Challenges Conducting Clinical Trials with Herbal Products in Oncology

  • Amit Sood
  • Kavita Prasad


Patients with cancer are increasingly using complementary and alternative medicine (CAM) therapies. As many as 90% of patients with cancer might use some form of CAM therapy [1]; over 50% initiate these treatments after the diagnosis of cancer [2]. Patients use these treatments despite substantial advances in conventional medicine and lack of evidence of efficacy of many CAM treatments. This ‘return to nature’ movement that is largely consumer driven is primarily directed to help relieve symptoms, improve quality of life, and prevent recurrence of the cancer and not for the cure of the primary tumor [3–5]. Because most natural cancer cures investigated in clinical trials to date have either shown no benefit (e.g., shark cartilage [6]) or have shown a potential for harm (e.g., Laetrile [7]), the use of these products as alternative treatments seems inappropriate; their use as complementary treatments should be judicious and individualized until further research data are available [8].


Oral Mucositis Herbal Product Black Cohosh Tripterygium Wilfordii Ginsenoside Content 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Yates JS, Mustian KM, Morrow GR, et al. Prevalence of complementary and alternative medicine use in cancer patients during treatment. Support Care Cancer 2005;13(10):806–11.CrossRefGoogle Scholar
  2. 2.
    Vapiwala N, Mick R, Hampshire MK, Metz JM, DeNittis AS. Patient initiation of complementary and alternative medical therapies (CAM) following cancer diagnosis. Cancer J 2006;12(6):467–74.CrossRefGoogle Scholar
  3. 3.
    Correa-Velez I, Clavarino A, Eastwood H. Surviving, relieving, repairing, and boosting up: reasons for using complementary/alternative medicine among patients with advanced cancer: a thematic analysis. J Palliat Med. 2005;8(5):953–61.CrossRefGoogle Scholar
  4. 4.
    Evans M, Shaw A, Thompson EA, et al. Decisions to use complementary and alternative medicine (CAM) by male cancer patients: information-seeking roles and types of evidence used. BMC Complement Altern Med. 2007;7:25.PubMedCrossRefGoogle Scholar
  5. 5.
    Verhoef MJ, Balneaves LG, Boon HS, Vroegindewey A. Reasons for and characteristics associated with complementary and alternative medicine use among adult cancer patients: a systematic review. Integr Cancer Ther. 2005;4 (4):274–86.CrossRefGoogle Scholar
  6. 6.
    Loprinzi CL, Levitt R, Barton DL, et al. Evaluation of shark cartilage in patients with advanced cancer: a North Central Cancer Treatment Group trial. Cancer 2005;104(1):176–82.Google Scholar
  7. 7.
    Moertel CG, Fleming TR, Rubin J, et al. A clinical trial of amygdalin (Laetrile) in the treatment of human cancer. N Engl J Med. 1982;306(4):201–6.Google Scholar
  8. 8.
    Helyer LK, Chin S, Chui BK, et al. The use of complementary and alternative medicines among patients with locally advanced breast cancer – a descriptive study. BMC Cancer 2006;6:39.PubMedCrossRefGoogle Scholar
  9. 9.
    Wu KM, Ghantous H, Birnkrant DB. Current regulatory toxicology perspectives on the development of herbal medicines to prescription drug products in the United States. Food Chem Toxicol. 2008;46(8):2606–10.Google Scholar
  10. 10.
    NCCAM. Interim applicant guidance: product quality: biologically active agents used in complementary and alternative medicine (CAM) and placebo materials. Accessed 12 Sept 2008.
  11. 11.
    CDER. Guidance for industry botanical drug products. Accessed 12 Sept 2008.
  12. 12.
    Cragg GM, Boyd M. Drug discovery and development at the National Cancer Institute: the role of natural products of plant origin. New York: Columbia University Press; 1996.Google Scholar
  13. 13.
    NIH N. Developmental therapeutics program. Accessed 12 Sept 2008.
  14. 14.
    Balunas MJ, Kinghorn AD. Drug discovery from medicinal plants. Life Sci. 22 Dec 2005;78(5):431–41.Google Scholar
  15. 15.
    Jachak SM, Saklani A. Challenges and opportunities in drug discovery from plants. Current Sci. 2007;92(9):7.Google Scholar
  16. 16.
    Capasso L. 5300 years ago, the Ice Man used natural laxatives and antibiotics. Lancet 5 Dec 1998;352(9143):1864.Google Scholar
  17. 17.
    Liu Y, Wang MW. Botanical drugs: challenges and opportunities: contribution to Linnaeus Memorial Symposium 2007. Life Sci. 27 Feb 2008;82(9–10):445–9.Google Scholar
  18. 18.
    Cragg GM, Boyd MR, Cardellina JH II, Newman DJ, Snader KM, McCloud TG. Ethnobotany and drug discovery: the experience of the US National Cancer Institute. Ciba Found Symp. 1994;185:178–190; discussion 190–176.PubMedGoogle Scholar
  19. 19.
    Patwardhan B, Warude D, Pushpangadan P, Bhatt N. Ayurveda and traditional Chinese medicine: a comparative overview. Evid Based Complement Alternat Med. Dec 2005;2(4):465–73.Google Scholar
  20. 20.
    Cardellina JH II. Challenges and opportunities confronting the botanical dietary supplement industry. J Nat Prod. Jul 2002;65(7):1073–84.Google Scholar
  21. 21.
    EGb 761: Ginkgo biloba extract, Ginkor. Drugs R D 2003;4(3):188–93.Google Scholar
  22. 22.
    Pockaj BA, Loprinzi CL, Sloan JA, et al. Pilot evaluation of black cohosh for the treatment of hot flashes in women. Cancer Invest. 2004;22(4):515–21.CrossRefGoogle Scholar
  23. 23.
    Pockaj BA, Gallagher JG, Loprinzi CL, et al. Phase III double-blind, randomized, placebo-controlled crossover trial of black cohosh in the management of hot flashes: NCCTG Trial N01CC1. J Clin Oncol. Jun 20 2006;24(18):2836–41.Google Scholar
  24. 24.
    Rietjens IM, Slob W, Galli C, Silano V. Risk assessment of botanicals and botanical preparations intended for use in food and food supplements: emerging issues. Toxicol Lett. 15 Aug 2008;180(2):131–6.Google Scholar
  25. 25.
    Herbal Roulette. Consumer Rep. 1995;60:698–705.Google Scholar
  26. 26.
    FDA US. Dietary supplement current good manufacturing practices (CGMPs) and interim final rule (IFR) facts.˜dms/dscgmps6.html. Accessed 12 Sept 2008.Google Scholar
  27. 27.
    White J. PC-SPES – a lesson for future dietary supplement research. J Natl Cancer Inst. 4 Sept 2002;94(17):1261–3.Google Scholar
  28. 28.
    Okada M. Chinese-herb nephropathy. Lancet 13 Nov 1999;354(9191):1732.Google Scholar
  29. 29.
    Ko RJ. Adulterants in Asian patent medicines. N Engl J Med. 17 Sept 1998;339(12):847.CrossRefGoogle Scholar
  30. 30.
    Miller GM, Stripp R. A study of western pharmaceuticals contained within samples of Chinese herbal/patent medicines collected from New York City's Chinatown. Leg Med. (Tokyo) Sept 2007;9(5):258–64.Google Scholar
  31. 31.
    Slifman NR, Obermeyer WR, Aloi BK, et al. Contamination of botanical dietary supplements by Digitalis lanata. N Engl J Med. Sept 17 1998;339(12):806–11.Google Scholar
  32. 32.
    Seeff LB. Herbal hepatotoxicity. Clin Liver Dis. Aug 2007;11(3):577–96, vii.Google Scholar
  33. 33.
    Cosyns JP. Aristolochic acid and 'Chinese herbs nephropathy': a review of the evidence to date. Drug Saf. 2003;26(1):33–48.PubMedCrossRefGoogle Scholar
  34. 34.
    Lupu R, Mehmi I, Atlas E, et al. Black cohosh, a menopausal remedy, does not have estrogenic activity and does not promote breast cancer cell growth. Int J Oncol. Nov 2003;23(5):1407–12.Google Scholar
  35. 35.
    Hirschberg AL, Edlund M, Svane G, Azavedo E, Skoog L, von Schoultz B. An isopropanolic extract of black cohosh does not increase mammographic breast density or breast cell proliferation in postmenopausal women. Menopause Jan–Feb 2007;14(1):89–96.CrossRefGoogle Scholar
  36. 36.
    Bardia A, Tleyjeh IM, Cerhan JR, et al. Efficacy of antioxidant supplementation in reducing primary cancer incidence and mortality: systematic review and meta-analysis. Mayo Clin Proc. Jan 2008;83(1):23–34.CrossRefGoogle Scholar
  37. 37.
    Omenn GS. Chemoprevention of lung cancers: lessons from CARET, the beta-carotene and retinol efficacy trial, and prospects for the future. Eur J Cancer Prev. Jun 2007;16(3):184–91.Google Scholar
  38. 38.
    Sugawara G, Nagino M, Nishio H, et al. Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized controlled trial. Ann Surg. Nov 2006;244(5):706–714.CrossRefGoogle Scholar
  39. 39.
    Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 23 Feb 2008;371(9613):651–9.Google Scholar
  40. 40.
    Vickers AJ. How to design a phase I trial of an anticancer botanical. J Soc Integr Oncol. Winter 2006;4 1:46–51.Google Scholar
  41. 41.
    Cerchietti LC, Navigante AH, Lutteral MA, et al. Double-blinded, placebo-controlled trial on intravenous L-alanyl-L-glutamine in the incidence of oral mucositis following chemoradiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys. 1 Aug 2006;65(5):1330–7.Google Scholar
  42. 42.
    Rubio IT, Cao Y, Hutchins LF, Westbrook KC, Klimberg VS. Effect of glutamine on methotrexate efficacy and toxicity. Ann Surg. May 1998;227(5):772–8; discussion 778–80.Google Scholar
  43. 43.
    Okuno SH, Woodhouse CO, Loprinzi CL, et al. Phase III controlled evaluation of glutamine for decreasing stomatitis in patients receiving fluorouracil (5-FU)-based chemotherapy. Am J Clin Oncol. Jun 1999;22(3):258–61.Google Scholar
  44. 44.
    Ansari MS, Gupta NP. Lycopene: a novel drug therapy in hormone refractory metastatic prostate cancer. Urol Oncol. Sep–Oct 2004;22(5):415–20.Google Scholar
  45. 45.
    Ansari MS, Gupta NP. A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int. Sept 2003;92(4):375–8; discussion 378.Google Scholar
  46. 46.
    Jatoi A, Burch P, Hillman D, et al. A tomato-based, lycopene-containing intervention for androgen-independent prostate cancer: results of a Phase II study from the North Central Cancer Treatment Group. Urology Feb 2007;69(2):289–94.Google Scholar
  47. 47.
    Sparreboom A, Cox MC, Acharya MR, Figg WD. Herbal remedies in the United States: potential adverse interactions with anticancer agents. J Clin Oncol. Jun 15 2004;22(12):2489–503.Google Scholar
  48. 48.
    Yeung KS, Gubili J. Clinical guide to herb-drug interactions in oncology. J Soc Integr Oncol. Summer 2007;5(3):113–17.Google Scholar
  49. 49.
    Meijerman I, Beijnen JH, Schellens JH. Herb-drug interactions in oncology: focus on mechanisms of induction. Oncologist Jul–Aug 2006;11(7):742–52.Google Scholar
  50. 50.
    McCune JS, Hatfield AJ, Blackburn AA, Leith PO, Livingston RB, Ellis GK. Potential of chemotherapy-herb interactions in adult cancer patients. Support Care Cancer Jun 2004;12(6):454–62.Google Scholar
  51. 51.
    Werneke U, Earl J, Seydel C, Horn O, Crichton P, Fannon D. Potential health risks of complementary alternative medicines in cancer patients. Br J Cancer 26 Jan 2004;90(2):408–13.Google Scholar
  52. 52.
    Cox MC, Low J, Lee J, et al. Influence of garlic (Allium sativum) on the pharmacokinetics of docetaxel. Clin Cancer Res 1 Aug 2006;12(15):4636–40.Google Scholar
  53. 53.
    van Erp NP, Baker SD, Zhao M, et al. Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan. Clin Cancer Res. 1 Nov 2005;11(21):7800–6.Google Scholar
  54. 54.
    Smith P, Bullock JM, Booker BM, Haas CE, Berenson CS, Jusko WJ. The influence of St. John's wort on the pharmacokinetics and protein binding of imatinib mesylate. Pharmacotherapy Nov 2004;24(11):1508–14.Google Scholar
  55. 55.
    Mathijssen RH, Verweij J, de Bruijn P, Loos WJ, Sparreboom A. Effects of St. John's wort on irinotecan metabolism. J Natl Cancer Inst. 21 Aug 2002;94(16):1247–9.Google Scholar
  56. 56.
    Wittkowsky AK. Dietary supplements, herbs and oral anticoagulants: the nature of the evidence. J Thromb Thrombol. Feb 2008;25(1):72–7.Google Scholar
  57. 57.
    Beckert BW, Concannon MJ, Henry SL, Smith DS, Puckett CL. The effect of herbal medicines on platelet function: an in vivo experiment and review of the literature. Plast Reconstr Surg. Dec 2007;120(7):2044–50.Google Scholar
  58. 58.
    Simmonds MS. Novel drugs from botanical sources. Drug Discov Today 15 Aug 2003;8(16):721–2.Google Scholar
  59. 59.
    Newman DJ, Cragg GM. Natural products as sources of new drugs over the last 25 years. J Nat Prod. Mar 2007;70(3):461–77.Google Scholar
  60. 60.
    Ohwada S, Ikeya T, Yokomori T, et al. Adjuvant immunochemotherapy with oral Tegafur/Uracil plus PSK in patients with stage II or III colorectal cancer: a randomised controlled study. Br J Cancer 8 Mar 2004;90(5):1003–10.Google Scholar
  61. 61.
    Sakamoto J, Morita S, Oba K, et al. Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curatively resected colorectal cancer: a meta-analysis of centrally randomized controlled clinical trials. Cancer Immunol Immunother. Apr 2006;55(4):404–11.Google Scholar
  62. 62.
    Oba K, Teramukai S, Kobayashi M, Matsui T, Kodera Y, Sakamoto J. Efficacy of adjuvant immunochemotherapy with polysaccharide K for patients with curative resections of gastric cancer. Cancer Immunol Immunother. Jun 2007;56(6):905–11.Google Scholar
  63. 63.
    Cowawintaweewat S, Manoromana S, Sriplung H, et al. Prognostic improvement of patients with advanced liver cancer after active hexose correlated compound (AHCC) treatment. Asian Pac J Allergy Immunol. Mar 2006;24(1):33–45.Google Scholar
  64. 64.
    Ghoneum M, Wimbley M, Salem F, McKlain A, Attallah N, Gill G. Immunomodulatory and anticancer effects of Active Hemicellulose Compound (AHCC). Int J Immunother. 1995;11:23–8.Google Scholar
  65. 65.
    Demidov LV, Manziuk LV, Kharkevitch GY, Pirogova NA, Artamonova EV. Adjuvant fermented wheat germ extract (Avemar) nutraceutical improves survival of high-risk skin melanoma patients: a randomized, pilot, phase II clinical study with a 7-year follow-up. Cancer Biother Radiopharm. Aug 2008;23(4):477–82.Google Scholar
  66. 66.
    Jakab F, Shoenfeld Y, Balogh A, et al. A medical nutriment has supportive value in the treatment of colorectal cancer. Br J Cancer 4 Aug 2003;89(3):465–9.Google Scholar
  67. 67.
    Yang H, Chen D, Cui QC, Yuan X, Dou QP. Celastrol, a triterpene extracted from the Chinese “Thunder of God Vine,” is a potent proteasome inhibitor and suppresses human prostate cancer growth in nude mice. Cancer Res 1 May 2006;66(9):4758–65.Google Scholar
  68. 68.
    Tao X, Younger J, Fan FZ, Wang B, Lipsky PE. Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: a double-blind, placebo-controlled study. Arthritis Rheum. Jul 2002;46(7):1735–43.Google Scholar
  69. 69.
    Rebbeck TR, Troxel AB, Norman S, et al. A retrospective case-control study of the use of hormone-related supplements and association with breast cancer. Int J Cancer 1 Apr 2007;120(7):1523–8.Google Scholar
  70. 70.
    Zepelin HH, Meden H, Kostev K, Schroder-Bernhardi D, Stammwitz U, Becher H. Isopropanolic black cohosh extract and recurrence-free survival after breast cancer. Int J Clin Pharmacol Ther. Mar 2007;45(3):143–54.Google Scholar
  71. 71.
    Klassen TP, Pham B, Lawson ML, Moher D. For randomized controlled trials, the quality of reports of complementary and alternative medicine was as good as reports of conventional medicine. J Clin Epidemiol. Aug 2005;58(8):763–8.Google Scholar
  72. 72.
    Li N, Sun Z, Han C, Chen J. The chemopreventive effects of tea on human oral precancerous mucosa lesions. Proc Soc Exp Biol Med. Apr 1999;220(4):218–24.Google Scholar
  73. 73.
    Manusirivithaya S, Sripramote M, Tangjitgamol S, et al. Antiemetic effect of ginger in gynecologic oncology patients receiving cisplatin. Int J Gynecol Cancer Nov–Dec 2004;14(6):1063–9.Google Scholar
  74. 74.
    Bloom BS, Retbi A, Dahan S, Jonsson E. Evaluation of randomized controlled trials on complementary and alternative medicine. Int J Technol Assess Health Care Winter 2000;16(1):13–21.CrossRefGoogle Scholar
  75. 75.
    Lawson ML, Pham B, Klassen TP, Moher D. Systematic reviews involving complementary and alternative medicine interventions had higher quality of reporting than conventional medicine reviews. J Clin Epidemiol. Aug 2005;58(8):777–84.Google Scholar
  76. 76.
    Pittler MH, Ernst E. Feverfew for preventing migraine. Cochrane Database Syst Rev. 2004(1):CD002286.Google Scholar
  77. 77.
    Vickers AJ, Kuo J, Cassileth BR. Unconventional anticancer agents: a systematic review of clinical trials. J Clin Oncol. 1 Jan 2006;24(1):136–40.Google Scholar
  78. 78.
    Daugherty CK, Ratain MJ, Emanuel EJ, Farrell AT, Schilsky RL. Ethical, scientific, and regulatory perspectives regarding the use of placebos in cancer clinical trials. J Clin Oncol. 10 Mar 2008;26(8):1371–8.Google Scholar
  79. 79.
    Pecking AP. Evaluation by lymphoscintigraphy of the effect of a micronized flavonoid fraction (Daflon 500 mg) in the treatment of upper limb lymphedema. Int Angiol. Sep 1995;14(3 Suppl 1):39–43.Google Scholar
  80. 80.
    Pecking AP, Fevrier B, Wargon C, Pillion G. Efficacy of Daflon 500 mg in the treatment of lymphedema (secondary to conventional therapy of breast cancer). Angiology Jan 1997;48(1):93–8.Google Scholar
  81. 81.
    Carl W, Emrich LS. Management of oral mucositis during local radiation and systemic chemotherapy: a study of 98 patients. J Prosthet Dent. Sep 1991;66(3):361–9.Google Scholar
  82. 82.
    Mazokopakis EE, Vrentzos GE, Papadakis JA, Babalis DE, Ganotakis ES. Wild chamomile (Matricaria recutita L.) mouthwashes in methotrexate-induced oral mucositis. Phytomedicine Jan 2005;12(1–2):25–7.Google Scholar
  83. 83.
    Gagnier JJ, Boon H, Rochon P, Moher D, Barnes J, Bombardier C. Reporting randomized, controlled trials of herbal interventions: an elaborated CONSORT statement. Ann Intern Med. 7 Mar 2006;144(5):364–7.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Integrative Medicine, Division of General Internal MedicineMayo Clinic College of MedicineRochesterUSA

Personalised recommendations