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Visual Screening for Oral Cancer May Reduce Oral Cancer Mortality in High-risk Adult Populations Through Early Diagnosis and Treatment
DIAGNOSIS/TREATMENT/PROGNOSIS
ARTICLE ANALYSIS & EVALUATION ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION Long term effect of visual screening on oral cancer incidence and mortality in a randomized trial in Kerala, India. Sankaranarayanan R, Ramadas K, Thara S, Muwonge R, Thomas G, Anju G, Mathew B. Oral Oncol 2013;49(4):314-21.
REVIEWER Britt C. Reid, DDS, PhD
PURPOSE/QUESTION
Visual Screening for Oral Cancer May Reduce Oral Cancer Mortality in High-risk Adult Populations Through Early Diagnosis and Treatment SUMMARY Subjects A total of 191,872 healthy adults age 35 years or older were recruited from 13 municipal administrative units of the Trivandrum District, Kerala, India in 1996. Seven of the administrative units were randomized to receive visual oral screening at 3-year intervals for up to four rounds and were followed for as many as 15 years. The other six units received usual care and no oral visual screening. Approximately 60% of all subjects were female, the mean age of all subjects was approximately 49 years, and approximately 44% of all subjects were users of tobacco, alcohol, or both.
Does visual oral screening in the general adult population result in reduced oral cancer mortality?
Key Exposure/Study Factor
SOURCE OF FUNDING
Main Outcome Measure
Non-profit charity: Imperial Cancer Research Fund partial funding support 1996–1998. Non-profit charity: Association for International Cancer Research, St. Andrews, UK, funding support 1996–2004
Mortality from oral cancer.
TYPE OF STUDY/DESIGN Cluster-randomized controlled trial
Visual screening for oral cancer provided by trained health care workers in the homes of subjects.
Main Results No statistically significant differences in oral cancer mortality between the intervention (visual screening) and control (routine care, no oral visual screening) groups were found after up to 15 years of follow-up. However, among users of tobacco, alcohol, or both, a statistically significant 24% reduction in oral cancer mortality was observed in the intervention arm.
Conclusions
LEVEL OF EVIDENCE
The authors conclude that their findings support the routine use of visual oral screening to reduce oral cancer mortality among the high-risk group of adult users of tobacco, alcohol, or both in the general adult population.
2B
COMMENTARY AND ANALYSIS
STRENGTH OF RECOMMENDATION GRADE Not applicable
J Evid Base Dent Pract 2013;13:174-176 1532-3382/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jebdp.2013.10.013
Among all head and neck cancers, the anatomic sites most relevant for a discussion of this randomized controlled trial are those within the field of view of an oral visual inspection, namely, the mouth (oral cavity) and tongue (anterior two-thirds). The American Cancer Society estimates there will be 24,990 new cases of mouth and tongue cancer with 3870 related deaths in the United States during 2013.1 The 5-year relative survival rate is highest among those diagnosed at a localized stage, but only about one-third of patients in the United States are diagnosed with localized oral cancers.2 Oral visual screening may offer an opportunity to detect cancers within the relevant field of view earlier than otherwise in hopes of benefitting patients by reducing cancer-specific mortality through earlier diagnosis and treatment. However, any disease screening, including cancer screening,
JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE
can have undesirable outcomes that must be outweighed by purported benefits in order to be recommended.3 Undesirable outcomes include false negatives (patient has cancer, but is falsely assured he or she does not) and false positives (patient unnecessarily endures the burdens of screening and follow-up procedures). Even in the case of true positives, undesirable outcomes may occur with the detection of indolent lesions that without treatment would not harm patients in their lifetimes or fastdeveloping lesions so aggressive treatment cannot alter the outcome. To recommend visual oral cancer screening in light of these potential harms to patients it is necessary to have clear benefit in the form of cancer-specific reductions in mortality. There have been no randomized controlled trails of visual screening for oral cancers in any Western or other low-prevalence populations. The randomized trial of visual screening for oral cancer versus usual care reported by Sankaranarayanan et al. is the best available evidence for making recommendations about visual screening for oral cancers available at this time. Earlier reports from this randomized trial have been previously included in reviews concerning oral cancer screening recommendations, including reviews by the American Dental Association,4 the National Cancer Institute,5 the Cochrane Collaboration,6 and the US Preventive Services Task Force.7 All of these prior reviews found substantial weaknesses that greatly limited the use of this randomized controlled trial for supporting visual oral cancer screening. In brief, these weaknesses included a small number of randomized units (seven administrative areas to the intervention arm and six to the control arm), lack of allocation concealment, poor compliance with follow-up, unclear accounting of withdrawals and dropouts, and uncertain applicability of the findings to the US population and health care system. Given this background, the two important questions at hand are whether this latest report changes prior reported study limitations and whether it has any new implications for oral cancer screening recommendations in the United States? This latest report adds data from another round of screenings and more years of follow-up, resulting in changes in some point estimates and confidence intervals compared to the prior report from this randomized trial. The investigators continue to report no statistically significant reduction in cancer-specific mortality for the overall population, the same results as the prior report from this randomized trial. They also continue to report a statistically significant reduction in cancer-specific mortality among a high-risk group of users of tobacco and/or alcohol, but this estimate is now 24% (95% CI: 3%-40%), just barely statistically significant and 10% points less than the 34% reduction reported in the prior analysis. An effective intervention may be expected to display stronger mortality reductions, not weaker, as time goes on. Volume 13, Number 4
Cancer-specific mortality varied among the high-risk group by number of screening rounds in which a subject participated. Compared to the controls, those attending one screening had a statistically significant 90% increased cancer-specific mortality, those attending two screenings had no significant changes, but those attending three and four screenings had statistically significant reductions in cancer-specific mortality of 47% and 81%, respectively. This is consistent with the less compliant and healthseeking subjects, who would also tend to have worse health outcomes, dropping out from the study over time. In weighing the strength of such evidence among the high-risk group, the typical cautions related to subgroup analyses must be considered.8 Such cautions include that subgroup analyses should be proposed a priori, the study should be designed with enough power for their assessment, and formal interaction tests should be used to assess their statistical significance. Otherwise, from a strength-of-evidence perspective, results from subgroup analyses would be considered hypothesis-generating as opposed to having the full inherent design strength of a randomized controlled trial.9 It is not clear whether this randomized trial was designed or powered for various analyses of the high-risk subgroup because this group is first mentioned and analyzed only after three rounds of screening and formal interaction tests do not appear to have been done. As a result, although the mortality changes reported for the subgroup analyses could prove true, they should not be assigned the highest level of evidence. Another concern, mentioned in previous reviews and still present, is the applicability of the findings in the high-risk group to the US population and health care system. The underlying incidences of oral cancers in this study population differ dramatically from those of the United States. The oral cancer incidence rate was 27.2 and 31.2 per 100,000 person/years for the control and intervention arms, respectively, and among the high-risk group 40.9 and 32.2 per 100,000 person/years for the control and intervention arms, respectively. In contrast, the general US adult population has incidence rates of less than 11 per 100,000 person/years.10 This suggests that even if the findings were shown to be valid for the population studied, they are not likely to hold in a relatively low-prevalence environment like the United States. In summary, due to concerns about a declining trend in mortality reduction, use of subgroup analyses, and markedly different incidence rates of the study population compared to those of the United States, this cluster-randomized controlled trial does not provide solid evidence of an oral cancer-specific mortality benefit associated with a US oral visual screening initiative.
ACKNOWLEDGMENT I would like to thank Brittany Stallworth for technical assistance in manuscript preparation. 175
JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE
REFERENCES 1. Cancer Facts and Figures 2013. American Cancer Society. Available at: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf; Accessed 08.10.13. 2. SEER Stat Fact Sheets: Oral Cavity and Pharynx. National Cancer Institute Surveillance, Epidemiology and End Results Program. Available at: http://www.seer.cancer.gov/statfacts/html/oralcav.html; Accessed 08.10.13. 3. Esserman LJ, Thompson IM, Reid B. Overdiagnosis and overtreatment in cancer: an opportunity for improvement. JAMA 2013;310(8):797-8. 4. Rethman MP, Carpenter W, Cohen EE, et al. Evidence-based clinical recommendations regarding screening for oral squamous cell carcinomas. J Am Dent Assoc 2010;141:509-20. 5. Oral Cancer Prevention (PDQ). National Cancer Institute. Available at: http://www.cancer.gov/cancertopics/pdq/screening/oral/Health Professional/page2; Accessed 08.10.13. 6. Kujan O, Glenny AM, Oliver RJ, Thakker N, Sloan P. Screening programmes for the early detection and prevention of oral cancer. Cochrane Database Syst Rev 2006;CD004150. 7. U.S. Preventive Services Task Force Screening for Oral Cancer: Recommendation Statement. Rockville, MD: Agency for Healthcare Research and Quality, AHRQ; 2004. Report No.: 05-0564-A.
176
8. Rothwell PM. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet 2005;365:176-86. 9. Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives. Health Technol Assess 2001;5:1-56. 10. Oral Cancer Prevention (PDQ). National Cancer Institute. Available at: http://www.cancer.gov/cancertopics/pdq/prevention/oral/Health Professional/page2; Accessed 08.10.13.
REVIEWER Britt C. Reid, DDS, PhD Chief, Modifiable Risk Factors Branch, Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences National Cancer Institute, 9609 Medical Center Drive, Room 4E128, Bethesda, MD 20892-9738, USA, Tel.: þ1 240 276 6725 [email protected]
December 2013
ARTICLE ANALYSIS & EVALUATION ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION Long term effect of visual screening on oral cancer incidence and mortality in a randomized trial in Kerala, India. Sankaranarayanan R, Ramadas K, Thara S, Muwonge R, Thomas G, Anju G, Mathew B. Oral Oncol 2013;49(4):314-21.
REVIEWER Britt C. Reid, DDS, PhD
PURPOSE/QUESTION
Visual Screening for Oral Cancer May Reduce Oral Cancer Mortality in High-risk Adult Populations Through Early Diagnosis and Treatment SUMMARY Subjects A total of 191,872 healthy adults age 35 years or older were recruited from 13 municipal administrative units of the Trivandrum District, Kerala, India in 1996. Seven of the administrative units were randomized to receive visual oral screening at 3-year intervals for up to four rounds and were followed for as many as 15 years. The other six units received usual care and no oral visual screening. Approximately 60% of all subjects were female, the mean age of all subjects was approximately 49 years, and approximately 44% of all subjects were users of tobacco, alcohol, or both.
Does visual oral screening in the general adult population result in reduced oral cancer mortality?
Key Exposure/Study Factor
SOURCE OF FUNDING
Main Outcome Measure
Non-profit charity: Imperial Cancer Research Fund partial funding support 1996–1998. Non-profit charity: Association for International Cancer Research, St. Andrews, UK, funding support 1996–2004
Mortality from oral cancer.
TYPE OF STUDY/DESIGN Cluster-randomized controlled trial
Visual screening for oral cancer provided by trained health care workers in the homes of subjects.
Main Results No statistically significant differences in oral cancer mortality between the intervention (visual screening) and control (routine care, no oral visual screening) groups were found after up to 15 years of follow-up. However, among users of tobacco, alcohol, or both, a statistically significant 24% reduction in oral cancer mortality was observed in the intervention arm.
Conclusions
LEVEL OF EVIDENCE
The authors conclude that their findings support the routine use of visual oral screening to reduce oral cancer mortality among the high-risk group of adult users of tobacco, alcohol, or both in the general adult population.
2B
COMMENTARY AND ANALYSIS
STRENGTH OF RECOMMENDATION GRADE Not applicable
J Evid Base Dent Pract 2013;13:174-176 1532-3382/$36.00 Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jebdp.2013.10.013
Among all head and neck cancers, the anatomic sites most relevant for a discussion of this randomized controlled trial are those within the field of view of an oral visual inspection, namely, the mouth (oral cavity) and tongue (anterior two-thirds). The American Cancer Society estimates there will be 24,990 new cases of mouth and tongue cancer with 3870 related deaths in the United States during 2013.1 The 5-year relative survival rate is highest among those diagnosed at a localized stage, but only about one-third of patients in the United States are diagnosed with localized oral cancers.2 Oral visual screening may offer an opportunity to detect cancers within the relevant field of view earlier than otherwise in hopes of benefitting patients by reducing cancer-specific mortality through earlier diagnosis and treatment. However, any disease screening, including cancer screening,
JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE
can have undesirable outcomes that must be outweighed by purported benefits in order to be recommended.3 Undesirable outcomes include false negatives (patient has cancer, but is falsely assured he or she does not) and false positives (patient unnecessarily endures the burdens of screening and follow-up procedures). Even in the case of true positives, undesirable outcomes may occur with the detection of indolent lesions that without treatment would not harm patients in their lifetimes or fastdeveloping lesions so aggressive treatment cannot alter the outcome. To recommend visual oral cancer screening in light of these potential harms to patients it is necessary to have clear benefit in the form of cancer-specific reductions in mortality. There have been no randomized controlled trails of visual screening for oral cancers in any Western or other low-prevalence populations. The randomized trial of visual screening for oral cancer versus usual care reported by Sankaranarayanan et al. is the best available evidence for making recommendations about visual screening for oral cancers available at this time. Earlier reports from this randomized trial have been previously included in reviews concerning oral cancer screening recommendations, including reviews by the American Dental Association,4 the National Cancer Institute,5 the Cochrane Collaboration,6 and the US Preventive Services Task Force.7 All of these prior reviews found substantial weaknesses that greatly limited the use of this randomized controlled trial for supporting visual oral cancer screening. In brief, these weaknesses included a small number of randomized units (seven administrative areas to the intervention arm and six to the control arm), lack of allocation concealment, poor compliance with follow-up, unclear accounting of withdrawals and dropouts, and uncertain applicability of the findings to the US population and health care system. Given this background, the two important questions at hand are whether this latest report changes prior reported study limitations and whether it has any new implications for oral cancer screening recommendations in the United States? This latest report adds data from another round of screenings and more years of follow-up, resulting in changes in some point estimates and confidence intervals compared to the prior report from this randomized trial. The investigators continue to report no statistically significant reduction in cancer-specific mortality for the overall population, the same results as the prior report from this randomized trial. They also continue to report a statistically significant reduction in cancer-specific mortality among a high-risk group of users of tobacco and/or alcohol, but this estimate is now 24% (95% CI: 3%-40%), just barely statistically significant and 10% points less than the 34% reduction reported in the prior analysis. An effective intervention may be expected to display stronger mortality reductions, not weaker, as time goes on. Volume 13, Number 4
Cancer-specific mortality varied among the high-risk group by number of screening rounds in which a subject participated. Compared to the controls, those attending one screening had a statistically significant 90% increased cancer-specific mortality, those attending two screenings had no significant changes, but those attending three and four screenings had statistically significant reductions in cancer-specific mortality of 47% and 81%, respectively. This is consistent with the less compliant and healthseeking subjects, who would also tend to have worse health outcomes, dropping out from the study over time. In weighing the strength of such evidence among the high-risk group, the typical cautions related to subgroup analyses must be considered.8 Such cautions include that subgroup analyses should be proposed a priori, the study should be designed with enough power for their assessment, and formal interaction tests should be used to assess their statistical significance. Otherwise, from a strength-of-evidence perspective, results from subgroup analyses would be considered hypothesis-generating as opposed to having the full inherent design strength of a randomized controlled trial.9 It is not clear whether this randomized trial was designed or powered for various analyses of the high-risk subgroup because this group is first mentioned and analyzed only after three rounds of screening and formal interaction tests do not appear to have been done. As a result, although the mortality changes reported for the subgroup analyses could prove true, they should not be assigned the highest level of evidence. Another concern, mentioned in previous reviews and still present, is the applicability of the findings in the high-risk group to the US population and health care system. The underlying incidences of oral cancers in this study population differ dramatically from those of the United States. The oral cancer incidence rate was 27.2 and 31.2 per 100,000 person/years for the control and intervention arms, respectively, and among the high-risk group 40.9 and 32.2 per 100,000 person/years for the control and intervention arms, respectively. In contrast, the general US adult population has incidence rates of less than 11 per 100,000 person/years.10 This suggests that even if the findings were shown to be valid for the population studied, they are not likely to hold in a relatively low-prevalence environment like the United States. In summary, due to concerns about a declining trend in mortality reduction, use of subgroup analyses, and markedly different incidence rates of the study population compared to those of the United States, this cluster-randomized controlled trial does not provide solid evidence of an oral cancer-specific mortality benefit associated with a US oral visual screening initiative.
ACKNOWLEDGMENT I would like to thank Brittany Stallworth for technical assistance in manuscript preparation. 175
JOURNAL OF EVIDENCE-BASED DENTAL PRACTICE
REFERENCES 1. Cancer Facts and Figures 2013. American Cancer Society. Available at: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/documents/document/acspc-036845.pdf; Accessed 08.10.13. 2. SEER Stat Fact Sheets: Oral Cavity and Pharynx. National Cancer Institute Surveillance, Epidemiology and End Results Program. Available at: http://www.seer.cancer.gov/statfacts/html/oralcav.html; Accessed 08.10.13. 3. Esserman LJ, Thompson IM, Reid B. Overdiagnosis and overtreatment in cancer: an opportunity for improvement. JAMA 2013;310(8):797-8. 4. Rethman MP, Carpenter W, Cohen EE, et al. Evidence-based clinical recommendations regarding screening for oral squamous cell carcinomas. J Am Dent Assoc 2010;141:509-20. 5. Oral Cancer Prevention (PDQ). National Cancer Institute. Available at: http://www.cancer.gov/cancertopics/pdq/screening/oral/Health Professional/page2; Accessed 08.10.13. 6. Kujan O, Glenny AM, Oliver RJ, Thakker N, Sloan P. Screening programmes for the early detection and prevention of oral cancer. Cochrane Database Syst Rev 2006;CD004150. 7. U.S. Preventive Services Task Force Screening for Oral Cancer: Recommendation Statement. Rockville, MD: Agency for Healthcare Research and Quality, AHRQ; 2004. Report No.: 05-0564-A.
176
8. Rothwell PM. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet 2005;365:176-86. 9. Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives. Health Technol Assess 2001;5:1-56. 10. Oral Cancer Prevention (PDQ). National Cancer Institute. Available at: http://www.cancer.gov/cancertopics/pdq/prevention/oral/Health Professional/page2; Accessed 08.10.13.
REVIEWER Britt C. Reid, DDS, PhD Chief, Modifiable Risk Factors Branch, Epidemiology and Genomics Research Program, Division of Cancer Control and Population Sciences National Cancer Institute, 9609 Medical Center Drive, Room 4E128, Bethesda, MD 20892-9738, USA, Tel.: þ1 240 276 6725 [email protected]
December 2013