1. A systematic review of the validity of endoscopic ultrasound for rectal carcinoma staging Class 1: Adília Rafael, Agostinho Cordeiro, Alberto Lourenço, Alexandre Sarmento, Ana Beatriz Noronha, Ana Carolina Afonso, Ana Catarina Gomes, Ana Catarina Pedrosa, Ana Cristina Duque, Ana Isabel Ponte Supervisors: Altamiro da Costa Pereira, MD, PhD; Mário Dinis Ribeiro, MD, PhD Introduction to Medicine; Porto Faculty of Medicine 2006

2. Index 1) Introduction 2) Objective 3) Planning 4) Material and Methods 4.1) Bibliographic research 4.2) Inclusion Criteria 4.3) Exclusion criteria 4.4) Methodological quality 4.5) Data extraction 5) Results 5.1) Sensitivity and Specificity of T staging 5.2) Sensitivity and Specificity of N staging 5.3) Characteristics of the studies 6) Website 7 ) References 8) Acknowledgements

3. Rectal cancer is the cancer with the highest rate of mortality within the Portuguese population. [Pinheiro et al, 2003] More than 2000 scientific papers published in the literature have demonstrated EUS’s high accuracy for the diagnosis and staging of rectal cancer. [Fusaroli and Caletti, 2005] Rectal cancer is staged using Tumor-Node-Metastasis (TNM) staging system. [Savides and Master, 2002] Introduction

4. According to the EUS stage, the management of the cancer is different. [Savides and Master, 2002] Careful assessment of the T and N stages is critical in directing treatment: local resections with curative intent are limited to patients with T1N0 or T2N0 rectal cancers, while patients with more advanced lesions undergo neoadjuvant chemoradiation followed by radical resection. [Kim and Wong, 2000] Introduction

5. StageInvolvesManagement of cancer T1Mucosa/submucosaTransanal local resection T2Into the muscularis propriaRadical resection and/or postoperative radiation T3Into the perirectal fat Preoperative chemo radiation before radical resection T4Into adjacent organs N1Metastasis in 1 to 3 regional lymph nodes N2Metastasis in 4 or more regional lymph nodes Savides T, Master S. EUS in rectal cancer. Gastrointestinal Endoscopy, Vol 56, No 4, 2002.

6. Introduction

7. To evaluate the validity and consistency of EUS for rectal carcinoma staging in relation to surgical specimens. To evaluate the sensitivity and specificity of the test in identifying the patients as T3/T4 and N+. Objective

8. ► Staging the cancer as T3/T4 or as N+ leads to preoperative treatment consisting of chemoradiation. ► Cancer staged as less than T3 or as N0 implies that patients must undergo surgery. Correct staging of T3/T4 and N+ is crucial to the adequate treatment of the patient. We considered this relevant to focus on due to the fact that: Objective

9. Planning

12. Bibliographic Research: A bibliographic research was carried out in Medline using the following query: (((((((((("sensitivity and specificity"[All Fields] OR "sensitivity and specificity/standards"[All Fields]) OR "specificity"[All Fields]) OR "screening"[All Fields]) OR "false positive"[All Fields]) OR "false negative"[All Fields]) OR "accuracy"[All Fields]) OR (((("predictive value"[All Fields] OR "predictive value of tests"[All Fields]) OR "predictive value of tests/standards"[All Fields]) OR "predictive values"[All Fields]) OR "predictive values of tests"[All Fields])) OR (("reference value"[All Fields] OR "reference values"[All Fields]) OR"reference values/standards"[All Fields])) OR ((((((((((("roc"[All Fields] OR "roc analyses"[All Fields]) OR "roc analysis"[All Fields]) OR "roc and"[All Fields]) OR "roc area"[All Fields]) OR "roc auc"[All Fields]) OR "roc characteristics"[All Fields]) OR "roc curve"[All Fields]) OR "roc curve method"[All Fields]) OR "roc curves"[All Fields]) OR "roc estimated"[All Fields]) OR "roc evaluation"[All Fields])) OR "likelihood ratio"[All Fields]) AND (("Endoscopic Ultrasound" [All Fields] OR "Endosonography"[All Fields]) AND ("Rectal neoplasms"[All Fields] OR "Colorectal neoplasms"[All Fields])) Material and Methods

13. This query was based on a search strategy in PubMed (MEDLINE) for publications about the evaluation of diagnostic accuracy, suggested by a research article Devillé, W. L. et. al., Conducting systematic reviews of diagnostic studies: didactic guidelines The research was limited to “items with abstracts”. 167 abstracts were obtained. Material and Methods

14. Inclusion Criteria Material and Methods The selected articles describe studies designed to evaluate the accuracy of endoscopic ultrasound (EUS) in rectal carcinoma staging. The accuracy of EUS is evaluated in a sample of patients with rectal carcinoma. The results of the application of EUS are compared to the surgical specimen (gold standard).

15. Material and Methods Exclusion Criteria The article describes a systematic review. The article uses a different reference standard. The article evaluates the accuracy of EUS in staging of other cancers rather than rectal carcinoma. The article does not allow the construction of a 2x2 table (for EUS and surgical specimen). The article is written in languages other than English, French or Spanish. The full paper is not available on the Internet, in the facilities of the School of Medicine or in the local libraries.

16. Material and Methods Of these selected articles we managed to find 34 full papers, of which we selected 20 applying once again inclusion/exclusion criteria. Each abstract of the articles obtained in the bibliographic research was read by two reviewers. A third element, the supervisor, was consulted in case of disagreement. Attending to the criteria defined, 82 abstracts were selected.

17. Material and Methods Methodological Quality: ►Each article was submitted to evaluation by two reviewers that independently graded them as far as quality was concerned. ►Disagreements were solved by consensus or arbitration (by the supervisor). ► Methodological quality was evaluated according to the Standard for Reporting of Diagnostic Accuracy (STARD) checklist Bossuyt, P. M. et. al., Towards Complete and Accurate Reporting of Studies of Diagnostic Accuracy: The STARD Initiative, Annals of Internal Medicine Vol 138 – No1, 7 January 2003

18. Section and topicDescribe # TITLE/ABSTRAC T/ KEYWORDS 1 The article as a study on diagnostic accuracy (recommend MeSH heading 'sensitivity and specificity') INTRODUCTION 2 The research question(s), such as estimating diagnostic accuracy or comparing accuracy between tests or across participant groups METHODS Participants3 The study population: the inclusion and exclusion criteria, setting(s) and location(s) where the data were collected 4 Participant recruitment: was this based on presenting symptoms, results from previous tests, or the fact that the participants had received the index test(s) or the reference standard? 5 Participant sampling: was this a consecutive series of patients defined by selection criteria in (3) and (4)? If not specify how patients were further selected. 6 Data collection: were the participants identified and data collected before the index test(s) and reference standards were performed (prospective study) or after (retrospective study)? Reference standard 7 The reference standard and its rationale Test methods8 Technical specification of material and methods involved including how and when measurements were taken, and/or cite references for index test(s) and reference standard 9 Definition and rationale for the units, cutoffs and/or categories of the results of the index test(s) and the reference standard 1010 The number, training and expertise of the persons (a) executing and (b) reading the index test(s) and the reference standard 1 Whether or not the reader(s) of the index test(s) and reference standard were blind (masked) to the results of the other test(s) and describe any information available to them STARD checklist Material and Methods

19. Statistical methods12 Methods for calculating measures of diagnostic accuracy or making comparisons, and the statistical methods used to quantify uncertainty (e.g. 95% confidence intervals) 13 Methods for calculating test reproducibility, if done RESULTS Participants14 When study was done, including beginning and ending dates of recruitment 15 Clinical and demographic characteristics (e.g. age, sex, spectrum of presenting symptom(s), comorbidity, current treatment(s), recruitment center) 16 How many participants satisfying the criteria for inclusion did or did not undergo the index test and/or the reference standard; describe why participants failed to receive either test (a flow diagram is strongly recommended) Reference standard17 Time interval and any treatment administered between index and reference standard 18 Distribution of severity of disease (define criteria) in those with the target condition; describe other diagnoses in participants without the target condition Test results19 A cross tabulation of the results of the index test(s) by the results of the reference standard; for continuous results, the distribution of the test results by the results of the reference standard 20 Indeterminate results, missing responses and outliers of index test(s) stratified by reference standard result and how they were handled 21 Adverse events of index test(s) and reference standard Estimation22 Estimates of diagnostic accuracy and measures of statistical uncertainty (e.g. 95% confidence intervals) 23 Estimates of variability of diagnostic accuracy between subgroups of participants, readers or centers, if done 24 Measures of test reproducibility, if done DISCUSSION 25 The clinical applicability of the study findings Material and Methods Bossuyt, P. M. et. al., Towards Complete and Accurate Reporting of Studies of Diagnostic Accuracy: The STARD Initiative, Annals of Internal Medicine Vol 138 – nº1, 7 January 2003

20. Material and Methods Data Extraction: ► Those two reviewers also independently extracted the required information from the primary studies. ► Disagreements were, in the same way as before, resolved by consensus or arbitration. ► The data was extracted using a standardised extraction form.

21. Material and Methods Data extracted ► Information about the article: title, authors and complete reference. ► Information about the study : location, initial number of participants, final number of participants, including mean age and number of feminine and masculine participants. ► Results: number of true positives, false positives, true negatives and false positives in TNM staging. ► Information about the equipment used: type of instrument, brand, number of operators. ► Quality assessment: presence or absence of the items in STARD checklist.

22. T-staging – Sensitivity Results

23. T-staging – Sensitivity

24. Results T-staging – Specificity

25. Results N-staging – Sensitivity

26. Results N-staging – Specificity

27. Results Quality assessment Median = 16 Maximum = 20 Minimum = 7

28. Final number of participants Results

29. Mean age of participants Results

30. Brand of instrument used in the study Results Location where the study was performed

31. Website

32. Kim HJ, Wong WD. Role of endorectal ultrasound in the conservative management of rectal cancers. Semin Surg Oncl, 2000, Vol 19. Fusaroli P, Caletti G. Endoscopic ultrasonography: current clinical role. Eur J Gastroenterol Hepatol, 2005. Pinheiro PS, Tyczynski JE, Bray F, Amado J, Matos E, Parkin DM. Cancer incidence and mortality in Portugal. Eur J Cancer, 2003. Savides T, Master S. EUS in rectal cancer. Gastrointestinal Endoscopy, Vol 56, No 4, 2002. References

33. Professor Altamiro da Costa Pereira Professor Mário Dinis Ribeiro Acknowledgements