Opinion statement
Standard-of-care treatment for the majority of patients with locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) is either upfront surgery followed by adjuvant treatment as indicated by intraoperative or pathologic findings or concurrent chemoradiation reserving surgical salvage for non-responsive disease. An attempt at upfront complete resection should be pursued if feasible in patients with oral cavity or paranasal sinus primary tumors. Given multimodality treatment paradigms, patients with locoregionally advanced SCCHN should be managed in a multidisciplinary setting. Modern radiation therapy, whether postoperative or definitive in intent, is based on target delineation guided by high-quality imaging, using an intensity-modulated radiation technique to spare organs at risk. In select groups of low-risk patients, most notably those with HPV-associated oropharyngeal SCC (OPSCC), several treatment deintensification approaches are currently under investigation. Major experimental strategies within this non-surgical organ preservation domain include reductions in the intensity of the chemotherapy or radiation therapy components of the chemoradiation program, use of induction chemotherapy, or imaging-based selection of patients eligible for deintensified radiation-based treatment. Of note, recent efforts to substitute cetuximab for cisplatin in low-risk HPV-associated OPSCC have demonstrated the inferiority of cetuximab to cisplatin in cisplatin-eligible patients, re-confirming cisplatin as the standard systemic therapy of choice in HNSCC. In patients who are not candidates for any type of cisplatin administration, carboplatin-based therapy or cetuximab remain options, and other non-cisplatin therapies are under investigation. Altered fractionation may be considered in patients who are not candidates for any type of systemic therapy. The role of immunotherapy in the management of locoregional SCCHN remains investigational.
Similar content being viewed by others
Explore related subjects
Discover the latest articles, news and stories from top researchers in related subjects.References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Peters LJ, Goepfert H, Ang KK, Byers RM, Maor MH, Guillamondegui O, et al. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial. IJROBP. 1993;26:3–11.
Fletcher GH, Evers WT. Radiotherapeutic management of surgical recurrences and postoperative residuals in tumors of the head and neck. Radiology. 1970;95:185–8.
Iyer NG, Tan DSW, Tan VKM, Wang W, Hwang J, Tan NC, et al. Randomized trial comparing surgery and adjuvant radiotherapy versus concurrent chemoradiotherapy in patients with advanced, nonmetastatic squamous cell carcinoma of the head and neck: 10-year update and subset analysis. Cancer. 2015;121:1599–607.
Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al. 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;27:843–50.
Pignon J-P, Le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol. 2009;92:4–14.
Ghi MG, Paccagnella A, Ferrari D, et al. Induction TPF followed by concomitant treatment versus concomitant treatment alone in locally advanced head and neck cancer. A phase II-III trial. Ann Oncol. 2017;28:2206–12.
Haddad R, O'Neill A, Rabinowits G, Tishler R, Khuri F, Adkins D, et al. 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. The Lancet Oncology. 2013;14:257–64.
Hitt R, Grau JJ, López-Pousa A, et al. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol. 2013;25:216–25.
Cohen EEW, Karrison TG, Kocherginsky M, Mueller J, Egan R, Huang CH, et al. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer. J Clin Oncol. 2014;32:2735–43.
Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, et al. 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;31:845–52.
Group TDOVALCS. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med. 1991;324:1685–90.
Janoray G, Pointreau Y, Garaud P, Chapet S, Alfonsi M, Sire C, et al. Long-term results of a multicenter randomized phase III trial of induction chemotherapy with cisplatin, 5-fluorouracil, ± docetaxel for larynx preservation. J Natl Cancer Inst. 2016. https://doi.org/10.1093/jnci/djv368.
Cooper JS, Mukherji SK, Toledano AY, et al. An evaluation of the variability of tumor-shape definition derived by experienced observers from CT images of supraglottic carcinomas (ACRIN protocol 6658). IJROBP. 2007;67:972–5.
Kyzas PA, Evangelou E, Denaxa-Kyza D, Ioannidis JPA. 18F-fluorodeoxyglucose positron emission tomography to evaluate cervical node metastases in patients with head and neck squamous cell carcinoma: a meta-analysis. J Natl Cancer Inst. 2008;100:712–20.
Lee JR, Kim JS, Roh J-L, Lee JH, Baek JH, Cho K-J, et al. Detection of occult primary tumors in patients with cervical metastases of unknown primary tumors: comparison of (18)F FDG PET/CT with contrast-enhanced CT or CT/MR imaging-prospective study. Radiology. 2015;274:764–71.
Leclerc M, Lartigau E, Lacornerie T, Daisne J-F, Kramar A, Gregoire V. Primary tumor delineation based on (18)FDG PET for locally advanced head and neck cancer treated by chemo-radiotherapy. Radiother Oncol. 2015;116:87–93.
Thiagarajan A, Caria N, Schöder H, Iyer NG, Wolden S, Wong RJ, et al. Target volume delineation in oropharyngeal cancer: impact of PET, MRI, and physical examination. Int J Radiat Oncol Biol Phys. 2012;83:220–7.
Daisne J-F, Duprez T, Weynand B, Lonneux M, Hamoir M, Reychler H, et al. Tumor volume in pharyngolaryngeal squamous cell carcinoma: comparison at CT, MR imaging, and FDG PET and validation with surgical specimen. Radiology. 2004;233:93–100.
Murakami R, Uozumi H, Hirai T, et al. Impact of FDG-PET/CT imaging on nodal staging for head-and-neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2007;68:377–82.
Lee M-C, Tsai H-Y, Chuang K-S, Liu C-K, Chen M-K. Prediction of nodal metastasis in head and neck cancer using a 3T MRI ADC map. AJNR Am J Neuroradiol. 2013;34:864–9.
Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. The Lancet Oncology. 2011;12:127–36.
Lee N, Xia P, Quivey JM, Sultanem K, Poon I, Akazawa C, et al. Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience. Int J Radiat Oncol Biol Phys. 2002;53:12–22.
Lee N, Harris J, Garden AS, Straube W, Glisson B, Xia P, et al. Intensity-modulated radiation therapy with or without chemotherapy for nasopharyngeal carcinoma: radiation therapy oncology group phase II trial 0225. J Clin Oncol. 2009;27:3684–90.
Eisbruch A, Schwartz M, Rasch C, Vineberg K, Damen E, Van As CJ, et al. Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys. 2004;60:1425–39.
Eisbruch A, Harris J, Garden AS, Chao CKS, Straube W, Harari PM, et al. Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiat Oncol Biol Phys. 2010;76:1333–8.
Geets X, Tomsej M, Lee JA, Duprez T, Coche E, Cosnard G, et al. Adaptive biological image-guided IMRT with anatomic and functional imaging in pharyngo-laryngeal tumors: impact on target volume delineation and dose distribution using helical tomotherapy. Radiother Oncol. 2007;85:105–15.
Schwartz DL, Garden AS, Shah SJ, et al. Adaptive radiotherapy for head and neck cancer—dosimetric results from a prospective clinical trial. Radiother Oncol. 2013;106:80–4.
Olteanu LAM, Berwouts D, Madani I, De Gersem W, Vercauteren T, Duprez F, et al. Comparative dosimetry of three-phase adaptive and non-adaptive dose-painting IMRT for head-and-neck cancer. Radiother Oncol. 2014;111:348–53.
Surucu M, Shah KK, Roeske JC, Choi M, Small W Jr, Emami B. Adaptive radiotherapy for head and neck cancer. Technol Cancer Res Treat. 2016;16:218–23.
Hansen EK, Bucci MK, Quivey JM, Weinberg V, Xia P. Repeat CT imaging and replanning during the course of IMRT for head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2006;64:355–62.
Chen AM, Daly ME, Cui J, Mathai M, Benedict S, Purdy JA. Clinical outcomes among patients with head and neck cancer treated by intensity-modulated radiotherapy with and without adaptive replanning. Head Neck. 2014;36:1541–6.
Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35.
Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100:261–9.
Cleary C, Leeman JE, Higginson DS, Katabi N, Sherman E, Morris L, et al. Biological features of human papillomavirus-related head and neck cancers contributing to improved response. Clin Oncol (R Coll Radiol). 2016;28:467–74.
Lydiatt W, O’Sullivan B, Patel S. Major changes in head and neck staging for 2018. Am Soc Clin Oncol Educ Book. 2018;38:505–14.
O’Sullivan B, Huang SH, Su J, et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal Cancer Network for Staging (ICON-S): a multicentre cohort study. The Lancet Oncology. 2016;17:440–51.
Trotti A, Pajak TF, Gwede CK, Paulus R, Cooper J, Forastiere A, et al. TAME: development of a new method for summarising adverse events of cancer treatment by the Radiation Therapy Oncology Group. Lancet Oncol. 2007;8:613–24.
Machtay M, Moughan J, Trotti A, Garden AS, Weber RS, Cooper JS, et al. Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. J Clin Oncol. 2008;26:3582–9.
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;103:49–56.
Garden AS, Kies MS, Morrison WH, et al. Outcomes and patterns of care of patients with locally advanced oropharyngeal carcinoma treated in the early 21st century. Radiat Oncol. 2013;8:21.
Hall SF, Griffiths RJ, O’Sullivan B, Liu F-F. The addition of chemotherapy to radiotherapy did not reduce the rate of distant metastases in low-risk HPV-related oropharyngeal cancer in a real-world setting. Head Neck. 2019;41:2271–6.
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. J Clin Oncol. 2013;31:543–50.
Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, et al. 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;11:21–8.
•• Mehanna H, Robinson M, Hartley A, et al. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet. 2019;393:51–60 This randomized controlled clinical trial demonstrated similar overall toxicity and worsened oncologic outcomes with concurrent cetuximab as compared to cisplatin.
•• Gillison ML, Trotti AM, Harris J, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet. 2019;393:40–50 This randomized controlled clinical trial demonstrated similar late toxicity and worsened oncologic outcomes with concurrent cetuximab as compared to cisplatin.
Fakhry C, Zhang Q, Gillison ML, et al. Validation of NRG oncology/RTOG-0129 risk groups for HPV-positive and HPV-negative oropharyngeal squamous cell cancer: implications for risk-based therapeutic intensity trials. Cancer. 2019;125:2027–38.
Trosman SJ, Koyfman SA, Ward MC, al-Khudari S, Nwizu T, Greskovich JF, et al. Effect of human papillomavirus on patterns of distant metastatic failure in oropharyngeal squamous cell carcinoma treated with chemoradiotherapy. JAMA Otolaryngol Head Neck Surg. 2015;141:457–62.
• Chera BS, Amdur RJ, Tepper JE, et al. Mature results of a prospective study of deintensified chemoradiotherapy for low-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cancer. 2018;124:2347–54. This phase II clinical trial demonstrated promising oncologic outcomes with reduced-dose radiation treatment combined with reduced-dose cisplatin.
Yeung AR, Amdur RJ, Morris CG, Morgan LS, Mendenhall WM. Long-term outcome after radiotherapy for FIGO stage IIIB and IVA carcinoma of the cervix. Int J Radiat Oncol Biol Phys. 2007;67:1445–50.
Al-Mamgani A, van Werkhoven E, Navran A, Karakullukcu B, Hamming-Vrieze O, Machiels M, et al. Contralateral regional recurrence after elective unilateral neck irradiation in oropharyngeal carcinoma: a literature-based critical review. Cancer Treat Rev. 2017;59:102–8.
Chin R-I, Rao YJ, Hwang MY, et al. Comparison of unilateral versus bilateral intensity-modulated radiotherapy for surgically treated squamous cell carcinoma of the palatine tonsil. Cancer. 2017;123:4594–607.
Rackley TP, Namelo WC, Palaniappan N, Cole N, Owens DMJ, Evans M. Unilateral radiotherapy for surgically resected lateralized squamous cell carcinoma of the tonsil. Head Neck. 2017;39:17–23.
Huang SH, Waldron J, Bratman SV, et al. Re-evaluation of ipsilateral radiation for T1-T2N0-N2b tonsil carcinoma at the Princess Margaret Hospital in the human papillomavirus era, 25 years later. Int J Radiat Oncol Biol Phys. 2017;98:159–69.
Castelijns JA, van den Brekel MWM. Imaging of lymphadenopathy in the neck. Eur Radiol. 2002;12:727–38.
Nguyen A, Luginbuhl A, Cognetti D, Van Abel K, Bar-Ad V, Intenzo C, et al. Effectiveness of PET/CT in the preoperative evaluation of neck disease. Laryngoscope. 2014;124:159–64.
Stack BC, Duan F, Sicks J, Romanoff J, Opanowski A, Horng D, et al. The negative predictive value (NPV) of FDG-PET/CT in the head and neck squamous cell carcinoma (HNSCC) N0 patient, the first report of the ACRIN 6685 trial. J Clin Oncol. 2017. https://doi.org/10.1200/JCO.2017.35.15_suppl.6041.
• Marur S, Li S, Cmelak AJ, et al. E1308: phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx—ECOG-ACRIN Cancer Research Group. J Clin Oncol. 2017;35:490–7. This phase II clinical trial demonstrated promising oncologic outcomes with induction chemotherapy used to select patients showing good response for subsequent reduced-dose radiation treatment combined with cetuximab.
• Chen AM, Felix C, Wang P-C, et al. Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study. The Lancet Oncology. 2017;18:803–11. This phase II clinical trial demonstrated promising oncologic outcomes with induction chemotherapy used to select patients showing good response for subsequent reduced-dose radiation treatment combined with paclitaxel.
Hegde JV, Shaverdian N, Daly ME, Felix C, Wong DL, Rosove MH, et al. Patient-reported quality-of-life outcomes after de-escalated chemoradiation for human papillomavirus-positive oropharyngeal carcinoma: findings from a phase 2 trial. Cancer. 2018;124:521–9.
• Villaflor VM, Melotek JM, Karrison TG, et al. Response-adapted volume de-escalation (RAVD) in locally advanced head and neck cancer. Ann Oncol. 2016;27:908–13. This phase II clinical trial demonstrated promising oncologic outcomes with induction chemotherapy used to select patients showing good response for subsequent reduced-volume radiation treatment combined with paclitaxel, fluorouracil, and hydroxyurea.
Melotek JM, Seiwert TY, Blair EA, et al. A phase 2 dose and volume de-escalation trial for high- and low-risk HPV+ oropharynx cancer: efficacy, toxicity, and dosimetric analyses. Int J Radiat Oncol Biol Phys. 2017;99:S135.
Seiwert T, Melotek JM, Foster CC, et al. OPTIMA—a phase 2 trial of induction chemotherapy response-stratified radiation therapy dose and volume de-escalation for HPV+ oropharyngeal cancer: efficacy, toxicity, and HPV subtype analysis. Int J Radiat Oncol Biol Phys. 2018;100:1309.
Bristow RG, Hill RP. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer. 2008;8:180–92.
Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1997;38:285–9.
Göttgens E-L, Ostheimer C, Span PN, Bussink J, Hammond EM. HPV, hypoxia and radiation response in head and neck cancer. Br J Radiol. 2018;20180047.
Lee N, Schöder H, Beattie B, et al. Strategy of using intratreatment hypoxia imaging to selectively and safely guide radiation dose de-escalation concurrent with chemotherapy for locoregionally advanced human papillomavirus-related oropharyngeal carcinoma. Int J Radiat Oncol Biol Phys. 2016;96:9–17.
Riaz N, Sherman E, Katabi N, et al. A personalized approach using hypoxia resolution to guide curative-intent radiation therapy dose-reduction to 30 Gy: a novel de-escalation paradigm for HPV-associated oropharynx cancers treated with concurrent chemoradiation therapy. Int J Radiat Oncol Biol Phys. 2017;99:S136.
Denis F, Garaud P, Bardet E, Alfonsi M, Sire C, Germain T, et al. 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. 2003;22:69–76.
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354:567–78.
Siu LL, Waldron JN, Chen BE, et al. 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;3:220–6.
Lacas B, Bourhis J, Overgaard J, Zhang Q, Grégoire V, Nankivell M, et al. Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis. The Lancet Oncology. 2017;18:1221–37.
Overgaard J, Hansen HS, Specht L, Overgaard M, Grau C, Andersen E, et al. Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet. 2003;362:933–40.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Susan Y. Wu declares that she has no conflict of interest.
Sue S. Yom has received research funding for clinical trials from Genentech, Bristol-Myers Squibb, Merck, and BioMimetix JV; has received royalties from Springer and UpToDate; and has received compensation from Galera Therapeutics for serving on a Data Safety Monitoring Committee.
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.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Head and Neck Cancer
Rights and permissions
About this article
Cite this article
Wu, S.Y., Yom, S.S. Current Standards for Organ Preservation in Locoregionally Advanced Non-nasopharyngeal Head and Neck Cancer and Evolving Strategies for Favorable-Risk and Platinum-Ineligible Populations. Curr. Treat. Options in Oncol. 20, 89 (2019). https://doi.org/10.1007/s11864-019-0688-4
Published:
DOI: https://doi.org/10.1007/s11864-019-0688-4