Dear Editor

The authors recommend that routine biliary drainage before assessing resectability or preoperatively should be avoided except in the context of acute cholangitis. They do not state the rationale for this approach. Presumably the argument against preoperative biliary drainage is the possible increased risk for perioperative complications, increased risk of bile leakage of chole-enteric anastomosis because of stent-induced inflammatory response or increased mortality. On the other hand, the argument for preoperative biliary drainage is equally persuasive. There may be improvement in nutritional and metabolic function, including restoration of enterohepatic circulation and improvement in hepatic synthetic function and coagulation; improvement in immune function, reduced risk for perioperative complications or reduced mortality. The authors quote two studies to support their recommendation (Nakeeb et al., Hochwald et al.[1,2]). However they ignore two other prospective randomized controlled trials comparing preoperative biliary drainage with no preoperative biliary drainage (Lai et al.; Lygidakis et al.[3,4]). Lai et al.[3] revealed no difference in morbidity and mortality while Lygidakis et al.[4] found that there was significantly reduced operative morbidity and mortality with preoperative biliary drainage. They also ignore at least eight retrospective studies comparing preoperative biliary drainage with no preoperative biliary drainage which have conflicting results. These individual studies are flawed by the heterogeneous nature of the patients included; whether a sphincterotomy was performed alone or in combination with stent; insufficient sample sizes and varying types of surgical procedures used. A recent meta-analysis of these prospective and retrospective studies found no evidence of either a positive or adverse effect of preoperative endoscopic biliary stent placement on the outcome of surgery (Saleh et al.[5]). We therefore feel that there is insufficently robust data to justify the recommendation by the guidelines that preoperative biliary drainage or before assessing resectability should be avoided. In practice, because of the delay in the work up of a patient for resectability and especially with the limited resources of the NHS, there is a danger that these patients may develop complications from their obstructed biliary system in the interim. The recommendations are not based on level A evidence but are in fact level D evidence.

In the algorithm for the management of cholangiocarcinoma, the authors state that if the lesion is resectable, patients should not have ERCP (unless infected) or percutaneous biopsy of the lesion. The implication is that patients will undergo major surgery which has a significant risk of mortality and morbidity without any prior attempt to obtain histology and therefore a definitive diagnosis. Discrimination of malignant from benign bile duct strictures is difficult although benign strictures are rare. However, up to 10% of bile duct strictures may turn out to be benign and may not be distinguishable from a malignant stricture even at surgery (Nakayama, et al.[6]). In summary, there is insufficient evidence to justify the recommendation that routine biliary drainage prior to resection or assessment for resection should be avoided. With the present data available, there is neither a positive or adverse effect of preoperative endoscopic biliary stent placement on the outcome of surgery. We also feel that prior to resection, attempts should be made to obtain histological confirmation with ERCP and brushings for cytology. If not, patients should be made aware that they may undergo resection for benign disease.

References

(1) Nakeeb A, Pitt HA. The role of preoperative biliary decompression in obstructive jaundice. Hepatogastroenterol 1995;42:332-7.

(2) Hochwald SN, Burke EC, Jarnagin WR, et al. Association of preoperative biliary stenting with increased postoperative infectious complications in proximal cholangiocarcinoma. Arch Surg 1999;134:261-6.

(3) Lai ECS, Mok FPT, Fan ST, Lo CM, Chu KM, Liu CL, et al. Preooperative endoscopc drainage for malignant obstructive jaundice. Br J Surg 1994;81:1195-8.

(4) Lygidakis NJ, van der Heyde MN, Lubbers MJ. Evaluation of preoperative biliary drainage in the surgical management of pancreatic head ccarcinoma. Acta Chir Scand 1987;153:665-8.

(5) Saleh MA, Norregaard P, Jorgensen HL, Andersen PK, Matzen P. Preoperative endoscopic stent placement before pancreaticododenoectomy: a meta-analysis of the effect on morbidity and mortality. Gastrointest Endosc 2002;56:529-34.

(6) Nakayama A, Imamura H, Shimada R, Miyagawa S, Makuuchi M, Kawasaki S. Proximal bile duct stricture disguised as malignant neoplasm. Surgery 1999;125:514-21.

Dear Editor

I read Dr Travis’ Therapy Update [1] with interest, the topic is timely in a market about to be challenged by new generic mesalazine brands. I note the choice of time dependent mesalazine (Pentasa), but, if mesalazine is to be relied upon exclusively, some evidence suggests pentasa may not be the best choice. The recent study by Kruis et al.[2] in the maintenance of remission in ulcerative colitis found that with pentasa 1.5g per day the 6 month remission rate was 56.8% compared to 77.5% with balsalazide 3g twice daily (p= 0.045).

The assertion that the advantages of the azo-bond delivery to the distal colon can be matched by simply increasing the dose of pH dependent (asacol), or time dependent release (pentasa), has not been born out by laboratory or clinical studies. Tissue level studies have indicated that double dose mesalazine is delivered to the kidney, not the colon.[3] A large clinical trial of pentasa in mild to moderate active ulcerative colitis found remission rates of 29% for both 2g/day and 4g/day.[4] This latter study highlights the lack of efficacy of mesalazine released by a time dependent delivery system in active UC. In contrast three studies comparing balsalazide with mesalazine (pH dependent release),[5-7] containing a total of 426 patients, all found balsalazide to be superior in active UC, with rapid resolution of symptoms (median 10 days in one study[5]) and superior sigmoidoscopic scores (in all three studies). Plasma concentrations of 5ASA were 4.5 fold lower in patients treated with balsalazide than mesalazine (p=0.018).[6] The patients with most to benefit are new patients with distal disease.[7] The use of 5ASA in the initial treatment of UC does not require mega doses as Dr Travis suggests, indeed mega doses of mesalazine delivered by asacol or pentasa are ineffective, but it does require a reliable delivery system, such as the azo-bond, and an inert carrier as with balsalazide. The clinical implication of this efficacy in mild to moderate active UC is that the threshold for the use of steroids can be raised. Of interest in the North American trials of balsalazide vs mesalazine, 60 patients failing mesalazine treatment were treated after the trial with balsalazide open label, with 60% response.[8]

The advocates of sulphasalazine (SASP) and those wishing to use the least expensive treatment cite trials of SASP vs. newer agents [9] and conclude that SASP is the most cost effective, these trials are in patients with known UC and specifically exclude patients who are SASP intolerant. In two recently published studies,[10,11] patients, with newly diagnosed, or previously untreated UC, were randomised to SASP or balsalazide, 34% were intolerant of SASP at the modest dose of 3g daily compared to 5% for balsalazide 6.75g daily. The number needed to treat to avoid SASP intolerance at this rate is only 3, and in new patients it seems particularly important to use well tolerated effective treatment first line and avoid the loss of confidence that drug intolerance produces.

It seems a sad reflection on the pharmaceutical industry sponsored research that the most recent trial on UC treatment with 5ASA quoted in the therapy update is from 1998. Large clinical trials of one 5ASA brand against another are expensive and the advent of generic mesalazine preparations is unlikely to improve this situation. My interpretation of recently published evidence is that the mesalazine release mechanism is important for the efficacy, reliability of delivery, and safety of the oral preparations and that balsalazide is now the gold standard for other agents to be judged against.

The author has accepted hospitality from the manufactures of all the current 5ASA preparations, and sat on an advisory panel for Shire.

References

(1) Travis SPL. Therapy update. Which 5ASA? Gut 2002;51:548-9

(2) Kruis W, Schreiber S, Theuer D, et al. Low does balsalazide (1.5g twice daily) and mesalazine (0.5g three times daily) maintained remission of ulcerative colitis but high dose balsalazide (3g twice daily) was superior in preventing relapses. Gut 2001;49:783-89

(3) Hussain FN, Ajjan RA, Riley SA. Dose loading with delayed release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters. Br J Clin Pharmacol 2000;49:323-30

(4) Hanauer S, Schwartz J, Robinson M, et al. Mesalamine capsules for treatment of active ulcerative colitis: Results of a controlled trial. Am J Gastroenterol 1993;88:1188-1197

(5) Green JRB, Lobo AJ, Holdsworth CD, et al. Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis. Gastroenterology 1998;114:15-22

(6) Levine DS, Riff DS, Pruitt R, et al. A randomized double blind dose response comparison of balsalazide 6.75g, balsalazide 2.25g and mesalamine 2.4g in the treatment of active mild-to-moderate ulcerative colitis. Am J Gastroenterol2002;97:1398-1407

(7) Pruitt R, Hanson J, Safdi M, et al. Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute ulcerative colitis. Gastroenterology 2000;118:A756

(8) Data on file. Shire pharmaceuticals Ltd.

(9) Sutherland L, Roth D, Beck P, May G, Makiyama K. Oral 5-aminosalicylic acid for inducing remission in ulcerative colitis.(Cochrane review) In the Cochrane Library, Issue 4. Oxford: Update software, 2000.

(10) Green JRB, Mansfield JC, Gibson JA, Kerr GD, Thornton PC. A double blind comparison of balsalazide 6.75g daily and sulfasalazine 3g daily in patients with newly diagnosed or recently relapsed active ulcerative colitis. Aliment Pharmacol Ther 2002;16:61-68

(11) Mansfield JC, Giaffer MH, Cann PA, et al. A double blind comparison of balsalazide 6.75g and sulfasalazine 3g as sole therapy in the management of ulcerative colitis. Aliment Pharmacol Ther 2002;16:69-77

Dear Editor

We read with interest the recent article by Gluecker et al. (Gut 2002; 51: 207-211) investigating the performance of multidetector computed tomography (MDCT) colonography in the detection of colorectal lesions in comparison with that of conventional colonoscopy. The authors concluded that MDCT colonography provides good sensitivity and specificity for the detection of colonic lesions larger than 10 mm in diameter, but certain weaknesses in the study design should be emphasised. We would like to comment further on two of these weaknesses, as they are potentially important in interpreting the results of Gluecker et al. (Gut 2002; 51: 207 -211).

First, the evaluation of MDCT colonographic data sets was performed by two observers with little (radiologist with experience of approximately 60 CT colonographic examinations) or no (gastroenterologist) experience in the procedure. We believe that this represents a major limitation to the study. It is already well known from the literature [1,2] that data interpretation of CT colonography requires a long learning process. The authors too acknowledged this key issue in the manuscript (Gluecker et al. Gut 2002; 51: 207-211). Indeed, the first reading of the MDCT colonography images identified 1/41 lesions 5 mm in diameter or smaller, 5/15 lesions between 6 and 9 mm, and 9/11 lesions 10 mm or larger. However, retrospective evaluation of the same data (i.e., a second reading) already allowed the authors to detect many of the lesions missed in the first reading session (18/40 lesions 5 mm or smaller; 7/10 lesions between 6 and 9 mm; 2/2 lesions 10 mm or larger). All lesions identified retrospectively were missed due to perceptive errors. Although perceptive errors may occur with MDCT, the high incidence of this type of errors in the study by Gluecker et al. (Gut 2002;51: 207-211) is best explained with the low experience of the observers, and should not be construed as an intrinsic limitation of MDCT colonography.

Second, it should be noted that one of the major advantages introduced by MDCT technology is represented by the ability of combining thin beam collimation (1 or 2.5 mm) with short acquisition times.[3] The use of 5 mm beam collimation considerably reduces this advantage and could explain the poor performance of MDCT in the detection of small lesions (lesions 6-9 mm, sensitivity 33 %; lesions 5 mm or smaller, sensitivity 4 %) in the hands of the authors. In particular, the use of a thin beam collimation would have significantly increased the spatial resolution of CT images with consequent improvement in image quality, while still allowing for short acquisition time and only slightly higher radiation exposure delivered to patients.[3,4]

In recent years, several studies have demonstrated that CT colonography has a performance similar to that of conventional colonoscopy in the detection of colorectal lesions 6 mm in diameter or larger.[5-7] In particular, with regard to CT colonography as peformed with thin-beam- collimation MDCT, both published[8,9] and unpublished [Laghi A, et al. Multi-slice spiral CT colonography for the detection of colorectal polyps and neoplasms, RSNA 2001, personal communication] data have shown that MDCT colonography can increase the detection rate of small lesions. In addition, the use of thin-beam-collimation MDCT colonography can reduce the number of false positive findings by enabling better assessment of the morphology and CT density of suspected lesions, thus allowing to better differentiate residual stool or hypertrophic colonic folds from colorectal lesions.[10]

We therefore believe that MDCT colonography can reliably detect lesions smaller than 10 mm (in particular those in the 6 to 9 mm range), provided that experienced readers interpret the results and that the technological potential of the current devices is fully exploited with the use of thin-beam-collimation protocols.

References

(1) Pescatore P, Gluecker T, Delarive J, et al. Diagnostic accuracy and interobserver agreement of CT colonography (virtual colonoscopy). Gut 2000; 47: 126-30.

(2) Spinzi G, Belloni G, Martegani A, et al. Computed tomographic colonography and conventional colonoscopy for colon diseases: a prospective, blinded study. Am J Gastroenterol 2001; 96: 394-400.

(3) Laghi A, Iannaccone R, Panebianco V, et al. Multislice CT colonography: technical developments. Semin Ultrasound CT MR 2001; 22: 425 -31.

(4) Laghi A, Iannaccone R, Mangiapane F, et al. Experimental colonic phantom for the evaluation of the optimal scanning technique for CT colonography using a multidetector spiral CT equipment. Eur Radiol 2002 (in press).

(5) Fenlon HM, Nunes DP, Schroy PC, et al. A comparison of virtual and conventional colonoscopy for the detection of colorectal polyps. N Engl J Med 1999; 341: 1496-503.

(6) Laghi A, Iannaccone R, Carbone I, et al. Computed tomographic colonography (virtual colonoscopy): blinded prospective comparison with conventional colonoscopy for the detection of colorectal neoplasia. Endoscopy 2002; 34: 441-6.

(7) Laghi A, Iannaccone R, Carbone I, et al. Detection of colorectal lesions with virtual computed tomographic colonography. Am J Surg 2002; 183: 124-31.

(8) Rogalla P, Meiri N, Rückert JC, et al. Colonography using multislice CT. Eur J Radiol 2000; 36: 81-5.

(9) Wessling J, Fischbach R, Domagk D, et al. Colorectal polyps: Detection with multi-slice CT colonography. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 2001; 173: 1069-71.

(10) Macari M, Bini EJ, Xue X, et al. Colorectal neoplasms: prospective comparison of thin-section low-dose multi-detector row CT colonography and conventional colonoscopy for detection. Radiology 2002 (in press).

Dear Editor

The recent report by MacDonald et al., despite provides promising findings for an effective adjuvant chemoradiotherapy of gastric cancer patients after gastrectomy has raised a numerous of questions and criticisms.[1,2] The weakness of this randomized trial and the lack of a surgical quality control have currently been extensively described [1,2,www.gastriccancer.net].

To avoid repetition, here we are focused on the importance of quality of surgery in prolonging survival. Undoubtedly, curative resection (R0) is generally accepted as the treatment of choice in gastric cancer and it has been repeatedly recognized in multivariate analyses as the most important and independent predictor of survival.[3] Although the aim of an R0 resection is primarily depended on patient's tumor stage, quality of surgery plays also an important role towards this goal. Because 90 % of the patients in this trial received a limited D0 or D1 node dissection, a substantial proportion of patients, approximately 30 %,[3] had residual disease in the level II lymph nodes (around the celiac axis), which were left behind. It is likely therefore that chemoradiotherapy prolonged survival only in these certain patients. The study raises important questions:
(a) should all patients after limited node dissection, even those with node-negative cancer, receive adjuvant chemoradiotherapy?
(b) can D0/D1 dissection plus chemoradiotherapy work better than standardized extended (D2) node dissection alone?
(c) should patients after D2 dissection receive this adjuvant regimen? Further phase III trials are needed for an evidence-based treatment-decision about chemoradiotherapy in the various subgroups of gastric cancer patients.

References

(1) Cuschieri A. Does chemoradiotherapy after intended curative surgery increase survival of gastric cancer patients? Gut 2002;50:751.

(2) Roukos DH. Adjuvant chemoradiotherapy in gastric cancer: wave goodbye to extensive surgery? Ann Surg Oncol 2002 Apr-May;9(3):220-1.

(3) Roukos DH. Current status and future perspectives in gastric cancer management. Cancer Treat Rev 2000 Aug;26(4):243-55.