The Cisplatin Total Dose and Concomitant Radiation in Locoregionally Advanced Head and Neck Cancer: Any Recent Evidence for Dose Efficacy?

  • Lindsay Carlsson
  • Scott V. Bratman
  • Lillian L. Siu
  • Anna SpreaficoEmail author
Head and Neck Cancer (L Licitra, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Head and Neck Cancer

Opinion statement

Concurrent chemoradiotherapy (CRT) with high-dose (100 mg/m2), single-agent cisplatin is considered the standard of care for locoregionally advanced head and neck cancer (LAHNC). Poor compliance often due to significant treatment-related toxicities observed during CRT regimen has stimulated research efforts to examine for evidence of the optimal cumulative cisplatin dose and schedule. The findings from this systematic literature review demonstrate that there are insufficient prospective, randomized controlled data to determine the optimal total dose (and schedule) of cisplatin to administer concomitantly with radiotherapy in the treatment of LAHNC. Given the clinical challenges associated with administering concurrent CRT with single-agent high-dose cisplatin, as well as the long-term toxicities accompanying this treatment, an examination of the available literature for evidence of dose efficacy is of continued clinical interest. Moving forward, it is critical that researchers include complete descriptions of key disease and treatment variables (i.e. treatment compliance and HPV status) to inform and strengthen clinical decisions. The substantial heterogeneity of LAHNC has led to the focus of recent research efforts to risk-stratify using a combination of clinical and molecular markers (e.g. HPV status). Thus, the optimal total dose (and schedule) of cisplatin may need to be modified to reflect the specific characteristics of the individual patient subpopulations being treated. At present, CRT remains the standard of care for LAHNC, but this field is rapidly evolving. National and international clinical trials are ongoing to evaluate treatment de-intensification in favourable risk patient subsets and treatment intensification in poor-risk patient subsets, these will provide evidence-based guidance to individualize therapy with the ultimate goal of improving patient outcomes.


Cisplatin Chemoradiotherapy Locoregionally advanced head and neck cancer 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet. 2006;368(9538):843–54.CrossRefPubMedGoogle Scholar
  2. 2.
    Gupta T, Kannan S, Ghosh-Laskar S, Agarwal JP. Concomitant chemoradiotherapy versus altered fractionation radiotherapy in the radiotherapeutic management of locoregionally advanced head and neck squamous cell carcinoma: an adjusted indirect comparison meta-analysis. Head Neck. 2015;37(5):670–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med. 2004;350(19):1945–52.CrossRefPubMedGoogle Scholar
  4. 4.
    Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med. 2004;350(19):1937–44.CrossRefPubMedGoogle Scholar
  5. 5.
    Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349(22):2091–8.CrossRefPubMedGoogle Scholar
  6. 6.
    Pignon JP, le Maitre A, Maillard E, Bourhis J, Group M-NC. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92(1):4–14.CrossRefPubMedGoogle Scholar
  7. 7.
    • Strojan P, Vermorken JB, Beitler JJ, et al. Cumulative cisplatin dose in concurrent chemoradiotherapy for head and neck cancer: a systematic review. Head Neck. 2016;38(Suppl 1):E2151–8. A systematic review of the literature published between 1978 and 2014 evaluating optimal dose and timing of cisplatin in both definitive chemoradiotherapy (CRT) and postoperative CRT for patients with locoregionally advanced squamous cell carcinoma of the head and neck. These authors highlight several of the limitations presented in the current paperGoogle Scholar
  8. 8.
    Wong SJ, Harari PM, Garden AS, et al. Longitudinal Oncology Registry of Head and Neck Carcinoma (LORHAN): analysis of chemoradiation treatment approaches in the United States. Cancer. 2011;117(8):1679–86.CrossRefPubMedGoogle Scholar
  9. 9.
    Trotti A, Pajak TF, Gwede CK, et al. TAME: development of a new method for summarising adverse events of cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol. 2007;8(7):613–24.CrossRefPubMedGoogle Scholar
  10. 10.
    Homma A, Inamura N, Oridate N, et al. Concomitant weekly cisplatin and radiotherapy for head and neck cancer. Jpn J Clin Oncol. 2011;41(8):980–6.CrossRefPubMedGoogle Scholar
  11. 11.
    Ang KK. Concurrent radiation chemotherapy for locally advanced head and neck carcinoma: are we addressing burning subjects? Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2004;22(23):4657–9.CrossRefGoogle Scholar
  12. 12.
    Rampino M, Ricardi U, Munoz F, et al. Concomitant adjuvant chemoradiotherapy with weekly low-dose cisplatin for high-risk squamous cell carcinoma of the head and neck: a phase II prospective trial. Clin Oncol (R Coll Radiol). 2011;23(2):134–40.CrossRefGoogle Scholar
  13. 13.
    Tsan DL, Lin CY, Kang CJ, et al. The comparison between weekly and three-weekly cisplatin delivered concurrently with radiotherapy for patients with postoperative high-risk squamous cell carcinoma of the oral cavity. Radiat Oncol. 2012;7:215.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Kunieda F, Kiyota N, Tahara M, et al. Randomized phase II/III trial of post-operative chemoradiotherapy comparing 3-weekly cisplatin with weekly cisplatin in high-risk patients with squamous cell carcinoma of head and neck: Japan Clinical Oncology Group Study (JCOG1008). Jpn J Clin Oncol. 2014;44(8):770–4.CrossRefPubMedGoogle Scholar
  15. 15.
    •• Ang KK, Zhang Q, Rosenthal DI, et al. 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(27):2940–50. A phase III randomized trial RTOG0522 comparing CRT (with single-agent, cisplatin 100mg/m2) with and without cetuximab in LAHNC. This trial randomized 891 patients, captured HPV status for the oropharyngeal subset and included data on survival, disease-related and toxicity outcomesGoogle Scholar
  16. 16.
    Arias F, Asin G, Uzcanga MI, et al. Final results of a phase II single-institutional trial with hyperfractionated radiation therapy (HFX) and four-weekly continuous cisplatin in locally advanced head and neck carcinoma. Clin Transl Oncol. 2014;16(6):555–60.CrossRefPubMedGoogle Scholar
  17. 17.
    Ghosh-Laskar S, Kalyani N, Gupta T, et al. 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;38(2):202–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Mesia R, Henke M, Fortin A, et al. Chemoradiotherapy with or without panitumumab in patients with unresected, locally advanced squamous-cell carcinoma of the head and neck (CONCERT-1): a randomised, controlled, open-label phase 2 trial. Lancet Oncol. 2015;16(2):208–20.CrossRefPubMedGoogle Scholar
  19. 19.
    •• Nguyen-Tan PF, Zhang Q, Ang KK, et al. 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32(34):3858–67. A phase III randomized trial RTOG0129 comparing the administration of accelerated versus conventional radiotherapy regimens administered concurrently with high-dose cisplatin (100mg/m2). Detailed treatment compliance data are provided. Multiple outcomes evaluated included OS, PFS, LRF and DM, as well as toxicity dataGoogle Scholar
  20. 20.
    Rodriguez CP, Adelstein DJ, Rybicki LA, et al. Randomized phase III study of 2 cisplatin-based chemoradiation regimens in locally advanced head and neck squamous cell carcinoma: impact of changing disease epidemiology on contemporary trial design. Head Neck. 2015;37(11):1583–9.CrossRefPubMedGoogle Scholar
  21. 21.
    • Driessen CM, Janssens GO, van der Graaf WT, et al. Toxicity and efficacy of accelerated radiotherapy with concurrent weekly cisplatin for locally advanced head and neck carcinoma. Head Neck. 2016;38(Suppl 1):E559–65. A retrospective review of 106 patients with LAHNC receiving CRT with weekly cisplatin (40mg/m2). This study reported acute toxicity data, as well as survival and disease-related outcomes, in addition to performing a sub-analysis of the oropharyngeal cohort based upon HPV statusGoogle Scholar
  22. 22.
    Gupta PK, Lal P, Bajpai R, et al. Long term results of comparison of concurrent low-dose daily cisplatin versus the standard weekly cisplatin with six fractions per week radiotherapy in locally advanced head neck cancer. South Asian J Cancer. 2016;5(2):80–4.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Levy A, Blanchard P, Bellefqih S, et al. Concurrent use of cisplatin or cetuximab with definitive radiotherapy for locally advanced head and neck squamous cell carcinomas. Strahlenther Onkol. 2014;190(9):823–31.CrossRefPubMedGoogle Scholar
  24. 24.
    Rades D, Seidl D, Janssen S, et al. Chemoradiation of locally advanced squamous cell carcinoma of the head-and-neck (LASCCHN): is 20mg/m(2) cisplatin on five days every four weeks an alternative to 100mg/m(2) cisplatin every three weeks? Oral Oncol. 2016;59:67–72.CrossRefPubMedGoogle Scholar
  25. 25.
    Sakashita T, Homma A, Hatakeyama H, et al. Clinical outcomes of weekly cisplatin chemoradiotherapy for patients with pyriform sinus cancer. Int J Clin Oncol. 2015;20(6):1081–5.CrossRefPubMedGoogle Scholar
  26. 26.
    Shapiro LQ, Sherman EJ, Riaz N, et al. Efficacy of concurrent cetuximab vs. 5-fluorouracil/carboplatin or high-dose cisplatin with intensity-modulated radiation therapy (IMRT) for locally-advanced head and neck cancer (LAHNSCC). Oral Oncol. 2014;50(10):947–55.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Strom TJ, Trotti AM, Kish J, et al. Comparison of every 3 week cisplatin or weekly cetuximab with concurrent radiotherapy for locally advanced head and neck cancer. Oral Oncol. 2015;51(7):704–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Prestwich RJ, Sen M. Absent benefit of accelerated concomitant chemoradiotherapy. Lancet Oncol. 2012;13(4):e136. author reply e-7 CrossRefPubMedGoogle Scholar
  29. 29.
    Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709–20.CrossRefPubMedGoogle Scholar
  30. 30.
    Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;29(32):4294–301.CrossRefGoogle Scholar
  31. 31.
    Mehanna H, Beech T, Nicholson T, et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer—systematic review and meta-analysis of trends by time and region. Head Neck. 2013;35(5):747–55.CrossRefPubMedGoogle Scholar
  32. 32.
    O’Sullivan B, Huang SH, Siu LL, et al. Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2013;31(5):543–50.CrossRefGoogle Scholar
  33. 33.
    O’Sullivan B, Huang SH, Perez-Ordonez B, et al. Outcomes of HPV-related oropharyngeal cancer patients treated by radiotherapy alone using altered fractionation. Radiother Oncol. 2012;103(1):49–56.CrossRefPubMedGoogle Scholar
  34. 34.
    Lassen P, Primdahl H, Johansen J, et al. Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. Radiother Oncol. 2014;113(3):310–6.CrossRefPubMedGoogle Scholar
  35. 35.
    • Spreafico A, Huang SH, Xu W, et al. Impact of cisplatin dose intensity on human papillomavirus-related and -unrelated locally advanced head and neck squamous cell carcinoma. Eur J Cancer. 2016;67:174–82. A retrospective analysis examining the impact of cisplatin dose intensity when administered concurrently with radiotherapy in the treatment of HPV-positive and HPV-negative LAHNC patients. Results suggest cumulative cisplatin dose of >200mg/m2 is associated with survival benefit in HPV-negative LAHNC patients but not in HPV-positive patients with the exception of T4 or N3 subset where higher cumulative cisplatin dose was associated with a trend in improved OSGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Lindsay Carlsson
    • 1
  • Scott V. Bratman
    • 2
  • Lillian L. Siu
    • 1
  • Anna Spreafico
    • 1
    Email author
  1. 1.Division of Medical Oncology and Hematology, Drug Development Program, Princess Margaret Cancer Centre, University Health NetworkUniversity of TorontoTorontoCanada
  2. 2.Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health NetworkUniversity of TorontoTorontoCanada

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