In discussions of natural cancer treatments, critics often ask, “Where are your clinical trials?” They gleefully assume that there is no human, clinical data to support holistic approaches, but only laboratory studies in cell lines or rodents. 

As I shall show, this is an unfair accusation. But let us start by acknowledging that we do not have as many high-quality RCTs as we want and need. But whose fault is that? Is it a sign of inadequacy on the part of proponents, or a basic feature of the drug testing system forged by and for conventional medicine?

The challenge of executing RCTs are many. I speak from experience, since one of the main purposes for helping to found the U.S. government’s Office of Alternative Medicine in the 1990s was to arrange clinical trials of controversial non-toxic approaches to cancer, tests that the National Cancer Institute refused to carry out. 

But doing so proved nearly impossible, and some of us on the advisory board felt like we were swimming in molasses as we pursued that goal. I don’t wish to reopen old wounds, but the history of the unconventional treatments associated with Lawrence Burton, Ph.D. (immunotherapy), Stanislaw Burzynski, MD, Ph.D. (peptides), and Ernesto Contreras, MD (amygdalin), to name just three, certainly bear out that contention.

But leaving medical politics aside, setting up RCTs requires money, skill and connections, and, despite that, often stumbles due to a lack of patients. In fact, about 80% of trials don’t meet their participant recruitment goals and nearly half of research sites end up enrolling few if any patients at all (Earls 2012). In fact, only 1.7% to 8.3% of clinical trials lead to F.D.A. approval (Wong CH 2019).

The cost of developing a new drug in the United States is staggering. According to some researchers, it averages US $2.2 billion to bring a new drug to market (Deloitte 2023).  

Yet the low cost of most natural approaches does not justify any such expenditures. So in the U.S. at least, such compounds are legally restricted to a lesser category called “dietary supplements,” the Minor Leagues of medical treatment. They can be marketed, but efficacy claims are severely limited by the Food and Drug Administration (FDA).

There is even a technical term for this problem in the field of drug development: it is called the “valley of death” of natural agents. This is the chasm between positive but relatively small studies and the “Grand Canyon” that looms into view when you attempt to proceed to full-scale trials (IOM 2001, U.S. House of Representatives 2005).

So there is in fact no incentive for manufacturers of dietary supplements to perform high-cost randomized controlled trials of these items. That’s the basic reason that there is not the same level of proof that patented drugs have. Anyone demanding such proof is either being disingenuous or is unaware of the realities of health economics in the 21st century.

Overcoming Hurdles

Yet, despite these numerous hurdles, some clinical trials on plant chemicals (phytochemicals) have occurred, often demonstrating very promising outcomes. Here are brief descriptions of some from around the world, arranged by date. Although they come from around the world, all were published in peer-reviewed scientific journals in the English language. 

Japan: Lentinan from shiitake mushrooms increased survival in advanced stomach cancer patients by approximately 100 days; one-year survival was 49.1% vs. 0% in the control group, an extraordinary result (Nakano 1999).

South Korea: A mushroom extract enhanced Natural Killer (NK) cell activity and reduced side effects in patients with gynecological cancers (Ahn 2004).

Italy: Green tea decreased high-grade prostate cancer incidence from 30% to 3% over one year, a study published in the top-drawer journal, Cancer Research (Bettuzzi 2006). 

Oregon, U.S.: A high-dose vitamin D formulation used with the standard chemotherapy drug docetaxel showed promising results by reducing cancer markers and improving survival rates (Beer 2007).

Sweden: A randomized trial from the famed Karolinska Institute, Sweden, to investigate the impact of a synbiotic mixture (i.e., a combination of prebiotics and probiotics) on colon cancer. Results indicated a reduction in cell growth and an improved immune response, suggesting protective effects against colon cancer development (Rafter 2007).

Japan: The mushroom extract lentinan extended survival in stomach cancer patients to 689 days versus 565 days with chemotherapy alone (Ina 2011).

Australia: In an RCT published in the American Journal of Hematology, curcumin decreased signs of multiple myeloma growth (Golombick 2012).

Minnesota, U.S.: At the Mayo Clinic, 42 chronic leukemia patients received a green tea extract twice daily for up to 6 months. About one-third (31%) had their lymphocyte counts decrease. For those with swollen lymph nodes, 69% had at least a 50% reduction in their size. In all, 69% had a therapeutic response over six months of treatment (Shanafelt 2013).

New York, U.S.: In a study from the University of Florida, Gainesville, daily intake of shiitake mushrooms boosted immunity and decreased inflammation (Dai 2015), and EGCG reduced cancer markers in breast cancer patients (Crew 2015).

Michigan, U.S.: In an RCT from Wayne State University, EGCG and another supplement, I3C, improved outcomes in ovarian cancer patients (Kiselev 2018).

United Kingdom: Just two grams per day of curcumin showed remarkable results in a colorectal cancer trial, more than doubling survival over FOLFOX, the classic chemo regimen alone (Howells 2019). 

New York, U.S.: Positive results from Mt. Sinai Hospital of a soy protein, genistein, with standard chemo for colorectal cancer (Pintova 2019).

India: Green tea and curcumin treatments enhanced response in precancerous mouth conditions (Neetha 2020).

China: Maitake mushroom D fraction alleviated side effects of chemotherapy. The frequency of severe adverse events were fewer than in the placebo group. (Hu Q 2022).

Indonesia: Myeloma patients received either standard treatment with 8 grams of curcumin for 28 days or a placebo. The overall remission rate was 75% with curcumin added vs. 33.3% without it. It also decreased four markers of inflammation (Santosa 2022).

Italy: The PROVIDENCE study examining the impact of vitamin D supplements on patients with advanced cancer undergoing immunotherapy. The group receiving vitamin D3 showed a remarkable improvement in their survival chances, with a 45% reduction in the risk of death compared to those who didn’t receive supplements (Bersanelli 2023).

Greece: In a study from four university hospitals, melatonin improved cancer-related fatigue in breast cancer patients adhering to a Mediterranean diet: “Only patients receiving melatonin improved cancer-related fatigue compared to baseline” (Nimee 2024).

Italy: In a large randomized trial, published in Clinical Cancer Research and involving 27 authors across Italy, strict adherence to a combined macrobiotic and Mediterranean diet resulted in a 41% reduction in breast cancer recurrences (Berrino 2024).

The Value of Natural Agents

This sample of studies illustrates the possible value of natural agents in enhancing cancer prevention and treatment and in patient quality of life using the same methodology as rigorous drug trials. I discuss some of these trials at greater length in my book, The Moss Method (2024). 

One limitation of many of these peer-reviewed reports is the relatively small number of participants in the trials, some of which are not randomized. Another is the obscurity of a few of the journals in which they are published. Nonetheless, numerous sign posts point to the efficacy of plant chemicals on their own, or by improving the outcome of mainstream therapies.

Yet, despite great promise, it has proven to be difficult, if not impossible, to proceed to full-scale randomized controlled trials (RCTs) for most of the natural methods that cannot be patented or otherwise monopolized. 

It is sometimes suggested that the lack of RCTs is the fault of the proponents of these methods. But the reality is that the whole testing system is geared to accommodate drug manufacturers, who are seeking a “pot of gold” at the end of the arduous testing rainbow. For example, in 2023, the annual sales of a single patented anticancer drug, pembrolizumab (Keytruda), reached an astonishing US $25 billion (Reuters 2024). 

Massive outlays and rewards are only possible under a strong patent system, which guarantees a legal monopoly for a specific number of years. But natural agents, by their nature, cannot be patented, as Johns Hopkins University found out when their broccoli sprout patent—and proposed monopoly—was ruled invalid in the courts (IATP 2001). 

So nutraceutical developers lack the economic incentive to perform extremely costly clinical trials. The difficulty of doing so has proven too much for even determined proponents of such methods. What is surprising is that any such trials have been done at all.

References

Ahn WS, Kim DJ, Chae GT, et al. Natural killer cell activity and quality of life were improved by consumption of a mushroom extract, Agaricus blazei Murill Kyowa, in gynecological cancer patients undergoing chemotherapy. Int J Gynecol Cancer. 2004 Jul-Aug;14(4):589-94. Doi: 10.1111/j.1048-891X.2004.14403.x. PMID: 15304151. 

Beer TM, Ryan CW, Venner PM, et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol. 2007 Feb 20;25(6):669-74. Doi: 10.1200/JCO.2006.06.8197. PMID: 17308271.

Berrino F, Villarini A, Gargano G, et al. The effect of diet on breast cancer recurrence: the DIANA-5 randomized trial. Clin Cancer Res. 2024 Mar 1;30(5):965-974. Doi: 10.1158/1078-0432.CCR-23-1615. PMID: 37847493; PMCID: PMC10905522. 

Bersanelli M, Cortellini A, Leonetti A, et al. Systematic vitamin D supplementation is associated with improved outcomes and reduced thyroid adverse events in patients with cancer treated with immune checkpoint inhibitors: results from the prospective PROVIDENCE study. Cancer Immunol Immunother. 2023 Nov;72(11):3707-3716. Doi: 10.1007/s00262-023-03522-3. Epub 2023 Aug 28. PMID: 37638980; PMCID: PMC10576732. 

Bettuzzi S, Brausi M, Rizzi F, et al. Chemoprevention of human prostate cancer by oral administration of green tea catechins in volunteers with high-grade prostate intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study. Cancer Res. 2006 Jan 15;66(2):1234-40. Doi: 10.1158/0008-5472.CAN-05-1145. PMID: 16424063.

Crew KD, Ho KA, Brown P, et al. Effects of a green tea extract, Polyphenon E, on systemic biomarkers of growth factor signaling in women with hormone receptor-negative breast cancer. J Hum Nutr Diet. 2015 Jun;28(3):272-82. Doi: 10.1111/jhn.12229. Epub 2014 Mar 19. PMID: 24646362; PMCID: PMC4205214. 

Dai X, Stanilka JM, Rowe CA, et al. Consuming Lentinula edodes (shiitake) mushrooms daily improves human immunity: a randomized dietary intervention in healthy young adults. J Am Coll Nutr. 2015;34(6):478-87. Doi: 10.1080/07315724.2014.950391. Epub 2015 Apr 11. PMID: 25866155. 

Earls, Ellis. Clinical trial delays: America’s patient recruitment dilemma. Clinicaltrialsarena.com, July 18, 2012. Clinical Trials Arena. Accessed January 10, 2024.

Erman, Michael and Leo, Leroy. Merck seeks more deals to prepare for Keytruda’s revenue decline. Reuters, February 1, 2024. Accessed August 9, 2024. 

Golombick T, Diamond TH, Manoharan A, et al. Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: a randomized, double-blind placebo-controlled crossover 4g study and an open-label 8g extension study. Am J Hematol. 2012 May;87(5):455-60. Doi: 10.1002/ajh.23159. Epub 2012 Apr 4. PMID: 22473809. 

Howells LM, Iwuji COO, Irving GRB, et al. Curcumin combined with FOLFOX chemotherapy is safe and tolerable in patients with metastatic colorectal cancer in a randomized Phase Iia trial. J Nutr. 2019 July 1;149(7):1133-1139. Doi: 10.1093/jn/nxz029. PMID: 31132111; PMCID: PMC6602900. 

Hu Q, Xie B. Effect of Maitake D-fraction in advanced laryngeal and pharyngeal cancers during concurrent chemoradiotherapy: A randomized clinical trial. Acta Biochim Pol. 2022 Sep 7;69(3):625-632. doi: 10.18388/abp.2020_5996. PMID: 36070433.

IATP [Institute for Agriculture & Trade Policy]. Broccoli sprout patent invalid, November 6, 2001. Accessed April 19, 2024.

Ina K, Furuta R, Kataoka T, et al. Lentinan prolonged survival in patients with gastric cancer receiving S-1-based chemotherapy. World J Clin Oncol. 2011 Oct 10;2(10):339-43. Doi: 10.5306/wjco.v2.i10.339. PMID: 21994907; PMCID: PMC3191325.

Institute of Medicine (U.S.) [IOM], Committee on Quality of HealthCare in America. Crossing the Quality Chasm: a New Health System for the 21st Century. Washington (DC): National Academies Press (U.S.); 2001. PMID: 25057539. [IOM is now the National Academy of Medicine, or NAM] 

Kiselev VI, Ashrafyan LA, Muyzhnek EL, et al. A new promising way of maintenance therapy in advanced ovarian cancer: a comparative clinical study. BMC Cancer. 2018 Sep 20;18(1):904. Doi: 10.1186/s12885-018-4792-9. PMID: 30236079; PMCID: PMC6148762. 

Nakano H, Namatame K, Nemoto H, et al. A multi-institutional prospective study of lentinan in advanced gastric cancer patients with unresectable and recurrent diseases: effect on prolongation of survival and improvement of quality of life. Kanagawa Lentinan Research Group. Hepatogastroenterology. 1999 Jul-Aug;46(28):2662-8. PMID: 10522061

Neetha MC, Panchaksharappa MG, Pattabhiramasastry S, et al. Chemopreventive synergism between green tea extract and curcumin in patients with potentially malignant oral disorders: a double-blind, randomized preliminary study. J Contemp Dent Pract. 2020 May 1;21(5):521-531. PMID: 32690834. 

Nimee F, Gioxari A, Papandreou P, et al. The effect of melatonin supplementation on cancer-related fatigue during chemotherapy treatment of breast cancer patients: adouble-blind, randomized controlled study. Cancers (Basel). 2024 Feb 16;16(4):802. Doi: 10.3390/cancers16040802. PMID: 38398193; PMCID: PMC10887218. 

Pintova S, Dharmupari S, Moshier E, et al. Genistein combined with FOLFOX or FOLFOX-Bevacizumab for the treatment of metastatic colorectal cancer: phase I/II pilot study. Cancer Chemother Pharmacol. 2019 Sep;84(3):591-598. doi: 10.1007/s00280-019-03886-3. Epub 2019 Jun 15. PMID: 31203390.

Rafter J, Bennett M, Caderni G, et al. Dietary synbiotics reduce cancer risk factors in polypectomized and colon cancer patients. Am J Clin Nutr. 2007 Feb;85(2):488-96. doi: 10.1093/ajcn/85.2.488. PMID: 17284748.

Santosa D, Suharti C, Riwanto I, et al. Curcumin as adjuvant therapy to improve remission in myeloma patients: A pilot randomized clinical trial. Caspian J Intern Med. 2022 Spring;13(2):375-384. doi: 10.22088/cjim.13.2.9. PMID: 35919637; PMCID: PMC9301229. 

Shanafelt TD, Call TG, Zent CS, et al. Phase 2 trial of daily, oral Polyphenon E in patients with asymptomatic, Rai stage 0 to II chronic lymphocytic leukemia. Cancer. 2013 Jan 15;119(2):363-70. doi: 10.1002/cncr.27719. Epub 2012 Jul 3. PMID: 22760587; PMCID: PMC3902473.

U,S, House of Representatives, Committee on Science, Subcommittee on Environment, Technology, and Standards. Hearing before the Subcommittee on Environment, Technology, and Standards, 2005 Jun 28; Washington. 109th Congress, 1st Session; Serial No. 109–20. Accessed December 22, 2023.

Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2019 Apr 1;20(2):273-286. doi: 10.1093/biostatistics/kxx069. Erratum in: Biostatistics. 2019 Apr 1;20(2):366. PMID: 29394327; PMCID: PMC6409418.