Head and neck cancer

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Adjuvant chemotherapy & radiation therapy

Cisplatin & concurrent RT

Regimen #1, Cooper, et al. 2004 (RTOG 9501, ECOG R9501, SWOG 9515)

Level of Evidence: Phase III

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."

• Cisplatin (Platinol) 100 mg/m2 IV once daily 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

7-week course

Supportive medications:

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

Regimen #2, Bernier, et al. 2004 (EORTC 22931)

Level of Evidence: Phase III

• Cisplatin (Platinol) 100 mg/m2 IV once daily 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)

7-week course

Supportive medications:

• "Prophylactic hydration and antiemetic agents"

Regimen #3, Bachaud, et al. 1996

Level of Evidence: Phase III

• 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.

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

Supportive medications:

• "Forced hydration" with cisplatin

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
2. 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
3. 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
4. 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
5. 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
6. 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. doi: 10.1016/j.ijrobp.2012.05.008. Epub 2012 Jun 30. link to original article contains verified protocol PubMed

Radiation therapy

Regimen

Level of Evidence: Phase III

Used as a comparator arm; included for reference purposes 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
2. 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
3. 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
4. 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
5. 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
6. 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. doi: 10.1016/j.ijrobp.2012.05.008. Epub 2012 Jun 30. link to original article contains verified protocol PubMed

Locally advanced disease, chemotherapy & radiation therapy

Carboplatin & concurrent RT -> Carboplatin & Fluorouracil

Regimen, Chitapanarux, et al. 2007

Level of Evidence: Phase III

This study only involved patients with locally advanced nasopharyngeal cancer.

Chemoradiation

• Carboplatin (Paraplatin) 100 mg/m2 IV over 1 hour once daily 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, followed by chemotherapy as described below

Chemotherapy

Chemotherapy starts 4 weeks after the end of radiation therapy.

• Carboplatin (Paraplatin) AUC 5 IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours (total dose per cycle: 4000 mg/m2) on days 1 to 4

28-day cycles x 3 cycles

References

1. Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, Sumitsawan Y, Tharavichitkul E, Sukthomya V, Ford J. Chemoradiation 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

Carboplatin, Fluorouracil, concurrent RT

Regimen, Denis, et al. 2004 (94-01) & Bourhis, et al. 2012 (GORTEC 99-02)

Level of Evidence: Phase III

• Carboplatin (Paraplatin) 70 mg/m2 IV once daily on days 1 to 4, 22 to 25, 43 to 46
• Fluorouracil (5-FU) 600 mg/m2/day IV continuous infusion over 4 days (total dose for each 4-day continuous infusion: 2400 mg/m2) on days 1 to 4, 22 to 25, 43 to 46
• 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. 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. doi: 10.1016/S1470-2045(11)70346-1. Epub 2012 Jan 18. link to original article contains verified protocol PubMed

Carboplatin, Paclitaxel, concurrent RT

Regimen, Conley, et al. 1997 & Suntharalingam, et al. 2000

Level of Evidence: Phase II

• 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 of paclitaxel 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

7.5-week course of therapy

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

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

Cetuximab & concurrent RT

Regimen, Bonner, et al. 2006; Curran, et al. 2007; Bonner, et al. 2010

Level of Evidence: Phase III

• Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours once 1 week before radiation therapy begins; then Cetuximab (Erbitux) 250 mg/m2 IV over 1 hour once per week during course of radiation therapy
  • A test dose of Cetuximab (Erbitux) 20 mg IV over 10 minutes, followed by 30 minutes of observation, was given prior to the first full dose of cetuximab
• Concurrent radiation therapy with one of the following regimens:
  • "Once daily" regimen: Concurrent radiation therapy, 2 Gy fractions x 35 fractions (total dose: 70 Gy), given once daily 5 times per week over 7 weeks
  • "Twice daily" 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 daily 5 times per week for 3.6 weeks; and twice daily 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

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
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. 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. doi: 10.1016/S1470-2045(09)70311-0. Epub 2009 Nov 10. link to original article contains partial protocol PubMed

Cisplatin & concurrent RT

Regimen #1, Adelstein, et al. 2003; Forastiere, et al. 2003 (RTOG 91-11)

Level of Evidence: Phase III

• Cisplatin (Platinol) 100 mg/m2 IV once daily on days 1, 22, 43
• Concurrent radiation therapy, 2 Gy fractions x 35 fractions (total dose: 70 Gy), given 5 times per week over 7 weeks

7-week course

Regimen #2, Chan, et al. 2005

Level of Evidence: Phase III

This study only involved patients with locoregionally advanced nasopharyngeal carcinoma.

• Cisplatin (Platinol) 40 mg/m2 in 1 liter normal saline IV over 2 hours once daily 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.

7-week course

References

1. 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
2. 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
3. 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
4. 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. doi: 10.1200/JCO.2012.43.6097. Epub 2012 Nov 26. link to original article contains partial protocol PubMed

Cisplatin & concurrent RT -> Cisplatin & Fluorouracil

Regimen #1, Al-Sarraf, et al. 1998 (Intergroup 0099)

Level of Evidence: Phase III

This study only involved patients with stage III and IV nasopharynx cancers without evidence of metastases.

Chemoradiation

• Cisplatin (Platinol) 100 mg/m2 IV over 15 to 20 minutes once daily on days 1, 22, 43
• Concurrent radiation therapy to the primary tumor, 1.8 to 2 Gy fractions x 35 to 39 fractions (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 ≤2 cm in size; 70 Gy for nodes >2 cm.

7 to 8-week course, followed by chemotherapy as described below

Supportive medications:

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

Chemotherapy

Chemotherapy starts 4 weeks after the last dose of cisplatin used in chemoradiation.

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

28-day cycles x 3 cycles

Supportive medications:

• Al-Sarraf, et al. 1998 did not specifically say whether the same hydration and antiemetics were used for this chemotherapy as in chemoradiation.

Regimen #2, Chitapanarux, et al. 2007

Level of Evidence: Phase III

This study only involved patients with locoregionally advanced nasopharyngeal carcinoma.

Chemoradiation

• Cisplatin (Platinol) 100 mg/m2 IV over 3 hours once daily on days 1, 22, 43
• 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, followed by chemotherapy as described below

Chemotherapy

Chemotherapy starts 4 weeks after the end of radiation therapy.

• Cisplatin (Platinol) 80 mg/m2 IV once on day 1
• Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours (total dose per cycle: 4000 mg/m2) on days 1 to 4

28-day cycles x 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. Chitapanarux I, Lorvidhaya V, Kamnerdsupaphon P, Sumitsawan Y, Tharavichitkul E, Sukthomya V, Ford J. Chemoradiation 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

Cisplatin, Fluorouracil (PF), concurrent RT

PF: Platinol, Fluorouracil

Regimen #1, Taylor, et al. 1994

Level of Evidence: Phase III

• 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 (total dose per cycle: 4000 mg/m2) on days 1 to 5

2-week cycles x 7 cycles given together with the following concurrent radiation therapy:

Radiation therapy

• 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

Regimen #2, Garden, et al. 2004 (RTOG 97-03)

Level of Evidence: Randomized Phase II, >20 per arm

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."

• Cisplatin (Platinol) 10 mg/m2 IV daily (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

References

1. 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
2. Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, Schuller DE, Forastiere AA. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003 Jan 1;21(1):92-8. link to original article contains verified protocol PubMed
3. 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

Cisplatin & Fluorouracil (PF) -> sequential RT

PF: Platinol, Fluorouracil

Regimen #1, Forastiere, et al. 2003 (RTOG 91-11)

Level of Evidence: Phase III

Induction chemotherapy

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

21-day cycles x 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.

Radiation therapy

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

Regimen #2, Taylor, et al. 1994

Level of Evidence: Phase III

Induction chemotherapy

• Cisplatin (Platinol) 100 mg/m2 IV over 15 minutes once on day 1
• Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 120 hours (total dose per cycle: 5000 mg/m2) on days 1 to 5

21-day cycles x 3 cycles, followed by radiation therapy

Radiation therapy

• 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

Regimen #3, Pointreau, et al. 2009 (GORTEC)

Level of Evidence: Phase III

Induction 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 5 days (total dose per cycle: 5000 mg/m2) on days 1 to 5

21-day cycles x 3 cycles; 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).

Supportive medications:

• Normal saline (use of mannitol, KCl, and magnesium sulfate per institutional protocol) 1000 mL IV given twice, before and after cisplatin

Radiation therapy

• 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.

Regimen #4, Vermorken, et al. 2007 (EORTC 24971, TAX 323)

Level of Evidence: Phase III

• 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 (total dose per cycle: 5000 mg/m2) on days 1 to 5

21-day cycles x 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

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."

Radiation therapy

• 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. 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
2. 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
3. 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
4. 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. doi: 10.1093/jnci/djp007. Epub 2009 Mar 24. link to original article contains verified protocol PubMed
5. 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. doi: 10.1038/sj.bjc.6605860. Epub 2010 Sep 14. link to original article contains verified protocol PubMed
6. 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. doi: 10.1200/JCO.2012.43.6097. Epub 2012 Nov 26. link to original article contains partial protocol PubMed

Cisplatin & Fluorouracil (PF) -> Carboplatin & concurrent RT

PF: Platinol, Fluorouracil

Regimen, Posner, et al. (TAX 324)

Level of Evidence: Phase III

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

21-day cycles x 3 cycles; then start chemoradiotherapy 3 to 8 weeks after the start of cycle 3

Chemoradiotherapy

• Carboplatin (Paraplatin) AUC 1.5 IV over 1 hour once daily 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. 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

Cisplatin & Fluorouracil (PF, CF) -> Cisplatin & concurrent RT

PF: Platinol, Fluorouracil
CF: Cisplatin, Fluorouracil

Regimen, Hitt, et al. 2005

Level of Evidence: Phase III

Induction chemotherapy

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

3-week cycles x 3 cycles; patients then undergo ENT evaluation and CT imaging of the primary tumor and neck. Patients with complete response (CR) or partial response of >80% in the primary tumor and no evidence of progression in neck lymph nodes proceeded to chemoradiotherapy. "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.

Chemoradiotherapy

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

References

1. 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

Cisplatin, Fluorouracil, Docetaxel (DCF, TPF) -> Carboplatin & concurrent RT

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

Regimen, Posner, et al. 2007 (TAX 324)

Level of Evidence: Phase III

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

21-day cycles x 3 cycles; then start chemoradiotherapy 3 to 8 weeks after the start of cycle 3

Supportive medications:

• Dexamethasone (Decadron) used (dose, route, schedule not specified) to prevent docetaxel-related side effects
• Prophylactic antibiotics (further details not given) on days 5 to 14
• Prophylactic granulocyte colony-stimulating factor not allowed

Chemoradiotherapy

• Carboplatin (Paraplatin) AUC 1.5 IV over 1 hour once daily 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. 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

Cisplatin, Fluorouracil, Docetaxel (DCF, TPF) -> Cisplatin & concurrent RT

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

Regimen #1, Adelstein, et al. 2010 (SWOG S0216)

Level of Evidence: Phase II

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

21-day cycles x 2 cycles; restaging of disease takes place 3 weeks after finishing cycle 2. Patients with stable or tumors which responded to therapy proceed to concurrent chemoradiation therapy. Patients with progressive disease are considered--if possible--for surgical resection and post-operative radiation. Patients who could not undergo surgery also received concurrent chemoradiation therapy.

Supportive medications:

• Ciprofloxacin (Cipro) prophylaxis x 10 days (dose/route/precise schedule not specified)
• "Standard anti-emetics, hydration and diuresis"

Concurrent chemoradiation therapy

• Cisplatin (Platinol) 100 mg/m2 IV once daily on days 1 & 22
• Concurrent radiation therapy, 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)

6-week course; "Surgical resection was considered after concomitant chemoradiotherapy for those patients with histologically confirmed residual or recurrent disease at the primary site."

Supportive medications:

• "Standard hydration and anti-emetic therapy"

Regimen #2, Lefebvre, et al. 2013 (TREMPLIN)

Induction chemotherapy

Level of Evidence: Non-randomized

• 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 daily on days 1 to 5 (total dose per cycle: 3750 mg/m2)

21-day cycles x 3 cycles; 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 chemoradiation. Patients who did not have at least 50% regression had salvage total laryngectomy.

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
• 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 daily was used if febrile neutropenia occurred.
• "Setrons" (5-HT3 antagonists) given twice, before and after cisplatin

Concurrent chemoradiation therapy

Level of Evidence: Randomized Phase II, >20 per arm

• Cisplatin (Platinol) 100 mg/m2 IV once daily on days 1, 22, 43
• Concurrent radiation therapy, 2 Gy fractions x 35 fractions (total dose: 70 Gy), given once daily 5 times per week over 7 weeks

Regimen #3, Bae, et al. 2010

Level of Evidence: Phase II

This study only involved patients with locoregionally advanced nasopharyngeal cancer.

Induction chemotherapy

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

21-day cycles x 3 cycles; then proceed to chemoradiotherapy

Supportive medications:

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

Concurrent chemoradiotherapy

• Cisplatin (Platinol) 100 mg/m2 IV once daily on days 1 & 22
• Concurrent radiation therapy, 1.8 to 2 Gy fractions (total dose: 68.4 Gy), given 5 times per week

References

1. 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. doi: 10.1002/hed.21179. link to original article contains verified protocol PubMed
2. 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. doi: 10.1007/s00280-009-1152-0. link to original article contains verified protocol PubMed
3. 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. doi: 10.1200/JCO.2012.42.3988. Epub 2013 Jan 22. link to original article contains verified protocol PubMed

Cisplatin, Fluorouracil, Docetaxel (DCF, TPF) -> sequential RT

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

Regimen #1, Vermorken, et al. 2007 & van Herpen, et al. 2010 (EORTC 24971, TAX 323)

Level of Evidence: Phase III

• 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 (total dose per cycle: 3750 mg/m2) on days 1 to 5
• Docetaxel (Taxotere) 75 mg/m2 IV over 1 hour once on day 1, given first before cisplatin

21-day cycles x 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

Supportive medications:

• Dexamethasone (Decadron) 8 mg PO x 6 doses (exact schedule not specified) starting the night before docetaxel
• 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."

Radiation therapy

• 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

Regimen #2, Pointreau, et al. 2009 (GORTEC)

Level of Evidence: Phase III

Induction chemotherapy

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

21-day cycles x 3 cycles; 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).

Supportive medications:

• Normal saline (use of mannitol, KCl, and magnesium sulfate per institutional protocol) 1000 mL IV given twice, before and after cisplatin
• Dexamethasone (Decadron) 8 mg PO once daily the day before, the day of, and day after docetaxel
• Ciprofloxacin (Cipro) 1000 mg PO (frequency not specified) on days 5 to 15
• Prophylactic granulocyte colony-stimulating factor not used

Radiation therapy

• 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.

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
2. 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. doi: 10.1093/jnci/djp007. Epub 2009 Mar 24. link to original article contains verified protocol PubMed content property of HemOnc.org
3. 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. doi: 10.1038/sj.bjc.6605860. Epub 2010 Sep 14. link to original article contains verified protocol PubMed

Cisplatin, Fluorouracil, Paclitaxel (PCF, PPF) -> Cisplatin & concurrent RT

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

Regimen, Hitt, et al. 2005

Level of Evidence: Phase III

Induction 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 (total dose per cycle: 2500 mg/m2) on days 2 to 6

3-week cycles x 3 cycles; patients then undergo ENT evaluation and CT imaging of the primary tumor and neck. Patients with complete response (CR) or partial response of >80% in the primary tumor and no evidence of progression in neck lymph nodes proceeded to chemoradiotherapy. "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.

Supportive medications:

• "Standard intravenous premedications with dexamethasone, diphenhydramine, and cimetidine or ranitidine were administered 30 minutes before paclitaxel infusion to prevent hypersensitivity reactions."

Chemoradiotherapy

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

References

1. 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

Cisplatin, Fluorouracil, Paclitaxel (PCF, PPF) -> Paclitaxel & concurrent RT

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

Regimen, Hitt, et al. 2002

Level of Evidence: Phase II

Induction chemotherapy

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

3-week cycles x 3 cycles; 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 chemoradiotherapy; radiation therapy alone was used "if concomitant treatment was not feasible."

Supportive medications:

• Dexamethasone (Decadron) 20 mg IV once 30 minutes prior to paclitaxel
• 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
• Cimetidine (Tagamet) 300 mg (or ranitidine, unspecified dosage, per Hitt, et al. 2005) IV once 30 minutes prior to paclitaxel
• Mannitol and IV hydration with cisplatin

Chemoradiotherapy

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

• 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 induction chemotherapy).

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

Cisplatin, Paclitaxel, concurrent RT

Regimen, Garden, et al. 2004 (RTOG 97-03)

Level of Evidence: Randomized Phase II, >20 per arm

• 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

Fluorouracil, Hydroxyurea, concurrent RT

Regimen, Garden, et al. 2004 (RTOG 97-03)

Level of Evidence: Randomized Phase II, >20 per arm

• Fluorouracil (5-FU) 800 mg/m2/day IV continuous infusion given 5 days per week (total dose per week: 4000 mg/m2) on weeks 1, 3, 5, 7, 9, 11, 13; 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 (total dose per week: 11,000 mg) on weeks 1, 3, 5, 7, 9, 11, 13; 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

Radiation therapy

Regimen

Level of Evidence: Phase III

Used as a comparator arm; included for reference purposes only.

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. Adelstein DJ, Li Y, Adams GL, Wagner H Jr, Kish JA, Ensley JF, Schuller DE, Forastiere AA. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. J Clin Oncol. 2003 Jan 1;21(1):92-8. link to original article contains verified protocol PubMed
3. 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
4. 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
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. 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
7. 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
8. 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. doi: 10.1016/S1470-2045(09)70311-0. Epub 2009 Nov 10. link to original article contains partial protocol PubMed
9. 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. doi: 10.1016/S1470-2045(11)70346-1. Epub 2012 Jan 18. link to original article contains verified protocol PubMed
10. 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. doi: 10.1200/JCO.2012.43.6097. Epub 2012 Nov 26. link to original article contains partial protocol PubMed

Recurrent or metastatic disease

Carboplatin & Docetaxel

Regimen, Samlowski, et al. 2007

Level of Evidence: Phase II

• 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

Regimen, Forastiere, et al. 1992

Level of Evidence: Phase III

• 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 (total dose per cycle: 4000 mg/m2) (Forastiere, et al. 1992 did not specify on which 4 days Fluorouracil (5-FU) was given)

28-day cycles

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

Carboplatin, Fluorouracil, Cetuximab

Regimen, Vermorken, et al. 2008

Level of Evidence: Phase III

• 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 (total dose per cycle: 4000 mg/m2) on days 1 to 4
• Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours once on cycle 1 day 1; then Cetuximab (Erbitux) 250 mg/m2 IV over 1 hour once daily on cycle 1 days 8 & 15; then on subsequent cycles, Cetuximab (Erbitux) 250 mg/m2 IV over 1 hour once daily on days 1, 8, 15. Cetuximab is given first before chemotherapy and ends at least 1 hour before chemotherapy starts.

21-day cycles x 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. doi: 10.1056/NEJMoa0802656. link to original article contains verified protocol PubMed

Cetuximab (Erbitux)

Regimen, Vermorken, et al. 2007

Level of Evidence: Phase II

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

Cisplatin

Regimen, Burtness, et al. 2005

Level of Evidence: Phase III

• 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. 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

Regimen, Burtness, et al. 2005

Level of Evidence: Phase III

• Cisplatin (Platinol) 100 mg/m2 IV once on day 1
• Cetuximab (Erbitux) 200 mg/m2 IV over 120 minutes once on cycle 1 day 1; then Cetuximab (Erbitux) 125 mg/m2 IV over 60 minutes once daily on cycle 1 days 8, 15, 22; then on subsequent cycles, Cetuximab (Erbitux) 125 mg/m2 IV over 60 minutes once daily 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 (or Carboplatin) & Fluorouracil (CF)

Regimen #1, Gibson, et al. 2005 (ECOG E1395)

Level of Evidence: Phase III

• Cisplatin (Platinol) 100 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 (creatinine clearance <50 mL/min; note: later in Gibson, et al. 2005, it says that carboplatin was used for patients who had creatinine clearance ≤50 mL/min)
• Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 4 days (total dose per cycle: 4000 mg/m2) on days 1 to 4

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."

Supportive medications:

• Hydration and forced diuresis (no further details given) with cisplatin

Regimen #2, Forastiere, et al. 1992

Level of Evidence: Phase III

• Cisplatin (Platinol) 100 mg/m2 IV over 15 to 30 minutes once on day 1
• Fluorouracil (5-FU) 1000 mg/m2/day IV continuous infusion over 96 hours (total dose per cycle: 4000 mg/m2) (Forastiere, et al. 1992 did not specify on which 4 days Fluorouracil (5-FU) was given)

21-day cycles

Supportive medications:

• Pretreatment and posttreatment hydration and mannitol diuresis with cisplatin
• "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. 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
3. 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. doi: 10.1056/NEJMoa0802656. link to original article contains verified protocol PubMed

Cisplatin, Fluorouracil, Cetuximab

Regimen, Vermorken, et al. 2008

Level of Evidence: Phase III

• 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 (total dose per cycle: 4000 mg/m2) on days 1 to 4
• Cetuximab (Erbitux) 400 mg/m2 IV over 2 hours once on cycle 1 day 1; then Cetuximab (Erbitux) 250 mg/m2 IV over 1 hour once daily on cycle 1 days 8 & 15; then on subsequent cycles, Cetuximab (Erbitux) 250 mg/m2 IV over 1 hour once daily on days 1, 8, 15. Cetuximab is given first before chemotherapy and ends at least 1 hour before chemotherapy starts.

21-day cycles x 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. doi: 10.1056/NEJMoa0802656. link to original article contains verified protocol PubMed

Cisplatin (or Carboplatin) & Paclitaxel (CP)

Regimen, Gibson, et al. 2005 (ECOG E1395)

Level of Evidence: Phase III

• 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 (creatinine clearance <50 mL/min; note: later in Gibson, et al. 2005, it says that carboplatin was used for patients who had creatinine clearance ≤50 mL/min)
• Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1

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."

Supportive medications:

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

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

Gemcitabine (Gemzar)

Regimen, Zhang, et al. 2008

Level of Evidence: Phase II

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

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

28-day cycles, given until progression of disease

Supportive medications:

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

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 (MTX)

Regimen, Forastiere, et al. 1992

Level of Evidence: Phase III

• 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