Comment
after metformin in most people with type 2 diabetes,
irrespective of whether or not they have established
atherosclerotic vascular disease, chronic kidney disease,
or heart failure.
*Subodh Verma, Peter Jüni, C David Mazer
Division of Cardiac Surgery, St Michael’s Hospital, University of
Toronto, Toronto M5B 1W8, ON, Canada (SV); and Applied
Health Research Centre, Li Ka Shing Knowledge Institute of
St Michael’s Hospital, Toronto, ON, Canada (SV, PJ, CDM)
vermasu@smh.ca.
SV has received research support and honoraria from Amgen, AstraZeneca,
Boehringer Ingelheim, Janssen, Merck, and Novo Nordisk, outside the area of
work commented on here. PJ has received research grants to the institution
from AstraZeneca, Biosensors International, Biotronik, Eli Lilly, and The
Medicines Company, and serves as an unpaid member of the steering group of
trials funded by AstraZeneca, Biosensors International, Biotronik, St Jude
Medical, and The Medicines Company, all outside the area of work commented
on here. CDM has received honoraria from Amgen, Boehringer Ingelheim, and
OctaPharma, outside the area of work commented on here.
1 Prospective Studies Collaboration, Asia Pacific Cohort Studies
Collaboration. Sex-specific relevance of diabetes to occlusive vascular and
other mortality: a collaborative meta-analysis of individual data from
980 793 adults from 68 prospective studies. Lancet Diabetes Endocrinol
2018; 6: 538–46.
2 Rawshani A, Rawshani A, Franzen S, et al. Mortality and cardiovascular
disease in type 1 and type 2 diabetes. N Engl J Med 2017; 376: 1407–18.
De-intensified treatment in human papillomavirus-positive
oropharyngeal cancer
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.1 Furthermore, HPV-positive oro­pharyngeal
squamous cell carcinoma is an entirely distinct
disease entity from HPV-negative oropharyngeal
squamous cell carcinoma.2 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.3 Smoking, alcohol
consumption, and the synergistic effect between the
two are well recognised risk factors for development
of HPV-negative oropharyngeal squa­ mous cell
www.thelancet.com Vol 393 January 5, 2019
3 McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. Heart failure:
a cardiovascular outcome in diabetes that can no longer be ignored.
Lancet Diabetes Endocrinol 2014; 2: 843–51.
4 Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of
cardiovascular benefit: a state-of-the-art review. Diabetologia 2018;
61: 2108–17.
5 Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular
and renal events in type 2 diabetes. N Engl J Med 2017; 377: 644–57.
6 Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and
secondary prevention of cardiovascular and renal outcomes in type 2
diabetes: a systematic review and meta-analysis of cardiovascular
outcome trials. Lancet 2018; published online Nov 10.
http://dx.doi.org/10.1016/S0140-6736(18)32590-X.
7 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular
outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;
373: 2117–28.
8 Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular
outcomes in type 2 diabetes. N Engl J Med 2018; published online Nov 10.
DOI:10.1056/NEJMoa1812389.
9 Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of
kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323–34.
10 Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in
type 2 diabetes, 2018. A consensus report by the American Diabetes
Association (ADA) and the European Association for the Study of
Diabetes (EASD). Diabetes Care 2018; published online Oct 4.
DOI:10.2337/dci18-0033.
11 Cornell JE, Mulrow CD, Localio R, et al. Random-effects meta-analysis of
inconsistent effects: a time for change. Ann Intern Med 2014;
160: 267–70.
carcinoma; however, these behaviours are in decline, Published Online
November 15, 2018
which is reflected in the diminishing incidence of HPV- http://dx.doi.org/10.1016/
negative head and neck squamous cell carcinoma.4 S0140-6736(18)32930-1
By contrast, the substantial increase in incidence of This online publication has been
corrected. The corrected version
HPV-positive oropharyngeal squamous cell carcinoma first appeared at thelancet.com
has been attributed to a probable increase in HPV on January 3, 2019
See Articles pages 40 and 51
infection. This increase could be due to changes in
sexual practices within the affected population during
the past four decades.1
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.1,5,6 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.3,6 However, traditional therapeutic
5
 Comment
Maurizio De Angelis/Science Photo Library
interventions are associated with substantial
morbidity and have a great impact on patient quality
of life.1 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 squa­
mous 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.2,7,8
In The Lancet, Hisham Mehanna and colleagues9
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.9
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
6 www.thelancet.com Vol 393 January 5, 2019
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,9 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 patients10 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.9
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 (oto­
logical 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 colleagues11
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.11 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.11 HPV-positive disease was established via
the surrogate of p16 positivity and, in contrast to
Mehanna and colleagues,9 recruitment was not limited
to low-risk patients.11 849 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,9,11 despite its well documented success in
the management of HPV-negative head and neck
squamous cell carcinoma,12 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.7
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).13 These results
www.thelancet.com Vol 393 January 5, 2019
Comment
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.
*Johannes Christiaan Oosthuizen, Jaime Doody
Department of Otolaryngology, Head and Neck Surgery, Ipswich
Hospital, Ipswich, QLD 4305, Australia (JCO); The University of
Queensland, Faculty of Medicine, Herston, QLD, Australia (JCO);
Department of Otolaryngology and Communication
Enhancement, Boston Children’s Hospital, Boston, MA, USA (JD);
and Department of Otolaryngology, Harvard Medical School,
Boston, MA, USA (JD)
c.oosth@gmail.com
We declare no competing interests.
Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open
Access article under the CC BY-NC-ND 4.0 license.
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in oropharyngeal cancer: the changing face of a disease.
Biochim Biophys Acta 2016; 1866: 141–50.
2 Mirghani H, Blanchard P. Treatment de-escalation for HPV-driven
oropharyngeal cancer: where do we stand? Clin Transl Radiat Oncol 2018;
8: 4–11.
3 Boscolo-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: 77–87.
4 Cohen N, Fedewa S, Chen AY. Epidemiology and demographics of the
head and neck cancer population. Oral Maxillofac Surg Clin North Am 2018;
30: 381–95.
5 Arenz 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: 839–46.
6 Bonilla-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: 521–43.
7 Masterson 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: 2636–48.
8 Chen 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: 803–11.
9 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 2018; published online Nov 15. http://dx.doi.org/10.1016/
S0140-6736(18)32752-1.
10 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.
11 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 2018; published online Nov 15. http://dx.doi.org/10.1016/
S0140-6736(18)32779-X.
12 Bonner 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: 567–78.
13 Lu 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: 195–204.
7