]
To summarize accumulated evidence and fastgrowing
body of data regarding HPV+ tumors, we
undertook an effort to highlight the most important
aspects of HPV+ HNC today.
Etiology
Role of HPV in oral and oropharyngeal carcinogenesis
seems to have been first proposed by Syrjanen et
al.[] in 1983 while HPV16 DNA was first detected in
invasive SQC HNC of the oral tongue by Southern blot
hybridization in 1986.[] The last two decades have
brought increasing evidence which firmly established a
connection between HPV infection and the existence of
a subgroup of SQC HNC, in particular, oral cavity and
oropharynx.[-] Gillison et al.[] used polymerase
chain reaction (PCR)?based assays, Southern blot, and
in situ hybridization (ISH), to detect HPV DNA in 62
(25%) of 253 cases with HPV16 being identified in 90%
of the HPV+ tumors. The HPV+ was detected in 12%
of the oral cavity, 57% of the oropharynx, 10% of the
hypopharynx, 19% of the larynx, and 0% of nasopharynx
cases. Correlating HPV status with other factors
disclosed that poor tumor grade (odds ratio, OR=2.4)
and oropharyngeal site (OR=6.2) independently increased
the probability of HPV presence by multivariate
analysis (MVA). As compared with HPV- OPC, HPV+
OPC were less likely to occur among moderate to heavy
drinkers (OR=0.17) and smokers (OR=0.16), had characteristic
basaloid morphology (OR=18.7), and were
less likely to have TP53 mutations (OR=0.06).
Although it was long ago recognized that histologically
HPV+ SQC HNC is poorly differentiated with a
basaloid morphology and lack of keratinization []
the diagnosis cannot be made based exclusively on histologic
criteria. Immunohistochemical (IHC) testing
and/or HPV DNA/RNA testing are required and are
considered the standard of care. p16 IHC is considered
useful surrogate for HPV+ HNC in OPC but is rarely
used in non-OPC, where HPV+ tumors are rare, leading
to a high false-positive rate. Recently, The College
of American Pathologists produced an evidence-based
guideline on testing, application, interpretation, and reporting of HPV and surrogate marker tests in HNC
[] while subsequently, American Society of Clinical
Oncology endorsed it with small modifications. [
It is nowadays believed that the high-risk HPV is
able to insert specific DNA fragments (early genes E5,
E6 and E7) into the cellular genome of its host. Some
key functions of tumor suppressor factors are then abrogated
(p21, p53 and pRb pathways) after which defects
can be detected in apoptosis, DNA repair mechanisms,
as well as in the cell cycle regulation, finally
leading to cellular immortalization.
Recent years has also brought increasing knowledge
about common genetic aberrations in key signaling
pathways. Although the mutation rate in HPV+ and
HPV- tumors is quantitatively similar [,], the specific
mutational signatures are distinct. In addition to
mutations, structural aberrations, too, are specific for
HPV+ tumors [-], including a recent study []
which points at two subtypes of HPV+ tumors based
on expression profiling, while preliminary data from
immunotherapy treatment with pembrolizumab in
PD-L1+ cancers indicated possible pathway in future
clinical research in this domain.[]
Epidemiology
The incidence of tobacco- (and alcohol-) related OPC
is decreasing. Contrary to the cancers deemed as HPV,
the incidence of HPV+ OPC is rising [-], while
both incidence and prevalence of HPV- cancers is decreasing,
and was mostly observed in tonsillar carcinoma
in younger U.S. populations (ages 20-44 years)
from 1973 to 2001, while the incidence of SQC carcinoma
in all other oral/pharyngeal sites remained constant
or decreased [], a similar finding from Sweden
[], Denmark [] or Australia.[] Regional differences
exist, too, as many urban centers report new
HNC cases mostly as HPV+ while non-urban centers
mostly report on HPV- tumors, partially related to regional
differences in tobacco use.
In a systematic review covering the US, Europe and
Asia, Kreimer et al.[] documented HPV+ prevalence
in the oropharynx, 35.6%; oral cavity, 23.5%; and larynx,
24.0%. HPV16 was the most common strain in
30.9% of OPC, followed by oral cavity SQC carcinoma
in 16% and 16.6% of laryngeal SQC carcinoma. HPV16
accounted for 86.7% of all OPC, 68.2% of all oral cavity
SQC carcinoma, and 69.2% of all laryngeal SQC carcinoma.
HPV18 was found in much less percentage
of cases. When studied by geographic/continental location,
HPV prevalence in OPC was in North America,
47%, and in Europe, 28.2%. Similarly, Termine et al.[] undertook meta-analysis with 62 studies containing
a total of 4852 samples. The pooled prevalence
of HPV DNA was 34.5%. The pooled prevalence of oral
SQC carcinoma was 38.1%, and that of not site-specific
SQC carcinoma was 24.1%. Exclusively focusing
on the prevalence of HPV in European populations,
Abogunin et al.[] undertook meta-analysis, which
showed the prevalence of HPV of any type in patients
with HNC was 40.0%. HPV was highest in tonsillar
cancer (66.4%) and lowest in pharyngeal (15.3%) and
tongue (25.7%) cancers. Contrasting these findings are
reports from other world regions. In South African
studies, HPV prevalence in oral SQC carcinoma in
South African patients was found to be 0-11.9% patients
[-] while the same in Sudanese patients was
found to be 0%.[] Zhu et al.[] investigated the relationship
between oral SQC carcinoma and HPV in
a Chinese population. The overall positivity of HPV
and HPV16 were 58.0% and 47.7%, respectively, both
being significantly higher than those found in normal
controls (10.44% and 7.1%, respectively). The combined
odds ratio of oral SQC carcinoma with HPV and
HPV16 infection were 12.7 and 9.0, respectively, when
compared with normal controls.
Gillison et al.[] conducted a first populationbased
cross-sectional study to concurrently examine
the epidemiology of oral HPV infection among men
and women aged 14-69 years. Participants (n=5579)
provided a 30-second oral rinse and gargle with
mouthwash. The overall prevalence of oral HPV infection
was 6.9%. The prevalence of high-risk vs low-risk
HPV infections was 3.7% vs 3.1%. The most prevalent
type was HPV16 (1.0%). The prevalence of oral HPV
infection among men and women aged 14 to 69 years
was 6.9% and of HPV16 was 1.0%. Peak prevalence was
among individuals aged 30 to 34 years (7.3%) and 60 to
64 years (11.4%). Men had a significantly higher prevalence
than women for any oral HPV infection (10.1%
vs 3.6%, p<0.001). Infection was less common among
those without vs those with a history of any sexual contact
(0.9% vs 7.5%, p<0.001) and increased with the
number of sexual partners (p<0.001 for trend) and cigarettes
smoked per day (p<0.001 for trend). Age, sex,
number of sexual partners, and the current number of
cigarettes smoked per day were independently associated
with oral HPV infection in MVA.
An important observation from various studies
included a specific history of sexual behavior.[-]
Schwartz et al.[
Similarly, Smith et al.[] found that in cancer cases,
the prevalence of HPV high-risk types was 20%. Risk
factors for HPV- high risk included younger age (<55
years vs >55 years; adjusted OR=3.4) and younger-age
cases who had more lifetime sex partners (adjusted
OR=3.8), practiced oral-genital sex (adjusted OR=4.3)
or oral-anal sex (adjusted OR=19.5). D"Souza et al.[]
investigated whether sexual behaviors that elevated
the odds of OPC developing in a case-control study
similarly elevated the odds of oral HPV infection developing
among controls. Among controls, the odds
of infection developing independently increased with
increases in the lifetime number of oral (p=0007, for
trend) or vaginal sex partners (p=0.003, for trend).
Among college-aged men, the odds of oral HPV infection
developing increased with increases in the number
of recent oral sex partners (p=0.046, for trend) or
open-mouthed kissing partners (p=0.023, for trend),
but not vaginal sex partners. In the study of Widdice
et al.[] on the sexual behavior of 25 heterosexual
couples, 68% of couples had a type-specific anogenital
concordance. Receiving finger-anal sex (p=0.05), sharing
towels (p=0.04), longer time since last intercourse
(women: p=0.03, men: p=0.02 men), and men washing
their genitals after sex (p=0.03) were associated
with decreased likelihood of concordance. Persistence
of incident HPV types in women was associated with
HPV in men (p=0.002). Studies of Heck et al.[] and
Dahlstrom et al.[] confirmed that OPC and tonsillar
cancer were associated with having a history of an
increasing number of lifetime sexual partners, lifetime
oral/genital sex partners having a history of same-sex
sexual contact among men and with an earlier age at
sexual debut. The studies of Pickard et al.[] and Edelstein
[] showed that ever having consumed alcohol
(OR, 0.2), >5 lifetime partners, open-mouth kissing
(OR, 4.0) or lifetime oral sex (OR, 4.0) were associated
with infection [] and in a multivariate model [],
incident oral HPV infection was associated with recent
frequency of performing oral sex (once per week: HR,
3.7), recent anal sex with men (HR, 42.9), current infection
with the same HPV type in the genitals (HR,
6.2), and hyponychium (HR, 11.8). Finally, D"Souza
et al.[61] focused on oral HPV infection and cancer
risk among long-term sexual partners of patients with
HPV+ OPC to show that oral HPV16 DNA is commonly
detected among patients with HPV+ OPC at diagnosis,
but not among their partners. Partners of patients
with HPV+ OPC did not seem to have elevated
oral HPV infection compared with the general population.
While an extensive body of data in the literature
identified sexual behavior as significantly contributing
factors to HPV infection and occurrence of HPV+ HNC, it must, however, be stressed that sexual behavior
is still considered as collinear. That said, it remains
difficult to distinguish which sexual behaviors are responsible
for HPV transmission from genital tract to
the mouth, including deep kissing (French kissing), or
rimming (oral-anal contact).[,,-,]
Prognostic Implications of Hpv Positivity
For about a quarter of a century, investigators have tried
to provide an insight into the influence of HPV positivity
in SQC HNC patients. Initial observations and
results were confusing [,,,,<-r67>] due to the
inclusion of HNC of various sites and treatment modalities
while reports frequently lacked detailed outcomes.
In one of the landmark studies, Gillison et al.[] documented
that when compared with HPV- OPC, HPV+
OPC achieved improved DFS (hazard ratio, HR, 0.26).
After adjustment for the presence of lymph node disease
(HR, 2.3), heavy alcohol consumption (HR, 2.6),
and age >60 years (HR, 1.4) all patients with HPV+
tumors had a 59% reduction in risk of death from cancer
when compared with HPV- HNC patients (HR,
0.41). Chaturvedi et al.[38] used SEER data covering
period 1973-2004 on oral SQC carcinoma classified by
anatomic site as potentially HPV-related (n=17.625) or
HPV-unrelated (n=28.144). When treated with RT, improvements
in OS across calendar periods were more
pronounced for HPV-related oral SQCs than HPVunrelated
oral SQC carcinomas. Using a meta-analytic
approach, Ragin and Taioli [] showed that patients
with HPV+ had a lower risk of dying (meta HR: 0.85),
and a lower risk of recurrence (meta HR: 0.62) than
HPV- patients. Site-specific analyses showed that patients
with HPV+ OPC had reduced risk of death (meta
HR: 0.72) as well as superior DFS (meta HR: 0.51),
with no difference, however, in OS between HPV+ and
HPV- non-OPC. A similar approach was performed
by Dayyani et al.[], who observed that the difference
in OS significantly favored HPV+ tumors (HR, 0.42;
p<0.0001). The survival benefit was similar in HPV16
patients (HR, 0.41; p<0.0001) and was improved even
more in OPC (HR, 0.40; p<0.0001).
Recent reports mostly focused on OPC using different
outcomes after various treatment modalities
had been used, attempting to correlate outcomes with
the various patient- and tumor- as well as treatment-
related characteristics. To assess the effects of HPV
infection on the response of these tumors to RT, Lindel
et al.[] retrospectively evaluated 99 patients who
underwent curative RT (median total dose, 74Gy;
range, 54-80.5Gy) given in five daily fractions a week
for 5-8 weeks. HPV+ patients achieved better local
control (p=0.050) and a better OS (p=0.046). In the MVA, HPV+ remained associated with a lower risk
of local failure (risk ratio, RR, 0.31; p=0.048). Fakhry
et al.[] provided an important correlative study included
in the original ECOG protocol 2399, which was
a phase II trial of radiochemotherapy (RT-CHT) for
organ preservation in resectable stage III or IV SQC
carcinomas of the larynx or oropharynx. Two cycles
of paclitaxel/carboplatin were followed by concurrent
radical RT (70 Gy in 35 daily fractions in 7 weeks) and
weekly administration of paclitaxel. After induction
CHT, there was significantly higher response rate for
HPV+ tumors: 82% vs 55%, p=0.01. The same was observed
when response was evaluated after RT-CHT in
85/96 (89%) patients: 84% vs 57%, p=0.007. Significant
differences remained when the analysis was restricted
to OPCs. HPV+ patients also achieved superior OS
and PFS at 2 years (OS, 95% vs 62%, respectively; PFS,
86% vs 53%, respectively). When MVA was performed,
HPV+ status remained independent prognosticator of
improved OS. When MVA were restricted to OPC, patients
with HPV+ tumors had a 61% lower risk of death
(HR=0.39; p=0.06) and a 62% lower risk of progression
(HR=0.38; p=0.09) than patients with HPV- tumors.
Ang et al.[] carried out a retrospective analysis of
the association between tumor HPV status and survival
among patients with stage III or IV OPC who were enrolled
in a phase III trial comparing accelerated fractionation
RT with concomitant boost (72 Gy in 42 fractions
in six weeks) with standard fractionation RT (70 Gy in
35 fractions over a 7-week period), each combined with
100 mg/sqm of CDDP (days 1 and 22 in the former and
1, 22 and 43 in the latter group). There was no difference
in 3-year OS between the two groups (70.3% vs 64.3%;
p=0.18; HR for death with accelerated fractionation RT,
0.90), as there was no difference in the rates of high-
-grade acute and late toxic events. HPV+ (detected in
OPC in 63.8% patients) achieved better 3-year OS than
HPV- (82.4%, vs 57.1%; p<0.001), which was confirmed
in MVA which showed that they had a 58% reduction in
the risk of death (HR, 0.42).
In another study, O"Sullivan et al.[] reported on
764 consecutive OPC patients treated with definitive
RT approaches (RT alone, 449; RT-CHT, 315). Of 358
(47%) evaluable cases 77% were HPV+ (RT alone, 148;
RT-CHT, 129) and 81 were HPV- (RT alone 59; RTCHT,
22). Standard institutional policy for stage I?II
OPC included RT alone, Stage III patients received either
RT-CHT or RT alone using altered fractionation
regimens, while Stage IV patients underwent RT-CHT,
RT alone being reserved for patients unsuitable for
CHT due to various reasons. HPV+ achieved better OS
(81% vs 44%), local control (LC) (93% vs 76%), regional
control (RC) (94% vs 79%) (all p<0.01), but similar distant control (DC) (89% vs 86%, p=0.87) compared to
HPV-. HPV+ stage IV treated with RT-CHT had better
OS (89% vs 70%, p<0.01), but similar LC (93% vs 90%,
p=0.41), RC (94% vs 90%, p=0.31) and DC (90% vs
83%, p=0.22) vs RT alone (n=96). Both HPV+ treated
with RT alone (n=37) and RT-CHT (n=67) stage IV
minimal smokers had favorable OS (86% vs 88%,
p=0.45), LC (95% vs 92%, p=0.52), RC (97% vs 93%,
p=0.22), and DC (92% vs 86%, p=0.37). RT alone and
heavy-smoking were independent predictors for lower
OS but not cancer specific survival (CSS).
More recently, Rosenthal et al.[] undertook a retrospective
analysis of the subgroup of p16-evaluable
patients from the IMCL-9815 study in which 253 OPC
patients with stage III to IV nonmetastatic SQC HNC
randomly received either conventional RT, or twice
daily RT, or accelerated RT with concomitant boost
alone or RT with weekly cetuximab. When treated with
RT alone, LRC, OS, and PFS were improved in p16+
patients when compared with their p16- counterparts
(HRs, 0.30, 0.40, and 0.30, respectively). When treated
with RT plus cetuximab, the HRs for LRC, OS, and PFS
also favored p16+ OPC patients (HRs, 0.12, 0.16, and
0.18, respectively). RT/cetuximab carried 3-year LRC
advantage over RT alone in both p16+ OPC and p16-
OPC patients (HRs, 0.31 and 0.78, respectively), as well
as it offered superior 3-year OS rate when compared to
RT alone in both p16+ OPC, and p16- OPC patients
(HR, 0.38 and 0.93, respectively). Analysis of PFS at
3-years recapitulated the outcome in OS and LRC.
RT/Cetuximab was superior to RT alone in both p16+
OPC and p16- OPC (HRs, 0.46 and 0.76, respectively).
However, despite the numerical advantage, due to a
relatively small patient subset, no significant interaction
between the treatment group and p16 status could
be shown for any of the endpoints. Spreafico et al.[]
evaluated CDDP dose density in both patients with
HPV+ and HPV- locally advanced SQC HNC treated
with RT-CHT. A pooled analysis included patients with
stage III/IV OPC, carcinoma of unknown primary
(CUP) and laryngo-hypopharyngeal cancer (LHC)
treated with single-agent CDDP CRT from 2000 to
2012. Three-year OS for CDDP <200, vs 200, and >200
mg/m2 subgroups were 52%, 60%, and 72% (p=0.001)
for the HPV- and 91%, 90%, and 91% (p=0.30) for the
HPV+ patients. MVA confirmed a survival benefit with
CDDP >200 mg/m2 for the HPV- (HR, 0.5, p<0.001),
but not for HPV+ (HR 0.6, p=0.104). There was a superior
OS trend in the HPV+ T4 or N3 high-risk subset
patients with CDDP >200 mg/m2 (HR, 0.5, p=0.07).
Several researchers attempted to identify possible
subgroups of HPV+ OPC that might request specific
(e.g. less intensive) approach due to their inherent characteristics leading to a different (e.g. superior)
outcome. In a retrospective analysis of The Radiation
Therapy Oncology Group (RTOG) 0129 study, Ang et
al.[] showed the importance of HPV status and called
for the separation of future trials addressing these two
entities. Using recursive partitioning analysis (RPA),
they classified patients" risk of death on the basis of
four factors: HPV status, pack-years of tobacco smoking,
T stage, and N stage. RPA analysis showed that the
HPV status of the tumor was the major determinant of
OS, followed by the number of pack-years of tobacco
smoking (≤10 vs >10) and then nodal stage (N0 to N2a
vs N2b to N3), for HPV+ tumors, or tumor stage (T2 or
T3 vs T4), for HPV- tumors. Three categories with respect
to the risk of death were identified: low risk, with
3-year OS of 93.0%; intermediate risk, with a 3-year OS
of 70.8% (HR for the comparison with low risk, 3.54);
and high risk, with a 3-year OS of 46.2% (HR for the
comparison with low risk, 7.16). Patients with HPV+
tumors were considered to be at low risk, with the exception
of smokers with a high nodal stage (i.e., N2b to
N3), who were considered to be at intermediate risk;
patients with HPV- tumors were considered to be at
high risk, with the exception of non-smokers with tumors
of stage T2 or T3, who were considered to be at
intermediate risk. One of the implications of their risk
model was that low-risk patients could potentially be
spared the intensive, multimodal therapy without compromising
their survival (yet, reducing rates of serious
adverse events). Similarly, beside HPV status, Canadian
group [] reconfirmed >10 smoking pack-years (HR,
1.68; p=0.034), older age (HR, 1.03; p=0.003), T4 (HR,
1.88; p=0.002), N2b?N3 (HR, 1.82; p=0.004), as independent
prognostic factors. In their further attempt,
O"Sullivan et al.[] retrospectively analyzed 899 OPC
patients treated with RT (mostly accelerated fractionation)
or RT-CHT. They have identified a subgroup of
HPV+ OPC patients deemed suitable candidates for
de-intensification of treatment approaches based on
their minimal risk of distant metastasis (DM). Based
on their distinct clinical characteristics leading to different
outcome among identified subgroups, RPA segregated
HPV+ patients into low (T1-3 N0-2c; distant
control (DC), 93%; locoregional control (LRC), 95%)
and high DM risk (N3 or T4; DC, 76%) groups and
HPV- patients into different low (T1-2N0-2c; DC,
93%) and high DM risk (T3-4N3; DC, 72%) groups.
The DC rates for HPV+, low-risk N0-2a or less than
10 pack-year N2b patients were similar for RT alone
and RT-CHT, but the rate was lower in the N2c subset
treated with RT alone (73% v 92% for RT-CHT;
p=0.02). What these results implicated was that this
low DM had been achieved with intensified treatment in patients with advanced N category, especially N2c
disease. Among the HPV+ low-risk group, RT alone,
using mostly (>90%) accelerated regimens in the study,
was equally effective regarding DC for N0-2a and N2b
minimal smokers, and might represent an alternative
option for low-risk HPV+ patients, at least for the N0-
2a patients and N2b minimal smokers, due to superiority
of accelerated RT in the HPV+ patients observed
in other studies, too.[] In the aforementioned study
of Spreafico et al.[], additional effort was undertaken
to focus upon HPV+ OPC high mortality risk patients
as defined by Ang et al.[] and consisting of N2b-N3
and >10 smoking pack-year. No survival difference was
found between CDDP >200 and <200 mg/m2 (3-year:
90% vs 90%, p=0.76) with an HR of 0.92 (p=0.85). In
contrast, a non-significant lower mortality risk for
CDDP >200 mg/m2 and <200 mg/m2 was found for the
high DM risk subset (T4 or N3), defined by O"Sullivan
et al.[] (3- year OS: 76% vs 79%, p=0.15) with the
adjusted HR of 0.5 by MVA (p=0.07).
Intensive clinical research [-] provided a fruitful
milieu for clinical investigators to embark on an
exploration of various efforts to optimize treatment
approaches by de-intensifying it when and where appropriate.
As summarized by Mirghani et al.[], these
efforts can broadly be divided between those substituting
CDDP by cetuximab, those aiming de-intensification
of RT and CHT, those using induction CHT
followed by lower RT dose, those using upfront surgery
as well as those using vaccines. Two past years brought
four prospective studies aiming to optimize the treatment
approaches in HPV+ OPC using combined RT
and CHT. First of the four important and recent studies
was a phase II trial of Marur et al.[] where patients
with HPV16 and/or p16+, stage III-IV SQC HNC received
three cycles of induction CDDP, paclitaxel and
cetuximab. Intensity-modulated RT (IMRT) with 54
Gy was offered concurrently with weekly cetuximab
to patients with clinically complete response (cCR) at
primary-site. In a risk-adapted approach, patients with
less than cCR to induction CHT at the primary site or
nodes received 69.3 Gy and cetuximab weekly. cCR
was achieved a primary-site in 70% while 64% of patients
continued to cetuximab with IMRT 54 Gy. PFS
and OS at two years were 80% and 94%, respectively,
for 51 patients with primary-site cCR treated with RT
with 54 Gy. For the favorable (low risk) group (
Chen et al.[] reported on a single-arm, phase 2 trial
in HPV+ patients with newly diagnosed stage III or IV
SQC OPC, and PS 0 or 1. Two cycles of induction paclitaxel
and carboplatin were followed by IMRT with
concurrent paclitaxel weekly. CRs and PRs to induction
CHT received 54 Gy in 27 fractions, and those
with less than partial or no responses received 60 Gy
in 30 fractions. Twenty-four (55%) patients received 54
Gy, and 20 (45%) received 60 Gy. Three (7%) patients
had LRF, and one (2%) had DM; 2-year PFS was 92%.
26 (39%) patients experienced grade 3 adverse events;
however, no grade 4 events were reported. The most
common grade 3 events during induction CHT were
leucopenia (39%) and neutropenia (11%), and during
RT-CHT were dysphagia (9%) and mucositis (9%).
Only one (2%) patient was a gastrostomy tube-dependent
at three months, but none of the patients had so
six months after treatment. The authors concluded that
reducing the RT dose by 15-20% was associated with
excellent results with an improved toxicity profile compared
with historical regimens using standard doses.
Remaining two studies were large prospective
phase III studies. RTOG 1016 [] was a randomized,
non-inferiority trial which included adult patients
with histologically confirmed HPV+ OPC; clinical categories
T1-2, N2a-3 M0 or T3-4, N0-3, good performance
status (Zubrod 0-1) and adequate bone marrow,
hepatic, and renal function. Patients received RT plus
either cetuximab or CDDP. Intravenous cetuximab at a
loading dose of 400 mg/m2 was administered 5-7 days
before the start of RT, followed by cetuximab 250 mg/
m2 weekly for seven doses, while CDDP 100 mg/m2
was administered on days 1 and 22 of RT. All patients
received accelerated IMRT (70 Gy in 35 fractions over
6 weeks). The primary endpoint was OS. RT/cetuximab
did not meet the non-inferiority criteria for OS (HR,
1.45, one-sided 95% upper CI 1.94; p=0.5056 for noninferiority;
one-sided log-rank p=0.0163). Estimated
5-year OS for the RT/cetuximab and RT/CDDP were
77.9% and 84.6%, respectively. PFS was significantly
lower in the RT/cetuximab than in RT/CDDP group of
patients (HR 1.72, 95% CI 1.29?2.29; p=0.0002; 5-year
PFS 67.3%, vs 78.4%), as well as LRF was significantly
higher in the RT /cetuximab than in the RT/CDDP
group (HR 2.05, 95% CI 1.35?3.10; 5-year: 17.3%, vs
9.9%). There was no difference in rates of either acute
moderate to severe toxicity (77.4%, vs 81.7%; p=0.1586)
or late moderate to severe toxicity (16.5%, vs 20.4%;
p=0.1904) between the cetuximab and CDDP groups.
Authors concluded that RT plus CDDP should be considered
the standard of care for eligible patients with
HPV+ OPC. Finally, in the prospective randomized
study of Mehanna et al.[], De-ESCALaTE HPV, cetuximab was administered to de-escalate the treatment
intensity and reduce side effects of standard CDDP
administration in a low-risk HPV+ OPC (non-smokers
or lifetime smokers with a smoking history of <10
pack-years). Patients received conventional RT, with
either concurrent CDDP (100 mg/sqm on days 1, 22,
and 43 of RT) or cetuximab (400 mg/m2 loading dose
followed by seven weekly infusions of 250 mg/m2). The
primary outcome was overall severe (grade 3-5) toxicity
events at 24 months from the end of treatment.
There was no difference in overall (acute and late) severe
(grade 3?5) toxicity between treatment groups
at two years (p=0·98) nor in overall all-grade toxicity
(p=0.49). There was, however, significantly superior
both OS at two years with CDDP vs cetuximab (97.5%
vs 89.4%; HR, 5.0 [95% CI 1.7-14.7]; p=0·001) and
2-year recurrence rate (6.0% vs 16.1%, HR, 3.4 [1.6-
7.2; p=0·0007). Similar to RTOG 1016 study [], De-
ESCALaTE study [] demonstrated that cetuximab
showed no benefit regarding toxicity when compared
to standard CDDP, but achieved significantly inferior
OS and tumour control, which led study authors to
conclude the same as RTOG: RT and CDDP should
be used as the standard of care for HPV+ low-risk patients
who are able to tolerate CDDP. Another matter
of concern was that <50% of patients received the full
CDDP dose, yet there was still a significant advantage
for CDDP over cetuximab although most patients received
the full regimen of the latter drug.
