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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
Adv Ther

both an aging population and improvements in symptoms. Tumors in the nasopharynx and
the treatment of infectious diseases that may hypopharynx are associated with late presenta-
previously have been fatal [3, 4]. There were an tion due to the lack of obvious symptoms. In
estimated 14.1 million cancer cases around the contrast, glottic tumors are often detected early
world in 2012 and, according to data from the because of the early onset of symptoms such as
World Cancer Research Fund International hoarseness. In malignancies of the nose and
(http://www.wcrf.org), this number is expected sinuses, the most common presenting symptoms
to increase to 24 million by 2035. In Europe, are nasal obstruction (56%), epistaxis (35%), and
head and neck squamous cell carcinoma nasal discharge (20%) [9]. These symptoms over-
(HNSCC) is the sixth most common group of lap with those of rhinosinusitis and other benign
cancers [5]. The overall prognosis of HNSCC is sinonasal diseases, usually resulting in a greater
relatively poor, with survival figures varying than 12-month delay in presentation [9] and a
between countries and per site of primary median delay in diagnosis of 20 months [10].
tumor. Five-year age-standardized relative sur- Finally, the complexities of multidisciplinary care
vival is low in Eastern countries, 47% for may pose additional logistical challenges that can
laryngeal primaries and 28% for all other adversely affect timely initiation of cancer ther-
HNSCCs combined, and high in Ireland and the apy. Moreover, with the intent of optimizing
UK, and Northern Europe (62% and 46%, quality of care, there is a tendency to centralize
respectively) [6]. cancer care which can further increase wait time
Delays before treatment may be due to patient, (WT) for treatment [11]. These factors contribute
professional, or facility-related factors [7]. Head to diagnostic and/or treatment delays that allow
and neck cancers are often diagnosed in patients the tumor to progress, which can ultimately lead
who abuse tobacco and alcohol. Such patients to impaired survival and/or functional outcomes
often wait months before seeking consultation for from more intensive therapies.
their symptoms, which can lead to tumors being Where a study from any author of this review
diagnosed at an advanced stage [8]. General is discussed, the references are clearly men-
practitioners often do not recognize the true cause tioned. This article is based on previously con-
of the complaints of the patient and give several ducted and reported studies and does contain
treatments for non-specific symptoms that also studies with human participants performed by
contribute to delays. Delay may also depend on any of the authors.
the tumor site and the onset and type of

V. J. Lund
EFFECTS ON SURVIVAL
Professorial Unit, Ear Institute, University College
London, London, UK In 2008, Chen et al. [12] published a systematic
review about the relationship between WT for
W. M. Mendenhall
Department of Radiation Oncology, University of radiotherapy and clinical outcomes. They found
Florida, Gainesville, FL, USA a significant increase in the risk of local failure
with increasing WT, with a relative risk (RR) of
I. J. Nixon
Department of Surgery and Otolaryngology, Head
1.15 per month of WT and a mortality RR of
and Neck Surgery, Edinburgh University, 1.16 per month. They concluded that ‘‘WTs for
Edinburgh, UK radiotherapy should be as short as reasonably
achievable’’, in part, because it is not possible to
M. Quer
Department of Otolaryngology, Hospital Santa Creu determine what exactly the ‘‘safe’’ WT period
i Sant Pau, Barcelona, Spain would be, without adverse impact on treatment
outcome and survival.
A. Rinaldo
University of Udine School of Medicine, Udine, Italy Tumor progression is the primary concern as
WT for treatment increases. In a study by Jensen
A. Ferlito et al. [13] the tumor volume doubling (TVD)
Coordinator of the International Head and Neck
Scientific Group, Padua, Italy
time for all patients was a median of 99 days.
Adv Ther

However, half of patients with the most should start preferably within 20–30 days of
aggressive tumors had a TVD of 30 days. They evaluation by a radiation oncologist. Also, in a
also reported that most patients developed study by Kowalski and Carvalho, the tumor
notable signs of tumor progression on cross- growth rate was found to correlate with tumor
sectional imaging within 4 weeks WT. Similarly, stage: the median time for disease of stages I–II
Waaijer et al. [14] found an average TVD of to reach stages III–IV was 11.3 months, whereas
96 days in a group of 13 oropharyngeal carci- the median time for tumors of stages III–IV to
nomas. During the mean WT of 56 days, the become untreatable was 3.8 months [19]. In this
mean increase in tumor volume was 70%; more study, the delay in commencing oncologic
importantly, as a result of delay in radiotherapy treatment influenced prognosis, especially in
the expected tumor control probability was clinical stage IV patients and in those with oral
reduced from 63–66% (no delay) to 47% (delay cavity primaries.
incorporated). Obviously, the consequences of However, a study by van Harten et al. [20],
delay in starting definitive radiotherapy are including all types of treatment in the Nether-
related to TVD. For a patient with a fast-growing lands Cancer Institute with 2493 patients,
tumor, an interval of more than 1 month can found no relationship between WT for treat-
have a significant adverse effect on treatment ment up to 90 days and impaired survival. They
outcome [15]. Tumor biology is, however, even showed that poorer survival was found for
extremely heterogeneous, with some tumors patients with shortest WT (\2 weeks) for treat-
displaying TVD of 15 days while others have ment, and better survival for patients with
minimal measurable growth during a prolonged moderate or longer WT. One explanation for
interval. Mackillop et al. [16] estimated that for this apparent paradox is that patients with more
tumors with a TVD of 90 days, an 8% reduction aggressive, more advanced stage, or who were
in local tumor control was associated with a more symptomatic, with an associated worse
4-week delay prior to the start of radiotherapy. prognosis, had been selected for earlier treat-
Jensen et al. [13] also estimated an overall ment than patients with longer WT. On the
decrease in local control rate of about 8% per other hand, the same authors in a more recent
month of delay for their overall patient popu- study [21] investigated 13,140 patients with a
lation. They showed that the impact of delay median WT of 37 days. They found that
would be expected to be considerably higher patients who were more likely to have pro-
(about 20% decrease in local control per month longed WT were men, patients with a low
of delay) for patients with tumors in the top socioeconomic status, oropharyngeal primaries,
quartile of tumor growth rate in their case stage IV tumors, patients to be treated with
series. radiotherapy or chemoradiotherapy, and
Translating the effects of TVD to survival, patients referred from another hospital. The
van Bockel et al. reported on the relationship 5-year overall survival was 58% for all patients.
between tumor growth rate and survival, with The multivariable Cox regression model showed
5-year disease-free and overall survival in fast that longer WT was significantly related to a
growing tumors of 56% and 40%, respectively. higher hazard of death (p\0.0001).
However, in slow growing tumors they were Similarly, Caudell et al. [22] performed a
78% (p = 0.008) and 65% (p = 0.013) [17]. A retrospective study of 427 patients and observed
strong association between N-classification sta- that the median number of days between the
tus and tumor growth rate was suggested in biopsy confirming malignancy and the first day
exploratory analysis. Similarly, analyzing treat- of radiotherapy was 34 days (range 7–44). A
ment results of 623 early-stage head and neck longer WT was not significantly associated with
cancer patients, Fortin et al. found a signifi- locoregional control (p = 0.11), distant metas-
cantly increased risk of local and neck failure tasis-free survival (p = 0.32), or overall survival
and poorer survival when delay in starting (p = 0.07).
definitive radiotherapy was greater than 40 days In a large population-level analysis [23] of
[18]. The authors concluded that radiotherapy over 51,000 patients in the National Cancer
Adv Ther

Database (USA) treated with curative intent in the oral cavity (median WT, 38 days) or
between 1998 and 2011, roughly one-quarter of oropharynx (median WT, 41 days). Patients
patients were estimated to experience treatment treated with definitive radiotherapy or
delay, defined as initiation of treatment greater chemoradiotherapy had to wait significantly
than 46 days after diagnosis. Number of days longer than patients who underwent primary
from diagnosis to initiation of curative-intent surgery (41 vs. 34 days). The median treatment
treatment significantly increased risk of death, delay was not related to tumor stage. They
with a recursive partition analysis-derived found that patients referred from other centers
threshold of 60 days beyond diagnosis predict- following diagnosis had to wait an average of
ing adverse survival outcomes. 13 days (from the day of biopsy) before their
While single institution data and popula- first visit to the Netherlands Cancer Institute,
tion-level analyses suggest an adverse impact of resulting in a mean total treatment delay of
increased WT on survival outcomes, there are 45 days. Caudell et al. [22] conducted multi-
less clear trends on meta-analysis. Huang et al. variate regression analysis of 427 patients with
[24] performed a systematic review of the world HNSCC finding that lower Karnofsky perfor-
literature to identify studies that described the mance status (p = 0.02), use of intensity-modu-
association between delay in radiotherapy and lated radiotherapy (p = 0.001), and insurance
the probability of local control, metastasis, and type (Commercial, Medicaid/charity, Medicare
survival based on data from 15,782 patients or Department of Veterans Affairs) (p = 0.001)
from 46 studies. Most of these studies focused were significantly associated with a WT of
on breast cancer or HNSCC. Combined analysis greater than 34 days. However, a longer WT was
showed that the local recurrence rate was sig- not significantly associated with worse locore-
nificantly higher among patients who received gional control (p = 0.12), distant metastases-
postoperative radiotherapy for HNSCC more free survival (p = 0.24), or overall survival
than 6 weeks after surgery compared with those (p = 0.14). Van Harten et al. [20] did not find a
treated within 6 weeks of surgery (OR = 2.89; relationship between stage at diagnosis and
95% CI 1.60–5.21). Yet, there was little evidence treatment delay. Patel and Brennan [25] descri-
that this delay in postoperative radiotherapy bed that WT was prolonged for 57 versus
was associated with the risk of metastases or the 30 days (p\0.001) for patients receiving pri-
probability of long-term survival in any subset mary radiotherapy compared to surgical ther-
of patients. 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
DETERMINANTS OF TREATMENT performed elsewhere also had a reduced WT
DELAY (p = 0.03). Several studies considered socioeco-
nomic status in relation to delays, with incon-
Several studies have investigated the determi- sistent results. For example, one study found no
nants of WT. van Harten et al. [20] found that association between treatment delay for surgery
the year of diagnosis, tumor site, and therapy and socioeconomic status [26], while another
type were significantly related to treatment showed a longer delay for patients with low
delay (p\0.05). The median treatment delay socioeconomic status [20, 21]. Another study
from this single institution study during the [27] investigated the relationship between
period of 1990 and 1994 was 31 days, signifi- comorbidities and socioeconomic level on
cantly shorter than in the subsequent time treatment delays. Comorbidities were associated
periods studied (1995–1999, 2000–2004, with a longer WT for patients with advanced
2005–2010), with a median ranging from 38 to stage HNSCC, probably because of the need for
41.5 days. Patients with tumors arising in the further evaluation and supportive care (im-
hypopharynx (median WT, 35 days) and larynx proved nutrition, dental care, etc.) before
(median WT, 35 days) experienced significantly treatment. The importance of logistical consid-
less WT (p = 0.000) compared with those arising erations impacting the duration of the
Adv Ther

treatment period was highlighted by Primdahl head and neck cancers at a UK multidisciplinary
et al. who reported the results of a Danish clinic that included a medical oncologist, radi-
nationwide study of time spans from initial ation oncologist, and head and neck surgeon.
symptoms to first healthcare contact and start Survival outcomes are not the sole measures
of treatment [28]. Reviewing charts of 288 of high-quality care. Although multidisciplinary
patients with pharyngeal and laryngeal cancers teams have not universally demonstrated sig-
mostly treated with radiotherapy, they com- nificant reduction of mortality rates, they are
pared time spans during 4-month periods in likely to have improved the quality of life of the
1992 and 2002. Although there was no differ- patients with HNSCC. Groups have reported
ence in time elapsed for diagnostics between the higher rates of dental assessment, nutritional
two time periods, total time from first health- assessment, positron emission tomography
care contact to treatment beginning was sig- staging, and a shorter interval between surgery
nificantly longer in 2002. The difference was and radiotherapy for patients managed within a
mainly due to longer WT as a consequence of a multidisciplinary team setting, as well as greater
shortage of radiotherapy capacities, thus pro- likelihood of speech pathology utilization in a
longing the time needed for treatment prepa- multidisciplinary care model. These changes are
ration and planning. Longer WT was estimated likely associated with improvements in
to result in 10% lower tumor control probability patients’ perceptions of the service provided
in 2002 compared to 1992. Following system- [30, 33, 34].
atic implementation of logistical improvements
in 2007, they observed a significant reduction in
delay of diagnosis and treatment in 2010. DISCUSSION
However, still less than half of the head and
neck cancer patients started treatment within In the age of multidisciplinary head and neck
the current standards [29]. cancer care, a more uniform and guideline-
based approach to therapy has been achieved.
In addition, coordination of care pathways has
ROLE OF MULTIDISCIPLINARY also been shown to offer potential for reducing
TEAM WT [35, 36]. These improvements may allow
more timely treatment, which in turn may lead
One of the aspects of cancer care which has to better outcomes. Evolvements in under-
been shown to positively impact patient out- standing of the biology and behavior of tumors
comes is the introduction of the multidisci- have led to an increasingly personalized
plinary team. Patil et al. [30] performed a approach to treatment. In the case of radio-
retrospective study, comparing mortality before therapy, refined treatment schedules and use of
(group 1) and after (group 2) implementation of newer technologies may require more prepara-
a multidisciplinary team model. Reduction in tion. Therefore, the factors that could influence
the times between consultation and the patient delays of radiotherapy are now multiple and
evaluation and between a diagnostic biopsy and could certainly be a handicap in centers that
date of initiating definitive treatment were have low volume or less coordinated cancer
noted despite the increased volume of patients care.
over time. However, the 2-year mortality was WT for radiotherapy was first identified as a
comparable between the two groups. Five-year cause for concern in the medical literature in a
mortality was slightly better in group 2 (50%) report from Norway almost 30 years ago [37].
versus group 1 (61%), though not statistically Since that publication, many articles have been
significant. Friedland et al. [31] showed superior published on the effect of this delay on the
survival in stage IV head and neck cancer prognosis of the HNSCC patients. In the vast
patients whose cases were reviewed by a multi- majority of the articles, longer WT is associated
disciplinary team. Similarly, Birchall et al. [32] with tumor progression [12–16, 20], but con-
noted significantly improved 2-year survival for versely there are articles such as the one by van
Adv Ther

Harten et al. [20] which concluded that ‘‘treat- sacrificing quality of care. A possible confound-
ment delay up to 90 days is not related to ing variable is that tumor progression may lead to
impaired survival’’, and found that patients intensified treatment that may compensate for
treated within 30 days had significantly worse potentially worse oncological outcomes but may
survival. León et al. [38], who performed a ret- also exacerbate toxicity that impacts quality of
rospective study of 797 patients and concluded life. Furthermore, prolonged WT is likely to result
that ‘‘within the range of the WT observed in in anxiety and potentially decreased satisfaction
our study, delay in the initiation of radiother- with the care provided. As a result of the hetero-
apy did not affect local control or survival in geneity of the studies with different definitions
patients with HNSCC’’. In laryngeal cancer, of WT, different end points, and difficulties in
Barton et al. [39] studied 581 patients with T1 comparing similar treatments and healthcare
and T2, N0–2 larynx cancer, with a median systems in different parts of the world, it is chal-
follow-up of 6.8 years. In that study, longer WT lenging to draw firm conclusions. However, in
was not a significant predictor of disease the era of multidisciplinary care, teams should
relapse. In the same way, Lee et al. [40] analyzed constantly review their practice to ensure a
290 patients with nasopharyngeal carcinoma minimum delay of patient care. Streamlining
(T1N0–3M0) and found that delay in initiation treatment pathways including reduction of WT is
of treatment did not affect the control rate at indicated to optimize quality of care of our
irradiated sites. patients, including oncological and functional
A factor influencing WT may be related to outcomes. Furthermore, robust public health
patient stage at presentation; it is conceivable that and primary care practitioner education is nee-
patients with advanced stage disease would be ded to improve awareness of the early signs and
diagnosed earlier and therefore treated more symptoms of head and neck cancer.
swiftly, because of the greater risk of becoming
inoperable or because they have more complaints.
Another factor may be the differences in ACKNOWLEDGEMENTS
tumor biology. It may be that patients with
more aggressive tumors have a worst prognosis This article was written by members of the
even when they are treated earlier. However, it International Head and Neck Scientific Group
is important to acknowledge the complexity of (http://www.IHNSG.com).
the matter. The varying results reported in the
literature may be related to differences in the
Funding. No funding or sponsorship was
patient/populations, the centers investigated,
received for this study or publication of this
and local or regional practices. Furthermore,
article.
reports may not be comparable given the lack of
control for these factors. Nonetheless, HNSCC is
Authorship. All named authors meet the
a complex disease requiring a multidisciplinary
International Committee of Medical Journal
team of experts and therefore patients with
Editors (ICMJE) criteria for authorship for this
HNSCC should be referred as soon as possible to
article, take responsibility for the integrity of
recognized multidisciplinary centers equipped
the work as a whole, and have given their
to treat these patients effectively and
approval for this version to be published.
expeditiously.
Disclosures. Andrés Coca-Pelaz, Robert P.
Takes, Kate Hutcheson, Nabil F. Saba, Missak
CONCLUSION Haigentz Jr., Carol R. Bradford, Remco de Bree,
Primož Strojan, Valerie J. Lund, William M.
Prolonged WT for treatment of HNSCC is likely
Mendenhall, Iain J. Nixon, Miquel Quer,
to negatively affect the prognosis of the patients.
Alessandra Rinaldo, and Alfio Ferlito have
On the basis of the aforementioned, we believe
nothing to declare.
that the best option is to minimize WT without
Adv Ther

Compliance with Ethics Guidelines. This sinuses: hospital of the University of Pennsylvania
article is based on previously conducted and Experience 1990–1997. Am J Rhinol.
1999;13:117–23.
reported studies and does contain studies with
human participants performed by some of the 11. Bilimoria KY, Ko CY, Tomlinson JS, et al. Wait times
authors, but does not contain any studies with for cancer surgery in the United States: trends and
animals performed by any of the authors. These predictors of delays. Ann Surg. 2011;253:779–85.
previously reported studies are clearly 12. Chen Z, King W, Pearcey R, Kerba M, Mackillop WJ.
referenced. The relationship between waiting time for radio-
therapy and clinical outcomes: a systematic review
Data Availability. Data sharing is not of the literature. Radiother Oncol. 2008;87:3–16.
applicable to this article as no datasets were
13. Jensen AR, Nellemann HM, Overgaard J. Tumor
generated or analyzed during the current study. progression in waiting time for radiotherapy in head
and neck cancer. Radiother Oncol. 2007;84:5–10.

14. Waaijer A, Terhaard CH, Dehnad H, et al. Waiting


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