Conclusions  and  future  directions

This thesis has examined whether new colonoscopic technologies can improve detection and in vivo characterisation of dysplasia. Although colonoscopy is a gold standard for detection of dysplastic lesons, a miss rate is recognised and colonoscopy has been found not to be protective for right- sided CRC. One explanation rests with inability to visualise the right colon in patients who have technically difficult colonoscopy. The randomised controlled trial of the use of MEI in patients with technically difficult colonoscopy did not show statisticaly significant improvement in caecal intubation rates, although all participants were very experienced colonoscopists with documented high caecal intubation rates. It is likely that MEI will be of benefit in less experienced colonoscopists and trainees and this will need to be tested in a large randomised multi-centre study.

Once the caecum has been reached and mucosa cleaned, adequate extubation technique is required in order to maximise the ability to detect subtle lesions. NBI enhances mucosal contrast and two studies in this thesis considered whether it improved detection of dysplasia. The first examined the use of NBI in patients with long-standing colitis. This was a first randomised, parallel arm, multi-centre study directly comparing NBI with WLE. The results showed that NBI did not lead to higher dysplasia detection rates compared to WLE, a finding consistent with two other studies published on the use of NBI in dysplasia detection in UC. Although this study was stopped early, it is unlikely that inclusion of more patients would have altered the findings. The second study was a meta-analysis of six randomised controlled studies on the use of NBI for detection of dysplasia. In this study, again, the use of NBI did not lead to improved detection of adenomas, although most of the studies included had a higher ADR than is reported in routine clinical practice. This is in contrast to hyperplastic polyps, where in pooled analysis NBI improved detection by, on average, 75%, when compared to WLE. There has been considerable recent interest in sub-type of hyperplastic polyps ‘sessile serrated adenomas’, as precursor lesions to microsatelite unstable (MSI-H) sporadic CRC. NBI may therefore have no role in detection of adenomas at colonoscopy, but may be useful in detecting sessile serrated

adenomas to aid CRC prevention. Therefore, in future studies hyperplastic polyps and sessile serrated adenomas need to be included in the outcome measures.

Increased use of colonoscopy combined with improved polyp detection rates as a result of advances in colonoscopic technology, has resulted in spiralling costs associated with the procedure as well as resultant histopathology. The NHS Bowel Cancer Screening Programme (BCSP) was introduced in 2006 and offers faecal occult blood screening every two years for patients aged 60-75, followed by colonoscopy for those who test positive. This has resulted in a dramatically increased demand; approximately 80,000 colonoscopies were performed within the BCSP since 2007 and at least one adenoma was found in just under half of all procedures (M. Rutter, personal communication). From 2011, flexible sigmoidoscopy will be introduced for screening all adults > 55 years – this extrapolates to an estimated 500,000 flexible sigmoidoscopies per year, with 75,000 procedures resulting in the identification of least one polyp. Consequently there will be significant new demands on current capacity to deliver histology services. An ability to correctly diagnose a small polyp (< 10mm) during colonoscopy (optical diagnosis) would allow for recto-sigmoid hyperplastic polyps to be left in situ and for small adenomas to be resected and discarded without a need to retrieve the polyp for formal histopathology. Thus, optical diagnosis would enable surveillance intervals to be determined immediately after colonoscopy and as such would potentially lead to significant time and cost savings. The risks of polypectomy are relatively uncommon but include bleeding and bowel perforation with severe and unwanted effects on patients and healthcare costs. Similarly, the costs of unnecessary histology are significant; a ‘resect and discard policy’ to reduce the number of unnecessary histology was recently estimated to deliver annual savings of $33 million when hypothetically applied to colonoscopy screening of the US population (118).

DISCARD study was a first prospective cohort study that assessed the impact of optical diagnosis on colonoscopy surveillance intervals. It demostrated that optical diagnosis was feasible and safe in routine clinical practice and would have allowed

prospective cohort study planned to take place in 5 district general hospitals in the North East recruiting over 2000 patients (Appendix 2: Discard 2 – Application for RfPB grant).

A number of studies have shown that is appreciable inter-observer variability when characterising small colonic polyps. In the study of inter-observer variation, NBI with magnification improved inter-obeserver agreement in expert colonoscopists when compared to WLE. The design of this study, using still images was a practical way of assessing four-way inteobserver agreement but is likely to have contributed to lower diagnostic accuracy than that reported from in vivo characterisation studies. Using still images does not allow for assessment of polyps on high-definition monitors from different diastances and angles available in clinical practice. As expert colonoscopists in general had better inter-observer agreement we assessed how this could be improved for less experienced colonoscopists in two studies. The first explored the development of a computer-based algorithm for small polyp characterisation, by exloiting the features that reflect clinically observed differences in the strength of vascularity and colour between these two types of polyps. The pilot results demonstrated that the algorithm developed using features extracted from NBI images could accurately differentiate adenomas from hyperplastic polyps. Future work will involve developing a more robust algorithm expoliting further features and different classifiers. Automatic boundary detection (polyp segmentation) will enable development of a more robust, user-friendly classification device, which will permit investigation of its impact in routine clinical practice. It is not clear at the moment how the algorithm will interact with human operators in routine clinical practice – it may be that it acts as a ‘second reader’ paradigm, where colonoscopist would make an independent classification decision prior to computer analysis. The second study assessed the impact of a training module on NBI characterisation and showed that accuracy of polyp characterisation and inter-observer agreement improved significantly for colonoscopists with all levels of experience after completing the module. This is consistent with the two other most recent studies addressing the same question (136, 216).

For the ‘resect and discard’ policy based on optical diagnosis using NBI to be accepted in routine clinical practice, adequate measures need to be in place to reassure patients and healthcare providers of the accuracy of diagnosis made. It is

likely that in the first instance, the still photographs will be stored for purposes of quality assurance of optical diagnosis. Using still images recorded as part of DISCARD study and showing them to four expert colonoscopists, we have demonstrated that high quality still photographs of polyps are adequate record of optical diagnosis and performance of a colonoscopist, with good inter-observer agreement and accuracy of diagnosis when reviewed by independent expert colonoscopists. The record would not only serve as a quality indicator, but also documentation of performance in medico-legal cases.

In conclusion, advanced colonoscopic technologies explored in this thesis did not lead to improved detection of dysplasia, but showed a clear benefit with polyp characterisation. Optical diagnosis using NBI has a potential to change the current practice of management of small colonic polyps, leading to more efficient colonoscopy service, which would be to advantage of patients and healthcare providers.

Chapter  11 Bibliography  

1. Seeff LC, Richards TB, Shapiro JA, Nadel MR, Manninen DL, Given LS, et al. How many endoscopies are performed for colorectal cancer screening? Results from CDC's survey of endoscopic capacity. Gastroenterology. 2004 Dec;127(6):1670-7.

2. Sant M, Capocaccia R, Coleman MP, Berrino F, Gatta G, Micheli A, et al. Cancer survival increases in Europe, but international differences remain wide. Eur J Cancer.

[Research Support, Non-U.S. Gov't]. 2001 Sep;37(13):1659-67.

3. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al.

Genetic alterations during colorectal-tumor development. N Engl J Med. 1988 Sep 1;319(9):525-32.

4. Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, et al.

Clues to the pathogenesis of familial colorectal cancer. Science. 1993 May 7;260(5109):812-6.

5. Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993 Jun 10;363(6429):558-61.

6. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science. 1993 May 7;260(5109):816-9.

7. Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, et al. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 1997 Mar 1;57(5):808-11.

8. Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD, et al. BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut. 2004 Aug;53(8):1137-44.

9. East JE, Saunders BP, Jass JR. Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification, molecular genetics, natural history, and clinical management. Gastroenterol Clin North Am. 2008 Mar;37(1):25-46, v.

10. Schlemper RJ, Riddell RH, Kato Y, Borchard F, Cooper HS, Dawsey SM, et al. The Vienna classification of gastrointestinal epithelial neoplasia. Gut. 2000 Aug;47(2):251-5.

11. Citarda F, Tomaselli G, Capocaccia R, Barcherini S, Crespi M. Efficacy in standard clinical practice of colonoscopic polypectomy in reducing colorectal cancer incidence. Gut.

[Multicenter Study

Research Support, Non-U.S. Gov't]. 2001 Jun;48(6):812-5.

12. Winawer SJ, Zauber AG, Ho MN, O'Brien MJ, Gottlieb LS, Sternberg SS, et al.

Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med. 1993 Dec 30;329(27):1977-81.

13. Rabeneck L, Paszat LF, Saskin R, Stukel TA. Association between colonoscopy rates and colorectal cancer mortality. The American journal of gastroenterology. 2010 Jul;105(7):1627-32.

14. Atkin WS, Edwards R, Kralj-Hans I, Wooldrage K, Hart AR, Northover JM, et al.

Once-only flexible sigmoidoscopy screening in prevention of colorectal cancer: a multicentre randomised controlled trial. Lancet. [Multicenter Study

Randomized Controlled Trial Research Support, Non-U.S. Gov't]. 2010 May 8;375(9726):1624-33.

15. Wexner SD, Garbus JE, Singh JJ. A prospective analysis of 13,580 colonoscopies.

Reevaluation of credentialing guidelines. Surg Endosc. 2001 Mar;15(3):251-61.

16. Paspatis GA, Vardas E, Theodoropoulou A, Manolaraki MM, Charoniti I, Papanikolaou N, et al. Complications of colonoscopy in a large public county hospital in Greece. A 10-year study. Dig Liver Dis. 2008 Dec;40(12):951-7.

17. Eckardt VF, Kanzler G, Schmitt T, Eckardt AJ, Bernhard G. Complications and adverse effects of colonoscopy with selective sedation. Gastrointest Endosc. 1999 May;49(5):560-5.

18. Nelson D, McQuaid K, Bond J, Lieberman D, Weiss D, Johnston T. Procedural success and complications of large-scale screening colonoscopy. Gastrointest Endosc.

2002;55(3):7.

19. Alberts DS, Martinez ME, Roe DJ, Guillen-Rodriguez JM, Marshall JR, van Leeuwen JB, et al. Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. Phoenix Colon Cancer Prevention Physicians' Network. The New England

20. Schatzkin A, Lanza E, Corle D, Lance P, Iber F, Caan B, et al. Lack of effect of a low-fat, high-fiber diet on the recurrence of colorectal adenomas. Polyp Prevention Trial Study Group. The New England journal of medicine. [Clinical Trial Multicenter Study Randomized Controlled Trial]. 2000 Apr 20;342(16):1149-55.

21. Robertson DJ, Sandler RS, Haile R, Tosteson TD, Greenberg ER, Grau M, et al. Fat, fiber, meat and the risk of colorectal adenomas. The American journal of gastroenterology.

[Comparative Study Research Support, N.I.H., Extramural]. 2005 Dec;100(12):2789-95.

22. Farrar WD, Sawhney MS, Nelson DB, Lederle FA, Bond JH. Colorectal cancers found after a complete colonoscopy. Clin Gastroenterol Hepatol. 2006 Oct;4(10):1259-64.

23. Bressler B, Paszat LF, Chen Z, Rothwell DM, Vinden C, Rabeneck L. Rates of new or missed colorectal cancers after colonoscopy and their risk factors: a population-based analysis. Gastroenterology. 2007 Jan;132(1):96-102.

24. Rex DK, Cutler CS, Lemmel GT, Rahmani EY, Clark DW, Helper DJ, et al.

Colonoscopic miss rates of adenomas determined by back-to-back colonoscopies.

Gastroenterology. 1997 Jan;112(1):24-8.

25. Rex DK, Petrini JL, Baron TH, Chak A, Cohen J, Deal SE, et al. Quality indicators for colonoscopy. Am J Gastroenterol. 2006 Apr;101(4):873-85.

26. Levin B, Lieberman DA, McFarland B, Andrews KS, Brooks D, Bond J, et al.

Screening and surveillance for the early detection of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. Gastroenterology.

2008 May;134(5):1570-95.

27. Rabeneck L, Rumble RB, Axler J, Smith A, Armstrong D, Vinden C, et al. Cancer Care Ontario Colonoscopy Standards: standards and evidentiary base. Can J Gastroenterol.

2007 Nov;21 Suppl D:5D-24D.

28. Baxter NN, Sutradhar R, Forbes SS, Paszat LF, Saskin R, Rabeneck L. Analysis of administrative data finds endoscopist quality measures associated with postcolonoscopy colorectal cancer. Gastroenterology. 2011 Jan;140(1):65-72.

29. Bowles CJ, Leicester R, Romaya C, Swarbrick E, Williams CB, Epstein O. A prospective study of colonoscopy practice in the UK today: are we adequately prepared for national colorectal cancer screening tomorrow? Gut. 2004 Feb;53(2):277-83.

30. Aslinia F, Uradomo L, Steele A, Greenwald BD, Raufman JP. Quality assessment of colonoscopic cecal intubation: an analysis of 6 years of continuous practice at a university hospital. The American journal of gastroenterology. 2006 Apr;101(4):721-31.

31. Shah HA, Paszat LF, Saskin R, Stukel TA, Rabeneck L. Factors associated with incomplete colonoscopy: a population-based study. Gastroenterology. 2007 Jun;132(7):2297-303.

32. Church JM. Complete colonoscopy: how often? And if not, why not? The American journal of gastroenterology. 1994 Apr;89(4):556-60.

33. Bernstein C, Thorn M, Monsees K, Spell R, O'Connor JB. A prospective study of factors that determine cecal intubation time at colonoscopy. Gastrointestinal endoscopy.

[Research Support, Non-U.S. Gov't]. 2005 Jan;61(1):72-5.

34. Anderson M, TM P, JA L. Endoscopic Perforation of the Colon: Lessons from 10 year study. Am J Gastroenterol. [retrospective review]. 2000;95(12):5.

35. Chung YW, Han DS, Yoo KS, Park CK. Patient factors predictive of pain and difficulty during sedation-free colonoscopy: a prospective study in Korea. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2007 Sep;39(9):872-6.

36. Anderson ML, Pasha TM, Leighton JA. Endoscopic perforation of the colon: lessons from a 10-year study. Am J Gastroenterol. 2000 Dec;95(12):3418-22.

37. Dafnis G, Granath F, Pahlman L, Ekbom A, Blomqvist P. Patient factors influencing the completion rate in colonoscopy. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. [Research Support, Non-U.S. Gov't]. 2005 Feb;37(2):113-8.

38. Kim WH, Cho YJ, Park JY, Min PK, Kang JK, Park IS. Factors affecting insertion time and patient discomfort during colonoscopy. Gastrointestinal endoscopy. [Clinical Trial]. 2000 Nov;52(5):600-5.

39. Hull T, Church JM. Colonoscopy--how difficult, how painful? Surgical endoscopy.

1994 Jul;8(7):784-7.

40. Rex DK. Achieving cecal intubation in the very difficult colon. Gastrointestinal

42. Church J. The unzygosed colon as a factor predisposing to difficult colonoscopy in slim women. Gastrointestinal endoscopy. [Comment Letter]. 2002 Jun;55(7):965-6; author reply 6.

43. Appleyard MN, Mosse CA, Mills TN, Bell GD, Castillo FD, Swain CP. The measurement of forces exerted during colonoscopy. Gastrointestinal endoscopy. [Clinical Trial Research Support, Non-U.S. Gov't]. 2000 Aug;52(2):237-40.

44. Shah SG, Brooker JC, Williams CB, Thapar C, Suzuki N, Saunders BP. The variable stiffness colonoscope: assessment of efficacy by magnetic endoscope imaging. Gastrointest Endosc. 2002 Aug;56(2):195-201.

45. Cotton S, Sharp L, Little J. The adenoma-carcinoma sequence and prospects for the prevention of colorectal neoplasia. Crit Rev Oncog. [Comparative Study Review]. 1996;7(5-6):293-342.

46. van Rijn JC, Reitsma JB, Stoker J, Bossuyt PM, van Deventer SJ, Dekker E. Polyp miss rate determined by tandem colonoscopy: a systematic review. The American journal of gastroenterology. [Review]. 2006 Feb;101(2):343-50.

47. Heresbach D, Barrioz T, Lapalus MG, Coumaros D, Bauret P, Potier P, et al. Miss rate for colorectal neoplastic polyps: a prospective multicenter study of back-to-back video colonoscopies. Endoscopy. 2008 Apr;40(4):284-90.

48. Pickhardt PJ, Nugent PA, Mysliwiec PA, Choi JR, Schindler WR. Location of adenomas missed by optical colonoscopy. Annals of internal medicine. [Multicenter Study Research Support, U.S. Gov't, Non-P.H.S.]. 2004 Sep 7;141(5):352-9.

49. Belsey J, Epstein O, Heresbach D. Systematic review: oral bowel preparation for colonoscopy. Alimentary Pharmacology & Therapeutics. [Research Support, Non-U.S. Gov't Review]. 2007 Feb 15;25(4):373-84.

50. Hsu CW, Imperiale TF. Meta-analysis and cost comparison of polyethylene glycol lavage versus sodium phosphate for colonoscopy preparation. Gastrointestinal endoscopy.

[Comparative Study Meta-Analysis Research Support, Non-U.S. Gov't]. 1998 Sep;48(3):276-82.

51. Froehlich F, Wietlisbach V, Gonvers JJ, Burnand B, Vader JP. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest Endosc. 2005 Mar;61(3):378-84.

52. Behrens C, Stevenson G, Eddy R, Mathieson J. Effect of intravenous Buscopan on colonic distention during computed tomography colonography. Can Assoc Radiol J. 2008 Oct;59(4):183-90.

53. Rogalla P, Lembcke A, Ruckert JC, Hein E, Bollow M, Rogalla NE, et al.

Spasmolysis at CT colonography: butyl scopolamine versus glucagon. Radiology.

[Comparative Study]. 2005 Jul;236(1):184-8.

54. East JE, Suzuki N, Arebi N, Bassett P, Saunders BP. Position changes improve visibility during colonoscope withdrawal: a randomized, blinded, crossover trial. Gastrointest Endosc. 2007 Feb;65(2):263-9.

55. Barclay RL, Vicari JJ, Doughty AS, Johanson JF, Greenlaw RL. Colonoscopic withdrawal times and adenoma detection during screening colonoscopy. N Engl J Med. 2006 Dec 14;355(24):2533-41.

56. Atkin W, Rogers P, Cardwell C, Cook C, Cuzick J, Wardle J, et al. Wide variation in adenoma detection rates at screening flexible sigmoidoscopy. Gastroenterology. [Evaluation Studies Research Support, Non-U.S. Gov't]. 2004 May;126(5):1247-56.

57. Rex DK. Endoscopists, polyp size, and post-polypectomy surveillance: making a mountain out of a molehill? Gastrointestinal endoscopy. [Comment Editorial]. 1997 Dec;46(6):571-4.

58. Bretagne JF, Ponchon T. Do we need to embrace adenoma detection rate as the main quality control parameter during colonoscopy? Endoscopy. 2008 Jun;40(6):523-8.

59. Kaminski MF, Regula J, Kraszewska E, Polkowski M, Wojciechowska U, Didkowska J, et al. Quality indicators for colonoscopy and the risk of interval cancer. N Engl J Med.

2010 May 13;362(19):1795-803.

60. Adachi M, Okinaga K, Muto T. Flat adenoma of the large bowel: re-evaluation with special reference to central depression. Dis Colon Rectum. 2000 Jun;43(6):782-7.

61. Rembacken BJ, Fujii T, Cairns A, Dixon MF, Yoshida S, Chalmers DM, et al. Flat and depressed colonic neoplasms: a prospective study of 1000 colonoscopies in the UK. Lancet.

2000 Apr 8;355(9211):1211-4.

62. Soetikno RM, Kaltenbach T, Rouse RV, Park W, Maheshwari A, Sato T, et al.

cancer screening: a prospective "back-to-back" endoscopic study. Am J Gastroenterol. 2005 Oct;100(10):2167-73.

64. Kiesslich R, von Bergh M, Hahn M, Hermann G, Jung M. Chromoendoscopy with indigocarmine improves the detection of adenomatous and nonadenomatous lesions in the colon. Endoscopy. 2001 Dec;33(12):1001-6.

65. Hurlstone DP, Cross SS, Slater R, Sanders DS, Brown S. Detecting diminutive colorectal lesions at colonoscopy: a randomised controlled trial of pan-colonic versus targeted chromoscopy. Gut. 2004 Mar;53(3):376-80.

66. Brooker JC, Saunders BP, Shah SG, Thapar CJ, Thomas HJ, Atkin WS, et al. Total colonic dye-spray increases the detection of diminutive adenomas during routine colonoscopy: a randomized controlled trial. Gastrointest Endosc. 2002 Sep;56(3):333-8.

67. Rex DK, Helbig CC. High yields of small and flat adenomas with high-definition colonoscopes using either white light or narrow band imaging. Gastroenterology. 2007 Jul;133(1):42-7.

68. Adler A, Pohl H, Papanikolaou IS, Abou-Rebyeh H, Schachschal G, Veltzke-Schlieker W, et al. A prospective randomised study on narrow-band imaging versus conventional colonoscopy for adenoma detection: does narrow-band imaging induce a learning effect? Gut. 2008 Jan;57(1):59-64.

69. East JE, Suzuki N, Stavrinidis M, Guenther T, Thomas HJ, Saunders BP. Narrow band imaging for colonoscopic surveillance in hereditary non-polyposis colorectal cancer.

Gut. 2008 Jan;57(1):65-70.

70. Morson B. President's address. The polyp-cancer sequence in the large bowel. Proc R Soc Med. 1974 Jun;67(6 Pt 1):451-7.

71. Stolte M, Bethke B. Colorectal mini-de novo carcinoma: a reality in Germany too.

Endoscopy. 1995 May;27(4):286-90.

72. Kuramoto S, Oohara T. Flat early cancers of the large intestine. Cancer. 1989 Aug 15;64(4):950-5.

73. Iishi H, Tatsuta M, Tsutsui S, Imanishi K, Otani T, Okuda S, et al. Early depressed adenocarcinomas of the large intestine. Cancer. 1992 May 15;69(10):2406-10.

74. Shimoda T, Ikegami M, Fujisaki J, Matsui T, Aizawa S, Ishikawa E. Early colorectal carcinoma with special reference to its development de novo. Cancer. 1989 Sep 1;64(5):1138-46.

75. Minamoto T, Mai M, Ogino T, Sawaguchi K, Ohta T, Fujimoto T, et al. Early invasive colorectal carcinomas metastatic to the lymph node with attention to their nonpolypoid development. Am J Gastroenterol. 1993 Jul;88(7):1035-9.

76. Sawhney MS, Farrar WD, Gudiseva S, Nelson DB, Lederle FA, Rector TS, et al.

Microsatellite instability in interval colon cancers. Gastroenterology. [Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.]. 2006 Dec;131(6):1700-5.

77. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. [Review]. 2007 Jan;50(1):113-30.

78. Arain MA, Abdul Qadeer A. Systematic review on "vitamin E and prevention of colorectal cancer". Pakistan journal of pharmaceutical sciences. [Meta-Analysis Review].

78. Arain MA, Abdul Qadeer A. Systematic review on "vitamin E and prevention of colorectal cancer". Pakistan journal of pharmaceutical sciences. [Meta-Analysis Review].