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Cost-effectiveness of colon cancer screening: Fecal occult blood test vs. colonoscopy
April 1995
Gastrointestinal Oncology A497
• SAFETY OF A SYSTEMATIC ENDOSCOPIC BIOPSY PROTOCOL IN BARRETT'S ESOPHAGUS. D.S. Levine, B.J. Reid, S. Irvine, GI Endoscopy Unit Staff• Dept. of Medicine, University of Washington, Seattle, WA. Prospective endoscopic biopsy surveillance is recommended for patients with Barrett's esophagus because of an increased risk of esophageal adenocarcinoma. Early diagnosis of neoplastic lesions that are curable by surgery is made possible by obtaining multiple, large biopsy samples. More widespread implementation of such protocols is hindered by concerns about staffing needs, procedural time, and safety of endoscopies during which > 10-20 esophageal biopsies may be taken. Our aim was to evaluate the safety of a systematic endoscopic biopsy protocol performed on a patient cohort with GE reflux and Barrett's esophagus. METHODS: Candidates for prospective surveillance are thoroughly counseled about Barrett's esophagus by MDs. Consented patients receive topical throat anesthesia, nasal O2; titrated doses of IV benzodiazepine and/or narcotic, and automatic ECG, BP, .and S,o~ monitoring. Large channel endoscopes are passed, a visual exam is completed, and a turn-and-suction method with "jumbo" biopsy forceps is used to obtain at least 5-10 biopsies from all visible abnormalities, at least 5-10 biopsies from areas of previously detected dysplasia, and at least 4-6 biopsies at 1-2 em levels of the Barrett's esophagus for histology, DNA content, and other research analyses: Endoscopies are staffed by 1-2 MDs, an endoscopy nurse, a biopsy forceps operator, and a biopsy handler. Sucralfate is prescribed for several days after endoscopies. Anti-reflux lifestyle changes are advised routinely and acid anti-secretory drugs are prescribed for symptoms of GE reflux or evidence of esophagitis. Clinic or telephone follow-up is carried out. RESULTS: From 7/83 to 6/94, 810 consecutive endoscopies on 394 patients were performed and 26,548 biopsies (average 33, maximum 120 per exam) were taken: Procedures lasted from 15 to 90 minutes during which l-2 biopsies were obtained per minute. Two significant medication reactions occurred (respiratory arrest, cardiac dysrhythmia) that were successfully treated without sequelae but which required overnight hospitalization. No esophageal perforations, aspiration, or esophageal scarring resulted. Significant bleeding developed in only 2 patients who had concomitant stricture dilatation. Complaints of sore throat or phlebitic reactions were rare. Compliance with recommended follow-up endoscopies exceeded 95%. CONCLUSIONS: A rigorous, systematic endoscopic biopsy protocol in patients with Barrett's esophagus does not produce esophageal perforation or bleeding complications when performed by an experienced team of MDs, RNs, and technicians. Patient acceptance of this diagnostic practice is very high and may relate to pre-procedural counseling. As with all procedures performed with conscious sedation, medication reactions may occur.
• ISOLATION AND TISSUE EXPRESSION OF A PUTATIVE PARTIAL cDNA F O R A NOVEL p-GALACTOSIDE ~ 2,3SIALYLTRANSFERASE (ST3N). M. Li, S.J. Samuel, V. Andersen, R. Vemulapalli, P. Lance. GI Division a n d Dept. of Medicine, VA Medical C e n t e r a n d S t a t e University of New York, Buffalo, NY T e r m i n a l ~2,3-1inked sialic acids, added by specific s i a l y l t r a n s f e r a s e s (ST3N's), are required for selectin-mediated a n d other cell recogntion events. Existence of multiple ST3N's is a s s u m e d but only one r a t (liver, r a t S T 3 N liv) or h u m a n (placenta, h u S T 3 N pla°) ST3N cDNA h a s been isolated. Preferred acceptors for r a t liver (type 1) a n d p l a c e n t a (type 2) ST3N's are distinct. METHODS: h u S T 3 N llv was isolated from a h u m a n liver cDNA library w i t h P C R primers based on the h u S T 3 N pI'~ sequence, Sequenced a n d used for S nuclease a n d N o r t h e r n analyses. Regulation of h u S T 3 N ~iv expresmon by n - b u t y r a t e (nB) a n d cAMP, both Fmown to alter expression of a n o t h e r sialyltransferase (ST6N), was studied in Hep G2, T84 a n d H e L a cells. RESULTS: Similarities with r a t S T 3 N liv a n d h u S T 3 N pI~ sequences, respectively, were: nucleotide, 96 a n d 74%; predicted amino acid, 9 8 a n d 96%. S nuclease analysis of h u m a n liver RNA confirmed t h a t hu.ST3N iv (1.] kb) corresponds to a h u m a n mRNA. N o r t h e r n analysis with h u . S T 3 N ~ revealed -1.6, 0.9 a n d 0.6 kb t r a n s c r i p t s not reported with h u . S T 3 N pla° hybridizations, a n d a faint -2.7 kb band corresponding to the single t r a n s c r i p t obtained with hu.ST3N pla°. Relative tissue levels of h u . S T 3 N nv m R N A (maximal in kidney) were distinct from those reported for hu.ST3N pj~c (maximal in skeletal muscle). Cyclic AMP (0.01-5 mM) caused dose-dependent inhibition of hu.ST3N Iiv m R N A levels in T84 cells but did not alter expression in Hep G2. In c o n t r a s t to previously reported induction of ST6N, nB inhibited expression of h u . S T 3 N l~v m R N A by H e L a cells. CONCLUSIONS: Transfection w i t h hu•ST3N ~iv cDNA a n d d e m o n s t r a t i o n of ST3N activity are awaited. In the meantime, distinct qualitative a n d q u a n t i t a t i v e p a t t e r n s of expression were found for a p u t a t i v e novel ST3N mRNA. Effects o f n B a n d cAMP on expression of this m R N A differed from those reported for ST6N. 1
•
• BILE ACIDS (BA's) AND P H O R B O L ESTERS ALTER GLYCOSYLTRANSFERASE (GT) EXPRESSION IN T84 CELLS BY D I F F E R E N T MECHANISMS. M. Li, V. Andersen, R. Vemulapalli, L. Izu, M.D. Duffey, P. Lance. Depts. of Medicine a n d Physiology, VA Medical C e n t e r a n d S t a t e University of New York, Buffalo, NY. Sodium deoxycholate (DOC), a secondary BA t h a t m a y play a role in the etiology of colorectal cancer, increases colonic microbial diacylglycerot (DAG) production. DAG activates protein kinase C, a n effect mimicked by phorbol esters, such as TPA. Cell differentiation and neoplastic t r a n s f o r m a t i o n are accompanied by altered expression of the sequentially acting N-glycan GT's, galactosyltransferase (GalT) and t e r m i n a l ~2,6-sialyltransferase (ST6N). METHODS: The following effects of p r i m a r y (cholic acid, CA) a n d secondary (DOC) BA's, a n d TPA were investigated in T84 cell cultures: morphological changes a n d cell adherence; altered expression of ST6N product (iectin affinity chromatography); altered GalT a n d ST6N expression (Northern analysis a n d nuclear run-on reactions); mediation by P K C p a t h w a y (specific inhibitor, GF 109203X); CaZ+-dependence (intracellular Ca 2~ fluctuations detected by fluorescent dye method and BAPTA-AM chelation). RESULTS: Morphological changes were: a p p a r e n t 4 h after exposure of T84 cells to 200-400 pM DOC (fecal range) but not CA; m a x i m a l by 24 h; a n d accompanied by reduced expression of N-glycans t e r m i n a t i n g in ~2~6 sialic acids. DOC (200400 ]aM) a n d TPA (20 ng/ml), but not cholic acid, reduced levels of ST6N m R N A a n d increased GalT m R N A expression. Run-on reactions showed these to be direct transcriptional effects of DOC and TPA. Effects of TPA but not DOC were blocked by GF 109203X. Increases in intracellular Ca ~÷ followed exposure to DOC. The presence of Ca 2÷ in culture m e d i a w a s required for DOC-induced elevation of i n t r a c e l l u a r Ca 2. or inhibition of ST6N mRNA expression to occur. CONCLUSIONS: Effects of phorbol esters, but not secondary bile acids, on GT expression in T 8 4 cells were PKCdependent. Inhibition of ST6N expression by DOC required the presence of extracellular Ca z÷, The lack of a n effect of a p r i m a r y BA, cholic acid, on GT expression could indicate t h a t the actions of DOC described here are of pathophysiologica] significance.
COST-EFFECTIVENESS OF COLON CANCER SCREENING: FECAL OCCULT BLOOD TEST vs. COLONOSCOPY. D Lieberman, Portland VAMC, Portland, OR. The cost-effectiveness of a colorectal cancer (CRC) screening program will be an important determinant of application in managed care settings. We have developed a model using published data to compare two screening programs: fecal occult blood test (FOBT) annually over 10 years versus one-time screening with colonoseopy. The purpose of the model was to determine the impact of manipulating key cost variables and expected patient compliance on costeffectiveness. Cost-effectiveness was defined as the cost per cancer prevented and the cost per life saved. The maximal expected impact of the screening programs over 10 years are shown below: % Cancer % Death Comnliance prevented prevented Annual FOBT 100% 22.5% 47.5% 50% 11.5% 26% Colonoscopy 100% "]0% 80% 50% 35% 48% 20% 15% 22% Results: FOBT achieves CRC mortality reduction by early detection of cancers; colonoscopy reduces CRC mortality by preventing cancers through removal of polyps. The model suggests that 100% compliance with FOBT would be needed to achieve the same mortality reduction as one-time colonoscopy with 50% compliance. Since FOBT prevents few cancers, the cost effectiveness is very sensitive to the cost of cancer care. One-time screening with colonoscopy can prevent most cancers, thus reducing the cost of cancer care. The costeffectiveness of colonoscopy screening is very sensitive to the cost of the initial colonoscopy and the subsequent costs for surveillance. In conclusion, modeling can demonstrate the impact of key variables in a colon screening program on cost-effectivaness. Compliance is a very important variable and must be considered in calculations of colon screening effectiveness.
Gastrointestinal Oncology A497
• SAFETY OF A SYSTEMATIC ENDOSCOPIC BIOPSY PROTOCOL IN BARRETT'S ESOPHAGUS. D.S. Levine, B.J. Reid, S. Irvine, GI Endoscopy Unit Staff• Dept. of Medicine, University of Washington, Seattle, WA. Prospective endoscopic biopsy surveillance is recommended for patients with Barrett's esophagus because of an increased risk of esophageal adenocarcinoma. Early diagnosis of neoplastic lesions that are curable by surgery is made possible by obtaining multiple, large biopsy samples. More widespread implementation of such protocols is hindered by concerns about staffing needs, procedural time, and safety of endoscopies during which > 10-20 esophageal biopsies may be taken. Our aim was to evaluate the safety of a systematic endoscopic biopsy protocol performed on a patient cohort with GE reflux and Barrett's esophagus. METHODS: Candidates for prospective surveillance are thoroughly counseled about Barrett's esophagus by MDs. Consented patients receive topical throat anesthesia, nasal O2; titrated doses of IV benzodiazepine and/or narcotic, and automatic ECG, BP, .and S,o~ monitoring. Large channel endoscopes are passed, a visual exam is completed, and a turn-and-suction method with "jumbo" biopsy forceps is used to obtain at least 5-10 biopsies from all visible abnormalities, at least 5-10 biopsies from areas of previously detected dysplasia, and at least 4-6 biopsies at 1-2 em levels of the Barrett's esophagus for histology, DNA content, and other research analyses: Endoscopies are staffed by 1-2 MDs, an endoscopy nurse, a biopsy forceps operator, and a biopsy handler. Sucralfate is prescribed for several days after endoscopies. Anti-reflux lifestyle changes are advised routinely and acid anti-secretory drugs are prescribed for symptoms of GE reflux or evidence of esophagitis. Clinic or telephone follow-up is carried out. RESULTS: From 7/83 to 6/94, 810 consecutive endoscopies on 394 patients were performed and 26,548 biopsies (average 33, maximum 120 per exam) were taken: Procedures lasted from 15 to 90 minutes during which l-2 biopsies were obtained per minute. Two significant medication reactions occurred (respiratory arrest, cardiac dysrhythmia) that were successfully treated without sequelae but which required overnight hospitalization. No esophageal perforations, aspiration, or esophageal scarring resulted. Significant bleeding developed in only 2 patients who had concomitant stricture dilatation. Complaints of sore throat or phlebitic reactions were rare. Compliance with recommended follow-up endoscopies exceeded 95%. CONCLUSIONS: A rigorous, systematic endoscopic biopsy protocol in patients with Barrett's esophagus does not produce esophageal perforation or bleeding complications when performed by an experienced team of MDs, RNs, and technicians. Patient acceptance of this diagnostic practice is very high and may relate to pre-procedural counseling. As with all procedures performed with conscious sedation, medication reactions may occur.
• ISOLATION AND TISSUE EXPRESSION OF A PUTATIVE PARTIAL cDNA F O R A NOVEL p-GALACTOSIDE ~ 2,3SIALYLTRANSFERASE (ST3N). M. Li, S.J. Samuel, V. Andersen, R. Vemulapalli, P. Lance. GI Division a n d Dept. of Medicine, VA Medical C e n t e r a n d S t a t e University of New York, Buffalo, NY T e r m i n a l ~2,3-1inked sialic acids, added by specific s i a l y l t r a n s f e r a s e s (ST3N's), are required for selectin-mediated a n d other cell recogntion events. Existence of multiple ST3N's is a s s u m e d but only one r a t (liver, r a t S T 3 N liv) or h u m a n (placenta, h u S T 3 N pla°) ST3N cDNA h a s been isolated. Preferred acceptors for r a t liver (type 1) a n d p l a c e n t a (type 2) ST3N's are distinct. METHODS: h u S T 3 N llv was isolated from a h u m a n liver cDNA library w i t h P C R primers based on the h u S T 3 N pI'~ sequence, Sequenced a n d used for S nuclease a n d N o r t h e r n analyses. Regulation of h u S T 3 N ~iv expresmon by n - b u t y r a t e (nB) a n d cAMP, both Fmown to alter expression of a n o t h e r sialyltransferase (ST6N), was studied in Hep G2, T84 a n d H e L a cells. RESULTS: Similarities with r a t S T 3 N liv a n d h u S T 3 N pI~ sequences, respectively, were: nucleotide, 96 a n d 74%; predicted amino acid, 9 8 a n d 96%. S nuclease analysis of h u m a n liver RNA confirmed t h a t hu.ST3N iv (1.] kb) corresponds to a h u m a n mRNA. N o r t h e r n analysis with h u . S T 3 N ~ revealed -1.6, 0.9 a n d 0.6 kb t r a n s c r i p t s not reported with h u . S T 3 N pla° hybridizations, a n d a faint -2.7 kb band corresponding to the single t r a n s c r i p t obtained with hu.ST3N pla°. Relative tissue levels of h u . S T 3 N nv m R N A (maximal in kidney) were distinct from those reported for hu.ST3N pj~c (maximal in skeletal muscle). Cyclic AMP (0.01-5 mM) caused dose-dependent inhibition of hu.ST3N Iiv m R N A levels in T84 cells but did not alter expression in Hep G2. In c o n t r a s t to previously reported induction of ST6N, nB inhibited expression of h u . S T 3 N l~v m R N A by H e L a cells. CONCLUSIONS: Transfection w i t h hu•ST3N ~iv cDNA a n d d e m o n s t r a t i o n of ST3N activity are awaited. In the meantime, distinct qualitative a n d q u a n t i t a t i v e p a t t e r n s of expression were found for a p u t a t i v e novel ST3N mRNA. Effects o f n B a n d cAMP on expression of this m R N A differed from those reported for ST6N. 1
•
• BILE ACIDS (BA's) AND P H O R B O L ESTERS ALTER GLYCOSYLTRANSFERASE (GT) EXPRESSION IN T84 CELLS BY D I F F E R E N T MECHANISMS. M. Li, V. Andersen, R. Vemulapalli, L. Izu, M.D. Duffey, P. Lance. Depts. of Medicine a n d Physiology, VA Medical C e n t e r a n d S t a t e University of New York, Buffalo, NY. Sodium deoxycholate (DOC), a secondary BA t h a t m a y play a role in the etiology of colorectal cancer, increases colonic microbial diacylglycerot (DAG) production. DAG activates protein kinase C, a n effect mimicked by phorbol esters, such as TPA. Cell differentiation and neoplastic t r a n s f o r m a t i o n are accompanied by altered expression of the sequentially acting N-glycan GT's, galactosyltransferase (GalT) and t e r m i n a l ~2,6-sialyltransferase (ST6N). METHODS: The following effects of p r i m a r y (cholic acid, CA) a n d secondary (DOC) BA's, a n d TPA were investigated in T84 cell cultures: morphological changes a n d cell adherence; altered expression of ST6N product (iectin affinity chromatography); altered GalT a n d ST6N expression (Northern analysis a n d nuclear run-on reactions); mediation by P K C p a t h w a y (specific inhibitor, GF 109203X); CaZ+-dependence (intracellular Ca 2~ fluctuations detected by fluorescent dye method and BAPTA-AM chelation). RESULTS: Morphological changes were: a p p a r e n t 4 h after exposure of T84 cells to 200-400 pM DOC (fecal range) but not CA; m a x i m a l by 24 h; a n d accompanied by reduced expression of N-glycans t e r m i n a t i n g in ~2~6 sialic acids. DOC (200400 ]aM) a n d TPA (20 ng/ml), but not cholic acid, reduced levels of ST6N m R N A a n d increased GalT m R N A expression. Run-on reactions showed these to be direct transcriptional effects of DOC and TPA. Effects of TPA but not DOC were blocked by GF 109203X. Increases in intracellular Ca ~÷ followed exposure to DOC. The presence of Ca 2÷ in culture m e d i a w a s required for DOC-induced elevation of i n t r a c e l l u a r Ca 2. or inhibition of ST6N mRNA expression to occur. CONCLUSIONS: Effects of phorbol esters, but not secondary bile acids, on GT expression in T 8 4 cells were PKCdependent. Inhibition of ST6N expression by DOC required the presence of extracellular Ca z÷, The lack of a n effect of a p r i m a r y BA, cholic acid, on GT expression could indicate t h a t the actions of DOC described here are of pathophysiologica] significance.
COST-EFFECTIVENESS OF COLON CANCER SCREENING: FECAL OCCULT BLOOD TEST vs. COLONOSCOPY. D Lieberman, Portland VAMC, Portland, OR. The cost-effectiveness of a colorectal cancer (CRC) screening program will be an important determinant of application in managed care settings. We have developed a model using published data to compare two screening programs: fecal occult blood test (FOBT) annually over 10 years versus one-time screening with colonoseopy. The purpose of the model was to determine the impact of manipulating key cost variables and expected patient compliance on costeffectiveness. Cost-effectiveness was defined as the cost per cancer prevented and the cost per life saved. The maximal expected impact of the screening programs over 10 years are shown below: % Cancer % Death Comnliance prevented prevented Annual FOBT 100% 22.5% 47.5% 50% 11.5% 26% Colonoscopy 100% "]0% 80% 50% 35% 48% 20% 15% 22% Results: FOBT achieves CRC mortality reduction by early detection of cancers; colonoscopy reduces CRC mortality by preventing cancers through removal of polyps. The model suggests that 100% compliance with FOBT would be needed to achieve the same mortality reduction as one-time colonoscopy with 50% compliance. Since FOBT prevents few cancers, the cost effectiveness is very sensitive to the cost of cancer care. One-time screening with colonoscopy can prevent most cancers, thus reducing the cost of cancer care. The costeffectiveness of colonoscopy screening is very sensitive to the cost of the initial colonoscopy and the subsequent costs for surveillance. In conclusion, modeling can demonstrate the impact of key variables in a colon screening program on cost-effectivaness. Compliance is a very important variable and must be considered in calculations of colon screening effectiveness.