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Interim results from a screening trial say little about the efficacy of oral visual examination for reducing oral cancer mortality
THERAPY
A RTICLE A NALYSIS & E VALUATION Original Article
Level of Evidence
Purpose
Source of Funding
Type of Study/Design
Interim results from a screening trial say little about the efficacy of oral visual examination for reducing oral cancer mortality
Ramadas K, Sankaranarayanan R, Jacob BJ, Thomas G, Somanathan T, Mahe C, et al. Interim results from a cluster randomized controlled oral cancer screening trial in Kerala, India. Oral Oncol 2003;39(6):580-8.
2b
The authors sought to evaluate the effectiveness of a community-based screening program in reducing oral cancer mortality Government: Primary source: International Association for Research on Cancer (IARC, Lyon, France); Additional funding: Imperial Cancer Research Fund (ICRF; UK) Community-based, cluster-randomized, controlled intervention trial
Summary SUBJECTS The investigators randomized 13 municipal administrative units (‘‘panchayaths,’’ or clusters) in rural areas in Kerala, India, into 2 groups beginning in October 1995. Within the clusters, they attempted to recruit all apparently healthy individuals 35 years of age or older. They excluded all individuals previously diagnosed with oral cancer. The intervention study arm comprised 7 clusters and 78,969 eligible subjects, of whom 89% were interviewed. The control study arm comprised 6 clusters and 74,739 eligible subjects, of whom 81% were interviewed.
J Evid Base Dent Pract 2004;4:290-2 D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.jebdp.2004.10.013
290
EXPOSURE The 2 clusters were randomly assigned to receive an oral visual screening intervention (n = 7) or a control intervention (n = 6). The current analysis refers to interim results after the second of 3 rounds of screening, administered at 3-year intervals. Health workers (HWs) were recruited from within a given cluster and trained. In the screening intervention clusters, the HW performed an oral visual inspection in bright daylight, aided with a flashlight, to identify referable lesions (white patch, ulcerated white patch, verrucous lesion, submucous fibrosis, red patch, suspicious ulcer or growth). Screen-positive subjects were referred for confirmatory examination and treatment of confirmed
oral cancer, precursor, or suspicious lesions. In the control clusters, HWs administered the study interview and distributed anti-tobacco health messages but did not perform any oral visual examination.
MAIN OUTCOME MEASURE The primary outcome measure was age-standardized mortality from oral cancer. The participants were linked with the records of a population-based cancer registry to determine the incidence of invasive oral cancer, stage of the cancer at diagnosis, treatment given, and mortality. Person-years for the mortality incidence estimate were calculated from the date of an individual’s entry into the study to June 30, 2002. MAIN RESULTS The authors report that the mortality rate ratio was 1.0, comparing the age-standardized mortality incidence rate from oral cancer of 21.2 per 100,000 person-years in the intervention clusters with a rate of 21.3 per 100,000 person-years in the control clusters. A greater proportion of oral cancers diagnosed in the intervention group were stage I or II (22% and 15%, respectively) at diagnosis compared to the control group (10% and 9%, respectively). CONCLUSIONS The authors conclude that there is insufficient evidence to recommend routine screening for oral cancer such as through the visual inspection intervention they studied.
Commentary and Analysis As the authors conclude, this study provides little evidence to recommend this community-based oral visual inspection intervention for the reduction of oral cancer incidence and mortality in rural India—not because they found mortality to be the same in the intervention and control arms, but because of methodological limitations that prevent a strong interpretation of these results. The investigators employed a cluster-based randomized trial design, meaning that clusters (in this case, the ‘‘panchayaths’’), rather than individuals, were randomized to a treatment arm. Such approaches can offer a powerful way to study interventions when there is concern about contamination from one treatment group to the other: assigning all individuals within a cluster to the same treatment minimizes the chance that participants could ‘‘transmit’’ any effects of the intervention.1 A problem with randomizing clusters, however, is that the number of clusters is often small relative to the number of participants. This study involved N150,000
Journal of Evidence-Based Dental Practice Volume 4, Number 4
eligible participants but only 13 clusters. Randomly allocating such a small number of clusters makes it likely that the 2 treatment arms will differ on some characteristics simply by chance,2 as was the case in the current study. Compared to the control arm, the intervention arm included a higher proportion of individuals who were male, younger, reported manual work as their occupation, were illiterate, and were poorer. They were more likely to have reported habits such as pan tobacco chewing (27% vs 20%), smoking cigarettes (26% vs 20%), and drinking alcohol (15% vs 12%). The analysis did not account for these differences, most of which are positively correlated with oral cancer incidence and mortality, and may therefore have produced results that were biased in the direction of no association. There was also no indication as to whether analytic techniques appropriate for cluster-based designs had been applied to the reported analyses.1 Finally, any attempt to extrapolate the current study results must acknowledge that the intervention was tested under the specific, practical circumstances in which it would be applied, which may differ in other contexts.1 At least 2 such characteristics might have influenced the effectiveness of the oral visual examination. First, HWs, rather than trained dentists or physicians, administered the screening examination. It is impossible to know whether the 385 oral cancers in screen-negative participants would have been referred by better-trained personnel. 3 Second, compliance among the screen-positive group was only approximately 60%, and screening would not be expected to influence cancer incidence or mortality unless treatment were undertaken after a positive screen.4 The apparent shifting to lower diagnostic stages in the screening group implies that there was at least an opportunity to improve prognosis in the screening arm.3,5,6 This article describes interim results from a field study of the effectiveness of oral visual examination in reducing oral cancer mortality in rural India. The study has particular relevance in India, where oral cancer is the most common cancer diagnosed in men and the third most common cancer in women. While the results must be extrapolated only cautiously to other contexts, the relative dearth of well conducted randomized trials on this topic3,6-8 will increase the importance of the final results of this study after the final round of screening and analyses have been completed. REFERENCES 1. Koepsell TD, Weiss NS. Epidemiologic Methods: Studying the Occurrence of Illness. New York, NY7 Oxford University Press, Inc; 2003. 2. Rothman KJ, Greenland SG. Modern Epidemiology. Philadelphia, PA7 Lippincott-Raven Publishers; 1998.
Ramadas et al 291
3. Franceschi S, Barzan L, Talamini R. Screening for cancer of the head and neck: if not now, when? Oral Oncol 1997;33:313-6. 4. Weiss NS. Clinical Epidemiology. New York, NY7 Oxford University Press, Inc; 1996. 5. Yeole BB, Ramanakumar AV, Sankaranarayanan R. Survival from oral cancer in Mumbai (Bombay), India. Cancer Causes Control 2003;14:945-52. 6. Mignogna MD, Fedele S, Russo LL. The World Cancer Report and the burden of oral cancer. Eur J Cancer Prev 2004;13:139-42. 7. Patton LL. The effectiveness of community-based visual screening and utility of adjunctive diagnostic aids in the early detection of oral cancer. Oral Oncol 2003;39:708-23. 8. Kujan O, Glenny AM, Duxbury AJ, Thakker N, Sloan P. Screening
292
Ramadas et al
programmes for the early detection and prevention of oral cancer. Cochrane Database Syst Rev 2003;CD004150.
Reviewer: Jacqueline R. Starr, PhD, MS, MPH Research Assistant Professor, Pediatrics and Epidemiology University of Washington Children’s Craniofacial Center Children’s Hospital and Regional Medical Center Seattle, Washington
Journal of Evidence-Based Dental Practice December 2004
A RTICLE A NALYSIS & E VALUATION Original Article
Level of Evidence
Purpose
Source of Funding
Type of Study/Design
Interim results from a screening trial say little about the efficacy of oral visual examination for reducing oral cancer mortality
Ramadas K, Sankaranarayanan R, Jacob BJ, Thomas G, Somanathan T, Mahe C, et al. Interim results from a cluster randomized controlled oral cancer screening trial in Kerala, India. Oral Oncol 2003;39(6):580-8.
2b
The authors sought to evaluate the effectiveness of a community-based screening program in reducing oral cancer mortality Government: Primary source: International Association for Research on Cancer (IARC, Lyon, France); Additional funding: Imperial Cancer Research Fund (ICRF; UK) Community-based, cluster-randomized, controlled intervention trial
Summary SUBJECTS The investigators randomized 13 municipal administrative units (‘‘panchayaths,’’ or clusters) in rural areas in Kerala, India, into 2 groups beginning in October 1995. Within the clusters, they attempted to recruit all apparently healthy individuals 35 years of age or older. They excluded all individuals previously diagnosed with oral cancer. The intervention study arm comprised 7 clusters and 78,969 eligible subjects, of whom 89% were interviewed. The control study arm comprised 6 clusters and 74,739 eligible subjects, of whom 81% were interviewed.
J Evid Base Dent Pract 2004;4:290-2 D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.jebdp.2004.10.013
290
EXPOSURE The 2 clusters were randomly assigned to receive an oral visual screening intervention (n = 7) or a control intervention (n = 6). The current analysis refers to interim results after the second of 3 rounds of screening, administered at 3-year intervals. Health workers (HWs) were recruited from within a given cluster and trained. In the screening intervention clusters, the HW performed an oral visual inspection in bright daylight, aided with a flashlight, to identify referable lesions (white patch, ulcerated white patch, verrucous lesion, submucous fibrosis, red patch, suspicious ulcer or growth). Screen-positive subjects were referred for confirmatory examination and treatment of confirmed
oral cancer, precursor, or suspicious lesions. In the control clusters, HWs administered the study interview and distributed anti-tobacco health messages but did not perform any oral visual examination.
MAIN OUTCOME MEASURE The primary outcome measure was age-standardized mortality from oral cancer. The participants were linked with the records of a population-based cancer registry to determine the incidence of invasive oral cancer, stage of the cancer at diagnosis, treatment given, and mortality. Person-years for the mortality incidence estimate were calculated from the date of an individual’s entry into the study to June 30, 2002. MAIN RESULTS The authors report that the mortality rate ratio was 1.0, comparing the age-standardized mortality incidence rate from oral cancer of 21.2 per 100,000 person-years in the intervention clusters with a rate of 21.3 per 100,000 person-years in the control clusters. A greater proportion of oral cancers diagnosed in the intervention group were stage I or II (22% and 15%, respectively) at diagnosis compared to the control group (10% and 9%, respectively). CONCLUSIONS The authors conclude that there is insufficient evidence to recommend routine screening for oral cancer such as through the visual inspection intervention they studied.
Commentary and Analysis As the authors conclude, this study provides little evidence to recommend this community-based oral visual inspection intervention for the reduction of oral cancer incidence and mortality in rural India—not because they found mortality to be the same in the intervention and control arms, but because of methodological limitations that prevent a strong interpretation of these results. The investigators employed a cluster-based randomized trial design, meaning that clusters (in this case, the ‘‘panchayaths’’), rather than individuals, were randomized to a treatment arm. Such approaches can offer a powerful way to study interventions when there is concern about contamination from one treatment group to the other: assigning all individuals within a cluster to the same treatment minimizes the chance that participants could ‘‘transmit’’ any effects of the intervention.1 A problem with randomizing clusters, however, is that the number of clusters is often small relative to the number of participants. This study involved N150,000
Journal of Evidence-Based Dental Practice Volume 4, Number 4
eligible participants but only 13 clusters. Randomly allocating such a small number of clusters makes it likely that the 2 treatment arms will differ on some characteristics simply by chance,2 as was the case in the current study. Compared to the control arm, the intervention arm included a higher proportion of individuals who were male, younger, reported manual work as their occupation, were illiterate, and were poorer. They were more likely to have reported habits such as pan tobacco chewing (27% vs 20%), smoking cigarettes (26% vs 20%), and drinking alcohol (15% vs 12%). The analysis did not account for these differences, most of which are positively correlated with oral cancer incidence and mortality, and may therefore have produced results that were biased in the direction of no association. There was also no indication as to whether analytic techniques appropriate for cluster-based designs had been applied to the reported analyses.1 Finally, any attempt to extrapolate the current study results must acknowledge that the intervention was tested under the specific, practical circumstances in which it would be applied, which may differ in other contexts.1 At least 2 such characteristics might have influenced the effectiveness of the oral visual examination. First, HWs, rather than trained dentists or physicians, administered the screening examination. It is impossible to know whether the 385 oral cancers in screen-negative participants would have been referred by better-trained personnel. 3 Second, compliance among the screen-positive group was only approximately 60%, and screening would not be expected to influence cancer incidence or mortality unless treatment were undertaken after a positive screen.4 The apparent shifting to lower diagnostic stages in the screening group implies that there was at least an opportunity to improve prognosis in the screening arm.3,5,6 This article describes interim results from a field study of the effectiveness of oral visual examination in reducing oral cancer mortality in rural India. The study has particular relevance in India, where oral cancer is the most common cancer diagnosed in men and the third most common cancer in women. While the results must be extrapolated only cautiously to other contexts, the relative dearth of well conducted randomized trials on this topic3,6-8 will increase the importance of the final results of this study after the final round of screening and analyses have been completed. REFERENCES 1. Koepsell TD, Weiss NS. Epidemiologic Methods: Studying the Occurrence of Illness. New York, NY7 Oxford University Press, Inc; 2003. 2. Rothman KJ, Greenland SG. Modern Epidemiology. Philadelphia, PA7 Lippincott-Raven Publishers; 1998.
Ramadas et al 291
3. Franceschi S, Barzan L, Talamini R. Screening for cancer of the head and neck: if not now, when? Oral Oncol 1997;33:313-6. 4. Weiss NS. Clinical Epidemiology. New York, NY7 Oxford University Press, Inc; 1996. 5. Yeole BB, Ramanakumar AV, Sankaranarayanan R. Survival from oral cancer in Mumbai (Bombay), India. Cancer Causes Control 2003;14:945-52. 6. Mignogna MD, Fedele S, Russo LL. The World Cancer Report and the burden of oral cancer. Eur J Cancer Prev 2004;13:139-42. 7. Patton LL. The effectiveness of community-based visual screening and utility of adjunctive diagnostic aids in the early detection of oral cancer. Oral Oncol 2003;39:708-23. 8. Kujan O, Glenny AM, Duxbury AJ, Thakker N, Sloan P. Screening
292
Ramadas et al
programmes for the early detection and prevention of oral cancer. Cochrane Database Syst Rev 2003;CD004150.
Reviewer: Jacqueline R. Starr, PhD, MS, MPH Research Assistant Professor, Pediatrics and Epidemiology University of Washington Children’s Craniofacial Center Children’s Hospital and Regional Medical Center Seattle, Washington
Journal of Evidence-Based Dental Practice December 2004