Adv Ther

https://doi.org/10.1007/s12325-018-0663-7

REVIEW

Head and Neck Cancer: A Review of the Impact

of Treatment Delay on Outcome
Andrés Coca-Pelaz . Robert P. Takes . Kate Hutcheson . Nabil F. Saba .
Missak Haigentz Jr. . Carol R. Bradford . Remco de Bree . Primož Strojan .
Valerie J. Lund . William M. Mendenhall . Iain J. Nixon . Miquel Quer .
Alessandra Rinaldo . Alfio Ferlito

Received: December 20, 2017

Ó Springer Healthcare Ltd., part of Springer Nature 2018

ABSTRACT demonstrable impact on survival. We review

the association between waiting times (time
Delay between the initial symptoms, diagnosis, between diagnosis and initiation of treatment)
and the definitive treatment of head and neck and clinical outcomes in patients with head and
cancers is associated with tumor progression neck squamous cell carcinoma (HNSCC).
and upstaging. These delays may lead to poor
outcomes and may mandate more aggressive
treatments with unnecessary morbidity and Keywords: Head and neck cancer; Oncology;
even mortality. The multidisciplinary team Prognosis; Survival; Treatment; Waiting time
approach for the treatment of patients with
head and neck cancers has improved organiza-
tion of standard clinical guidelines, but this INTRODUCTION
development has yet to translate into a
It is well recognized that the incidence of cancer
is increasing worldwide, despite a reduction of
Enhanced content To view enhanced content for this
article go to http://www.medengine.com/Redeem/ tobacco consumption [1, 2]. This is likely due to
DF3B4F605BD6EDA9.

A. Coca-Pelaz (&) M. Haigentz Jr.

Department of Otolaryngology, Hospital Division of Hematology/Oncology, Department of
Universitario Central de Asturias, Oviedo, Spain Medicine, Morristown Medical Center/Atlantic
e-mail: acocapelaz@yahoo.es Health System, Morristown, NJ, USA

R. P. Takes C. R. Bradford
Department of Otolaryngology-Head and Neck Department of Otolaryngology-Head and Neck
Surgery, Radboud University Medical Center, Surgery, University of Michigan, Ann Arbor, MI,
Nijmegen, The Netherlands USA

K. Hutcheson R. de Bree
Department of Head and Neck Surgery, Section of Department of Head and Neck Surgical Oncology,
Speech Pathology and Audiology, MD Anderson UMC Utrecht Cancer Center, University Medical
Cancer Center, Houston, TX, USA Center Utrecht, Utrecht, The Netherlands

N. F. Saba P. Strojan
Department of Hematology and Medical Oncology, Department of Radiation Oncology, Institute of
The Winship Cancer Institute of Emory University, Oncology, Ljubljana, Slovenia
Atlanta, GA, USA

both an aging population and improvements in
the treatment of infectious diseases that may
previously have been fatal [3, 4]. There were an
estimated 14.1 million cancer cases around the
world in 2012 and, according to data from the
World Cancer Research Fund International
(http://www.wcrf.org), this number is expected
to increase to 24 million by 2035. In Europe,
head and neck squamous cell carcinoma
(HNSCC) is the sixth most common group of
cancers [5]. The overall prognosis of HNSCC is
relatively poor, with survival figures varying
between countries and per site of primary
tumor. Five-year age-standardized relative sur-
vival is low in Eastern countries, 47% for
laryngeal primaries and 28% for all other
HNSCCs combined, and high in Ireland and the
UK, and Northern Europe (62% and 46%,
respectively) [6].
Delays before treatment may be due to patient,
professional, or facility-related factors [7]. Head
and neck cancers are often diagnosed in patients
who abuse tobacco and alcohol. Such patients
often wait months before seeking consultation for
their symptoms, which can lead to tumors being
diagnosed at an advanced stage [8]. General
practitioners often do not recognize the true cause
of the complaints of the patient and give several
treatments for non-specific symptoms that also
contribute to delays. Delay may also depend on
the tumor site and the onset and type of
V. J. Lund
Professorial Unit, Ear Institute, University College
London, London, UK
W. M. Mendenhall
Department of Radiation Oncology, University of
Florida, Gainesville, FL, USA
I. J. Nixon
Department of Surgery and Otolaryngology, Head
and Neck Surgery, Edinburgh University,
Edinburgh, UK
M. Quer
Department of Otolaryngology, Hospital Santa Creu
i Sant Pau, Barcelona, Spain
A. Rinaldo
University of Udine School of Medicine, Udine, Italy
A. Ferlito
Coordinator of the International Head and Neck
Scientific Group, Padua, Italy
Adv Ther
symptoms. Tumors in the nasopharynx and
hypopharynx are associated with late presenta-
tion due to the lack of obvious symptoms. In
contrast, glottic tumors are often detected early
because of the early onset of symptoms such as
hoarseness. In malignancies of the nose and
sinuses, the most common presenting symptoms
are nasal obstruction (56%), epistaxis (35%), and
nasal discharge (20%) [9]. These symptoms over-
lap with those of rhinosinusitis and other benign
sinonasal diseases, usually resulting in a greater
than 12-month delay in presentation [9] and a
median delay in diagnosis of 20 months [10].
Finally, the complexities of multidisciplinary care
may pose additional logistical challenges that can
adversely affect timely initiation of cancer ther-
apy. Moreover, with the intent of optimizing
quality of care, there is a tendency to centralize
cancer care which can further increase wait time
(WT) for treatment [11]. These factors contribute
to diagnostic and/or treatment delays that allow
the tumor to progress, which can ultimately lead
to impaired survival and/or functional outcomes
from more intensive therapies.
Where a study from any author of this review
is discussed, the references are clearly men-
tioned. This article is based on previously con-
ducted and reported studies and does contain
studies with human participants performed by
any of the authors.
EFFECTS ON SURVIVAL
In 2008, Chen et al. [12] published a systematic
review about the relationship between WT for
radiotherapy and clinical outcomes. They found
a significant increase in the risk of local failure
with increasing WT, with a relative risk (RR) of
1.15 per month of WT and a mortality RR of
1.16 per month. They concluded that ‘‘WTs for
radiotherapy should be as short as reasonably
achievable’’, in part, because it is not possible to
determine what exactly the ‘‘safe’’ WT period
would be, without adverse impact on treatment
outcome and survival.
Tumor progression is the primary concern as
WT for treatment increases. In a study by Jensen
et al. [13] the tumor volume doubling (TVD)
time for all patients was a median of 99 days.
Adv Ther
However, half of patients with the most
aggressive tumors had a TVD of 30 days. They
also reported that most patients developed
notable signs of tumor progression on cross-
sectional imaging within 4 weeks WT. Similarly,
Waaijer et al. [14] found an average TVD of
96 days in a group of 13 oropharyngeal carci-
nomas. During the mean WT of 56 days, the
mean increase in tumor volume was 70%; more
importantly, as a result of delay in radiotherapy
the expected tumor control probability was
reduced from 63–66% (no delay) to 47% (delay
incorporated). Obviously, the consequences of
delay in starting definitive radiotherapy are
related to TVD. For a patient with a fast-growing
tumor, an interval of more than 1 month can
have a significant adverse effect on treatment
outcome [15]. Tumor biology is, however,
extremely heterogeneous, with some tumors
displaying TVD of 15 days while others have
minimal measurable growth during a prolonged
interval. Mackillop et al. [16] estimated that for
tumors with a TVD of 90 days, an 8% reduction
in local tumor control was associated with a
4-week delay prior to the start of radiotherapy.
Jensen et al. [13] also estimated an overall
decrease in local control rate of about 8% per
month of delay for their overall patient popu-
lation. They showed that the impact of delay
would be expected to be considerably higher
(about 20% decrease in local control per month
of delay) for patients with tumors in the top
quartile of tumor growth rate in their case
series.
Translating the effects of TVD to survival,
van Bockel et al. reported on the relationship
between tumor growth rate and survival, with
5-year disease-free and overall survival in fast
growing tumors of 56% and 40%, respectively.
However, in slow growing tumors they were
78% (p = 0.008) and 65% (p = 0.013) [17]. A
strong association between N-classification sta-
tus and tumor growth rate was suggested in
exploratory analysis. Similarly, analyzing treat-
ment results of 623 early-stage head and neck
cancer patients, Fortin et al. found a signifi-
cantly increased risk of local and neck failure
and poorer survival when delay in starting
definitive radiotherapy was greater than 40 days
[18]. The authors concluded that radiotherapy
should start preferably within 20–30 days of
evaluation by a radiation oncologist. Also, in a
study by Kowalski and Carvalho, the tumor
growth rate was found to correlate with tumor
stage: the median time for disease of stages I–II
to reach stages III–IV was 11.3 months, whereas
the median time for tumors of stages III–IV to
become untreatable was 3.8 months [19]. In this
study, the delay in commencing oncologic
treatment influenced prognosis, especially in
clinical stage IV patients and in those with oral
cavity primaries.
However, a study by van Harten et al. [20],
including all types of treatment in the Nether-
lands Cancer Institute with 2493 patients,
found no relationship between WT for treat-
ment up to 90 days and impaired survival. They
even showed that poorer survival was found for
patients with shortest WT (\2 weeks) for treat-
ment, and better survival for patients with
moderate or longer WT. One explanation for
this apparent paradox is that patients with more
aggressive, more advanced stage, or who were
more symptomatic, with an associated worse
prognosis, had been selected for earlier treat-
ment than patients with longer WT. On the
other hand, the same authors in a more recent
study [21] investigated 13,140 patients with a
median WT of 37 days. They found that
patients who were more likely to have pro-
longed WT were men, patients with a low
socioeconomic status, oropharyngeal primaries,
stage IV tumors, patients to be treated with
radiotherapy or chemoradiotherapy, and
patients referred from another hospital. The
5-year overall survival was 58% for all patients.
The multivariable Cox regression model showed
that longer WT was significantly related to a
higher hazard of death (p\0.0001).
Similarly, Caudell et al. [22] performed a
retrospective study of 427 patients and observed
that the median number of days between the
biopsy confirming malignancy and the first day
of radiotherapy was 34 days (range 7–44). A
longer WT was not significantly associated with
locoregional control (p = 0.11), distant metas-
tasis-free survival (p = 0.32), or overall survival
(p = 0.07).
In a large population-level analysis [23] of
over 51,000 patients in the National Cancer

Database (USA) treated with curative intent
between 1998 and 2011, roughly one-quarter of
patients were estimated to experience treatment
delay, defined as initiation of treatment greater
than 46 days after diagnosis. Number of days
from diagnosis to initiation of curative-intent
treatment significantly increased risk of death,
with a recursive partition analysis-derived
threshold of 60 days beyond diagnosis predict-
ing adverse survival outcomes.
While single institution data and popula-
tion-level analyses suggest an adverse impact of
increased WT on survival outcomes, there are
less clear trends on meta-analysis. Huang et al.
[24] performed a systematic review of the world
literature to identify studies that described the
association between delay in radiotherapy and
the probability of local control, metastasis, and
survival based on data from 15,782 patients
from 46 studies. Most of these studies focused
on breast cancer or HNSCC. Combined analysis
showed that the local recurrence rate was sig-
nificantly higher among patients who received
postoperative radiotherapy for HNSCC more
than 6 weeks after surgery compared with those
treated within 6 weeks of surgery (OR = 2.89;
95% CI 1.60–5.21). Yet, there was little evidence
that this delay in postoperative radiotherapy
was associated with the risk of metastases or the
probability of long-term survival in any subset
of patients.
DETERMINANTS OF TREATMENT
DELAY
Several studies have investigated the determi-
nants of WT. van Harten et al. [20] found that
the year of diagnosis, tumor site, and therapy
type were significantly related to treatment
delay (p\0.05). The median treatment delay
from this single institution study during the
period of 1990 and 1994 was 31 days, signifi-
cantly shorter than in the subsequent time
periods studied (1995–1999, 2000–2004,
2005–2010), with a median ranging from 38 to
41.5 days. Patients with tumors arising in the
hypopharynx (median WT, 35 days) and larynx
(median WT, 35 days) experienced significantly
less WT (p = 0.000) compared with those arising
Adv Ther
in the oral cavity (median WT, 38 days) or
oropharynx (median WT, 41 days). Patients
treated with definitive radiotherapy or
chemoradiotherapy had to wait significantly
longer than patients who underwent primary
surgery (41 vs. 34 days). The median treatment
delay was not related to tumor stage. They
found that patients referred from other centers
following diagnosis had to wait an average of
13 days (from the day of biopsy) before their
first visit to the Netherlands Cancer Institute,
resulting in a mean total treatment delay of
45 days. Caudell et al. [22] conducted multi-
variate regression analysis of 427 patients with
HNSCC finding that lower Karnofsky perfor-
mance status (p = 0.02), use of intensity-modu-
lated radiotherapy (p = 0.001), and insurance
type (Commercial, Medicaid/charity, Medicare
or Department of Veterans Affairs) (p = 0.001)
were significantly associated with a WT of
greater than 34 days. However, a longer WT was
not significantly associated with worse locore-
gional control (p = 0.12), distant metastases-
free survival (p = 0.24), or overall survival
(p = 0.14). Van Harten et al. [20] did not find a
relationship between stage at diagnosis and
treatment delay. Patel and Brennan [25] descri-
bed that WT was prolonged for 57 versus
30 days (p\0.001) for patients receiving pri-
mary radiotherapy compared to surgical ther-
apy: early stage tumors had a shorter WT than
late stage tumors, 38 versus 57 days (p = 0.02),
and patients presenting with a positive biopsy
performed elsewhere also had a reduced WT
(p = 0.03). Several studies considered socioeco-
nomic status in relation to delays, with incon-
sistent results. For example, one study found no
association between treatment delay for surgery
and socioeconomic status [26], while another
showed a longer delay for patients with low
socioeconomic status [20, 21]. Another study
[27] investigated the relationship between
comorbidities and socioeconomic level on
treatment delays. Comorbidities were associated
with a longer WT for patients with advanced
stage HNSCC, probably because of the need for
further evaluation and supportive care (im-
proved nutrition, dental care, etc.) before
treatment. The importance of logistical consid-
erations impacting the duration of the
Adv Ther
treatment period was highlighted by Primdahl
et al. who reported the results of a Danish
nationwide study of time spans from initial
symptoms to first healthcare contact and start
of treatment [28]. Reviewing charts of 288
patients with pharyngeal and laryngeal cancers
mostly treated with radiotherapy, they com-
pared time spans during 4-month periods in
1992 and 2002. Although there was no differ-
ence in time elapsed for diagnostics between the
two time periods, total time from first health-
care contact to treatment beginning was sig-
nificantly longer in 2002. The difference was
mainly due to longer WT as a consequence of a
shortage of radiotherapy capacities, thus pro-
longing the time needed for treatment prepa-
ration and planning. Longer WT was estimated
to result in 10% lower tumor control probability
in 2002 compared to 1992. Following system-
atic implementation of logistical improvements
in 2007, they observed a significant reduction in
delay of diagnosis and treatment in 2010.
However, still less than half of the head and
neck cancer patients started treatment within
the current standards [29].
ROLE OF MULTIDISCIPLINARY
TEAM
One of the aspects of cancer care which has
been shown to positively impact patient out-
comes is the introduction of the multidisci-
plinary team. Patil et al. [30] performed a
retrospective study, comparing mortality before
(group 1) and after (group 2) implementation of
a multidisciplinary team model. Reduction in
the times between consultation and the patient
evaluation and between a diagnostic biopsy and
date of initiating definitive treatment were
noted despite the increased volume of patients
over time. However, the 2-year mortality was
comparable between the two groups. Five-year
mortality was slightly better in group 2 (50%)
versus group 1 (61%), though not statistically
significant. Friedland et al. [31] showed superior
survival in stage IV head and neck cancer
patients whose cases were reviewed by a multi-
disciplinary team. Similarly, Birchall et al. [32]
noted significantly improved 2-year survival for
head and neck cancers at a UK multidisciplinary
clinic that included a medical oncologist, radi-
ation oncologist, and head and neck surgeon.
Survival outcomes are not the sole measures
of high-quality care. Although multidisciplinary
teams have not universally demonstrated sig-
nificant reduction of mortality rates, they are
likely to have improved the quality of life of the
patients with HNSCC. Groups have reported
higher rates of dental assessment, nutritional
assessment, positron emission tomography
staging, and a shorter interval between surgery
and radiotherapy for patients managed within a
multidisciplinary team setting, as well as greater
likelihood of speech pathology utilization in a
multidisciplinary care model. These changes are
likely associated with improvements in
patients’ perceptions of the service provided
[30, 33, 34].
DISCUSSION
In the age of multidisciplinary head and neck
cancer care, a more uniform and guideline-
based approach to therapy has been achieved.
In addition, coordination of care pathways has
also been shown to offer potential for reducing
WT [35, 36]. These improvements may allow
more timely treatment, which in turn may lead
to better outcomes. Evolvements in under-
standing of the biology and behavior of tumors
have led to an increasingly personalized
approach to treatment. In the case of radio-
therapy, refined treatment schedules and use of
newer technologies may require more prepara-
tion. Therefore, the factors that could influence
delays of radiotherapy are now multiple and
could certainly be a handicap in centers that
have low volume or less coordinated cancer
care.
WT for radiotherapy was first identified as a
cause for concern in the medical literature in a
report from Norway almost 30 years ago [37].
Since that publication, many articles have been
published on the effect of this delay on the
prognosis of the HNSCC patients. In the vast
majority of the articles, longer WT is associated
with tumor progression [12–16, 20], but con-
versely there are articles such as the one by van

Harten et al. [20] which concluded that ‘‘treat-
ment delay up to 90 days is not related to
impaired survival’’, and found that patients
treated within 30 days had significantly worse
survival. León et al. [38], who performed a ret-
rospective study of 797 patients and concluded
that ‘‘within the range of the WT observed in
our study, delay in the initiation of radiother-
apy did not affect local control or survival in
patients with HNSCC’’. In laryngeal cancer,
Barton et al. [39] studied 581 patients with T1
and T2, N0–2 larynx cancer, with a median
follow-up of 6.8 years. In that study, longer WT
was not a significant predictor of disease
relapse. In the same way, Lee et al. [40] analyzed
290 patients with nasopharyngeal carcinoma
(T1N0–3M0) and found that delay in initiation
of treatment did not affect the control rate at
irradiated sites.
A factor influencing WT may be related to
patient stage at presentation; it is conceivable that
patients with advanced stage disease would be
diagnosed earlier and therefore treated more
swiftly, because of the greater risk of becoming
inoperable or because they have more complaints.
Another factor may be the differences in
tumor biology. It may be that patients with
more aggressive tumors have a worst prognosis
even when they are treated earlier. However, it
is important to acknowledge the complexity of
the matter. The varying results reported in the
literature may be related to differences in the
patient/populations, the centers investigated,
and local or regional practices. Furthermore,
reports may not be comparable given the lack of
control for these factors. Nonetheless, HNSCC is
a complex disease requiring a multidisciplinary
team of experts and therefore patients with
HNSCC should be referred as soon as possible to
recognized multidisciplinary centers equipped
to treat these patients effectively and
expeditiously.
CONCLUSION
Prolonged WT for treatment of HNSCC is likely
to negatively affect the prognosis of the patients.
On the basis of the aforementioned, we believe
that the best option is to minimize WT without
Adv Ther
sacrificing quality of care. A possible confound-
ing variable is that tumor progression may lead to
intensified treatment that may compensate for
potentially worse oncological outcomes but may
also exacerbate toxicity that impacts quality of
life. Furthermore, prolonged WT is likely to result
in anxiety and potentially decreased satisfaction
with the care provided. As a result of the hetero-
geneity of the studies with different definitions
of WT, different end points, and difficulties in
comparing similar treatments and healthcare
systems in different parts of the world, it is chal-
lenging to draw firm conclusions. However, in
the era of multidisciplinary care, teams should
constantly review their practice to ensure a
minimum delay of patient care. Streamlining
treatment pathways including reduction of WT is
indicated to optimize quality of care of our
patients, including oncological and functional
outcomes. Furthermore, robust public health
and primary care practitioner education is nee-
ded to improve awareness of the early signs and
symptoms of head and neck cancer.
ACKNOWLEDGEMENTS
This article was written by members of the
International Head and Neck Scientific Group
(http://www.IHNSG.com).
Funding. No funding or sponsorship was
received for this study or publication of this
article.
Authorship. All named authors meet the
International Committee of Medical Journal
Editors (ICMJE) criteria for authorship for this
article, take responsibility for the integrity of
the work as a whole, and have given their
approval for this version to be published.
Disclosures. Andrés Coca-Pelaz, Robert P.
Takes, Kate Hutcheson, Nabil F. Saba, Missak
Haigentz Jr., Carol R. Bradford, Remco de Bree,
Primož Strojan, Valerie J. Lund, William M.
Mendenhall, Iain J. Nixon, Miquel Quer,
Alessandra Rinaldo, and Alfio Ferlito have
nothing to declare.
Adv Ther
Compliance with Ethics Guidelines. This
article is based on previously conducted and
reported studies and does contain studies with
human participants performed by some of the
authors, but does not contain any studies with
animals performed by any of the authors. These
previously reported studies are clearly
referenced.
Data Availability. Data sharing is not
applicable to this article as no datasets were
generated or analyzed during the current study.
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