National center for complementary and alternative medicine definition

Integrative Therapy Domains and Their Use

According to the NCCIH, “most integrative therapies fall into one of two subgroups—natural products or mind and body practices” (Table 156.1). There is also an abundance of whole-systems practices that include ayurvedic medicine and traditional Chinese medicine. The whole-systems approaches incorporate many of the integrative therapies. Mind–body approaches include meditation, mindfulness meditation, guided imagery, music therapy, creative arts therapy, self-hypnosis, yoga, tai chi, and qigong, among many other types of physical and spiritual practices. Energy-based therapies include reiki and healing touch. Body-based manipulative therapies include chiropractic and massage therapy. Examples of natural products include dietary supplements, antioxidants, vitamin megadoses, specialized diets, and herbs.

In the literature, there is a paucity of information on the use of integrative therapies in the treatment of hematologic malignancies.8 In India there is a significant use of ayurvedic medicine. In a German study of a large group of patients with chronic lymphocytic leukemia (CLL), approximately 44% used integrative therapies with 26% using vitamin supplementation, 18% mineral supplementation, 14% homeopathy, 7% acupuncture, and 9% mistletoe therapy. In the United States, 30% to 80% of pediatric hematology/oncology patients used one or more complementary therapies in conjunction with their conventional care. In the US pediatric group, there is an especially high use of vitamin and nutritional supplements,8,9 with mind–body therapies a close second. Because many patients do not report their use of complementary therapies to their primary care hematologist/oncologist, there are markedly disparate data from one study to another. In other countries, such as Mexico, Ireland, and Canada, there is a high use of CAM therapies ranging from 42% to 60% in the pediatric patients. Therapies include vitamins, minerals, reflexology, etc.10,11

In a review by Wesa and Cassileth,12 the major reason why leukemia patients use integrative therapies or remedies not prescribed by their hematologist/oncologist is in an effort to improve their treatment outcome and to manage their symptoms. For those with leukemia, the integrative therapies that were felt to be most beneficial included mind–body interventions such as self-hypnosis, meditation, guided imagery, and breath awareness. Massage and reflexology are also frequently used to decrease symptoms (see subsequent discussion on massage). Acupuncture is very beneficial for symptom management with minimal side effects (see later discussion of acupuncture).

IHM Modalities

Due to increasing interest in therapies outside of conventional Western medicine, the US Congress established the National Center for Complementary and Integrative Health (NCCIH) within the National Institutes of Health in 1999. NCCIHs mission is to define, through rigorous scientific investigation, the usefulness and safety of complementary health approaches, and their roles in improving health care. NCCIH established a classification system for the various modalities, dividing them into one of five different groups: (1) biologically based systems which consist of herbal supplements, therapeutic foods, and overall diet, (2) manipulative and body-based systems which include massage, chiropractic, and osteopathic medicine, (3) mind-body medicine spanning the practices of yoga, tai chi, and medication, (4) alternative medical systems which include homeopathy, naturopathy, traditional Chinese medicine, and Ayurveda, and (5) energy therapy consisting of Reiki, magnet therapy, therapeutic touch, and qi gong. (Fig. 1) It should be noted that while the examples listed above are representative of each group, the list is not all inclusive. In regard to terminology, “complementary medicine” is defined as a nonmainstream approach used in conjunction with, or to complement, conventional medicine.3 “Integrated health and medicine,” or IHM, includes the various therapies but also describes an interface with mainstream medicine, incorporating the provider-patient relationship and supporting the integration between traditional medicine and complementary therapies. “Herbal therapies” are defined as medicines that include a plant or plant part for culinary, aromatherapy or therapeutic properties, sold in the United States as dietary supplements.3

Introduction

Integrative therapies have been used for centuries in a variety of cultures to promote health and well-being. The National Center for Complementary and Integrative Health distinguishes two types of integrative approaches: natural products (e.g., dietary supplements) and mind-body practices (e.g., meditation, yoga, and Tai Chi, as well as body-manipulative methods, such as chiropracty, massage, or acupuncture).1 Interest in mind-body therapies among rehabilitation patients has grown considerably in recent years. Data from the 2002 National Health Interview Survey (NHIS) indicate that roughly one in five individuals with a physical disability, including persons with multiple sclerosis (MS), cerebral palsy, spinal cord injury (SCI),2 arthritis,3 and stroke,4 reported engaging in at least one mind-body therapy (i.e., meditation, yoga, or Tai Chi). NHIS data from 2007 indicate that the use of mind-body therapies nearly doubled for all populations,5 including those with functional limitations.6 Recent studies suggest that 40% to 80% of patients with physical disabilities engage in some form of mind-body therapy.7, 8 This chapter will: (1) review the evidence for in-person and telerehabilitation meditation, yoga, and Tai Chi for persons participating in rehabilitation; (2) highlight areas for future research; (3) present practical strategies to deliver these telerehabilitation mind-body therapies; and (4) present a case study of the delivery of a telerehabilitation meditation program for neurorehabilitation patients.

Integrative Mental Health

Integrative medicine has increasingly become recognized as a valid and effective approach to healthcare and is gaining increasing acceptance among both the general population and among allopathic physicians and healthcare delivery systems. The establishment of the National Center for Complementary and Integrative Health (NCCIH; formerly the National Center for Complementary and Alternative Medicine exemplifies this trend. In addition, the emergence of integrative medicine departments in leading academic medical centers and the establishment of specialty training and board certification for allopathic physicians in Integrative Medicine, as well as the creation of a Consortium of Academic Health Centers for Integrative Medicine, emphasizes this growth, acceptance and possibly moving from marginal to mainstream.

Despite the steady acceptance of integrative medicine for physical conditions, integrative approaches to mental healthcare have only recently begun to receive more attention (Sarris et al., 2014). However, given the factors described below, IMH is likely to receive increasing attention and application over the next decade.

Overview

Integrative healthcare is defined by the United States National Institutes of Health as a comprehensive, often interdisciplinary approach to treatment, prevention, and health promotion that brings together complementary and conventional therapies.42 In the United States, the National Center for Complementary and Integrative Health (NCCIH) is responsible for research on promising integrative health approaches. The mission of NCCIH is to define, through rigorous scientific investigation, the usefulness and safety of complementary and integrative health approaches and their roles in improving health and healthcare.42 Budget for NCCIH in the United States exceeded USD$146 million in 2019, testifying to interest by the public and governmental agencies in exploring efficacy and safety of many of these approaches.43 Complementary and integrative health approaches contrast with alternative medicine, which is defined as unproven practices used in place of conventional health approaches. Some examples of complementary and integrative health approaches commonly used in the United States and other parts of the world to treat acute and chronic pain are delineated as follows. In light of the recent opioid crisis in the United States, and in search of alternatives to long-term opioid therapy to treat chronic nonmalignant pain, interest in complementary and integrative approaches has grown and adapted by many patients and clinicians alike.

Medicine Gets the Message

The popularity of CAM therapies created a need for research in these areas. In 1993, an Office of Alternative Medicine was started within the National Institutes of Health (NIH). The initial budget was $2 million, a fraction of the $80 billion budget of the NIH. The office was later upgraded to the National Center for Complementary and Alternative Medicine (NCCAM), and in 2014, the name was changed to the National Center for Complementary and Integrative Health (NCCIH). The amount of money available for scholarly research kept pace with this growth. By 2010, the NCCAM budget grew to $127 million.9 Unfortunately, with a shrinking NIH budget, the NCCIH budget dropped in 2013 to $120.6 million and rose only to $124.5 million in 2015, still lower than in the previous decade.10 Despite the challenges in research funding, there was still the opportunity to explore ways in which these areas of medicine could enhance health care delivery. At first, researchers tried to use traditional methods to learn about CAM therapies. These methods were sufficient for studying some areas such as botanicals. The limitations of the reductionist model became apparent, however, when it was applied to more dynamic systems of healing such as homeopathy, traditional Chinese medicine, and energy medicine. New methods were required to understand the multiple influences involved. Outcome studies with attention to quality of life were initiated. Research grants in “frontier medicine” were created to help learn about fields such as energy medicine, homeopathy, magnet therapy, and therapeutic prayer. Interest grew in learning how to combine the successes of the scientific model with the potential of CAM to improve the delivery of health care.

Introduction

The World Health Organization (WHO) defines traditional medicine as a culmination of knowledge, skills and practices used to maintain health or prevent, diagnose, improve or treat human illness that is indigenous to differing cultures. WHO considers integrative, complementary and alternative medicine (CAM) as interchangeable terms to refer to health care practices that are not integral to a country's own traditions or dominant health care system [1S].

The United States Department of Health and Human Services, National Institutes of Health, National Center for Complementary and Integrative Health (NCCIH) considers complementary practices those that use health care approaches developed outside of mainstream Western conventional medicine along with conventional practices. Integrative health practice coordinates conventional and complementary approaches within care settings. Alternative medicine would be the sole use of traditional systems from outside of the Western conventional medicine practice [2S,3S].

CAM treatments and practices are divided by NCCIH into sectors of mind/body practices, biologic-based therapies and alternative systems. Mind and body practices include yoga, meditation, relaxation techniques (e.g., deep breathing exercises, guided imagery), massage, and chiropractic or osteopathic manipulation. Biologic-based therapies include vitamins, minerals, natural dietary supplements and probiotics. Alternative medical systems would include homeopathy, naturopathy, Ayurvedic medicine, and traditional Chinese medicine [4S].

This approach informs the United States National Health Interview Survey (NHIS) which is answered by tens of thousands of US citizens every year. The survey requests information on the use of complementary health approaches every 5 years. In 2012, the most recent data were collected and reported, and the use of complementary health practices was reported by 33.2% of adults and 11.6% of children, aged 4–17 years [2S,3S]. In the United States, 34 billion dollars a year was spent on CAM self-care therapies, classes, and practitioners, estimated at over 11% of total out of pocket healthcare expenses [5S].

CAM health practices often have been around for centuries but not accepted by many practitioners of Western conventional health practice, even in countries where some of these practices originated, e.g. Germany. WHO published guidelines for research and evaluation of traditional medicine practices in 2000 with the purpose of standardizing and improving the quality of research methodologies and thus, acceptance of the data generated by healthcare practitioners and the public [1S]. According to WHO estimates, 80% of the world's population relies primarily on traditional medicine. WHO estimates that the demand for medicinal plants is $14 billion annually (2012 data). The increase in global demand has raised concerns for the safety of using medicinal herbs [6R].

Safety of complementary therapies, both biologically based and mind–body based, is found in mainstream medical literature. Mind–body therapy safety concerns including serious side effects are not reported with the frequency of those for natural dietary supplements. This may be due to the lack of standardization of adverse effect nomenclature [7R], the rise of self-care for many of these techniques, including yoga [8M], and the lack of regulations or structure for reporting for both the public and providers of touch and manipulative therapies [9M]. The reports of safety concerns of dietary supplement use and interactions with prescription medications and/or existing disease states are more frequent but less than would be projected by the number of substances available and the population size and diversity [10C]. The mechanisms and structure for reporting adverse reactions or other concerns regarding dietary supplements in the US and other countries do not give a complete collection of data from all potential adverse effects. It is estimated that less than 10% of all adverse events due to taking dietary supplements are ever reported to companies or governments. Reasons for the reduced number of complaints may be due to the perception by the consumer of the natural origins and low risks of dietary supplement intake, leading to discounting of association of any adverse effects with the product [11R].

TACT

Despite the lack of convincing data or approval by the US FDA in the United States, enthusiasts of chelation therapy have continued to use and advocate its off-label usage as a complementary health approach for various illnesses [3]. To definitively determine the effectiveness and safety of chelation therapy, the National Center for Complementary and Integrative Health (NCCAM) and the National Heart, Lung, and Blood Institute (NHLBI) sponsored a definitive study of EDTA treatment in subjects with CAD. Trial to Assess Chelation Therapy (TACT) was a double-blind placebo-controlled multicenter study to clarify whether chelation therapy as practiced in the community was effective in reducing vascular events and mortality in patients with prior cardiac events.

TACT was conducted between September 2003 and October 2010 and included 1708 participants aged 50 years and older (median age 65 years, 18% female, 9% nonwhite, 31% diabetic, 83% with prior coronary artery bypass or percutaneous coronary intervention) who had suffered myocardial infarction (MI) at least 6 weeks before initiation of therapy and were without any significant renal impairment (serum creatinine level ≤2.0 mg/dL) and on conventional, evidence-based therapies. Subjects were randomly assigned to one of four groups: active intravenous (IV) chelation solution (containing 3 g disodium EDTA) plus active oral multivitamins and minerals (OMVM) versus active IV chelation plus placebo OMVM versus placebo IV chelation, and active OMVM regimen versus placebo IV chelation plus placebo OMVM [5].

A total of 40 infusions were delivered, weekly infusions for 30 weeks and the last 10 infusions given 2–8 weeks apart. During a mean follow-up of 4.6 years, the primary composite endpoint (total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina) occurred less frequently in the EDTA chelation group versus placebo (26% vs. 30%; HR, 0.82, 95% CI, 0.69–0.99; P = .035; Fig. 37.1A) [5]. There was no significant effect on total mortality (10% vs. 11% in placebo group; HR, 0.93 [95% CI, 0.70–1.25]; P = .64) or individual components of the primary endpoint with chelation therapy compared to placebo: MI (6%; vs. 8%; HR, 0.77; 95% CI, 0.54–1.11); stroke (1.2%; vs. 1.5%; HR, 0.77; 95% CI, 0.34–1.76); coronary revascularization (15% vs. 18%; HR, 0.81; 95% CI, 0.64–1.02); or hospitalization for angina (1.6% vs. 2.1%; HR, 0.72; 95% CI, 0.35–1.47). Overall, a modest reduction in the risk of adverse cardiovascular outcomes in chelation-treated patients was observed, many of which were revascularization procedures. Subgroup analysis showed considerable reduction in composite endpoints among patients with anterior MI (37% HR, 0.63, 95% CI 0.47–0.86; P = .03) and with diabetes (39% reduction, HR: 0.61; 95% CI: 0.45–0.83; P = .02; Fig. 37.1B) but not in nondiabetics (Fig. 37.1C) [5]. The subgroup analysis demonstrating a beneficial effect in diabetics is encouraging but insufficient to recommend the routine use of chelation therapy in post-MI patients with diabetes mellitus. However, these results have generated enough excitement for a follow-up study (TACT2) in post-MI diabetic patients that is currently in its early stages of recruitment [5–7].

Although TACT was the largest and well-designed study, it was still criticized for proper consent relating to misrepresentation of chelation risk and incomplete fact disclosure. The sponsors, NHLBI and NCCAM, were intentionally unblinded during the entirety of the study and subjective endpoints were used by investigators, which is a deviation from the acceptable norms of a supervised clinical trial and could have influenced outcomes by incorporating bias [8].

The trial did not describe nor was designed to determine the chelation therapy mechanism of action in MI patients. Despite demonstrating a modest benefit in reducing primary composite endpoints, individual outcomes did not differ significantly between groups. No effect was seen on total mortality or quality of life outcomes over 2 years of follow-up [5,8]. Furthermore, TACT investigators themselves recommended against the routine use of chelation therapy to reduce symptoms or cardiovascular complications in patients with symptomatic ischemic heart disease [5].

Diagnosis and Management of Chronic Pain—A Daunting Unmet Need

Pain is now the most common reason to seek medical attention, outnumbering those who suffer from cancer, heart disease, and diabetes combined [1]. Chronic pain affects almost 50 million adults in the United States, according to a study performed in 2015 by the National Center for Complementary and Integrative Health [2], costing the US healthcare system as much as $635 billion in total expenses, including imaging and treatment costs [3]. Living in chronic pain is one of the most debilitating experiences for an individual. For example, a survey of chronic back pain patients has shown that only about one-third of the patients were able to perform daily activities [4]. Another study on patients with fibromyalgia, rheumatoid arthritis, and low back pain has demonstrated that chronic pain from these conditions significantly deteriorates the patient's quality of life, both mentally and physically [5]. The considerable burden from chronic pain on the individual's life as well as its rapidly growing impact on the healthcare economy has rendered the significance of the effective diagnosis and management of chronic pain greater than ever.

Unfortunately, the accurate diagnosis of chronic pain is very challenging due to complicated contributions from both central and peripheral pain pathways. In the early 1980s, it was discovered that the central nervous system (CNS) can be reconfigured to make the body system hyperalert immediately after an intense stimulus [6]. This change of the CNS is dubbed as central sensitization. Numerous investigations have followed since then to identify alterations of the brain and spinal cord under chronic pain conditions and hypersensitivities developed by those changes in return. It is now well accepted that chronic pain can have a substantial contribution from central sensitization but its relationship to peripheral pathology, in terms of its presence, impact, or duration, remains poorly characterized and understood [7]. In fact, an increasing number of reports, which are further detailed later, has revealed that our inability to accurately identify local pain generators has led to suboptimal medical management and unnecessary surgical procedures [8,9].

It is, therefore, no surprise that therapies for chronic pain, which are dependent upon inadequate diagnostic methods, are on the average 30% efficacious in managing pain [10]. Our inability to accurately diagnose the source of pain invariably leads to suboptimal medical management and unnecessary surgical procedures. Furthermore, our diagnostic failure to localize and treat pain generators not only leads to depression, significant disability, decreased appetite, and sleep disturbances, but also to lost time from work and diminishing hope as patients are passed from doctor to doctor. Because the management of chronic pain is further limited by a narrow repertoire of effective medications, some of the blame of the current opioid crisis can be attributed to challenges in chronic pain management since physicians have no other option than to treat symptoms of pain with opioid analgesics rather than treat the underlying pathology.

Unfortunately, the accurate diagnosis and characterization of pain remain a significant clinical challenge. Especially in adults and elderly patients, inflammatory or degenerative changes observed with radiography, magnetic resonance imaging (MRI), or computed tomography (CT) may represent actively painful and symptomatically relevant changes of a disease process. However, they may also be simply part of the normal aging process. In the past couple of decades, we have learned that anatomic-based imaging approaches, such as conventional MRI, are unhelpful in identifying causative pain generators of many chronic pain conditions. In patients who suffer from chronic low back pain, for example, the etiology of one's back pain is unknown in up to 80% of the cases [11]. Additionally, significant intervertebral disc abnormalities using conventional MRI can be found in 27%–31% of asymptomatic subjects [12,13]. The natural progression of degenerative disc disease on MRI also does not highly correlate with the development of pain symptomology [14]. Provocative discography and MR-based morphometric measurements have only a weak association with back pain episodes [15]. Indeed, a meta-analysis on imaging strategies for lower back pain concluded that imaging did not improve clinical outcomes when performed on patients without indications for serious underlying conditions and that clinicians should refrain from routine immediate lumbar imaging in these patients [16]. Furthermore, the risk for labeling patients with an anatomical diagnosis via advanced imaging with MRI may not correlate with the actual cause of pain and give rise to unnecessary surgeries without clearly favorable outcomes [17].

More specifically, chronic sciatica, which is a specific subset of those suffering from low back pain, is a relatively common plight suffered in the general population. With a lifetime incidence of 14%–40% and an annual incidence of 1%–5% [18], sciatica is one of many pain syndromes where a subset of sufferers are inadequately treated because of the lack of accurate diagnostic tests. The most common cause of sciatica is a herniated intervertebral disc impinging upon a lumbar spinal nerve resulting in low back pain and pain radiating downward from the buttocks along the course of the sciatic nerve [19,20]. However, MRI is currently the imaging modality of choice for sciatica diagnosis, and its findings often do not well explain symptoms [21]. A wide variety of other spinal and nonspinal causes have been implicated as the source of sciatica [22–24], which naturally introduces complexity into the management of these patients since differing causes necessarily confer different therapeutic decisions. As no clinical test has been established that offers both high sensitivity and specificity in identifying the source of sciatica [25], many patients are relegated to empiric treatments for a herniated disc that are inevitably inadequate for a subset of those individuals suffering from “sciatica.” It is therefore no surprise that 20%–30% of the sciatica patients are left with chronic pain [26].

With regards to knee pain, meniscal tears detected on MRI have been found to be nearly equally prevalent (~60%) in symptomatic and asymptomatic knees of middle-aged and elderly persons, again, underscoring the poor relationship between MR findings and pain causation [27]. Similarly, abnormal shoulder MRI findings, such as rotator cuff and bone irregularities can be found in asymptomatic individuals, consequently questioning the value of these findings in those with shoulder pain [28,29]. Thus, our ability to objectively refine our diagnosis and render a meaningful management plan that leads to a favorable outcome remains extremely limited with current diagnostic approaches. Yet, despite such evidence to the contrary, the use of such anatomy-based imaging findings, unfortunately, remains an important part of the treatment algorithm for a wide range of pain syndromes. Accordingly, there is an unmet medical need to develop accurate, objective molecular imaging assays that accurately localize the source of heightened nociceptive activity and/or painful inflammation with high sensitivity and specificity.

5 Anticancer natural products in clinical trials (in the drug development chain)

In 2013, about 100 unaltered natural products as well as their analogues were in clinical trials for various ailments, and a majority of them were for the treatment of various forms of cancers and tumors.4 Some examples of natural products of plant origins that are currently at various stages of clinical trials on their route to emerging as new anticancer agents for cancer chemotherapy, or very recently introduced in the market, may include anhydrovinblastine, combretastatins, curcumin, indirubin, ingenol mebutate, paclitaxel poliglumex, salvicine and triptolide (Fig. 11).2 In 2015, clinicaltrials.gov listed more than 1200 active clinical trials evaluating one or more of Vinca alkaloids, in combination with other drugs, as interventions in clinical trials to treat cancer.

Anhydrovinblastine, a Vinca alkaloid isolated from Catharanthus roseus (also known as Vinca rosea), which produces the well-known anticancer drugs, vincristine and vinblastine, is an investigational anticancer drug, currently in clinical trials studying the treatment of unspecified adult solid tumors, and belongs to the family of drugs called mitotic inhibitors.58

Combretastatins are diarylethanoids or dihydrostilbenoids, predominantly produced by Combretum caffrum, which is commonly known as South African Bush Willow. Among the natural combretastatins, combretastatins A-1 and A-4 are the most potent in terms of tubulin binding ability and cytotoxicity, and are currently in clinical trials.59 These compounds bind to the β-subunit of tubulin, inhibit tubulin polymerization and thereby prevent cancer cells from producing microtubules, which are fundamental to cytoskeleton production, intercellular movement, cell movement, and formation of the mitotic spindle used in chromosome segregation and cellular division59,60; they are also vascular targeting agents.

Curcumin, a diarylheptanoid, isolated from Curcuma longa, commonly known as turmeric, has long been in various clinical trials without any fruitful outcome, mainly because of its poor bioavailability.61 In fact, the US government spent several million dollars in research into curcumin through the National Center for Complementary and Integrative Health, and could not find any support for curcumin as a medical treatment. However, curcumin and its modified analogues are still in clinical trials for the potential treatment of various cancers.62,63 A recent randomized Phase II clinical trial with curcumin compared to placebo in treating patients with prostate cancer that was removed by surgery suggested that curcumin might be able to stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and help to decrease or prevent prostate cancer from returning after surgery (also see Chapter 9).64 Another randomized Phase IIb trial indicated that this compound, being a potent antioxidant, might be able to stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Curcumin has also been evaluated in a clinical trial for its application in combination with chemotherapy in advanced breast cancer, especially combining with paclitaxel.63

Ingenol mebutate, found in the sap of Euphorbia peplus, commonly known as milkweed and used traditionally for the treatment of dermatological lesions, is a cytotoxic drug that has been introduced for the treatment of actinic keratosis on the face of scalp, usually caused by excessive exposure to the sun or UV radiations.65 This anticancer drug was developed and approved in Australia in 2013.

Indirubin, an investigational drug, is a constituent of a Traditional Chinese Medicine (TCM), indigo naturalis (also known as Qing Dai). Qing Dai is the leaf of Baphicacanthus cusia and Isatis tinctoria. Indirubin and related compounds are also obtained from Indigofera tinctoria (also known as I. sumatrana), but most often produced as a by-product of bacterial metabolism. Indirubin has been identified as the major active ingredient of the TCM formulation known as Danggui Longhui Wan, which has long been used for the treatment of chronic myelogenous leukemia in China. Currently, indirubin is under investigation in clinical trial for its antineoplastic applications, particularly against chronic myelocytic and chronic granulocytic leukemia.66

Paclitaxel poliglumex, a macromolecular taxane, is yet another investigational anticancer drug, which has undergone several clinical trials assessing its therapeutic potential against several forms of cancer including mainly advanced colorectal cancer, breast cancer, ovarian cancer, squamous cell carcinoma, lung cancer, and esophageal cancer.67–69 Paclitaxel poliglumex originates from linking paclitaxel, isolated from Taxus brevifolia, to a biodegradable, water-soluble polyglutamate polymer. The polyglutamate residue enhances the water solubility of paclitaxel and thus allows delivery of higher doses than those achievable with paclitaxel alone, and at the same time it increases the therapeutic index of paclitaxel.

Salvicine, diterpenoid quinone obtained by structural modification of a natural product lead isolated from the Chinese herb, Salvia prionitis,70 is a topoisomerase II inhibitor, and has been in clinical trials for possible anticancer applications.71

Triptolide, isolated from the thunder god vine (Tripterygium wilfordii) is an investigational drug for pancreatic cancer. It has been shown that triptolide can suppress the proliferation and promote apoptotic cell death in various cancers, especially prostate and pancreatic cancers.46 However, because of its severe toxicity, a synthetic water-soluble prodrug (minnelide), based on triptolide, has been in various clinical trials.72 Its Phase II clinical trials have just been concluded in February 2019.73

Flavopiridol, a synthetic compound, inspired by the phytochemical rohitukine, isolated from Dysoxylum bunectariferum (Meliaceae), showed growth inhibitory activity against breast and lung cancer cell lines both in vitro and in vivo (animal) studies. As a result, this compound being a pan-cyclin-dependent kinase (CDK) inhibitor that induces cell cycle arrest and apoptosis in many cancer cells, entered in the clinical trials at Phase I and Phase II, either alone or in combination with other chemotherapeutic agents for the potential treatment of leukemias, lymphomas and solid tumors, but with limited success.74

Since the approval of cytarabine about half a century ago, the marine-derived anticancer pharmaceutical pipeline incorporates four approved drugs, and at least 18 in clinical trials with six at a late developmental stage.75 In fact, several cytotoxic compounds from marine sources are also currently in various stages of pre-clinical and clinical trials for their therapeutic applications as anticancer and antitumor drugs. For example, several dolastatins, isolated from Dollabella auricularia, are in the clinical trial, and one of them, monomethyl auristatin E, is already in the market as an antitumor drug.33 Similarly, the depsipeptide dehydrodidemnin B, also known as aplidine or plitidepsin, isolated from the Mediterranean tunicate Aplidium albicans has been under clinical trials, initiated by PharmaMar for the development of Aplidin® for the treatment of multiple myeloma (Phase III), and for solid and hematological malignant neoplasias, like T-cell lymphoma (Phase II) (Fig. 12). Halimide (also known as phenylahistin) (Fig. 12), isolated from a marine Aspergillus spp. paved the way for the development of its synthetic analogue, plinabulin, which has been in the Phase I, II and III clinical trials against solid tumors and lymphomas, initiated by Nereus Pharmaceuticals, and continued by BeyondSpring Pharmaceuticals. Other marine compounds or their synthetic analogues that have been under clinical trials, especially Phase I, include marizomib, bryostatin 1, analogue of hemiasterlin and lurbinectedin (Fig. 12). In fact, bryostatin 1 has recently entered Phase II clinical trial against melanoma, non-Hodgkin's lymphoma, renal cancer and colorectal cancer.16 ET-743, a tetrahydroisoquinilone alkaloid isolated from tunicate Ecteinascidia turbinate, entered Phase I clinical trials; the antiproliferative effect of this compound is produced through selective alkylation of guanine residues in the DNA minor groove, whereas dolastatin 10, a member of a peptide family isolated from the mollusk Dolabella auricularia, reached Phase II clinical trials. Dolastatin 10 inhibits microtubule assembly, which eventually leads to metaphase arrest in the cell cycle.16

Nearly five decades after the approval of cytarabine, over 1000 clinical trials have been listed in European and US databases, with more than 150 studies in Phase III.75 Marine-derived natural products that are currently in clinical trials are shown in Table 2, grouped under various phases, Phase I to Phase III.

Table 2. Marine-derived natural products in Phase I, II and III clinical trials.

Adopted from Perreira, R.B.; Evdokimov, N.M.; Lefranc, F.; Valentao, P.; Kornienko, A.; Perreira, D.M.; Andrade, P.B.; Gomes, N.G.M. Mar. Drugs Marine Drugs 2019, 17(6), 329, DOI:10.3390/md17060329.

Among the antibiotic anticancer and antitumor agents, bleomycin, albeit has long been used in the treatment of various cancers, is currently in clinical trials for its potential applications in other forms of cancers. Similarly, some of the epothilones are also currently in clinical trials. Ixabepilone, an epothilone B analogue, developed by Bristol-Myers Squibb as an anticancer drug, was FDA approved in 2007 for the treatment of unresponsive aggressive metastatic or locally advanced breast cancer, and has recently been in Phase II trial in the treatment of recurrent/persistent carcinosarcoma of the uterus.76

Rapamycin, wortmannin, and geldanamycin (Fig. 13), because of their significant antiproliferative activities, are in clinical trials for the development of novel chemotherapeutic agents.77 While rapamycin, obtained from Streptomyces rapamycinicus, possesses antitumor activity mediated by hindering proliferation, triggering apoptosis, and inhibiting angiogenesis, wortmannin, a fungal furanosteroid produced by Penicillium funiculosum also offer similar anticancer effects by acting as an effective selective inhibitor of phosphoinositide 3-kinases (PI3Ks) and PI3K- related enzymes. Geldanamycin, a benzoquinone ansamycin antitumor compound from Streptomyces hygroscopicus var. geldanus, prevents ATPase activity by binding to the heat shock protein and affecting the stability and function of oncogenic protein kinases involved in signal amplification cascade that controls proliferation and apoptosis. Geldanamycin and its analogues have been in clinical trials for multiple myeloma, breast, and prostate cancers.