Key points and time intervals for early diagnosis in symptomatic oral cancer: a systematic review

Abstract

The aim of this study was to identify key points and time intervals in the patient pathway to the diagnosis of oral cancer, from the detection of a bodily change to the start of treatment. A systematic search of three databases was performed by two researchers independently. Articles reporting original data on patients with symptomatic primary oral or oropharyngeal squamous cell carcinoma that was pathologically confirmed were included. These articles had to include an outcome variable of ‘diagnostic delay’, ‘time interval’, or ‘waiting time to diagnosis’, or report time intervals from first symptom to treatment. Furthermore, the outcome variable had to have a clearly defined start point and end point, with the time measurement presented as a continuous or categorical variable. A total of 1175 reports were identified; 28 articles on oral cancer studies and 13 on oral and oropharyngeal cancer studies were finally included. These papers showed poor quality in terms of questionnaire validation, acknowledgement of biases influencing time-point measurements, and strategies for verification of patient self-reported data. They also showed great heterogeneity. The review findings allowed the definition of key points and time intervals within the Aarhus framework that may better suit the features of the diagnostic process of this neoplasm, particularly when assessing the impact of waiting time to diagnosis.

Oral and pharyngeal cancer (OPC), as a whole, is the sixth most common malignancy worldwide, with broad variations (up to 20-fold) in incidence. Areas with the highest incidences include South Asia (Sri Lanka, India, Pakistan, and Taiwan), Eastern Europe (Hungary, Slovakia, and Slovenia), Latin America (Brazil, Uruguay, Puerto Rico, and Cuba), Southern Africa (Namibia, Botswana, and Mozambique), and certain regions in the Pacific (Melanesia and Papua New Guinea). OPC is the most common cancer in certain countries (Malaysia and Sri Lanka), and two-thirds of these malignancies occur in developing countries.

Regrettably, about half of oral cancers have already reached an advanced stage (III or IV) when diagnosed, probably due to delays in diagnosis; this has an influence on survival rates (5-year survival 20–50% depending on the tumour site). It has been suggested that if these malignancies were diagnosed and treated at an earlier stage, survival rates would exceed 80%. However, the actual impact of the diagnostic and therapy delay on cancer outcomes is poorly defined, to the point that some authors wonder “Do diagnostic delays in cancer matter?”. Regarding oral cancer, the answer is ‘yes’: the larger the diagnostic delay, the more advanced the stage at diagnosis, with a longer interval from first symptom to referral for diagnosis being a risk factor for advanced stage and mortality from oral cancer.

Furthermore, oropharyngeal and laryngeal cancers have reached the longest median patient intervals when compared to another 28 common and rarer cancers. As a result of these findings, studies on the early detection and diagnostic delays in oral cancer are a priority for research on secondary and tertiary prevention, as the early diagnosis of symptomatic cancer is considered to be central to the achievement of better outcomes.

Although the term ‘cancer diagnostic delay’ has proven to be inconsistent and inaccurate, and also to bear strong legal implications, it has taken root in the scientific literature in the last 75 years. During this period it has been impossible to reach a consensus on a time-point beyond which a cancer diagnosis should be considered as delayed. Different definitions have been suggested to this end, using heterogeneous criteria (mean or median time distribution, or arbitrary time points ), which has severely hampered comparisons among studies. Moreover, the rare usage of conceptual frameworks in these investigations has often led to excessively simplistic approaches to the problem, considering only patient delay, professional delay, and health system delay, even assuming the existence of overlaps between these time periods.

In an attempt to simplify the design and monitoring of interventions aimed at reducing the time to diagnosis in symptomatic cancer, the use of different conceptual frameworks has been recommended. Amongst the most robust of these frameworks are the ‘general model of total patient delay’ (Anderson model), which comprises five delay stages between the detection of an unexplained sign(s) or symptom(s) and the beginning of treatment for the illness, and the ‘model of pathways to treatment’ (the Aarhus statement), a refined version of the former consisting of a description of events, processes, intervals, and contributing factors involved in the path towards symptomatic cancer diagnosis. However, no reports dealing with this topic in regard to oral cancer with a systematic approach could be identified. Thus, the present study was designed to identify key points and time intervals in the patient pathway to the diagnosis for symptomatic oral cancer, from the detection of a bodily change to the definitive treatment.

Methods

A study protocol was designed for the study, which included a document search and data retrieval. The resulting systematic search followed a narrative synthesis of the literature guided by the PRISMA statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). The search was undertaken in June 2015 (updated in January 2016) in the MEDLINE, Embase (from 1980), and Proceedings Web of Science (Conference Proceedings Citation Index—Science since 1990) databases, according to the following strategy: ((oral cancer OR oral squamous cell carcinoma OR oropharyngeal cancer) AND (diagnostic delay OR time interval)), using both medical subject headings (MeSH) and free text terms. The search strategy (MEDLINE) was as follows: #1 delayed diagnosis [MeSH Terms]; #2 diagnostic delay; #3 patient delay; #4 professional delay; #5 doctor delay; #6 provider delay; #7 total delay; #8 time interval; #9 waiting time to diagnosis; #10 treatment delay; #11 pathways to treatment; #12 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11); #13 mouth neoplasm; #14 oral cancer [MeSH Terms]; #15 oropharyngeal cancer [MeSH Terms]; #16 (#13 or #14 or #15); #17 (#12 and #16).

The sources identified were deemed relevant if they met the following criteria: (1) reported original data, without restrictions in terms of study design; (2) included only patients with symptomatic primary, pathologically confirmed, oral or oropharyngeal squamous cell carcinoma; (3) the outcome variable was ‘diagnostic delay’ or ‘time interval’ or ‘waiting time to diagnosis’, or the reference reported one or several time intervals in the patient pathway from first symptom to treatment ; (4) the outcome variable was clearly defined by a start and an end point, and the time lapse measurement was presented as a continuous or categorical variable.

Data collection and extraction

Two researchers (PVC and JMSR) extracted the data in an unblinded manner, but independently, and entered it into a custom-made form following a standardized procedure. Disagreements were resolved by a third researcher who was blinded to the study hypothesis. Inter-observer concordance for the two categories was calculated by means of Epidat 3.1 statistical software (Programa para Análisis Epidemiológico de Datos Tabulados, Xunta de Galicia, Santiago de Compostela, Spain).

Quality assessment

The Aarhus checklist for research in early cancer diagnosis was used as a framework for assessing the quality of the selected sources. This list includes 20 items, seven related to definitions of time-points and intervals (date of first symptom, date of first presentation to healthcare, date of referral, and date of diagnosis) and 13 related to measurements (three general, eight for studies using questionnaires and/or interviews with patients and/or healthcare providers, and two for studies using primary case-note audit and database analyses).

Again, two researchers assessed the reports independently and a third researcher was called on in the case of disagreement, and the score sheet was discussed until a consensus was reached. The presence of biases related to systematic reviews, such as publication bias, time lag bias, and outcome-reporting bias, was also considered by directly contacting the corresponding authors of the papers included in this systematic review by e-mail.

Results

A total of 1175 potentially eligible reports were identified; 1085 of these were discarded after assessing both the titles and abstracts, because they were not related to ‘diagnostic delay’ or ‘time intervals’ ( κ = 0.83). Another 49 articles did not meet the inclusion criteria ( Fig. 1 ). Finally, 28 papers reporting on oral cancer studies and 13 reporting studies on cancers of closely related sites (oral and oropharyngeal cancers) were included ( κ = 0.75). Information from these articles is summarized in Tables 1 and 2 .

Fig. 1
Flow chart of the study.

Table 1
Summary of reports on oral cancer diagnostic delay included in this systematic review.
Author, year Country Site Design Sample size Period of data collection Diagnostic delay Criteria for diagnostic delay Outcome (prognostic) Association Quality score
Cooke and Tapper-Jones, 1977 UK Oral HB 50 1955–74 3 periods (onset of symptoms to start of treatment) Categorical: 1, 2, 3, and 4 weeks, 1–2, 2–6, and >6 months Reasons for delay NA 5
Carrassi et al., 1980 Italy Oral HB 40 1970–80 R1 (first symptom to HCP presentation)
R2 (HCP first visit to diagnosis)
Continuous: days (descriptive) T stage Descriptive study 4
Elwood and Gallagher, 1985 Canada Oral CS 134 1977–80 First symptom to histological diagnosis Categorical: <2, 2–<4, 4–<7, and ≥7 months TNM No 9
Scully et al., 1986 UK Oral HB 58 1982–85 Delay by patient
Delay by practitioner
Delay by the hospital
Continuous: median days Referral patterns NA 4
Dimitroulis et al., 1992 Australia Oral HB 51 NG Patient delay
Clinician delay
Continuous: mean days Referral patterns NA 8
Schnetler, 1992 UK Oral HB 96 1986–91 Practitioner delay in referral Dichotomous, >2 days Referral patterns NA 6
Jovanovic et al., 1992 Netherlands Oral HB 50 1990–91 Patient delay
Doctor delay
Overall delay
Categorical: <4, 5–16, and >16 weeks Tumour size No 4
Wildt et al., 1995 Denmark Oral HB 167 1986–90 Patient delay
Professional delay
Total delay
Continuous: mean and median Survival No 8
Rubright et al., 1996 USA Oral HB 53 1990–94 Delay in diagnosis: discovery of tumour to tumour staging Continuous: months (descriptive) TNM (I–II vs. III–IV) No 8
Kerdpon and Sriplung, 2001 Thailand Oral HB 161 1996–98 Patient delay
Professional delay
Total delay
Categorical: >1, 1–3, and >3 months TNM (I–II vs. III–IV) No 6
Kantola et al., 2001 Finland Tongue CB 75 1974–94 Referral delay Dichotomous: patient referred vs. patient not referred, months Survival TNM stages (I–II–III vs. IV) Yes 11
Kumar et al., 2001 India Oral CS (HB) 27 NG Primary delay
Secondary delay
Tertiary delay
NG Stage of cancer, early vs. advanced Yes 6
Onizawa et al., 2003 Japan Oral HB 152 1991–2000 Step1
Step2
Step 3
Step 4
Dichotomous: beyond the median (2.7 months) Stage (T category and N category) No 9
Scott et al., 2005 UK Oral HB 245 1992–2003 Diagnostic delay (first noticed symptoms to diagnosis) Dichotomous: >3 months TNM (I–II vs. III–IV) No 6
McLeod et al., 2005 UK Oral HB 120 1995–2000 Patient delay
Referral delay
Continuous Referral patterns NA 8
Morelatto et al., 2007 Argentina Oral HB 70 1992–2004 Patient delay
Professional delay
Hospital delay
Categorical: >30, 30–60, 60–120, and >120 days TNM (I–II vs. III–IV) Yes 8
Abdo et al., 2007 Brazil Oral HB 180 1999–2001 ET (first symptoms to hospital)
RT (referral to hospital)
TT (hospital to start of treatment)
TTE total time (ET + TT)
Continuous: mean days TNM No 6
Peacock et al., 2008 USA Oral HB 50 2003–07 Time intervals (T1–T6)
Aware of symptoms to definitive treatment
Continuous: mean days Reasons for delay Descriptive, NA 4
Teppo and Alho, 2008 Finland Tongue HB, CB 62 1986–96 Patient delay
Professional delay
Dichotomous: ≥3 months
Categorical: <1 month; ≥1, <3 months; ≥3 months; ≥6 months
Survival No 10
Gao and Guo, 2009 China Oral HB 102 2005–06 Patient delay
Professional delay
Dichotomous: >1 week Predictors for delay NA 6
Sargeran et al., 2009 Iran Oral HB 100 2004–06 Patient delay
Professional delay
Total diagnostic delay
Categorical: ≤2 months, ≤1 months, and >4 months Determinants of the diagnostic delay Yes, descriptive 11
Seoane et al., 2010 Spain Oral HB 63 1997–2002 Total diagnostic delay Dichotomous: >45 days Survival No 8
Seoane-Romero et al., 2012 Spain Oral HB 88 1998–2003 Total diagnostic delay Dichotomous: >45 days TNM (I–II vs. III–IV) No 8
Amar et al., 2014 Brazil Oral HB 153 1996–2007 Start of treatment to adjuvant therapy Categorical: <6 vs. 6–8 vs. >8 weeks Local recurrences No 4
Joshi et al., 2014 India Oral HB 201 2011–12 Delay in treatment (primary, secondary, tertiary delay) Dichotomous: ≤3 vs. >3 months Reasons for delay NA 3
Panzarella et al., 2014 Italy Oral HB 156 2000–05 Patient delay Dichotomous and categorical: ≤1 vs. >1 month; <1 vs. 1–3 vs. >3 months Reasons for delay NA 8
Tong et al., 2014 China Oral HB 77 2009–11 Total diagnostic delay (symptom-definitive diagnosis) Dichotomous: >2 months Survival, recurrence Yes 4
Kaing et al., 2015 Australia Oral HB 70 2008–10 Patient delay
Professional delay
Treatment delay
Continuous: mean and median Stage (TNM), referral patterns, survival No 7
CB, community-based; CS, case series in a wide regional area; HB, hospital-based; HCP, health care provider; NA, not available; NG, not given; TNM, tumour size, node status, metastasis.

Table 2
Summary of reports on oral and oropharyngeal cancer diagnostic delay included in this systematic review.
Author, year Country Site Design Sample size Period of data collection Diagnostic delay Criteria for diagnostic delay Outcome (prognostic) Association Quality score
Williams, 1981 UK Oral and OPH PB 223 1962–76 Patient delay
Referral delay
Hospital delay
Categorical: 1, 1–2, 3–4, >5 months T stage (I vs. II–III–IV) No 3
Guggenheimer et al., 1989 USA Oral and OPH HB 149 NG Patient delay
Professional delay
Categorical: ≤4, 5–20, >20 weeks T stage at diagnosis No 7
Gorsky and Dayan, 1995 Israel Oral and OPH HB and CR 543 NG Delay in diagnosis (first symptoms to histological diagnosis) Categorical: ≤1, 1–2, 2–4, >4 months TNM at diagnosis (I–II vs. III–IV) No 10
Hollows et al., 2000 UK Oral and PH HB 100 1993–98 Patient delay
Practitioner (referral) delay
Continuous: weeks, days T stage No 10
Bastit et al., 2001 France OPH and HP HB 804 1981–92 Delay between surgery and beginning radiation therapy Dichotomous: 30 days TNM and survival No 6
Pitiphat et al., 2002 Greece Oral and PH CC, CB 105 1995–98 Delay in diagnosis (first symptoms to histological diagnosis) Dichotomous: ≥21 days TNM (I–II–III vs. IV) Yes 8
Ho et al., 2004 USA OPH HB 87 1994–2001 Presentation to diagnosis (PDI) Dichotomous: >3 months Survival No 5
Llewellyn et al., 2004 UK Oral and OPH HB a 70 1999–2001 Patient delay (awareness of symptoms to first professional) Dichotomous: >3 weeks Factors related to delay NA 8
Brouha et al., 2005 Netherlands Oral and PH HB 134 2000–02 Patient delay
Specialist delay
Dichotomous: 30 days TNM (I–II vs. III–IV) Yes 11
Pitchers and Martin, 2006 UK OPH HB 110 1995–2005 Delay in referral (from symptom onset to date of referral letter) Dichotomous: >6 weeks TNM, survival Yes 9
Rogers et al., 2011 UK OPH HB 559 1992–2002 Patient delay
Professional delay
Continuous: median days T stage No 10
Sandoval et al., 2009 Spain Oral and OPH HB, CC 146 1996–99 Referral delay (first symptom to suspicion of cancer) Categorical: <1, 1–3, >3 months Recurrence, survival Yes 5
Esmaelbeigi et al., 2014 Iran Oral and OPH HB 206 2009–10 Patient delay
Professional delay
Total delay
Continuous: mean (SD) and median TNM stage Yes 4
CB, community-based; CC, case–control studies; CR, cancer registry; HB, hospital-based; HP, ; NA, not available; NG, not given; OPH, oropharynx; PB, ; PH, pharynx; SD, standard deviation; TNM, tumour size (T), node status (N), metastasis (M).
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Dec 14, 2017 | Posted by in Oral and Maxillofacial Surgery | Comments Off on Key points and time intervals for early diagnosis in symptomatic oral cancer: a systematic review
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