untitled ORGINAL ARTICLE 17 SA JOURNAL OF RADIOLOGY • December 2005 Abstract OObbjjeeccttiivvee. To test: (i) the sensitivity and positive predictive value of tagged material in delineating ulcerations of the oesopha- gus in the pre- and post-treatment periods and at follow-up; and (ii) whether tagging could reduce the need for invasive endo- scopic procedures in patients with carcino- ma of the oesophagus. MMaatteerriiaallss aanndd mmeetthhooddss.. Twenty-nine patients with carcinoma of the oesophagus selected for radiation therapy underwent the 99mTc sucralfate scintimaging prior to radiation therapy. Patients were asked to drink 10 ml suspension of 10 mci 99mTc sucralfate. The sequential images of the oesophagus were acquired at 2 minutes, 2 hours, 4 hours and 6 hours following inges- tion. In some patients images were also acquired at 24 hours and at follow-up. The comparison was done with endoscopy as the gold standard. RReessuullttss aanndd oobbsseerrvvaattiioonnss.. The overall positivity of the test was 83% at 4 hours (24 of 29 patients), 34% at 6 hours (10 of 29 patients) and 24% at 24 hours (7 of 29 patients). The sensitivity of the test was 85%, and the positive predictive value 50%. CCoonncclluussiioonn.. Due to low positive pre- dictive value, this investigation cannot Can ulceration in carcinoma of the oesophagus be detect- ed by 99mTc- sucralfate scan? V Sharma MD, PhD Johannesburg Hospital and Tata-Memorial Hospital and Radiation Medicine Centre Mumbai, Inda S Awasare MSc V Rangrajan DRM, DNB H H Shimpi MSc U Mahantshetty MD, DNB Tata Memorial Hospital and Radiation Medicine Centre Mumbai, India P S Choudhary DRM, DNB Rajeer Gandhi Hospital and Research Institute New Delhi, India Fig. 1a. Pre-radiation scan. Static sucralfate study scans at varying intensities at 2 minutes, 2 hours and 4 hours post ingestion. sharma 11/30/05 10:50 AM Page 17 18 SA JOURNAL OF RADIOLOGY • December 2005 ORGINAL ARTICLE replace endoscopy to diagnose ulcerative disease in patients with carcinoma of the oesophagus. Introduction The diagnosis of presence of deep ulceration in the oesophagus due to disease has value for both diagnosis and manage- ment. Patients with ulcerative tumours are treated with surgery as the first choice unless found inoperable because of advanced disease at presentation or poor general conditioin. Radiation therapy can aggravate the condition of the patient as ulceration may become worse with higher doses of radiation leading to severe pain and sometimes fistula formation. Sucralfate (the aluminium salt of sulphated sucrose) labelled with selenium75 and 99m technetium (99m Tc) has been shown to give variable results for detection of ulcera- tion throughout the gastrointestinal tract (GIT).1-5 The results have, however, been mainly negative for oesophageal ulceration from static imaging scans. A non-invasive scan would be much better tolerated by patients than oesophagoscopy and might be more accurate than a barium swallow which is frequently non-diagnostic in patients with oesophagitis.6 Objectives The purpose of the study was to test: (i) the sensitivity and positive predictive value of tagged material in delineating ulcera- tions in the oesophagus pre-treatment, post-treatment and at follow-up; and (ii) whether it could reduce the need for inva- sive endoscopic procedures in patients with carcinoma of the oesophagus. We evaluated the use of 99mTc labelled sucralfate in the investigation of oesophageal mucosal ulcerations in the pre- and post-radiotherapy periods in patients with carcinoma of the oesophagus with endoscopy as the gold standard. The results form the basis of this report. Material and methods Twenty-nine patients with carcinoma of the oesophagus selected for radiation therapy underwent the 99mTc sucralfate scintiimaging prior to starting radiation therapy. The lesions involved the upper- third in 2 patients, mid-third in 20 patients and lower-third in 7 patients. All patients had endoscopy to confirm the diagnosis of malignancy. The morphological appear- ances of the lesions were grouped into ulcerative in 14 patients (ulcerative 6, ulceroproliferative in 8) and non-ulcerative in 15 patients (infiltrative in 8, polypoidal in 7). Labelling and sucralfate tag- ging with 99mTc Sucralfate and other chemicals were obtained from commercial sources. 99mTc04 was obtained from alkaline 99M004 using 2 butanole by the solvent extraction process and further processed into an injectable form.7 Instant labelling kits of sucralfate prepared at the Radiation Medicine Centre in Mumbai, India were used.8 The lyophilised sucralfate was suspended in 2.0 - 3.0 ml of distilled water. A desired amount Fig. 1b. Post radiation scan. Static sucralfate study scans at varying intensities at 2 minutes, 2 hours and 4 hours post ingestion. sharma 11/30/05 10:50 AM Page 18 of 99mTc 04- in 0.5 - 1.5 ml was added to it and incubated for 10 minutes at room tem- perature. Unlabelled 99mTc04 was removed following centrifugation for 1 - 2 minutes at 3 000 revolutions per minute (rpm). Distilled water was used for addi- tional rinses. The percentage of labelling was calculated from the observed radioac- tivity in the final suspension and that pre- sent in the combined supernatant layer.9 Imaging protocol Patients were asked to drink a 10 ml suspension of 10 mCi 99mTc sucralfate. An initial dynamic acquisition was carried out for 30 seconds with a frame rate of 0.5 sec- onds/frame. One minute post ingestion an oesophageal view was acquired and the patient was then asked to drink 20 ml water to wash out the labelled sucralfate that had not adhered to the affected mucosa. Following this sequential images of the oesophagus were acquired for 2 minutes, 2 hours, 4 hours and 6 hours (Fig 1a and b). In some patients images were also acquired at 24 hours and at follow-up. Pre-radio- therapy scans were performed on 29 patients, pre-radiotherapy scans as well as post-radiotherapy scans on 13 patients, and post-radiotherapy scans on 18 patients. All patents underwent endoscopy at follow-up evaluation to confirm whether ulceration was present. Results and observa- tions The criteria used for positivity of the scans were an increased concentration of the tagged material, for at least 4 hours. The criteria used for positivity were taken from the report by Bailer et al.10 True-positive was defined as ulceration on endoscopy and increased concentration on scan. True-negative was defined as no ulceration on endoscopy and no uptake on scan. False-positive was defined as no ulceration on endoscopy but increased uptake on scan. False-negative was defined as ulceration on endoscopy but no uptake on scan. The overall positivity of the test was 83% at 4 hours (24 of 29 patients), 34% at 6 hours (10 of 29 patients), and 24% at 24 hours (7 of 29 patients). The sensitivity of the test was 85% at 4 hours but the positive predictive value was 50%. The specificity of the test was 20% and negative predictive value was 60%. The false-positive rate was 50% and it was due to stasis of the radioiso- tope in the cases with no evidence of ulcer- ation on endoscopy (Table I). In 18 patients, for whom only post- radiotherapy scans were done, an increased uptake was noted in 9 patients (50%) at 4 hours, 4 patients (22%) at 6 hours and 3 patients (17%) at 24 hours. In the 13 patients who had pre- and post-radiation scans, 6/13 patients (46%) at 4 hours, 3/13 patients (23%) at 6 hours and 2/13 patients (15%) at 24 hours had positive scans. Six patients were followed up between 3 months and 6 months post-radiation; 5/6 patients (83%) showed positivity at 4 hours, with evidence of ulceration in 2 patients on endoscopy and a positive pre- dictive value of 40% (Table II). Discussion Dynamic radionuclide scintigraphy is becoming an established test in the assess- ment of functional abnormalities of the oesophagus such as strictures, spasm and achalasia.11 It is non-invasive, simple to per- form, is well tolerated by patients, and can produce quantitative indices of function. However, this technique will only identify sites of mucosal damage in the oesophagus if they are gross enough to precipitate tran- sit abnormalities, and as such it is of no value in the early detection and follow-up of oesophageal ulceration. Reports have described the labelling of sucralfate with selenium-75 and technetium-99m with variable results for the detection of ulcera- tion throughout the GIT.1-5 ORGINAL ARTICLE 19 SA JOURNAL OF RADIOLOGY • December 2005 Table I. Correlation between sucralfate tagging and endoscopy pre-radiotherapy SSuuccrraallffaattee EEnnddoossccooppyy tteecchhnneettiiuumm--9999mm ssccaann PPoossiittiivvee NNeeggaattiivvee Positive (N) 24 12 12 Negative (N) 5 2 3 Total (N) 29 14 15 Sensitivity 12/14 = 85% Specificity 03/15 = 20% Positive predictive value 12/24 = 50% Negative predictive value 03/05 = 60% Table II. Correlation between sucralfate tagging and endoscopy at follow-up SSuuccrraallffaattee EEnnddoossccooppyy tteecchhnneettiiuumm--9999mm ssccaann PPoossiittiivvee NNeeggaattiivvee Positive (N) 5 2 3 Negative (N) 1 0 1 Total (N) 6 2 4 Sensitivity 2/2 = 100% Specificity 1/4 = 25% Positive predictive value 2/5 = 40% sharma 11/30/05 10:50 AM Page 19 ORGINAL ARTICLE 20 SA JOURNAL OF RADIOLOGY • December 2005 The results in our study showed almost similar uptake in 13 patients who had scans both before and on completion of radiation at 4 hours, 6 hours and 24 hours when compared with 18 patients who had scans only on completion of radiation at the same intervals. Mearns et al11 have shown a 92% positive predictive value for dynamic sucralfate imaging of oesophageal ulcera- tion. The present study, however, showed the sensitivity of the test to be 85%, but the positive predictive value was only 50%. The most probable explanation for the low pos- itive predictive value is the stasis of the radioisotope in cases with non-ulcerative disease at endoscopy. Previous work has focused on the applications of labelled sucralfate in the imaging of the stomach and small and large bowel, but its use has been documented in the oesophagus11 with mainly negative results from static imaging techniques. Due to positive results from their study, Mearns et al.11 suggest limiting endoscopy to initial evaluation using histological examination to exclude the possibility of a malignant process. This is not supported by the present study due to the low positive predictive value. Although Mearns et al. suggested that the 99mTc sucralfate dynamic study has a real value, firstly as a screening test in deciding who should be endoscoped, and secondly as a test suitable for following the progress of patients undergoing thera- py for oesophageal ulceration, we are unable to recommend the use of sucralfate tagging in the follow-up period. In conclusion, this study does not sup- port the use of sucralfate tagging to replace endoscopy in cancer of the oesophagus due to a low positive predictive value. We would like to sincerely acknowledge Professor Bernard Donde, Head of Department of Radiation Oncology, Johannesburg Hospital, for corrections to the manuscript. References 1. Vasquez TE, Bridges RL, Braunstein P, Jansholt AL, Meshkinpour H. Gastrointestinal ulceration: detection using a technetium-99m. Labelled ulcer avid agent. Radiology 1983; 114488:: 227-231. 2. Dawson DJ, Khan AN, Nuttall P, Shreeve DR. Technetium-99m labelled sucralfate isotope scan- ning in the detection of peptic ulceration. Nucl Med Commun 1985; 66:: 319-325. 3. Dawson DJ, Khan AN, Miller V, Ratcliffc JF, Shreeve DR. Detection of inflammatory bowel dis- ease in adults and children: evaluation of a new isotope technique. BMJ 1985; 229911:: 1227-1230. 4. Maurer AH, Knight LC, Kollman M et al. Validation of binding of 75Se-labelled scralfate to sites of gastrointestinal ulceration (abstract). European Nuclear Medicine Society Congress, London, 1985. 5. Crump BJ, Field S, Rake MO, Kettle AG, Buxton Thomas MS, Coakley AJ. 99mTc sucralfate imaging in inflammatory bowel disease – Poor correlation with radiology (abstract). London: British Nuclear Medicine Society Annual Meeting, 1987. 6. Goff JS, Adcock KA, Schmelter R. Detection of esophageal ulcerations with Technetium-99m albumin sucralfate. J Nucl Med 1986; 2277:: 1143- 1146. 7. Naronha OPD. Solvent extraction technology of 99Mo-99mTc-generator system performance, char- acteristics. Proceedings of the 1984 Radiopharmaceuticals and Labelled Compound Conference, Tokyo: 223-232. 8. Shimpi HH, Naronha OPD, Samuel AM. Development of 99mTc. Sucralfate as a diagnostic agent for ulcers of gastrointestinal (GI) tract: Physicochemical factors affecting the oral dosage form. Indian Journal of Nuclear Medicine 1996; 1111:: 42 - 46. 9. Shimpi HH, Naronha OPD, Samuel AM. Transport patterns and orally fed 99mTc sucralfate in ulcer induced animal model. Indian Journal of Nuclear Medicine 1996; 1111:: 93 - 97. 10. Bailer JC, Mosteller F. Medical technology assess- ment. In: Bailer JC III, Mosteller F, eds. Medical Uses of Statistics. 2nd ed Boston: N Engl J Med Books, 11999922:: 393 - 411. 11. Mearns AJ, Hart GC, Cox JA. Dynamic radionu- clide imaging with 99mTc-sucralfate in the detec- tion of oesophageal ulceration. Gut 1989; 3300::1256- 1259. To order contact: The South African Medical Association, Health & Medical Publishing Group 1-2 Lonsdale Building, Gardener Way, Pinelands, 7405. Tel: (021) 530-6520/27 Fax: (021) 531-4126/3539 email: carmena@hmpg.co.za or avrilm@hmpg.co.za HMPG Price R145.00 Price R110.00 Price R110.00 sharma 11/30/05 10:51 AM Page 20