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Slide 1: American Journal of Gastroenterology ISSN 0002-9270 C 2008 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2007.01482.x Published by Blackwell Publishing Preoperative Versus Postoperative Helicobacter pylori Eradication Therapy in Gastric Cancer Patients: A Randomized Trial Chan Gyoo Kim, M.D.,1 Ho June Song, M.D.,1 Myeong-Cherl Kook, M.D., Ph.D.,1 Eun Kyung Hong, M.D., Ph.D.,1 Sohee Park, Ph.D.,2 Jong Yeul Lee, M.D.,1 Jun Ho Lee, M.D.,1 Keun Won Ryu, M.D., Ph.D.,1 Young-Woo Kim, M.D. Ph.D.,1 Jae-Moon Bae, M.D., Ph.D.,1 and Il Ju Choi, M.D., Ph.D.1 1 Research Institute and Hospital and 2 Cancer Biostatistics Branch, National Cancer Center, Goyang, Korea [Correction added after online publication 21-Aug-2007. Dr. Park’s affiliation has been updated.] OBJECTIVES: Helicobacter pylori (H. pylori) eradication is strongly recommended for gastric cancer patients who undergo subtotal gastrectomy. The efficacy of proton pump inhibitor-based triple therapy for H. pylori eradication has not been adequately assessed in the gastric remnant. The aim of this study was to compare the efficacy of postoperative versus preoperative H. pylori eradication therapy. METHODS: A total of 138 distal gastric cancer patients with H. pylori infection were randomized to receive either preoperative (preop, N = 68) or postoperative (postop, N = 70) proton pump inhibitor-based triple therapy for H. pylori eradication. The regimen consisted of rabeprazole 10 mg, clarithromycin 500 mg, and amoxicillin 1,000 mg, all twice daily for 7 days. Eradication was assessed by rapid urease test and histology 12 wk after surgery. RESULTS: By intention-to-treat (ITT) analysis, H. pylori eradication rates were 84.6% (95% CI 73.5–92.4) in the preop group and 83.1% (95% CI 71.7–91.2) in the postop group (P = 0.99). By per protocol (PP) analysis, the rates were 87.3% (95% CI 76.5–94.4) in the preop group and 86.9% (95% CI 75.8–94.2) in the postop group (P = 0.99). In the postop group, eradication rates did not differ with reconstruction method (Billroth I vs II, 80.4% [95% CI 66.1–90.6] vs 89.5% [95% CI 66.9–98.7] by ITT analysis (P = 0.49), and 85.7% [95% CI 71.5–94.6] vs 89.5% (95% CI 66.9–98.7) by PP analysis, P = 0.99). CONCLUSIONS: In distal gastric cancer patients, the effect of proton pump inhibitor-based triple therapy for H. pylori eradication was not different whether given postoperatively or preoperatively. (Am J Gastroenterol 2008;103:48–54) INTRODUCTION tal gastrectomy intraoperatively, and the eradication therapy would have been unnecessary. Helicobacter pylori (H. pylori) is a primary etiological agent The efficacy of postoperative eradication therapy remains for chronic gastritis and peptic ulcer. Chronic infection by this unclear, and it could be poorer than that of preoperative ther- organism is also associated with the development of noncar- apy because gastric surgery places patients in a different con- diac gastric cancer (1–4). Thus, its eradication in postgastric dition from those with an intact stomach. Subtotal gastrec- cancer resection patients is strongly recommended (5, 6). tomy can lead to rapid or delayed gastric emptying (10, 11), H. pylori eradication by proton pump inhibitor (PPI)-based an impairment of the hydrophobic gastric mucosal barrier triple therapy is 80–90% successful in patients with pep- due to bile reflux (12), or enhanced blood flow in the remnant tic ulcer or chronic gastritis who have an intact stomach gastric body (13). These factors may affect local or systemic (7–9), and we would expect a similar success rate if the ther- delivery of antimicrobials, and enhance or compromise the apy were administered to distal gastric cancer patients be- outcome of eradication therapy. fore their surgery. Preoperative eradication therapy, however, A few studies have evaluated the efficacy of H. pylori erad- might cause clinical problems. At least 1 wk is needed for ication therapy in partial gastrectomy patients, and their erad- the eradication therapy, and potential drug-related adverse ication rates vary widely (41–90%) (14–16). These studies, events may delay surgical treatment. In some cases, the sur- however, did not have preoperative control subjects, had a geon might convert a planned subtotal gastrectomy to a to- small sample size, or used a nonstandard regimen of dual 48

Slide 2: H. pylori Eradication in Gastric Cancer Patients 49 therapy. In the present study, we investigated in a random- Determination of H. pylori Status ized controlled trial the efficacy of post- versus preoperative H. pylori infection was determined on the basis of histology PPI-based triple therapy in patients undergoing subtotal gas- and the rapid urease test. Endoscopic examination was per- trectomy for distal gastric cancer. formed with a gastroduodenoscope (GIF XQ240 or XQ260; Olympus, Tokyo, Japan) while the patient was under IV mi- MATERIALS AND METHODS dazolam (0.05 mg/kg) sedation. During initial and follow- up endoscopy, four biopsy specimens were obtained with an Study Population elongated cup forceps (Olympus FB-24k-1, Olympus) for Patients aged 18–75 yr with distal gastric carcinoma stage IA, histological examination of H. pylori: two were taken from IB, II, or IIIA (International Union Against Cancer tumor- the lesser curvature of the corpus, which was about 4 cm dis- node-metastasis classification) (17) and H. pylori infection tal to the gastroesophageal junction, and two were taken from were eligible for inclusion in this study. The cancer was eval- the greater curvature. Specimens were sectioned, stained with uated preoperatively by esophagogastroduodenoscopy with Wright-Giemsa, and examined by two experienced gastroin- biopsy, and abdominal computed tomography. The tumor had testinal pathologists who were blinded to the clinical infor- to be on the antrum or distal third of the corpus so that subtotal mation. One additional biopsy specimen was obtained from gastrectomy was feasible. the greater curvature of the corpus and subjected to a rapid Patients with recurrent gastric cancer, previous gastric urease test (Pronto Dry, Medical Instruments Corporation, surgery, severe concomitant illness (e.g., cardiac, respiratory, Solothurn, Switzerland) according to the manufacturer’s in- hepatic, or renal insufficiency), history of H. pylori eradica- structions (19). tion therapy, contraindication for study medications, or use of H. pylori infection was diagnosed at study entry if both antimicrobials in the preceding 30 days were excluded from histology and rapid urease test were positive. At follow-up the study, as were patients who underwent total gastrectomy examination, H. pylori was considered eradicated if both tests or palliative surgery, were unable to resume oral intake by were negative. 2 wk after surgery, or received antibiotics postoperatively for Adverse Reactions more than 5 days. The use of antacids, bismuth, H2 -receptor One week after completion of treatment, enrolled patients antagonists, and PPIs was not allowed during the study were interviewed and asked to respond to a questionnaire period. evaluating the onset, frequency, and intensity of adverse re- The study protocol was approved by the local ethics com- actions (taste disturbance, nausea or vomiting, diarrhea, ab- mittee of the National Cancer Center, Korea. Written in- dominal pain, headache, or dizziness) that occurred within formed consent was obtained from all participants before the 14 days that followed the start of therapy. they entered the study. Statistical Analysis Study Design We subjected the H. pylori eradication rates to intention- We conducted this study as a prospective randomized study to-treat (ITT) and per protocol (PP) analyses. All patients performed in a tertiary cancer center hospital. Esophagogas- were included in the ITT analysis, except for those who did troduodenoscopy with biopsy was performed for the diag- not receive any study drugs. Patients excluded from the ITT nosis of gastric cancer and H. pylori status for eligibility. analysis were also excluded from the PP analysis. Patients Eligible patients were assigned into either the preoperative were excluded from the PP analysis if their post-treatment (preop, study medication taken before surgery) or postoper- H. pylori status was unknown (but they were considered cases ative (postop, study medication taken 2–4 wk after surgery) of eradication failure in the ITT analysis), if they showed treatment groups. The allocation for each patient, which was poor compliance (took less than 75% of any study drug), told to the research nurse by means of a central telephone, if H. pylori evaluation was performed less than 28 days after was made from a computer-generated random number. The the end of therapy, or if they took disallowed medications. endoscopists and pathologist were blinded to the randomiza- Demographic characteristics of patients are presented as me- tion results throughout the study. However, the patients were dian (range) for age and frequency (%) for other categorical not blinded because they were told to have the medication variables. We used the nonparametric Wilcoxon rank sum test either before or after surgery according to the group they be- for continuous variables and Fisher’s exact test for categori- long to. Patients in both groups received the following twice cal variables to test the differences between two groups. H. daily for 7 days: rabeprazole 10 mg, clarithromycin 500 mg, pylori eradication rates were presented as binomial propor- and amoxicillin 1,000 mg. Follow-up esophagogastroduo- tion (in %) along with the exact 95% confidence intervals. denoscopy with biopsy was performed 12 wk after surgery P values were reported as 2-sided at a 5% significance level. to determine H. pylori status. Bile reflux into the remnant All statistical analyses were performed using SAS software stomach was defined as grade 1, its absence as grade 0 (18). version 9.1 (SAS Institute Inc., Cary, NC). Our primary interest was the eradication rate of H. pylori in pre- versus postoperative therapy. Our secondary interest was Sample Size Determination how the gastroinstestinal reconstruction method or bile reflux We calculated the sample size needed to detect a difference of into the remnant stomach affected the eradication rate. 20% in the eradication rate between the preop group (assumed

Slide 3: 50 Kim et al. to have an eradication rate of 90%) and the postop group (Table 2). The eradication rates in the postop group did not (assumed to have an eradication rate of 70%), with a power of differ significantly by the type of gastrointestinal reconstruc- 0.80 and a significance level of 0.05 (alpha = 0.05, 2-sided). tion method (Table 3) or the presence of bile reflux in the We anticipated a dropout rate of 10%. The final calculated remnant stomach (Table 4). sample size was 138 patients. Adverse Reactions RESULTS All the patients took all the medications except for one in the Patient Population postop group who stopped after three doses because the med- From September 2003 to May 2005, 470 consecutive patients ications caused vomiting. The most common adverse reac- were screened for eligibility and 138 patients were enrolled in tions, in order of frequency, were taste disturbance, diarrhea, the study (Fig. 1). Of these, 68 were randomized to the preop and abdominal pain. The incidence of adverse reactions did group and 70 to the postop group. Four patients who had a not differ significantly between the preop and postop groups total gastrectomy and 4 who did not receive the study med- (Table 5). ications were excluded. The causes of no medication were postoperative complications in the postop group (2 cases) and DISCUSSION surgery immediately after randomization in the preop group (2 cases). The remaining 130 patients, 65 in each group, were In this prospective randomized study, postoperative and included in the ITT analysis. preoperative PPI-based triple therapies were not significantly The baseline demographic characteristics were similar in different in the effect of H. pylori eradication in gastric can- both groups (Table 1). In the postop group, 46 patients under- cer patients undergoing subtotal gastrectomy. Furthermore, went Billroth I and 19 underwent Billroth II gastrointestinal neither the gastrointestinal reconstruction method (Billroth reconstruction procedures. Six patients were excluded from I or II) nor bile reflux into the remnant stomach affected the PP analysis; 4 because post-treatment H. pylori status efficacy. was not assessed and 2 because of protocol violations (one H. pylori infection is associated with gastric cancer, and for too early assessment of H. pylori and one for discontinu- the International Agency for Research on Cancer catego- ation of medication due to adverse reactions). A total of 124 rizes the organism as a human carcinogen (4). Asian (5) and patients, 63 in the preop and 61 (42 Billroth I, 19 Billroth II European (6) guidelines strongly recommend the eradica- reconstruction) in the postop group, were analyzed on the PP tion of H. pylori in cancer patients undergoing gastric re- basis. section. In a meta-analysis, mean H. pylori eradication rates with PPI-based triple therapy with clarithromycin and amox- H. pylori Eradication icillin were 81% (95% CI 79–83) by ITT and 84% (82– The H. pylori eradication rates in the preop and postop groups 86%) by PP in patients with intact stomachs (8). The con- did not differ significantly by both the ITT and PP analyses ditions in cancer patients who have gastric remnants as a Figure 1. Flowchart. This flow diagram shows the number of patients entered into and withdrawn from the study. TG = total gastrectomy; ITT = intention-to-treat; PP = per protocol.

Slide 4: H. pylori Eradication in Gastric Cancer Patients 51 Table 1. Demographic Characteristics of Patients Randomized to the Table 3. Helicobacter pylori Eradication Rates According to Re- Preop or Postop Group Included in the Intention-to-Treat Analysis construction Procedure (N = 65 for Each Group) Reconstruction Method in Postop Group Preop Postop P∗ Billroth I Billroth II P∗ Male/female (N) 45/20 45/20 1.00 Median age (range), yr 57 (26–75) 57 (24–75) 0.71 ITT analysis Reconstruction method % Eradication (ratio) 80.4 (37/46) 89.5 (17/19) 0.49 Billroth I/II (N) 46/19 46/19 1.00 95% CI 66.1–90.6 66.9–98.7 Clinical stage (N) 0.81 PP analysis I 48 45 % Eradication (ratio) 85.7 (36/42) 89.5 (17/19) 0.99 II 12 15 95% CI 71.5–94.6 66.9–98.7 IIIA 5 5 ITT = intention-to-treat; PP = per protocol; CI = confidence interval. ∗ Lauren classification (N) 0.69 Billroth I versus Billroth II, 2-sided P values obtained from Fisher’s exact test. Intestinal 34 37 Diffuse 30 26 Mixed 1 2 systemic delivery (21–24). In gastric remnants, the transfer barriers may change as a result of bile reflux into the stom- Preop = preoperative treatment group; Postop = postoperative treatment group. ∗ Two-sided P values obtained from Wilcoxon rank sum test for age and Fisher’s exact ach (12, 25) or a change in gastric blood flow (13), which in test for all other variables. turn would influence the permeability and drug concentration gradient. Gastric luminal pH is another important factor that af- result of surgery, however, are different. Successful treat- fects the efficacy of H. pylori eradication therapy. Co- ment depends, in part, on adequate gastric concentrations administration of antisecretory drugs to increase intragastric of antimicrobials that are delivered into the lumen either pH substantially improves the efficacy of the therapy by de- directly via oral administration or indirectly via the circu- creasing gastric mucus viscosity, which enhances antibiotic lation (20). Given the unique intragastric environment, the penetration (26), or by stabilizing the activity of acid-labile bioavailability of anti-H. pylori drugs is determined by local antimicrobials such as clarithromycin (27, 28). Vagotomy and or systemic factors such as drug residence time, mucosal bar- antrectomy, together with alkaline reflux, may create a favor- riers, gastric blood flow, and luminal pH. These factors are able environment in the remnant stomach for anti-H. pylori altered inevitably in the postoperative remnant stomach, and therapy by increasing intragastric pH or by reducing gastric thus are likely to affect the efficacy of antimicrobials against mucus barrier function. Estimating the effect of each of these H. pylori. factors on eradication therapy is difficult because of the lack After partial gastrectomy, gastric emptying is either ac- of standardized models and the heterogeneity of their contri- celerated secondary to the removal of the antro-pylorus or bution. However, our results showed that the efficacy of post- slowed due to motility disturbance in the gastric remnant or operative H. pylori eradication therapy was not significantly efferent loop (10, 11). In the former situation, drugs may not different from that of the preoperative one. Thus, we could stay in the stomach long enough to reach topical therapeutic conclude that physiological changes in the remnant stomach levels and not be absorbed in the proximal intestine to reach might not exert an adverse effect collectively on the efficacy effective systemic concentrations. In the latter situation, dys- of H. pylori therapy. motility may hamper the even distribution of drugs within the PPI-based H. pylori eradication therapy is more effec- gastric remnant. H. pylori colonizes mainly the mucus layer tive with two antibiotics than with one antibiotic in pa- and adheres to gastric epithelial cells. To eradicate the or- tients with an intact stomach (29–31). PPI-based dual ther- ganism, antimicrobials must cross the mucosal barriers from apy in patients with a remnant stomach also showed low the luminal space on local delivery or from the blood on eradication rates (50–70%) (14), while reported rates for Table 2. Helicobacter pylori Eradication Rates in Preop and Postop Table 4. Helicobacter pylori Eradication Rate According to Pres- Groups (N = 65 for Each Group) by Intention-to-Treat and Per ence or Absence of Bile Reflux into the Remnant Stomach Protocol Analysis % Eradication (Ratio) Preop Postop P∗ Bile + Bile − P∗ ITT analysis All (N = 124) 88.4 (38/43) 81.5 (66/81) 0.44 % Eradication (ratio) 84.6 (55/65) 83.1 (54/65) 0.99 95% CI 74.9–96.1 71.3–89.2 95% CI 73.5–92.4 71.7–91.2 Preop (N = 63) 89.5 (17/19) 77.3 (34/44) 0.32 PP analysis 95% CI 66.9–98.7 62.2–88.5 % Eradication (ratio) 87.3 (55/63) 86.9 (53/61) 0.99 Postop (N = 61) 87.5 (21/24) 86.5 (32/37) 0.99 95% CI 76.5–94.4 75.8–94.2 95% CI 67.6–97.3 71.2–95.5 Preop = preoperative treatment group; Postop = postoperative treatment group; ITT Bile + = presence of bile; Bile − = absence of bile; Preop = preoperative treatment = intention-to-treat; PP = per protocol; CI = confidence interval. group; Postop = postoperative treatment group; CI = confidence interval. ∗ ∗ Two-sided P values obtained from Fisher’s exact test. Bile presence versus absence, 2-sided P values from Fisher’s exact test.

Slide 5: 52 Kim et al. Table 5. Incidence Rate of Treatment-Related Adverse Reactions reported to be significantly lower in Billroth II than in Bill- Adverse Reaction % (Ratio) in Preop % (Ratio) in Postop P∗ roth I reconstruction, probably due to more severe bile reflux (39), our study showed that neither reconstruction method Taste disturbance 58.5 (38/65) 50.8 (33/65) 0.48 Nausea/vomiting 4.6 (3/65) 6.2 (4/65) 0.99 nor bile reflux affected the efficacy of postoperative eradi- Diarrhea 23.1 (15/65) 16.9 (11/65) 0.51 cation therapy. This could be because (a) the time (about 12 Abdominal pain 15.4 (10/65) 6.2 (4/65) 0.16 wk) from surgery to H. pylori evaluation was too short for Headache/dizziness 1.5 (1/65) 3.1 (2/65) 0.99 the chronic effect of bile reflux to become evident, or (b) H. Preop = preoperative treatment group; Postop = postoperative treatment group. pylori eradication therapy was so effective that the propor- ∗ Preop versus postop, 2-sided P values from Fisher’s exact test. tion of treatment failure was too small to be affected by bile reflux. Compliance in the two arms was similar. The incidence PPI-based triple therapy are 41% (16), 90% (15), and 93% rates of drug-related adverse reactions were also similar, and (32) (PP analysis). While the studies with the lowest and they were comparable to rates reported in recent studies that highest rates did not have preoperative controls (16, 32), evaluated the efficacy of triple therapy consisting of PPI, the study that reported the 90% rate had a comparable 88% clarithromycin, and amoxicillin (40–42). Although an ear- rate in the nonsurgery patients (15). However, the number lier study (9) reported a lower prevalence of taste disturbance of subjects in that study was too small (N = 20), and the (11%)—a common side effect of clarithromycin—than we time from operation to eradication therapy was long (more found (>50%), a recent large-scale study (40) and two stud- than 5 yr). It is difficult to interpret eradication rates in the ies that focused on the side effects of eradication therapy (41, gastric remnant without comparable control subjects (pre- 42) showed prevalence rates (50–67%) that were comparable operative arm) and an adequate sample size because con- with ours. Other side effects, such as loose stools and nausea founding factors such as local prevalence rates of antibiotic- and vomiting, were transient and well tolerated except by one resistant H. pylori could influence the eradication rates (33). patient, as noted. In our study, all patients underwent subtotal gastrectomy and In summary, in patients undergoing subtotal gastrectomy had the same disease (distal gastric adenocarcinoma). They for distal gastric cancer, 1 wk of rabeprazole-amoxicillin- were randomized to preoperative and postoperative treatment clarithromycin therapy administered postoperatively was as groups whose demographics did not differ significantly. In effective and as well tolerated as the same therapy adminis- both groups, the therapy was confined to the perioperative pe- tered preoperatively. In addition, the efficacy was not affected riod, and H. pylori infection status was determined 12 wk after by Billroth reconstruction method or bile reflux. surgery. All patients were given prophylactic antibiotics for 3 days, beginning 1 h before surgery. We used IV first generation ACKNOWLEDGMENTS cephalosporin (cefazolin, 1 g, three times per day) and amino- glycoside (amikacin, 15 mg/kg body weight once daily) be- This work was supported by grant 0310050 from the National cause gastric cancer surgery is a clean-contaminated wound Cancer Center, Korea. The authors thank Se Eun Lee, RN, (34). In vitro, H. pylori is far less sensitive to those drugs for her expert coordination skills. than to amoxicillin (35). Moreover, the duration of the pro- phylactic antibiotic administration was short (3 days) and it STUDY HIGHLIGHTS was not accompanied by a proton pump inhibitor. Thus, we believe that any H. pylori eradication caused by the prophy- What Is Current Knowledge lactic treatment would be much less than the 25% caused r H. pylori eradication is strongly recommended for gas- by amoxicillin and clarithromycin dual therapy without PPI tric cancer patients who undergo subtotal gastrectomy. for 7 days at the recommended doses (9). Furthermore, r The efficacy of proton pump inhibitor-based triple ther- the prophylactic antibiotics were not likely to confound the apy for H. pylori eradication has not been adequately study results because they were given to all patients in both assessed in the gastric remnant. groups. After subtotal gastrectomy, postgastrectomy syndromes What Is New Here such as the dumping and afferent loop syndrome or bile reflux r In patients undergoing subtotal gastrectomy for dis- gastritis sometimes develop (36). Bile suppresses H. pylori growth and has the potential to eradicate the organism in tal gastric cancer, 1 wk of rabeprazole-amoxicillin- patients with subtotal gastrectomy (37). Billroth I and II re- clarithromycin therapy administered postoperatively construction methods allow bile reflux; they therefore cause was as effective and as well tolerated as the same ther- apy administered preoperatively. more severe gastritis with decreased H. pylori infection than r The efficacy was not affected by Billroth reconstruction the jejunal interposition reconstruction method that prevents bile reflux (38). Although the H. pylori infection rate was method or bile reflux.

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Slide 7: 54 Kim et al. 38. Abe H, Murakami K, Satoh S, et al. Influence of bile reflux and Helicobacter pylori infection on gastritis in the rem- CONFLICT OF INTEREST nant gastric mucosa after distal gastrectomy. J Gastroenterol 2005;40:563–9. Guarantor of the article: Il Ju Choi, M.D., Ph.D. 39. Tomtitchong P, Onda M, Matsukura N, et al. Helicobac- Specific author contributions: Chan Gyoo Kim: obtain- ter pylori infection in the remnant stomach after gastrec- ing informed consent, endoscopy, data analysis, drafting the tomy: With special reference to the difference between Bill- manuscript; Ho June Song: obtaining informed consent, en- roth I and II anastomoses. J Clin Gastroenterol 1998;27: doscopy, data analysis, drafting of the manuscript; Myeong- S154–8. 40. Katelaris PH, Forbes GM, Talley NJ, et al. A randomized Cherl Kook: histological analysis; Eun Kyung Hong: histo- comparison of quadruple and triple therapies for Helicobac- logical analysis; Sohee Park: statistical analysis; Jong Yeul ter pylori eradication: The QUADRATE Study. Gastroen- Lee: obtaining informed consent, endoscopy; Jun Ho Lee: terology 2002;123:1763–9. surgery and monitoring postoperative complications; Keun 41. Nista EC, Candelli M, Cremonini F, et al. Bacillus clausii Won Ryu: surgery and monitoring postoperative complica- therapy to reduce side-effects of anti-Helicobacter py- lori treatment: Randomized, double-blind, placebo con- tions; Young-Woo Kim: surgery and monitoring postopera- trolled trial. Aliment Pharmacol Ther 2004;20:1181– tive complications; Jae-Moon Bae: surgery and monitoring 8. postoperative complications; Il Ju Choi: design of the trial, 42. Myllyluoma E, Veijola L, Ahlroos T, et al. Probiotic supple- endoscopy, interpretation of the data. mentation improves tolerance to Helicobacter pylori eradi- Financial support: This work was supported by grant cation therapy–a placebo-controlled, double-blind random- ized pilot study. Aliment Pharmacol Ther 2005;21:1263– 0310050 from the National Cancer Center, Korea. 72. Potential competing interests: None.