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Predictive Factors for Diagnosis of Advanced-Stage Squamous Cell Carcinoma of the Head and Neck
André L. Carvalho, MD;
Javier Pintos, MD, MS;
Nicolas F. Schlecht, MS;
Benedito V. Oliveira, MD;
Antonio S. Fava, MD, PhD;
Maria P. Curado, MD;
Luiz P. Kowalski, MD, PhD;
Eduardo L. Franco, PhD
Arch Otolaryngol Head Neck Surg. 2002;128:313-318.
ABSTRACT
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Objective To identify the predictive factors (with emphasis on diagnostic delay)
associated with the diagnosis of an advanced–clinical stage head and
neck cancer.
Design Cross-sectional study of patients with head and neck cancer originally
recruited for a case-control study.
Setting Three referral oncological centers in metropolitan areas in southern
Brazil: São Paulo, Curitiba, and Goiânia.
Patients The study population comprised 679 patients recently diagnosed as having
a previously untreated head and neck squamous cell carcinoma.
Main Outcome Measure Diagnosis of advanced disease (clinical stage III-IV) head and neck
cancer.
Results Patients with laryngeal and hypopharyngeal cancers were more likely
to be diagnosed as having advanced disease than those with lip, oral, and
oropharyngeal cancers (88.0% vs 74.6%) (P<.001).
Patient delay was inversely associated with clinical stage at diagnosis in
patients with the same cancers, while professional delay was directly associated
with a higher risk of advanced clinical stage at diagnosis (P = .001 and P = .006, respectively). In the
analysis of laryngeal and hypopharyngeal cancer, both patient and professional
delays were associated with advanced disease, with patient delay being a stronger
predictive factor than professional delay.
Conclusions Clinical stage at diagnosis was associated with sociodemographic characteristics,
patient delay, and professional delay. Our results indicate that continued
educational programs for the population and health care professionals regarding
the identification of early symptoms of head and neck cancers are warranted.
INTRODUCTION
THERE IS general consensus that clinical stage at the time of diagnosis
is the most important predictor of recurrence and death in patients with cancers
of the head and neck.1-6
Clinical stage at the time of diagnosis is influenced by several clinical
and sociodemographic variables, including patient delay in consulting a health
care professional and professional delay in diagnosing and treating the disease.7-9
Patient delay in seeking professional health care and professional delay
regarding cancer diagnosis have been found to predict clinical stage of oral
cancer at diagnosis,10-12
with direct consequences on the complexity and cost of treatment and on disease
prognosis. Patient delay in consulting a health care professional can be attributed
to 2 major factors: patient delay in recognizing the signs or symptoms of
cancer or difficulties in accessing professional care.13-14
Professional delay can be attributed to failure in recognizing the signs and
symptoms suggestive of cancer.15-16
We evaluated the relationship between sociodemographic and clinical factors
on clinical stage in a large case-control study in Brazil to identify the
predictive factors (with emphasis on diagnostic delay) associated with the
diagnosis of an advanced head and neck cancer.
PATIENTS AND METHODS
Between February 1986 and January 1989 we conducted a case-control study
of head and neck cancers in 3 metropolitan areas of southern Brazil: São
Paulo, Curitiba, and Goiânia. All patients presenting with a diagnosis
of primary squamous cell carcinoma of lip, oral cavity, oropharynx, larynx,
and hypopharynx (International Statistical Classification
of Diseases, 10th Revision codes C00-C06, C09-C10, C12-C13, and C32)
were eligible for this study. All cases were confirmed histopathologically
as squamous cell carcinoma. With the exception of the head and neck surgery
service in São Paulo, which was responsible for approximately 20% of
all incident cases in the city, patient accrual in the 2 other centers approached
100% of all incident cases in each area for the study period. Data were collected
prior to any medical treatment by interview using a 40- to 60-minute structured
questionnaire. Interviews elicited detailed information on socioeconomic and
demographic variables, dental health, history and habit of tobacco smoking,
and lifetime alcoholic beverage consumption. Questionnaires also included
information on the date of recognition of first signs or symptoms of the disease
and which health professional (dentist or physician) was visited by the patient
before being referred to the hospital for definitive diagnosis and treatment.
Dates of consultation with each professional were also recorded.
Tumor sites were classified into 2 different groups: tumors visible
with the naked eye in a clinical examination, such as cancers of the oral
cavity, including the lip, mouth, and oropharynx (group 1) and tumors visible
only with special equipment such as a laryngoscope or endoscope, which included
tumors of the larynx and hypopharynx (group 2).
Patient delay was defined as the time between date of recognition of
first sign or symptom of the disease by the patient and date of first visit
to a professional who was qualified to refer the patient for definitive diagnosis
and treatment: physician or dentist for group 1 and physician for group 2.
Professional delay was defined as the time between this consultation and the
date of histopathological diagnosis.
Clinical stage was classified according to the International Union Against
Cancer (UICC) criteria17 and grouped as early
clinical stage (clinical stage I-II) or advanced clinical stage (clinical
stage III-IV). Neck mass was one of the signs recorded and used in the analysis
regarding number of symptoms for both groups. However, this sign was not used
as a variable in the analysis because almost all patients in these groups
had clinically metastatic disease, which were therefore classified as advanced
clinical stage.
Statistical analysis was performed using the SPSS statistical software
(SPSS Inc, Chicago, Ill). Means and proportions were calculated to describe
the distribution of characteristics in the patient population. Odds ratios
(ORs) for diagnosis of advanced disease (clinical stage III-IV) and their
respective 95% confidence intervals (CIs) were estimated using multivariate
logistic regression. Trends for linear association were assessed by including
the categorical factors as ordinal variables in the regression models. The
regression models were adjusted for the variables found to be important in
predicting patient or professional delay. The variables adjusted for in model
1 included age, sex, education, and monthly income, and in model 2, number
of symptoms, tobacco and alcohol consumption, and dental health were also
adjusted for. Adjustment for patient and professional delays were included
in both models. The relationship between patient delay and professional delay
time was examined using Pearson product moment correlation after transforming
both variables into a logarithmic scale to correct for the skewness in the
distributions.
RESULTS
Of the 679 patients initially recruited, 3 were excluded owing to their
inability to remember the onset date of their signs or symptoms. The distribution
of patients according to metropolitan area was as follows: 204 patients (30.2%)
from São Paulo; 310 (45.9%) from Curitiba, and 162 (23.9%) from Goiânia.
Of the 676 patients, 595 (88.0%) were male adolescents or men, 569 (84.2%)
were of European descent, and ages ranged from 15 to 82 years (median, 58
years). There were 60 patients (8.9%) with cancer of the lip, 219 (32.4%)
with cancer of the oral cavity, 138 (20.4%) with cancer of the oropharynx,
96 (14.2%) with cancer of the hypopharynx, and 163 (24.1%) with cancer of
the larynx. Patient delay ranged from 1 week to 96 months (median, 3 months).
Professional delay ranged from 1 day to 31 months (median, 1 month). Patient
and professional delays were inversely correlated (Pearson correlation coefficient, -0.361; P<.001), ie, longer patient delay was linked with shorter
professional delay, and vice versa.
Of the 676 patients analyzed, 535 (79.1%) were diagnosed as having an
advanced–clinical stage cancer. Patients in group 2 were more likely
to be diagnosed as having an advanced–clinical stage cancer than patients
in group 1 (88.0% and 74.6%, respectively; P<.001).
Table 1 gives the univariate
analysis for the association of selected study variables with the diagnosis
of advanced clinical stage cancer. Table
2 gives the association between patient and professional delays
with advanced disease among group 1 patients. Both patient and professional
delays were associated with advanced clinical stage. While professional delay
was positively associated with advanced-stage disease, there was a negative
association between patient delay and stage III and IV cancer. When adjusting
for age, sex, education, monthly income, number of symptoms, dental health,
and tobacco and alcohol consumption, patients who waited 3 or more months
before consulting a health professional were less likely to be diagnosed as
having advanced disease compared with patients who consulted within the first
month (OR, 0.46; 95% CI, 0.2-0.9). On the other hand, patients who experienced
a professional delay of more than 3 months had a higher risk of advanced disease
compared with a professional delay of less than 1 month (OR, 1.69; 95% CI,
0.7-4.3).
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Table 1. Odds Ratios (ORs) With 95% Confidence Intervals (CIs) for
Diagnosis of an Advanced Upper Aerodigestive Tract Cancer (Stages III and
IV) by Sociodemographic and Health-Related Variables for Tumor Site Grouping*
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Table 2. Odds Ratios (ORs) With 95% Confidence Intervals (CIs) for
Diagnosis of an Advanced Upper Aerodigestive Tract Cancer (Stages III and
IV) by Patient, Professional, and Total Delay for Lip, Oral Cavity, and Oropharynx
Tumors
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Table 3 gives the association
of patient and professional delays for group 2 patients. For this group, both
patient and professional delays were positively associated with advanced-stage
cancer in the fully adjusted statistical model (model 2, Table 3), although professional delay was not a statistically significant
predictor. For patient delays of more than 3 months, the OR for advanced disease
was 3.37 (95% CI, 1.0-11.8), and for professional delay of more than 3 months,
the OR was 1.67 (95% CI, 0.5-5.9), compared with a delay of less than 1 month.
It is interesting that the total delay (time of patient delay plus professional
delay) for groups 1 and 2 was not associated with advanced clinical status
at diagnosis.
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Table 3. Odds Ratios (ORs) With 95% Confidence Intervals (CIs) for
Diagnosis of an Advanced Upper Aerodigestive Tract Cancer (Stages III and
IV) by Patient, Professional, and Total Delay for Hypopharynx and Larynx Tumors
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COMMENT
Clinical stage is the most important prognostic factor for patients
with head and neck cancer.1-6
Various factors have been investigated as predictors for a diagnosis of an
advanced–clinical stage cancer.7-9
However, there is controversy in the medical literature regarding the association
between patient and professional delays with clinical stage at diagnosis.
Although it seems logical that longer patient and professional delays would
be associated with a diagnosis of an advanced-stage disease, not all studies
of this issue arrived at similar findings. Some studies observed that variables
usually associated with patient and professional delays, such as sex, dental
status, alcohol consumption, and socioeconomic status, are associated with
clinical stage at diagnosis.7-8
Most of the studies, however, could not find a direct association between
diagnostic delay and clinical stage. Nonetheless, it is difficult to reject
the hypothesis that diagnostic delays contribute to a poor prognosis.1, 11
Rubright et al8 found an association
between older age and poor dental status with diagnosis of an advanced–
clinical stage cancer; however, they did not observe an association between
diagnostic delay and clinical stage. Elwood and Gallagher7
observed that high socioeconomic status, low level of alcohol consumption,
and regular dental care were associated with diagnosis of an early-stage cancer.
They also observed that diagnostic delay was different for oral cancer compared
with other head and neck tumors and failed to find an association between
diagnostic delay and clinical stage. In agreement with these studies, Wildt
et al10 did not find a correlation between
patient or professional delays and clinical stage. Two other studies did not
observe an association between diagnostic delays and tumor size.18-19
On the other hand, Gorsky and Dayan,9 found
a positive association between diagnostic delay and clinical stage in patients
with cancer of the lip.
Several factors may explain, at least partially, the weak or null association
seen between diagnostic delay and clinical stage. While professional delay
can be measured in a relatively accurate way, patient delay is prone to measurement
error. The date of onset of symptoms is based on perception, which is highly
subjective and may be influenced by several social and cultural factors. Patients
often neglect the importance of feeble symptoms, but when they seek medical
care for early symptoms, the condition is often labeled as benign and the
diagnosis is delayed.20 Patients with fast-growing
tumors can be diagnosed relatively rapidly but often after an advanced clinical
stage develops given the nature of the disease. On the other hand, patients
with slow-growing tumors usually experience long diagnostic delays and are
diagnosed as having early-stage disease (Figure 1).11
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Graphic presentation of diagnostic delay hypotheses.
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In our study, we observed that the factors associated with an advanced
oral cancer (group 1) are different from those associated with hypopharyngeal
and laryngeal cancer (group 2). For oral cancer, female sex and dental status
(use of non–well-fitted dentures) were associated with a lower risk
of being diagnosed as having advanced-stage disease, while patients who were
single, who were current smokers, and those with poor dentition presented
a higher risk. For patients with laryngeal or hypopharyngeal cancers, older
age was associated with a lower risk of being diagnosed as having advanced-stage
disease. Patients with more than 1 symptom were at higher risk of advanced
cancer in both groups compared with patients with only 1 symptom. Obviously,
different tumor sites will manifest with different symptoms. Tumor symptomology
may play an important role in the diagnostic process, given its influence
on attention by the patient and professional care.7
In the analysis of diagnostic delay as a predictor of advanced disease,
we found that oral cancers were influenced in a different way than laryngeal
and hypopharyngeal cancers. For patients with cancer of the lip, mouth, and
oropharynx, longer patient delay was associated with lower risk of being diagnosed
as having an advanced clinical stage. These results favor the tumor biology
hypothesis (Figure 1), according
to which patients with slow-growing tumors have a longer delay and are more
likely to be diagnosed as having early disease than patients with fast-growing
tumors. On the other hand, we found that professional delay was positively
associated with clinical stage at diagnosis. This finding favors the logical
hypothesis (Figure 1). For patients
with laryngeal and hypopharyngeal cancers, both patient and professional delays
were associated with advanced clinical stage, also favoring the logical hypothesis.
It should be noted that the association of patient delay with advanced disease
was substantially stronger than that of professional delay. Two additional
factors may contribute to bias the associations of disease burden with patient
and professional delays, but their role is difficult to establish in studies
such as the present one. The first of these factors is the contribution of
the overall health system delay, which includes the professional referral.
The patient may seek prompt medical attention for his or her symptoms and
the first professional may immediately recognize the sign or symptom, but
there may be a delay in referring to the specialist for definitive diagnosis
or to establish the diagnosis. The second factor that may contribute to bias
the association is related to errors in diagnosis, but we have no indication
of that in our study.
In summary, regarding laryngeal and hypopharyngeal cancers, our results
support the logical hypothesis, according to which patient and professional
delay are associated with a more advanced clinical stage. In the analysis
of lip, mouth, and oropharyngeal cancers, professional delay was a predictor
of more advanced disease. However, we found a negative association between
patient delay and clinical stage. One of the possible explanations for this
finding is the tumor biology hypothesis. Future studies assessing the influence
of diagnostic delay in the prognosis of patients with head and neck cancers
should take into consideration this hypothesis and would benefit from using
biomarkers capable of identifying slow- and fast-growing tumors.
Although collecting information on tumor biology markers would have
been useful in the present and other investigations, patient and professional
delays are undeniably critical factors influencing clinical stage. Our results
support the adoption of continued educational programs for the population
and health care professionals regarding the identification of early symptoms
of head and neck cancers.
AUTHOR INFORMATION
Accepted for publication November 27, 2001.
Mr Schlecht is a recipient of a Doctoral Research Award and Dr Franco
is a recipient of a Distinguished Scientist Award, both from the Medical Research
Council of Canada, Ottawa, Ontario. This work was supported in part by International
Scientific Exchange Award 910035/99-7 from the Medical Research Council of
Canada–Conselho Nacional de Pesquisa (Dr Carvalho [visiting fellow]).
This study was presented at the annual meeting of the American Head
and Neck Society, Palm Desert, Calif, May 15, 2001.
We are indebted to the following participants in the Ludwig Institute
for Cancer Research's Upper Respiratory and Digestive System Cancer Study
Group: clinical committee—M. B. Carvalho, MD, A. Rapoport, MD, J. Andrade-Sobrinho,
MD, G. Ramos, MD, J. L. Kanda, MD, J. F. Gois, MD, J. S. Chagas, MD, and G.
A. Teixeira, MD; pathology committee—H. Torloni, MD (coordinator), W.
T. Vieira, MD, L. A. Sampaio, MD, and V. M. Cardoso, MD; data acquisition
and management—M. E. Silva (social worker); R. N. Pereira (statistician);
N. Campos-Filho (statistician); L. Fanes, RN; V. N. Souza, MD; and M. S. Morais,
MD.
Corresponding author and reprints: Luiz Paulo Kowalski, MD, PhD,
Rua Antonio Prudente, 211, São Paulo 01509-900, Brazil (e-mail: lp_kowalski{at}uol.com.br).
From the Hospital do Cancer A. C. Camargo, São Paulo, Brazil
(Drs Carvalho and Kowalski); the Division of Cancer Epidemiology, McGill University,
Montreal, Quebec (Drs Pintos and Franco and Mr Schlecht); Hospital Erasto
Gaertner, Curitiba, Brazil (Dr Oliveira); Hospital Heliópolis, São
Paulo (Dr Fava); and Hospital Araújo Jorge, Goiânia, Brazil (Dr
Curado).
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