 1

21-day cycle for up to 6 cycles

Patients could choose to continue panitumumab maintenance.

References

1. 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 & Gemcitabine

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Regimen

Study	Evidence	Comparator	Efficacy
Zhang et al. 2016	Phase III	CF	Superior PFS

Note: this regimen was intended for recurrent or metastatic nasopharyngeal carcinoma.

Chemotherapy

• Cisplatin (Platinol) 80 mg/m² IV once on day 1
• Gemcitabine (Gemzar) 1000 mg/m²/day IV once per day on days 1 & 8

21-day cycle for up to 6 cycles

References

1. Zhang L, Huang Y, Hong S, Yang Y, Yu G, Jia J, Peng P, Wu X, Lin Q, Xi X, Peng J, Xu M, Chen D, Lu X, Wang R, Cao X, Chen X, Lin Z, Xiong J, Lin Q, Xie C, Li Z, Pan J, Li J, Wu S, Lian Y, Yang Q, Zhao C. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma:a multicentre, randomised, open-label, phase 3 trial. Lancet. 2016 Oct 15;388(10054):1883-1892. Epub 2016 Aug 23. 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	CF	Seems not superior

Chemotherapy

• Cisplatin (Platinol) 75 mg/m² IV once on day 1
  • Carboplatin (Paraplatin) 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

• Hydration and forced diuresis (no further details given) with Cisplatin (Platinol)
• Dexamethasone (Decadron) 20 mg PO given twice, 12 and 6 hours prior to Paclitaxel (Taxol)
• Diphenhydramine (Benadryl) (no dose specified) IV within 60 minutes prior to Paclitaxel (Taxol)
• H2 receptor antagonist (no further details given) IV within 60 minutes prior to Paclitaxel (Taxol)

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. 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
et al. 1992	Phase III	Cisplatin	Seems not superior
		Cisplatin & 5-FU	Seems not superior

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

Gemcitabine monotherapy

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Regimen

Study	Evidence
Zhang et al. 2008	Phase II

This study only involved patients with advanced (stage IV) or metastatic nasopharyngeal cancer who had already received previous platinum-based chemotherapy.

Chemotherapy

• Gemcitabine (Gemzar) 1000 mg/m² in 100 mL normal saline IV over 30 minutes once per day on days 1, 8, 15

Supportive medications

• 5-HT3 receptor antagonists prior to chemotherapy
• G-CSF and GM-CSF were not used

28-day cycles, given until progression of disease

References

1. Zhang L, Zhang Y, Huang PY, Xu F, Peng PJ, Guan ZZ. Phase II clinical study of gemcitabine in the treatment of patients with advanced nasopharyngeal carcinoma after the failure of platinum-based chemotherapy. Cancer Chemother Pharmacol. 2008 Jan;61(1):33-8. Epub 2007 Mar 20. link to original article contains verified protocol PubMed

Methotrexate monotherapy

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Regimen

Study	Evidence	Comparator	Efficacy
Forastiere et al. 1992	Phase III	Carboplatin & Fluorouracil	Seems to have inferior ORR
		CF	Inferior ORR
Stewart et al. 2009	Phase III	Gefitinib	Seems not superior
Machiels et al. 2015 (LUX-Head & Neck 1)	Phase III	Afatinib	Seems to have inferior PFS

Chemotherapy

• Methotrexate (MTX) 40 mg/m² IV once per week

Supportive medications

• "Standard antiemetic regimens"

References

1. Forastiere AA, Metch B, Schuller DE, Ensley JF, Hutchins LF, Triozzi P, Kish JA, McClure S, VonFeldt E, Williamson SK et al. 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
3. 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
4. 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 PubMed

Nivolumab monotherapy

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Regimen

Study	Evidence	ORR	Comparator	Comparator ORR	Efficacy	Pt Population
Ferris et al. 2016 (CheckMate 141)	Phase III	13% (95% CI 9-18)	Investigators' choice of: Methotrexate Docetaxel Cetuximab	6% (95% CI 2-12)	Superior OS	Recurrent disease, previously treated

Immunotherapy

• Nivolumab (Opdivo) 3 mg/kg IV over 60 minutes on day 1

14-day cycles, given until progression of disease or unacceptable toxicity

References

1. 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

Immunotherapy

• Pembrolizumab (Keytruda) 10 mg/kg IV once on day 1

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

References

1. 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