De-intensified treatment in human papillomavirus-positive oropharyngeal cancer
Authors: Johannes Christiaan Oosthuizen, Jaime Doody
Journal: The Lancet (2018)

The recognition of human papillomavirus (HPV) infection as a risk factor for the development of oropharyngeal squamous cell carcinoma was a substantial development in the field of head and neck oncology. HPV-positive oropharyngeal squamous cell carcinoma is widely considered a potential epidemic because of its rapidly increasing incidence.1Mallen-St Clair J Alani M Wang MB Srivatsan ES Human papillomavirus in oropharyngeal cancer: the changing face of a disease.Biochim Biophys Acta. 2016; 1866: 141-150PubMed Google Scholar Furthermore, HPV-positive oropharyngeal squamous cell carcinoma is an entirely distinct disease entity from HPV-negative oropharyngeal squamous cell carcinoma.2Mirghani H Blanchard P Treatment de-escalation for HPV-driven oropharyngeal cancer: where do we stand?.Clin Transl Radiat Oncol. 2018; 8: 4-11Summary Full Text Full Text PDF PubMed Scopus (133) Google Scholar There are differences in the oncogenesis between these two entities, which mean a much younger, healthier patient population has HPV-positive oropharyngeal squamous cell carcinoma, which frequently does not have the risk factors associated with HPV-negative oropharyngeal squamous cell carcinoma.3Boscolo-Rizzo P Del Mistro A Bussu F et al.New insights into human papillomavirus-associated head and neck squamous cell carcinoma.Acta Otorhinolaryngol Ital. 2013; 33: 77-87PubMed Google Scholar Smoking, alcohol consumption, and the synergistic effect between the two are well recognised risk factors for development of HPV-negative oropharyngeal squamous cell carcinoma; however, these behaviours are in decline, which is reflected in the diminishing incidence of HPV-negative head and neck squamous cell carcinoma.4Cohen N Fedewa S Chen AY Epidemiology and demographics of the head and neck cancer population.Oral Maxillofac Surg Clin North Am. 2018; 30: 381-395Summary Full Text Full Text PDF PubMed Scopus (149) Google Scholar By contrast, the substantial increase in incidence of HPV-positive oropharyngeal squamous cell carcinoma has been attributed to a probable increase in HPV infection. This increase could be due to changes in sexual practices within the affected population during the past four decades.1Mallen-St Clair J Alani M Wang MB Srivatsan ES Human papillomavirus in oropharyngeal cancer: the changing face of a disease.Biochim Biophys Acta. 2016; 1866: 141-150PubMed Google Scholar HPV-positive oropharyngeal squamous cell carcinoma is more sensitive to chemotherapy and radiotherapy than is HPV-negative oropharyngeal squamous cell carcinoma, which translates to a much better prognosis with conventional treatment protocols in this group of patients.1Mallen-St Clair J Alani M Wang MB Srivatsan ES Human papillomavirus in oropharyngeal cancer: the changing face of a disease.Biochim Biophys Acta. 2016; 1866: 141-150PubMed Google Scholar, 5Arenz A Ziemann F Mayer C et al.Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis.Strahlenther Onkol. 2014; 190: 839-846Crossref PubMed Scopus (85) Google Scholar, 6Bonilla-Velez J Mroz EA Hammon RJ Rocco JW Impact of human papillomavirus on oropharyngeal cancer biology and response to therapy: implications for treatment.Otolaryngol Clin North Am. 2013; 46: 521-543Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar Hence, HPV status is considered the most important prognostic indicator in head and neck oncology, reflected by the inclusion of p16 status in the eighth edition of the American Joint Committee on Cancer Staging System.3Boscolo-Rizzo P Del Mistro A Bussu F et al.New insights into human papillomavirus-associated head and neck squamous cell carcinoma.Acta Otorhinolaryngol Ital. 2013; 33: 77-87PubMed Google Scholar, 6Bonilla-Velez J Mroz EA Hammon RJ Rocco JW Impact of human papillomavirus on oropharyngeal cancer biology and response to therapy: implications for treatment.Otolaryngol Clin North Am. 2013; 46: 521-543Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar However, traditional therapeutic interventions are associated with substantial morbidity and have a great impact on patient quality of life.1Mallen-St Clair J Alani M Wang MB Srivatsan ES Human papillomavirus in oropharyngeal cancer: the changing face of a disease.Biochim Biophys Acta. 2016; 1866: 141-150PubMed Google Scholar This impact is especially pertinent for patients with HPV-positive oropharyngeal squamous cell carcinoma because they are typically much younger and therefore have to live with the consequences of their treatment for far longer. These factors have led to the investigation of de-intensified therapies for patients with HPV-positive oropharyngeal squamous cell carcinoma. Various strategies have been considered, such as reduction in radiotherapy dose following induction chemotherapy, radiotherapy alone, minimally invasive surgical techniques, or substituting platinum-based chemotherapy with cetuximab.2Mirghani H Blanchard P Treatment de-escalation for HPV-driven oropharyngeal cancer: where do we stand?.Clin Transl Radiat Oncol. 2018; 8: 4-11Summary Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 7Masterson L Moualed D Liu ZW et al.De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of current clinical trials.Eur J Cancer. 2014; 50: 2636-2648Summary Full Text Full Text PDF PubMed Scopus (223) Google Scholar, 8Chen AM Felix C Wang PC et al.Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study.Lancet Oncol. 2017; 18: 803-811Summary Full Text Full Text PDF PubMed Scopus (220) Google Scholar In The Lancet, Hisham Mehanna and colleagues9Mehanna 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. 2018; (published online Nov 15.)http://dx.doi.org/10.1016/S0140-6736(18)32752-1Summary Full Text Full Text PDF PubMed Scopus (536) Google Scholar report the outcome of their international, randomised controlled trial (De-ESCALaTE HPV), which investigated the substitution of cisplatin with cetuximab in patients with advanced HPV-positive oropharyngeal squamous cell carcinoma.9Mehanna 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. 2018; (published online Nov 15.)http://dx.doi.org/10.1016/S0140-6736(18)32752-1Summary Full Text Full Text PDF PubMed Scopus (536) Google Scholar 334 patients with low-risk (non-smoker or lifetime smoker with <10 pack-year smoking history) HPV-positive oropharyngeal squamous cell carcinoma were randomly assigned to receive either cisplatin or cetuximab in addition to a standardised radiotherapy treatment regimen. The authors considered the use of cisplatin as the standard of care and hence substitution with cetuximab could be considered deviation or de-escalation from the established standard. In this trial,9Mehanna 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. 2018; (published online Nov 15.)http://dx.doi.org/10.1016/S0140-6736(18)32752-1Summary Full Text Full Text PDF PubMed Scopus (536) Google Scholar HPV-positive disease was established by use of p16 positivity as a surrogate marker and retrospective in-situ hybridisation analysis. This confirmation of HPV positivity combined with the inclusion of only low-risk patients10Ang KK Harris J Wheeler R et al.Human papillomavirus and survival of patients with oropharyngeal cancer.N Engl J Med. 2010; 363: 24-35Crossref PubMed Scopus (4712) Google Scholar represented a safe de-escalation trial design that selected patients with the most favourable prognosis. The primary outcome of this study was overall severe (grade 3–5) toxicity events, and secondary outcomes included overall survival, time to recurrence, quality of life, and swallowing outcomes.9Mehanna 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. 2018; (published online Nov 15.)http://dx.doi.org/10.1016/S0140-6736(18)32752-1Summary Full Text Full Text PDF PubMed Scopus (536) Google Scholar Despite observing a significantly higher number of serious adverse events in the cisplatin group than in the cetuximab group, there was no difference in overall severe toxicity between the two groups. However, the spectrum of toxicity varied substantially between the two groups, with skin toxicity and infusion reactions more common in the cetuximab group and gastrointestinal and labyrinthine (otological symptoms including hearing loss, tinnitus, and vertigo) symptoms predominating in the cisplatin group. Equally, there was no difference between the groups in quality of life or swallowing outcomes. Far more concerning was the significant reduction in 2-year overall survival (97·5% vs 89·4%, hazard ratio [HR] 5·0 [95% CI 1·7–14·7], p=0·0012) and increase in disease recurrence (6·0% vs 16·1%, HR 3·4 [1·6–7·2], p=0·0007) observed in the cetuximab group. Also in The Lancet, Maura Gillison and colleagues11Gillison 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. 2018; (published online Nov 15.)http://dx.doi.org/10.1016/S0140-6736(18)32779-XSummary Full Text Full Text PDF PubMed Scopus (667) Google Scholar report the findings of their randomised, multicentre, non-inferiority clinical trial (NRG Oncology RTOG 1016). They investigated the substitution of cisplatin with cetuximab in patients with HPV-positive oropharyngeal squamous cell carcinoma in a non-inferiority trial. Both cetuximab and cisplatin have been approved by the US Food and Drug Administration for use in the treatment of head and neck squamous cell carcinoma and are supported by category 1 evidence; therefore, the authors did not consider the substitution of cisplatin with cetuximab as a deviation from standard of care or a form of de-escalation.11Gillison 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. 2018; (published online Nov 15.)http://dx.doi.org/10.1016/S0140-6736(18)32779-XSummary Full Text Full Text PDF PubMed Scopus (667) Google Scholar This difference between the two study designs might reflect regional practice patterns, with cisplatin commonly substituted with cetuximab in older patients, patients with poorer performance status, and those stratified as low risk in North America.11Gillison 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. 2018; (published online Nov 15.)http://dx.doi.org/10.1016/S0140-6736(18)32779-XSummary Full Text Full Text PDF PubMed Scopus (667) Google Scholar HPV-positive disease was established via the surrogate of p16 positivity and, in contrast to Mehanna and colleagues,9Mehanna 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. 2018; (published online Nov 15.)http://dx.doi.org/10.1016/S0140-6736(18)32752-1Summary Full Text Full Text PDF PubMed Scopus (536) Google Scholar recruitment was not limited to low-risk patients.11Gillison 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. 2018; (published online Nov 15.)http://dx.doi.org/10.1016/S0140-6736(18)32779-XSummary Full Text Full Text PDF PubMed Scopus (667) Google Scholar 849 patients were enrolled and randomly assigned to receive a standardised radiotherapy treatment regimen plus either cisplatin or cetuximab. After a median follow-up of 4·5 years, radiotherapy plus cetuximab did not meet the criteria for non-inferiority for overall survival (HR 1·45, one-sided 95% upper CI 1·94; p=0·5056) and was associated with a 45% increased risk of death. Furthermore, the risks of cancer progression or death and locoregional failure were increased. Severe acute and late toxicity were similar between the cetuximab and cisplatin groups. Although both Articles should be considered landmark studies in their own right, it is the harmonising findings that are most notable. The differing study designs and primary outcomes are complementary and serve to offset any substantial limitations of either study in isolation. Both trials showed that substitution of cisplatin with cetuximab resulted in significantly worse survival outcomes, without any difference in acute or late toxicity. The lack of efficacy of cetuximab in HPV-positive disease,9Mehanna 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. 2018; (published online Nov 15.)http://dx.doi.org/10.1016/S0140-6736(18)32752-1Summary Full Text Full Text PDF PubMed Scopus (536) Google Scholar, 11Gillison 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. 2018; (published online Nov 15.)http://dx.doi.org/10.1016/S0140-6736(18)32779-XSummary Full Text Full Text PDF PubMed Scopus (667) Google Scholar despite its well documented success in the management of HPV-negative head and neck squamous cell carcinoma,12Bonner JA Harari PM Giralt J et al.Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006; 354: 567-578Crossref PubMed Scopus (4197) Google Scholar might be related to the difference in epidermal growth factor receptor (EGFR) expression in HPV-negative versus HPV-positive oropharyngeal squamous cell carcinoma. Although HPV-negative head and neck squamous cell carcinoma is associated with overexpression of EGFR, there is evidence to suggest that an inverse association exists in HPV-positive oropharyngeal squamous cell carcinoma.7Masterson L Moualed D Liu ZW et al.De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma: a systematic review and meta-analysis of current clinical trials.Eur J Cancer. 2014; 50: 2636-2648Summary Full Text Full Text PDF PubMed Scopus (223) Google Scholar Cisplatin should be used as the radiosensitiser of choice in all eligible patients with advanced HPV-positive oropharyngeal squamous cell carcinoma. This recommendation is pertinent as there is emerging evidence showing a substantial increase in HPV-positive oropharyngeal squamous cell carcinoma in older patient groups (>70 years).13Lu DJ Luu M Mita A et al.Human papillomavirus-associated oropharyngeal cancer among patients aged 70 and older: dramatically increased prevalence and clinical implications.Eur J Cancer. 2018; 103: 195-204Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar These results also serve as a timely reminder that although HPV-positive oropharyngeal squamous cell carcinoma has an excellent prognosis with existing well established treatment protocols, treatment de-intensification strategies should only be evaluated within the confines of well designed clinical trials. This online publication has been corrected. The corrected version first appeared at thelancet.com on January 3, 2019 This online publication has been corrected. The corrected version first appeared at thelancet.com on January 3, 2019 We declare no competing interests. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trialCompared with the standard cisplatin regimen, cetuximab showed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatin and radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin. Full-Text PDF Open AccessRadiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trialFor patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma. Full-Text PDF Department of ErrorOosthuizen JC, Doody J. De-intensified treatment in human papillomavirus-positive oropharyngeal cancer. Lancet 2019; 393: 5–7—In the fifth paragraph of this Comment (published Online First on Nov 15, 2018), the study by Maura Gillison and colleagues was incorrectly referred to as a phase 2 study, rather than a non-inferiority study. The fourth sentence of this paragraph should read "This difference between the two study designs might reflect regional practice patterns, with cisplatin commonly substituted with cetuximab in older patients…". Full-Text PDF Open Access