550038

research-article2014

ICTXXX10.1177/1534735414550038Integrative Cancer TherapiesLee et al

Article

Dietary Supplement Use Among Patients With Hepatocellular Carcinoma

Integrative Cancer Therapies 2015, Vol. 14(1) 35­–41 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1534735414550038 ict.sagepub.com

Valerie Lee, MD1, Abhishek Goyal, MD, MPH1, Christine C. Hsu, MD1, Judith S. Jacobson, DrPH, MBA1, Rosa D. Rodriguez, MD1, and Abby B. Siegel, MD, MS1

Abstract Background. More than 50% of US adults, and an even larger proportion of cancer patients, use dietary supplements. Since many supplements require hepatic metabolism, they may be particularly likely to cause toxicities in patients with hepatocellular carcinoma (HCC). However, little is known about supplement use in patients with HCC. Methods. From 2008 to 2012, we gave newly diagnosed HCC patients at our institution a standardized questionnaire about dietary supplement use, demographic factors, and clinical characteristics. We then followed patients for four years or until time to death to examine the relationship with supplement use. Results. Of 146 patients, 71% had used vitamins and 45% herbal supplements. Most commonly used supplements were antioxidants (51%), multivitamins (46%), vitamin D (25%), and milk thistle (23%). People in mid-higher income brackets were more likely to use herbal supplements (19% of those earning $60 000 used supplements). Hepatitis C (HCV) patients were more likely to use milk thistle than those without HCV (30% vs 13%, P = .03), and patients with hepatitis B (HBV) were more likely than non-HBV patients to use vitamin C (32% vs 14%, P = .01). Supplement use was not associated with overall survival. Conclusions. Like cancer patients in other studies, the majority of our HCC patients used dietary supplements. Supplement use was not associated with overall survival but should be studied in larger patient samples. Keywords hepatocellular carcinoma, vitamins, dietary supplements, complementary therapies, milk thistle, survival

Introduction From 1975 to 2005, the incidence of hepatocellular carcinoma (HCC) tripled in the United States.1 Although HCC patients diagnosed in early stages may receive curative therapy, treatment options are limited for those with advanced disease.2 Many patients with cancer or liver disease take dietary supplements often without informing their providers, hoping to improve their health and/or quality of life.3,4 According to data from the National Health and Nutrition Examination Surveys (NHANES) III, dietary supplement use has increased from 42% in the period between 1988 and 1994 to 53% from 2003 to 2006 in the general population.5,6 Supplement use is common in patients with cancer (26% to 87%) and in patients with liver disease (27% to 43%),7-9 despite the lack of clear evidence regarding efficacy or safety.7,10,11 Our goal was to measure the prevalence of dietary supplement use in a prospective study of subjects with HCC and to determine demographic and clinical characteristics associated with supplement use. In this study, we also examined

whether use of these agents was associated with overall survival. To our knowledge, this study is the first to assess supplement use and survival prospectively in a US HCC cohort.

Materials and Methods Study Population From October 2008 to November 2012, we recruited 146 HCC patients to participate in the study and followed them until December 2012. Patients were eligible if they were age 18 years or older and had an HCC diagnosis based on American Association for the Study of Liver Diseases (AASLD) guidelines, or biopsy. Previous resection or locoregional therapy were allowed as long as measurable disease was seen on imaging by Response Evaluation 1

Columbia University, New York, NY, USA

Corresponding Author: Abby B. Siegel, 622 W 168th Street, 14th Floor 105C, New York, NY 10032, USA. Email: [email protected]

36 Criteria in Solid Tumors (RECIST). Exclusion criteria included a diagnosis of another malignancy within the last 5 years, decompensated Child-Pugh (CP) B or C liver disease, prior liver transplant, or prior systemic therapy for HCC.

Measures On enrollment, subjects completed a questionnaire examining demographic factors (race, ethnicity, education level, employment, and income status), medications (including dosing, frequency, indication, and timing of usage), and social history (including drug, tobacco, and alcohol use [categorized as having consumed 2 or more standard drinks per day (28 g) for more than a year at any point in the patient’s life]). Subjects were asked about their use of supplements, specifically multivitamins, vitamins A, B-complex, C, D, and E, calcium, DHEA, gingko biloba, ginseng, glucosamine chondroitin, milk thistle, St John’s wort, and echinacea; participants were also asked for names of any additional supplements used. Baseline blood samples were drawn, including complete blood count, basic metabolic panel, liver function, coagulation function, and tumor markers (including α-fetoprotein [AFP] levels). We also checked a viral hepatitis panel, autoimmune serologies (antinuclear antibody, antismooth muscle antibody, antimitochondrial antibody), iron studies, ceruloplasmin, and α-1 antitrypsin levels to determine etiology of liver disease. Diabetes diagnosis was based on fasting glucose level, hemoglobin A1c, or clinical history obtained through the medical record system. Nonalcoholic steatohepatitis was defined as having an elevated body mass index or diabetes, with no other underlying cause of liver disease. Radiologic, pathologic, and laboratory reports were collected from the electronic medical record at the time of enrollment and were used to calculate CP score and Barcelona Clinic Liver Cancer (BCLC) stage. Survival data were obtained from hospital records and the Social Security Death Index. The protocol was approved by our university’s institutional review board, and written informed consent was obtained from all subjects.

Statistical Analysis Associations between the use of different supplements and baseline clinical characteristics of study participants (all as categorical variables) were analyzed using χ2 tests. Each supplement was analyzed individually and in the following categories: vitamins (A, B-complex, C, D, E), antioxidants (vitamins C, E, and selenium), and herbal supplements (nonvitamin dietary supplements). Kaplan–Meier plots and Cox proportional hazard models were used to determine the associations between each supplement use and time to death.

Integrative Cancer Therapies 14(1) Variables that were clinically relevant and showed statistical significance in univariable analysis were included in the multivariable Cox proportional hazards models. Subjects contributed person-time to the study from the date of enrollment to the date of death/date of censoring. Subjects were censored if they were either lost to follow-up or at the end of the study period (December 2012). Baseline overall supplement use was not different for the 18 patients that were lost to follow-up compared with the rest of the cohort. All tests of statistical significance were 2-sided. All analyses were done using SAS, Version 9.3 (SAS Institute Inc, Cary, NC).

Results Of 146 patients in our cohort, 115 (79%) were men. The median age at enrollment was 62 years. Many subjects had more than one underlying etiology of cirrhosis: 60% had underlying hepatitis C virus (HCV), 38% had hepatitis B virus (HBV), 27% reported significant alcohol use, and 33% had diabetes. Overall, 57% of subjects initially met the Milan criteria by imaging (disease limited to the liver without vascular invasion, with 1 lesion 5 cm or less or 3 lesions each less than 3 cm). Not all patient records had complete data in each category; we excluded patients from analyses who lacked relevant data. Overall, 71% of subjects reported using vitamins prior to or at the time of their HCC diagnosis, and 45% reported using herbal supplements. Most commonly used were antioxidants (51%), multivitamins (46%), vitamin D (25%), and milk thistle (23%). Vitamin use overall and vitamin D use were more common in women than in men (82% vs 68%, P = .15, and 43% vs 21%, P = .02, respectively) (Table 1 and Supplemental Table 1; supplemental tables are available online at http://ict.sagepub.com/supplemental). Only 19% of patients earning $60 000 Employment  Unemployed  Employed Alcohol use  Negative  Positive HCV  Negative  Positive HBV  Negative  Positive NASH  Negative  Positive Child-Pugh score  A  B BCLC stage   0 or A   B or C AFP   ≤47.9  >47.9

Uses Any Vitamin, N = 94 (71%)

Uses No Vitamin, N = 39 (29%)

71 (68) 23 (82)

33 (32) 5 (18)

47 (71) 47 (71)

19 (29) 19 (29)

45 (67) 11 (79) 33 (71)

22 (33) 3 (21) 13 (29)

68 (72) 23 (70)

26 (28) 10 (30)

52 (66) 42 (78)

27 (34) 12 (22)

25 (63) 17 (74) 36 (72)

15 (38) 6 (26) 14 (28)

53 (72) 38 (72)

21 (28) 15 (28)

67 (72) 26 (68)

26 (28) 12 (32)

42 (75) 52 (68)

14 (25) 24 (32)

59 (73) 35 (67)

22 (27) 17 (33)

80 (69) 14 (88)

36 (31) 2 (12)

63 (74) 30 (67)

22 (26) 15 (33)

34 (69) 60 (71)

15 (31) 24 (29)

49 (77) 43 (65)

15 (23) 23 (35)

P Value

Uses Any Herb, N = 45 (34%)

Uses No Herbs, N = 86 (66%)

.15 33 (32) 12 (43)

69 (68) 16 (57)

21 (32) 24 (37)

44 (68) 41 (63)

21 (32) 3 (21) 19 (41)

44 (68) 11 (79) 27 (59)

32 (35) 12 (35)

59 (65) 22 (65)

24 (30) 21 (40)

55 (70) 32 (60)

8 (19) 11 (50) 16 (34)

34 (81) 11 (50) 31 (66)

20 (27) 24 (47)

55 (73) 27 (53)

34 (37) 10 (28)

59 (63) 26 (72)

16 (30) 29 (38)

37 (70) 48 (62)

25 (31) 20 (40)

56 (69) 30 (60)

40 (35) 5 (33)

75 (65) 10 (67)

31 (37) 13 (29)

52 (63) 32 (71)

15 (31) 30 (37)

34 (69) 52 (63)

21 (34) 24 (36)

41 (66) 42 (64)

1.00

.67

.77

.14

.53

.99

.68

.41

.49

.12

.37

.80

.15

P Value .30     .58     .34       .99     .24     .04       .02     .35     .38     .28     .91     .34     .49     .77    

Abbreviations: HCV, hepatitis C virus; HBV, hepatitis B virus; NASH, nonalcoholic steatohepatitis; BCLC, Barcelona Clinic Liver Cancer; AFP, α-fetoprotein. a Data are presented as n (%).

Discussion The American Cancer Society recommends that patients not use dietary supplements, particularly while receiving radiation

or chemotherapy.12 In our single-institution study, at the time of diagnosis, 71% of patients reported prior vitamin use and 45% reported using some form of herbal supplement. Like

38

Integrative Cancer Therapies 14(1)

Figure 1.  Kaplan–Meier survival curves for (A) any vitamin, (B) antioxidants, (C) herbal supplements, and (D) milk thistle.

other studies of cancer patients, ours found supplement users to be more educated and more often female than nonusers,5 but the differences were not statistically significant. Although dietary supplements have been popularized as preventive agents against cancer, the US Preventive Services Task Force has found insufficient evidence to support this use, and a recent editorial in the Annals of Internal Medicine recommended strongly against supplement use for this purpose.13-15 However, observational studies have shown that vegetables and fruits high in antioxidants may be protective against some cancers, and the Physicians Health Study II showed that use of multivitamins may provide a small, but significant, decrease in risk of cancer.16,17 In addition, the Vitamin D and OmegaA-3 Trial (VITAL) suggest that grapeseed extract may protect against prostate cancer, and fish oil may protect against breast cancer.18,19 In contrast, in the Alpha-Tocopherol, Beta-Carotene (ATBC) and the Beta-Carotene and Retinol Efficacy trials, highdose β-carotene was associated with an 18% increase in risk of lung cancer (although in ATBC, vitamin E users had a 32% lower risk of prostate cancer than nonusers).20-22 A

recent study using NHANES III data suggested a more complex relationship between various antioxidant levels and overall mortality,23 as those with antioxidant insufficiency were at higher risk of cardiovascular and cancer mortality, but the benefit of higher serum levels of supplements plateaued. Similarly, in prior studies in Linxian, China, remediating some known vitamin insufficiencies helped decrease mortality from esophageal and gastric cancer; however, supplementation in well-nourished populations in Venezuela did not show as beneficial an effect in preventing gastric cancer.24-26 The idea that antioxidants might protect cancer cells from effects of cytotoxic chemotherapy or radiation is not yet clearly supported by evidence.11,27 However, the ability to study supplement use rigorously in both cancer prevention and treatment has been limited by the lack of standardization of supplement formulations and dosing.28-30 Despite the unclear benefits of supplements, use tends to increase after a cancer diagnosis.8,9,31 In 1998, Ernst and Cassileth reported a systematic review of 26 studies evaluating complementary alternative medicine (CAM) use in cancer patients, and they found that 40% of patients reported

39

Lee et al Table 2.  Hazard Ratios for Supplements Use and Overall Survival as Adjusted for Known Risk Factors for Mortality in Patients With HCC. Hazard Ratio (95% CI)

  Any vitamin Multivitamins Vitamin C Vitamin D Vitamin E Antioxidants Any herb Milk thistle

Unadjusted

Adjusted for Alcohol Use, AFP, CP Score, and BCLC Stage

0.95 (0.51-1.78) 1.15 (0.65-2.01) 1.09 (0.56-2.12) 1.20 (0.64-2.22) 1.11 (0.54-2.29) 1.28 (0.75-2.20) 1.13 (0.62-2.09) 1.78 (0.90-3.52)

1.22 (0.62-2.38) 1.44 (0.78-2.69) 0.89 (0.43-1.88) 0.97 (0.50-1.89) 0.71 (0.32-1.56) 1.16 (0.66-2.05) 1.13 (0.60-2.14) 1.67 (0.83-3.36)

Abbreviations: HCC, hepatocellular carcinoma; CI, confidence interval; AFP, α-fetoprotein; CP, Child-Pugh score; BCLC, Barcelona Clinic Liver Cancer.

alternative medicine use. This review was limited as each individual study defined CAM differently, including both nonpharmacologic treatments and dietary supplements.32 Subsequent meta-analyses through 2008 have showed the continued rise of supplement use to 64% to 81% among cancer patients.9 Prostate cancer patients are generally the least likely to report supplement use (26% to 35%), while breast cancer patients tend to be more likely to report use (67% to 87%).9 International studies confirm the increased use of alternative medicine among cancer patients worldwide.8,29,31,33 This use is also often not disclosed to treating oncologists, in part due to discordant beliefs of patients and healthcare providers regarding the benefits of supplements.34 Gender differences may be partially responsible for the differences between prostate and breast cancer patients in reported use of supplements. However, although our sample was predominantly male (79%), many of our patients were supplement users, perhaps because of their concurrent or previously diagnosed liver disease. In studies of patients with chronic liver disease, 27% to 39% reported alternative medicine use, and among Canadian patients with hepatitis C, 46% reported using dietary supplements.35-37 Vitamin E and other antioxidants have been evaluated in treatment of nonalcoholic fatty liver disease,38 and remedies such as milk thistle (Silybum marianum) have been used for centuries as treatments for liver disease.39 A recent randomized controlled trial of 154 patients with chronic HCV showed no effect of high dose oral silymarin on hepatic function or viral load, although several smaller studies showed suppression of HCV viral load with high-dose IV milk thistle.40,41 Other herbal remedies marketed for patients with liver disease, such as licorice root, phyllanthus, or Liv52, continue to be studied, but are used by less than 1% of

the population of patients with liver disease,37 and none of the participants in our study reported using these supplements. Patients with HCC are at risk for drug–drug interactions that may be exacerbated by complications of cirrhosis (hypoalbuminemia, alterations of P450 systems, coagulation abnormalities, etc).42-44 Reassuringly, we found no significant adverse relationship between supplement use and survival. However, our observation that milk thistle users had slightly higher overall mortality than nonusers is potentially worrisome in light of a recent study of milk thistle use among patients with advanced liver disease. The study was closed early due to higher than expected early mortality.45 These studies call for further study of supplement use among HCC patients. Our findings also reinforce recommendations that physicians discuss supplement use with patients to minimize potential risks and drug interactions. Our study involved a relatively small cohort at a single institution. However, our institution is a quaternary referral center that also serves as a primary care center for a diverse patient population. Another limitation is that we were not able to collect data on time period, duration, and dosage of supplements for most patients. Future studies should attempt to elicit more specifics regarding both supplement use and the clinical features and outcomes of those using and not using supplements. Our study found that general supplement use was widespread among our HCC patients. Though we saw no overall survival benefit of supplements, subgroups with vitamin/supplement insufficiency may benefit more from supplementation than those who have adequate levels of micronutrients. Future studies might measure serum levels to examine that possibility. Further studies of the relationship of supplement use with outcomes among patients with HCC should provide a basis for more informed discussions between patients and providers.

Conclusion Our study showed that the majority of patients with HCC use some form of dietary supplements. We found no clear association between supplement use and survival, but future studies may benefit from identifying subgroups that may be more affected by dietary supplementation. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: NIH K23 CA 149084-01 A1 and the Steven J. Levinson Medical Research Foundation (ABS).

40 References 1. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol. 2009;27: 1485-1491. 2. Benson AB 3rd, Abrams TA, Ben-Josef E, et al. NCCN clinical practice guidelines in oncology: hepatobiliary cancers. J Natl Compr Canc Netw. 2009;7:350-391. 3. Saxe GA, Madlensky L, Kealey S, Wu DP, Freeman KL, Pierce JP. Disclosure to physicians of CAM use by breast cancer patients: findings from the Women’s Healthy Eating and Living Study. Integr Cancer Ther. 2008;7:122-129. 4. Luk JM, Wang X, Liu P, et al. Traditional Chinese herbal medicines for treatment of liver fibrosis and cancer: from laboratory discovery to clinical evaluation. Liver Int. 2007;27:879-890. 5. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008;(12):1-23. 6. Gahche J, Bailey R, Burt V, et al. Dietary supplement use among U.S. adults has increased since NHANES III (19881994). NCHS Data Brief. 2011;(61):1-8. 7. Bjelakovic G, Gluud LL, Nikolova D, Bjelakovic M, Nagorni A, Gluud C. Antioxidant supplements for liver diseases. Cochrane Database Syst Rev. 2011;(3):CD007749. 8. Girgis A, Adams J, Sibbritt D. The use of complementary and alternative therapies by patients with cancer. Oncol Res. 2005;15:281-289. 9. Velicer CM, Ulrich CM. Vitamin and mineral supplement use among US adults after cancer diagnosis: a systematic review. J Clin Oncol. 2008;26:665-673. 10. Kushi LH, Byers T, Doyle C, et al. American Cancer Society Guidelines on Nutrition and Physical Activity for cancer prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J Clin. 2006;56:254-281. 11. Ladas EJ, Jacobson JS, Kennedy DD, Teel K, Fleischauer A, Kelly KM. Antioxidants and cancer therapy: a systematic review. J Clin Oncol. 2004;22:517-528. 12. Doyle C, Kushi LH, Byers T, et al. Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices. CA Cancer J Clin. 2006;56:323-353. 13. Martinez ME, Jacobs ET, Baron JA, Marshall JR, Byers T. Dietary supplements and cancer prevention: balancing potential benefits against proven harms. J Natl Cancer Inst. 2012;104:732-739. 14. Fortmann SP, Burda BU, Senger CA, Lin JS, Whitlock EP. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: an updated systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013;159:824-834. 15. Guallar E, Stranges S, Mulrow C, Appel LJ, Miller ER 3rd. Enough is enough: stop wasting money on vitamin and mineral supplements. Ann Intern Med. 2013;159:850-851. 16. Hercberg S, Galan P, Preziosi P, Alfarez MJ, Vazquez C. The potential role of antioxidant vitamins in preventing cardiovascular diseases and cancers. Nutrition. 1998;14: 513-520.

Integrative Cancer Therapies 14(1) 17. Gaziano JM, Sesso HD, Christen WG, et al. Multivitamins in the prevention of cancer in men: the Physicians’ Health Study II randomized controlled trial. JAMA. 2012;308:1871-1880. 18. Brasky TM, Kristal AR, Navarro SL, et al. Specialty supplements and prostate cancer risk in the VITamins and Lifestyle (VITAL) cohort. Nutr Cancer. 2011;63:573-582. 19. Brasky TM, Lampe JW, Potter JD, Patterson RE, White E. Specialty supplements and breast cancer risk in the VITamins and Lifestyle (VITAL) Cohort. Cancer Epidemiol Biomarkers Prev. 2010;19:1696-1708. 20. Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for preventing gastrointestinal cancers. Cochrane Database Syst Rev. 2008;(3):CD004183. 21. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The AlphaTocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994;330:1029-1035. 22. Watters JL, Gail MH, Weinstein SJ, Virtamo J, Albanes D. Associations between alpha-tocopherol, beta-carotene, and retinol and prostate cancer survival. Cancer Res. 2009;69:3833-3841. 23. Goyal A, Terry MB, Siegel AB. Serum antioxidant nutrients, vitamin A, and mortality in US adults. Cancer Epidemiol Biomarkers Prev. 2013;22:2202-2211. 24. Blot WJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/ mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst. 1993;85:1483-1492. 25. Qiao YL, Dawsey SM, Kamangar F, et al. Total and cancer mortality after supplementation with vitamins and minerals: follow-up of the Linxian General Population Nutrition Intervention Trial. J Natl Cancer Inst. 2009;101:507-518. 26. Taylor PR. Prevention of gastric cancer: a miss. J Natl Cancer Inst. 2007; 99(2):101-3. 27. Greenlee H, Hershman DL, Jacobson JS. Use of antioxidant supplements during breast cancer treatment: a comprehensive review. Breast Cancer Res Treat. 2009;115:437-452. 28. Newmaster SG, Grguric M, Shanmughanandhan D, Ramalingam S, Ragupathy S. DNA barcoding detects contamination and substitution in North American herbal products. BMC Med. 2013;11:222. 29. Tascilar M, de Jong FA, Verweij J, Mathijssen RH. Complementary and alternative medicine during cancer treatment: beyond innocence. Oncologist. 2006;11:732-741. 30. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst. 2008;100:773-783. 31. Choi JY, Chang YJ, Hong YS, et al. Complementary and alternative medicine use among cancer patients at the end of life: Korean national study. Asian Pac J Cancer Prev. 2012;13:1419-1424. 32. Ernst E, Cassileth BR. The prevalence of complementary/ alternative medicine in cancer: a systematic review. Cancer. 1998;83:777-782. 33. Hyodo I, Amano N, Eguchi K, et al. Nationwide survey on complementary and alternative medicine in cancer patients in Japan. J Clin Oncol. 2005;23:2645-2654.

Lee et al 34. Richardson MA, Masse LC, Nanny K, Sanders C. Discrepant views of oncologists and cancer patients on complementary/ alternative medicine. Support Care Cancer. 2004;12:797-804. 35. Ferrucci LM, Bell BP, Dhotre KB, et al. Complementary and alternative medicine use in chronic liver disease patients. J Clin Gastroenterol. 2010;44:e40-e45. 36. White CP, Hirsch G, Patel S, Adams F, Peltekian KM. Complementary and alternative medicine use by patients chronically infected with hepatitis C virus. Can J Gastroenterol. 2007;21:589-595. 37. Strader DB, Bacon BR, Lindsay KL, et al. Use of complementary and alternative medicine in patients with liver disease. Am J Gastroenterol. 2002;97:2391-2397. 38. Mullin GE. The use of complementary and alternative medicine for liver disease: part I. Nutr Clin Pract. 2013;28:138-139. 39. Flora K, Hahn M, Rosen H, Benner K. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol. 1998;93:139-143. 40. Fried MW, Navarro VJ, Afdhal N, et al. Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis

41 C unsuccessfully treated with interferon therapy: a randomized controlled trial. JAMA. 2012;308:274-282. 41. Ferenci P, Scherzer TM, Kerschner H, et al. Silibinin is a potent antiviral agent in patients with chronic hepatitis C not responding to pegylated interferon/ribavirin therapy. Gastroenterology. 2008;135:1561-1567. 42. Seeff LB, Curto TM, Szabo G, et al. Herbal product use by persons enrolled in the hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial. Hepatology. 2008;47:605-612. 43. Lewis JH, Stine JG. Review article: prescribing medica tions in patients with cirrhosis—a practical guide. Aliment Pharmacol Ther. 2013;37:1132-1156. 44. Posadzki P, Watson L, Ernst E. Herb-drug interactions: an overview of systematic reviews. Br J Clin Pharmacol. 2013;75:603-618. 45. Siegel AB, Narayan R, Rodriguez R, et al. A phase I dosefinding study of silybin phosphatidylcholine (milk thistle) in patients with advanced hepatocellular carcinoma. Integr Cancer Ther. 2014;13:46-53.