Oral Oncology (2006) 42, 551 560

available at www.sciencedirect.com

journal homepage: http://intl.elsevierhealth.com/journals/oron/

REVIEW

A systematic review of measures of effectiveness in screening for oral cancer and precancer
Martin C. Downer Paul M. Speight d
a

a,b,*

, David R. Moles a, Stephen Palmer c,

Eastman Dental Institute for Oral Health Care Sciences, University College London, 256 Grays Inn Road, London WC1X 8LD, UK b Manchester University Dental School, Higher Cambridge Street, Manchester M15 6FH, UK c Centre for Health Economics, University of York, Heslington, York YO1 5DD, UK d University of Shefeld, School of Clinical Dentistry, Claremont Crescent, Shefeld S10 2TA, UK Received 4 August 2005; accepted 9 August 2005

KEYWORDS
Oral; Cancer; Precancer; Systematic review; Screening; Effectiveness; Process measurement; Outcome measurement

Summary Nine databases were searched for studies reporting a range of measures on the effectiveness of screening for oral cancer and precancer in primary care. Of 1114 papers generated in a search of nine databases, full texts of 90 were scrutinised by two reviewers to ensure that they were concerned with oral cancer/precancer, reported an oral cancer screening programme/exercise and included at least one effectiveness outcome. Criteria for considering studies for the review covered types of studies, participants, interventions and outcome measures. The latter included measures of both end point and interim outcome and also process. Of 90 full text articles screened, examiners agreed on the inclusion of 28 (initial agreementkappa = 0.60). The remaining 62 were excluded and the reasons recorded. The studies included showed substantial heterogeneity regarding objectives and study design, location and setting, numbers and characteristics of participants, screening personnel, methods of recruitment and types of data collected. Only one study, from the Indian sub-continent, reported a randomised controlled trial: interim results showed 14.9% of intervention subjects died after 3 years compared with 56.3% of non-intervention controls. The review overall produced no evidence in favour of or against the potential benets associated with an oral cancer screening programme. It was concluded that there are insufcient available data to make an unequivocal determination as to the effectiveness of oral cancer screening programmes at

* Corresponding author. Present address: 16A Westbury Park, Westbury Park, Bristol BS6 7JA, UK. Tel.: +44 117 974 3703. E-mail address: m.downer@mailbox.ulcc.ac.uk (M.C. Downer). 1368-8375/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2005.08.006

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M.C. Downer et al.

the present time. However, a recent further report on the Indian study published after completion of the review, provides some evidence that screening for oral cancer may be effective, at least in developing countries with a high incidence of the disease. c 2005 Elsevier Ltd. All rights reserved.

Introduction
The principal objective of this systematic review was to establish, from a range of outcome measures, the effectiveness of screening for oral cancer and precancer. The data were required in order to populate a probabilistic decision analysis model designed to determine the costs and outcomes of oral cancer screening programmes conducted in primary care environments. The review was designed to produce ranges of values for all available process and health outcome measures of effectiveness for inclusion in the computer simulation model.

prove and nalise the protocol; to monitor progress in identifying studies and deciding their suitability for inclusion (assessment of validity); to discuss the proposals for analysis of the material and completion of the review; and to agree the nal report.

Criteria for considering studies for review

For prospective inclusion, studies of any design reporting either a process or health outcome measure of effectiveness in oral cancer or precancer screening were deemed eligible. Only studies involving adult participants were considered irrespective of whether the research was based on whole populations or sub-groups. Types of interventions considered were:  Any screening intervention irrespective of whether this was solely a visual examination; or a visual examination followed by a specialist examination (with or without verication by biopsy).  Any setting.  Any form of recruitment. The health related outcomes selected as being of potential use (although not all were reported in the literature) were:        Morbidity. Mortality. Survival. Stage shift. Case-fatality. Yield of cancer. Yield of precancer.

Methods
General
Nine databases were searched up to the end of 2002. One thousand one hundred and fourteen potentially useful papers were identied. Of these, 92 articles were deemed potentially relevant and retrieved for full text screening. Two articles could not be obtained, one because of current lack of availability1 and one because of incorrect referencing in the database.2 Of the remaining 90, agreement was reached for the inclusion of 28 studies.330 The initial kappa score for agreement was reasonable (k = 0.60). Of the 62 excluded studies, 59 were reviews or epidemiological surveys and either did not report any outcomes or contained no data. Of the remainder, two papers were not concerned with oral cancer and the other reference was to a thesis, the results of which were reported elsewhere. A full list of these publications, and also the 1022 which were rejected after initial review of their titles and/or abstracts, is available on request. The review was conducted in accordance with guidelines promulgated by the NHS Centre for Reviews and Dissemination.31

The process measures selected as being of potential use (although not all were reported in the literature) were:     Recruitment. Compliance to invitation and/or follow-up. Number of referrals to secondary care per annum. Proportion of target population screened per year (population screening programmes).

Advisory group
An advisory group was formed, consisting of core members of a research team, other advisers and an experienced information ofcer from the NHS Centre for Reviews and Dissemination who undertook the searches. Members were afliated to several different institutions and represented a range of appropriate expertise. Four consultative meetings were held during 2001/2002 and members communicated extensively by e-mail in the intervening periods. The tasks of the advisory group were to decide the scope of the review and specic questions to be addressed; to ap-

Search strategy for identication of studies

The following databases were searched: Medline, Embase, CancerLit, Cinahl, AMED, BNI, HMIC, DARE T System and Cochrane Library. The search was conned to English lan-

A systematic review of measures of effectiveness in screening for oral cancer and precancer guage papers from 1980 to January 2002 inclusive. For those papers subsequently selected for full text screening, the bibliographical reference lists were hand-searched for other relevant citations. No attempt was made to obtain grey literature.

553

years old), and other risk behaviours such as tobacco and alcohol consumption. In some instances screening was the only intervention, while in others this was combined with a health education campaign. Programmes varied in reported length from two days to several years.

Selection of studies
The titles and abstracts identied by the electronic searches were screened by two reviewers (PMS, DRM) to exclude any studies that were clearly irrelevant. At this rst stage, if it was unclear whether a study was relevant it was retained. Similarly if either reviewer believed that a study was potentially relevant it was retained. Available full text articles were obtained for all potentially relevant studies. The full text articles were independently screened, again by the same two reviewers (PMS, DRM), to ensure that they were concerned with oral cancer/precancer and fullled the following criteria: (1) an oral cancer screening programme/exercise was reported; (2) at least one effectiveness outcome was included. Disagreements were resolved by discussion. It was not necessary to include a third reviewer to adjudicate at any stage. Data on study characteristics and all documented outcomes were abstracted and summarised in evidence tables. Where more than one article reported the same study, only the most contemporary (and complete) results were included to avoid duplication. Where several articles reported different aspects of the same programme these were combined as appropriate and indicated as multiple articles in the evidence tables. It was determined that formal synthesis by meta-analysis was inappropriate due to substantial heterogeneity in the data. Moreover, such an analysis would not contribute useful additional information to the computer simulation modelling process.

Compliance
A little under half of the studies reported compliance to invitation. The rates varied according to the recruitment method and target population. At best this was close to 100% uptake in the case of a group of participants who were invited to have an oral cancer screening along with a routine dental check.7 At the other extreme it was as low as 12% in a population-based screening programme for people aged over 60 years old.9 For people who screened positive for potential oral cancer or precancer the rates of compliance in referral to a diagnostic centre or hospital differed according to the geographical setting. Most industrialised countries reported very high levels of compliance of up to 100%. By comparison the programmes that were carried out in the Indian sub-continent had compliance rates in the order of 50%. The lowest levels of compliance were reported in Cuba and were less than 30%.8

Health outcomes
Five studies reported health outcomes.8,16,21,22,28 Fernandez Garrote et al.8 reported true population health outcomes based on the national population cancer registry. There was an increase in the proportion of stage I cancers across the population as a whole; a decrease in stage II and III cancers and no change in the proportion of stage IV cancers. Mathew et al.15 reported 5-year survival in the patients identied by the screening programme but there was no suitable comparison group. Riley et al.21 compared the stage distribution of cancers according to the method of payment to the health care provider, but this was not a comparison between differing screening interventions. Sankaranarayanan et al.22 reported a higher proportion of stage I and II cancers in the screening intervention group than in the non-intervention control in their cluster-randomised controlled trial. They also showed a lower proportion of deaths after three years in the intervention group (14.9%) compared with the control (56.3%). Wesley et al.28 reported different proportions of early versus late cancers in their two intervention groups favouring the cancer detection camps over the youth volunteers.

Results
The study characteristics for the included reports are summarised in Table 1. Table 2 summarises the results from studies that reported measures of compliance while Table 3 presents the results from studies reporting yield, stage shift or survival.

Study characteristics
A wide range of screening initiatives were reported. Most programmes were based in industrialised countries,37,9 13,1821,23,2830 and were generally of short-duration, recruited relatively small numbers of participants and utilised health professionals to undertake the screening. The only long-term large-scale population-based studies in an industrialised country were from Japan.911,18,19 All other population-based programmes were carried out in either the Indian subcontinent1517,22,2428 or Cuba8 and tended to rely on non-professional personnel or specically trained health workers/volunteers to screen large numbers of participants. Scrutiny of Table 1 indicates that methods of recruitment varied from opportunistic to invitational, while targeted populations varied both in terms of age (from 20+ to 60+

Discussion
Only one other systematic review reporting the effectiveness of oral cancer screening, published after the current review was undertaken, was found in the literature. This was conducted by Kujan et al.32 according to Cochrane Collaboration guidelines and the primary outcome considered was oral cancer specic mortality. Although those reviewers search found 100 citations which were reviewed, only onea randomised controlled trial of screening strategies for oral cancer33was identied as meeting their inclusion criteria. Whilst the optimum research method in evaluating

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Table 1

Characteristics of included studies Year of publication 1990 Time frame of study December 1988May 1989 Population/target group Attendees at general medical practice with history of tobacco use and/ or 4+ glasses of wine/day, North-Eastern Italy Stratied random sample of men aged 40+, Italian Island Staff over 40 yrs at company headquarters, London, UK Not specied. Based in metropolitan Detroit Patients registered at an industrial dental clinic, UK All population aged >= 15 yrs, Cuba Factory and ofce workers from two companies in Aichi prefecture + population over 60 from Tokoname city, Japan All residents of Tokoname city, Japan who where aged 60 during study period Intervention Invited to check-up by 1 of 2 ENT specialists at a cancer referral centre

First author (reference) Barra3

Campisi4 Downer5

2001 1995

Not specied 1 year

Examination in local dental clinic Screening by on-site dentists + validation by oral medicine specialist. Multiple publicity on site to advertise programme Screening by 147 dental hygienists. Based in regional service centres and outreach target sites Screening as part of routine recall. Letters of invitation to 1949 patients. Screened by 3 dentists Mostly opportunistic screening based on regional clinics All factory workers and city pop >60 yrs notied by post and requested to attend screenings. Four dentists providing screening in medical clinics attached to workplaces and health centre in the city Questionnaire sent to all residents aged 60, followed up by invitation for responders to attend screening. 1 day of screening each year in October/November in health centre. Screened patients also assessed by oral medicine specialist Opportunistic recruitment for screening at dental hospital and postal invitation for medical practice. Soft gold standard provided by oral medicine specialist Screening following 2 rounds of postal invitations

Eckert6

1982

27 months 19791981 Not specied

Field7

1995

Fernandez Garrote8 Ikeda9

1995 1991

19841990 September 1986June 1988

Ikeda10,11

1995a,b

19861993

Jullien13

1995a

1 year

Jullien13

1995b

Not specied

People aged 40+ either outpatients at a London dental hospital or outpatients at an inner city medical practice Patients aged 40+ registered at an inner city medical practice, London, UK

M.C. Downer et al.

A systematic review of measures of effectiveness in screening for oral cancer and precancer

Lynch14

1985

2 days

Village residents in rural Thailand aged 20+

Mathew15

1995

AprilMay 1988

Villagers with tobacco habits aged 30+ years old in Kerala, India

Mathew16

1997

December 1995May 1996

90,000 people aged 3564 years old in 13 rural administrative regions (panchayaths) High risk individuals (35 yrs+ and tobacco habits) in Ernakulam district, Kerala, India Adults aged 40 yrs+ in Tokoname city, Japan Bangladeshi medical care users aged 40+ in inner city London SEER data from several US registries comparing stage at diagnosis between Health Maintenance Organisation (HMO) and Fee For Service (FFS) patients People aged 35+ years resident in 13 panchayaths in Trivandrum district, Kerala, India. 59,894 in intervention group and 54,707 in control People aged 60+ (setting not specied) 2 studies reported in same publication (1) Kadugannawa population: Kadugannawa area of Sri Lanka (87,277 adults 20 yrs+) (2) Gampola population: Gampola area of Sri Lanka

Mehta17

1986

Nagao18

2000a,b

December 1982December 1983 19961998

Community programme involving lay volunteers to raise awareness and recruit subjects for screening at community social centre (screening included other cancers in addition to oral) Distribution of Mouth Self Examination leaets to households by 450 students, with people being invited to attend for screening if they suspect they have a positive lesion Community based RCT. Visual inspection by trained health workers in 7 intervention panchayaths (+ health education component advising smokers to stop) Examination by Basic Health Worker + health education to discontinue tobacco habits Annual letter of invitation to all 40 yrs+ (2039 yrs olds also encouraged to attend) for general + oral health screen Opportunistic examination of people in GP waiting rooms Descriptive: type of patient care received HMO vs. FFS

Pearson20 Riley21

2001 1994

Not specied 19851989

Sankaranarayanan22

2000

From October 1995. Duration not given

Tye23 Warnakulasuriya24,26,27

1986 1984, 1988, 1990

Not specied 1 year

Warnakulasuriya25

1991

1 year

72,867 adults aged 20+ in Galle Sri Lanka

Community based RCT. Visual inspection by trained health workers. Aiming for 3 exams at 3-yearly intervals in 7 intervention panchayaths (+health education component advising smokers to stop) Not specied (1) Screening by 35 Primary health care workers (PHCW) house to house visits. PHCW responsible to arranging referral. Letter sent to non-attenders at referral centre. Travel costs of patients reimbursed and PHCW paid for conrmed lesions. (2) Opportunistic screening by Drs. and Dentists in hospital setting Screening by PHCW + health education vigorous health education programme included as attempt to improve compliance
(continued on next page)

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M.C. Downer et al. a clinical intervention is a prospective randomised clinical trial, Chamberlain34 has suggested that various interim measures can be used to indicate whether or not a screening programme is likely to achieve an effect. However, while these indicators are necessary ndings in a successful programme they are not sufcient to prove the value of screening. Chamberlain specied yield, initial increased preponderance of early stage lesions and improved survival. Among factors affecting the quality of a screening programme she included participation rate and test performance (sensitivity and specicity). A further important consideration was the frequency of routine screening and the adequacy of follow up of positive test results. A systematic review of test performance in screening for oral cancer and precancer was reported previously by the present authors.35 The current review considered other relevant interim and surrogate measures of effectiveness but the extent to which reports of these were found in the literature was limited. With regard to health related outcome measures, among the papers reviewed were reports of yield of oral precancer and cancer, stage shift, survival and mortality. As regards process, reported measures included response rates to screening invitation, compliance in follow up for full diagnosis and the proportion of target populations screened per year. The studies included in the review exhibited considerable heterogeneity in target populations, methods, and choice of outcomes reported. As noted, while many reported short term health outcomes and process measures, very few studies followed patients long enough to report end point health outcomes. Fewer still were able to report such outcomes on a population basis as opposed to solely for the screened sub-group. Those studies that did report health outcomes appeared to indicate that oral cancers were being detected at an earlier stage and that survival was possibly improved. However, these measures are all subject to the potential inuences of both length bias and lead time bias. The unequivocal measure of the success of an oral cancer screening programme in this respect would be to see a reduction in population mortality. None of the studies identied in this review reported that measure. Subsequent to completing the literature searches, the further interim results, referred to above, published by Ramadas et al.33 of the Trivandrum group compared population-based mortality between the intervention and control arms of their trial. This study was unable to demonstrate any signicant difference between the groups with respect to age standardised oral cancer mortality rates. It was concluded that, after completing two rounds of screening, oral cancer mortality rates were similar in both groups. However, a recently published third follow up study by the same investigators36 reported a mortality rate of 16.4 deaths per 100,000 in the intervention group compared with 20.7 per 100,000 in the control with corresponding incidence rates of 43.7 and 37.6 per 100,000 respectively. Also 41% of cancers diagnosed in the intervention group were at stages I or II compared with 23% of those in the control group. In male users of tobacco or alcohol, or both, the reduced mortality rates in the intervention group compared with the control were statistically signicant. The authors stated that their ndings supported the use of oral visual screening in high risk groups of tobacco and/or

Intervention

From 1990. Duration not specied

Not specied 1992 Westman29

Year of publication

1992

Table 1 (continued)

First author (reference)

Wesley28

Westman30

1994

Not specied

Time frame of study

US Veterans Affairs general medical patients Consecutive patients attending a Veterans Affairs medical centre in Durham, North Carolina

Population/target group

Adults 20+ yrs old in Trivandrum area of India

Two intervention groups (1) six cancer detection camps + publicity, (2) youth volunteers trained and asked to visit all households in their area Opportunistic screening at GP appts by primary care clinicians Each patient examined opportunistically by two primary care clinicians then a dentist (gold standard)

A systematic review of measures of effectiveness in screening for oral cancer and precancer

Table 2

Studies reporting compliance Year of publication No. invited No. screened (% of invited) No. referred for follow-up (% of screened) Compliance to follow-up (% of referred) Proportion of target population screened per year (population programmes only)

First author (reference)

Barra3 Campisi4 Downer5 Eckert6 Field7 Fernandez Garrote8 Ikeda9

1990 2001 1995 1982 1995 1995 1991

671 180 553

1949

Ikeda10,11 Jullien13 Jullien13 Lynch14 Mathew15 Mathew15 Mehta17 Nagao18,19 Pearson20 Sankaranarayanan22 Tye23 Warnakulasuriya24,26,27

1995a,b 1995a 1995b 1985 1995 1995 1986 2000a,b 2001 2000 1986 1984, 1988, 1990 1991 1992 1994

5187 3826

47,513 185 59,894

436 (65%) 118 (66%) 292 (53%) (+17 from another site) 6841 1947 (100%) 12,990,677 3131 compliance to invitation: 76.5% and 59.7% at 2 factories, 12.2% for city residents 60+ 802 (15%) 2027 985 (26%) 349 247 9000 39,331 19,056 (40%) 137 (74%) 49,179 (82%)

1534 (22%) 4 (<1%) 30,244 (<1%)

1162 (76%) 4 (100%) 8703 (29%)

11.926.8%

32 (4%)

25 (78%)

4 (1%)

3 (75%)

523 (1%) 200 (1%) 3585 (7%)

377 (72%) 137 (69%) 1877 (52%) Compliance to referral/ advice 26% 614 (50%) 66 (50%) 2193 (62%)

Warnakulasuriya25 Wesley28 Westman30

(1) 87,277 (2) 72,867

92

29,295 (34%) 21,318 (24%) Not reported 57,124 (78%) (1) 1552 (2) 3571 86 (93%)

1220 (4%) 133 (<1%) 3559 (6%)

557

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Table 3

Studies reporting yield, stage shift, mortality or survival Year of publication 1990 2001 Yield precancer (% of screened) 55 (13%) 15 leukoplakia (13%) 5 actinic chelitis (4%) 1 smokers palate (1%) 17 (6%) 15 (<1%) 3 (<1%) 2367 leukoplakia (<1%) 852 other premalignant (<1%) Yield cancer (% of screened) 10 (2%) Stage shift/mortality/survival

First author (reference) Barra3 Campisi4

1 18 (<1%) 1 (<1%) 705 (<1%)

Downer5 Eckert6 Field7 Fernandez Garrote8

1995 1982 1995 1995

Stage shift from National Cancer Registry Stage I increased from 24% in 1983 to 49% in 1989 Stage II decreased from 26% in 1983 to 15% in 1989 Stage III decreased from 30% in 1983 to 15% in 1989 Stage IV remained at 20% incidence and mortality were unchanged

Ikeda9 Ikeda10,11 Jullien13 Lynch14 Mathew15

1991 1995a,b 1995 1985 1995

77 leukoplakia (2%) 51 (3%) 52 leukoplakia (21%) 2 (<1%) 3 (<1%) 4 (1%) 7 (+8 with recurrent ca) (6%)

Nagao18 Pearson20

2000a 2001

20 oral submucous brosis (8%) 37 (<1%) 34 leukoplakia (25%) 1 erythroplakia (<1%) 1 submucous brosis (<1%)

Stage I, 5 out of 6 survived to 5 years (1 pt refused treatment and died within 2 yrs) Stage III, 0 out of 1 survived to 5 years

2 (<1%)

Riley21

1994

Stage distribution for buccal cavity and pharynx: In situ Local Regional Distant Unstaged HMO (%) 3.2 49.0 42.3 5.5 6.9 FFS (%) 2.8 40.6 49.0 7.7 6.7

M.C. Downer et al.

A systematic review of measures of effectiveness in screening for oral cancer and precancer

559

alcohol users and was potentially capable of preventing at least 37,000 oral cancer deaths worldwide.
0 (0%) 2 (12.5%) 4 (25.0%) 10 (62.5%) 9 (56.3%) Control (n = 16)

Conclusions
Although many interim and surrogate measures of effectiveness were reported by the studies identied in the current review, there is no unequivocal evidence in favour of or against the potential health benets associated with an oral cancer screening programme. Nevertheless, the outcomes identied would be useful in informing potential screening scenarios to be modelled in a computer simulation aimed at estimating the notional cost-effectiveness of screening for oral cancer and precancer in primary care. At the same time, they would not be sufcient on their own to provide all the necessary input data. Overall, this review conrms that there are insufcient available data to make a determination as to the effectiveness of oral cancer screening programmes at the present time. However, since the review was completed evidence has emerged that screening high risk individuals, in developing countries at least, could be an effective prevention strategy.

Intervention (n = 47)

I II III IV

22 (46.8%) 12 (25.5%) 9 (19.2%) 4 (8.5%) 7 (14.9%)

36 directly from screening (<1%) but 47 in total intervention group

Early vs. late cancers (1) 4 vs. 13 (2) 28 vs. 11

Deaths after 3 years:

Stage distribution:

Acknowledgements
3 (<1%) 9 (<1%) 20 (<1%) 17 (1%) 39 (1%)

The authors are grateful to Ms. Kate Misso, NHS Centre for Reviews and Dissemination, University of York for designing and undertaking the literature searches, and to Dr. David Smith, Center for Health Research, Kaiser Permanente and Dr. Nick Summerton, Department of Primary Care Medicine, University of Hull for their invaluable advice. The work was supported by NHS, R&D HTA Grant No. 99/46/02. The views and opinions expressed do not necessarily reect those of the NHS Executive.

(1) 338 (1%) (2) 29 (<1%) 1716 (3%) (1) 108 (7%) (2) 378 (11%)

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