Authors: Julia Bita, Tanishkka Dhawan, Eva Florent, Alexandra Maggio, Seohee Min, and Adia Nygaard
Mentor: May Sin Ke. May is currently a doctoral candidate in the Department of Oncology at the University of Oxford.
Abstract
This review paper examines the potential of natural remedies as adjuvant cancer treatments. There are many limitations of conventional therapies such as side effects, high costs and limited efficacy of treatment for certain cancers, it is important to explore alternative approaches in the treatment of cancer. We conducted a comprehensive analysis of recent studies investigating various natural remedies and their effects on cancer. From these findings, we created an overview of both plant-based and non-plant-based derivatives of Complementary and Alternative Medicine (CAM) and included case studies of its use around the world. Our review highlights promising remedies, such as Paclitaxel, Nigella sativa, and Camptothecin which have demonstrated anti-cancer properties in preclinical studies. Additionally, we discussed the mechanisms of action through which these remedies may inhibit tumor proliferation and some preclinical data. The findings of this review highlights the potential of CAM and the need for future research in clinical studies.
Introduction
Cancer is the leading life-threatening illness in the world and plagues much of the worlds’ population. According to the National Center for Health Statistics, 1,958,310 new cancer cases and 609, 820 cancer deaths are projected for 2023 (Siegel et al., 2023). In order to meet this rate of new cancer cases and deaths, the Consolidated Appropriations Act of 2023 has allocated $7.3 billion to the National Cancer Institute of the United States (NCI Budget and Appropriations - NCI, 2015). This funding for cancer research which has increased over the years has allowed for many improvements, for instance, the 5‐year relative survival rate for all cancers combined has increased from 49% for diagnoses during the mid‐1970s to 68% for diagnoses during 2012 through 2018 (Siegel et al., 2023).There will be an estimated 153,020 new cases of CRC in the United States in 2023, including 106,970 tumors in the colon and 46,050 tumors in the rectum (Siegel et al., 2023). Europe accounts for 23.4% of the total cancer cases and 20.3% of the cancer deaths, followed by the Americas’ 21% of incidence and 14.4% of mortality worldwide. In contrast to other regions, the shares of cancer deaths in Asia (57.3%) and Africa (7.3%) are higher than the shares of incidence (48.4% and 5.8%, respectively) because of the different distribution of cancer types and higher case fatality rates in these regions (Bray et al., 2018). Therefore, it is important to study cancer comprehensively, develop innovative treatment strategies, and promote early detection and prevention measures to further improve patient outcomes. The ongoing cancer efforts and their funding is crucial in advancing our understanding of cancer biology, identifying new therapeutic targets and facilitating the development of more effective interventions. Moreover, the disparities observed in cancer incidence and mortality rates across different regions underscore the need for targeted interventions and tailored healthcare approaches. Addressing the specific challenges faced by each region, such as variations in cancer types and case fatality rates or their population’s specific access to advanced healthcare facilities, can help optimize cancer care and reduce the global burden of the disease.
The current standard of care for cancer centers around common treatment options used to treat patients including surgery, chemotherapy and radiation. Surgery is the most direct form of treatment in which the tumor is taken out directly.
Chemotherapy is the administration of cytotoxic chemicals aiming to eradicate the tumor or at least, reduce the tumor burden including its symptoms to prolong life (Nygren, 2001). The cytotoxic drugs are mostly given in the intravenous route but can also be given orally or into one specific region all of which is based on the patient’s tumor histology and data from clinical trials (Nygren, 2001). Chemotherapy is used in (1) primary induction treatment for advanced disease or for cancers for which there are no other effective treatment approaches, (2) neoadjuvant treatment for patients who present with localized disease, for whom local forms of therapy such as surgery of radiation, or both, are inadequate by themselves, (3) adjuvant treatment to local methods of treatment, including surgery, radiation therapy, or both. (Chu, 2017).
Another form of cancer treatment is radiation therapy, aimed at disrupting the ability of cancer cells to divide. This is achieved by generating ions and delivering energy to the cells of the tissues affected by radiation, killing cancer cells by causing DNA damage (Baskar et al., 2012). Radiation is commonly administered alone in the treatment of localized tumors such as early-stage larynx or prostate cancer, non-melanoma skin cancer, head and neck cancers, and radiosensitive tumors like seminomas and lymphomas (Hoppe et al., 2012). Radiation therapy is also used concurrently with chemotherapy and has been beneficial for treating lung, cervix, neck, head, vulva, and anal canal cancers, and as adjuvant treatment following surgery commonly used for the cancers of the head, neck, breast, lung, rectum, and for soft tissue sarcomas (Jaffary & Gospodarowizc, 2015). Radiation therapy maximizes the radiation dose to kill only abnormal cancer cells while minimizing the exposure to normal cells and since normal cells can repair themselves more effectively than cancer cells, only cancer cells are targeted (Baskar et al., 2012).
Examples of other neoadjuvant therapy of cancer include immunotherapy, which is used to treat cancer as it uses various approaches such as vaccines which can activate host T cells against tumor antigens and preventative vaccines are used in defense against cancer-causing infectious diseases (Kaufman et al., 2015). Another part of immunotherapy is oncolytic virus therapy which employs native or engineered viruses that selectively replicate in and kill cancer cells through acute tumor debulking owing to tumor cell infection, and lysis and induction of systemic antitumor immunity (Lichty et al., 2014). Also, adoptive cell therapy may be used in immunotherapy transferring immune cells such as lymphocytes into a patient to eradicate primary and metastatic tumor cells (Rosenberg et al., 2008). Immune checkpoint blockade is another subcategory in which there is a blockade of immune-inhibitory pathways activated by cancer cells (Topalian & Pardoll, 1998). Most patients will use a combination of these subcategories to treat their cancers as it is seen to be more effective to achieve complete remission (Sharma et al., 2011). Another form of standard cancer treatment is hormonal therapy which targets hormone sensitive cancer cells by interfering with the effects of hormones or blocking the body’s ability to produce hormones, which is commonly used for prostate and breast cancers (Brawer, 2006). These are the standard forms of care for cancer treatment which are used depending on the patient to treat them in the best way possible.
Literature Review
Limitations in current standard of care
Side effects of current standard of care
A substantial drawback with various forms of current care is the intensity of the side-effects, creating new avenues for decreased quality of life. Nausea and vomiting are among the most feared side-effects of cancer chemotherapy. Delayed chemotherapy-induced nausea and vomiting (CINV) is difficult to manage, and substance P's effect on neurokinin-1 (NK-1) receptors is a key factor in its development (Andrews & Sanger, 2014). Gastrointestinal side-effects of cancer chemotherapy, such as mucositis, constipation, and diarrhea, can be distressing and potentially fatal. Prevention and treatment strategies for these side-effects are still lacking, though some promising pre-clinical and clinical studies have been conducted. Some platinum-based chemotherapies, like carboplatin and cisplatin, may lead to hypersensitivity reactions, cardiovascular disease, and nephrotoxicity. Chemotherapy-induced peripheral neuropathy (CIPN) can last for many years after treatment, leading to reduced functional capacity and decreased quality of life (Younus et al., 2022). Several studies explore the mechanisms and potential interventions for preventing and treating CIPN. However, the use of non-approved combinations of drugs can lead to severe side-effects and toxicities (Zhou et al., 2017). Many aspects of cancer chemotherapy's impact on sensory functioning, fertility, and long-term health in cancer survivors deserve further attention and research (Nurgali et al., 2018). By exploring the significant compromises that come with every form of treatment, integrative cancer treatments may provide more promising options for patients.
Radiation therapy has great opportunity, however it also comes with life-changing side effects. The type of radiation therapy used also plays a role in the side effects experienced by patients. Different types of radiation therapy, such as external-beam radiation therapy and internal radiation therapy (brachytherapy), have their specific side effect profiles. For example, external-beam radiation therapy can cause acute effects on skin, mucosa, and the digestive tract, while internal radiation therapy may result in swelling and tenderness in the affected area. The clinical significance of these side effects varies depending on the site of irradiation. For instance, head and neck irradiation can lead to mucositis, salivary gland dysfunction, and neurologic symptoms. In the thorax, lung irradiation can cause pneumonitis, while heart irradiation may lead to cardiac complications. In the abdomen and pelvis, gastrointestinal and urinary system complications are common, along with gonadal dysfunction and vaginal and cervical issues. Proper management of these side effects is essential to minimize their impact on patients' quality of life (Hall, 2006). Treatment strategies include symptomatic management, use of anti-inflammatory agents, pain management, hyperbaric oxygen therapy, and surgical interventions for severe or refractory complications. Proper evaluation and management of these side effects by an interprofessional team are crucial to ensure the best possible outcomes for patients undergoing radiotherapy (Majeed & Gupta, 2022).
Immunotherapy tends to have milder side effects compared to chemotherapy and radiotherapy as it usually involves activation of one’s own immune system. For example, gastrointestinal (GI) symptoms and mucositis commonly observed in chemotherapy are much milder for immunotherapy treatments (Kroschinsky et al., 2017). Instead, new forms of immune related toxicities are observed, such as immune hepatitis (liver inflammation) from Nivolumab Pembrolizumab (a drug used to target PD-1 immune checkpoint) and neurotoxicities from Chimeric antigen receptor (CAR) T-cell therapy (CAR T-cell -a new class of cancer drug that targets CD19) therapies (Kroschinsky et al., 2017).
In brief, developing new therapy methods could help to provide alternative solutions to improve a patient's quality of life.
Drug resistance
Drug resistance is a phenomenon that occurs when diseases become tolerant to pharmaceutical treatments. Drug resistance in cancer can manifest in different ways. Resistance to cancer drugs is a significant challenge in cancer treatment and often leads to a reduced response to therapy. Initially, many types of cancers are sensitive to chemotherapy. However, over time, they can develop resistance to these treatments through various mechanisms. One common mechanism is drug efflux, which occurs when cancer cells pump out the drugs meant to kill them, making the treatments less effective. In addition, cancer cells may acquire DNA mutations and metabolic changes that evade the effects of the drugs, leading to reduced effectiveness of the treatment (Housman et al., 2014). For patients, drug resistance can lead to disease progression, recurrence and limited therapeutic options. In addition, the development of drug resistance can complicate treatment decisions and necessitate the use of alternative therapies, which may be less effective or have more serious side effects.
However, drug resistance doesn’t only exist for chemotherapy, but also concerns radiation treatments. Radiotherapy uses high-energy radiation to target and destroy cancer cells. Nonetheless, certain cancer cells can develop resistance to radiation over time. There are multiple ways in which radiotherapy resistance can develop, mainly due to the tumor's heterogeneity and the surrounding microenvironment, along with various gene alterations (Kim et al., 2015; Yard et al., 2016; Olivares-Urbano et al., 2020; Kabakov et al., 2021). Despite advancements in novel radiotherapy techniques and the adoption of new treatment approaches, radiation resistance remains a significant hurdle in improving treatment outcomes (Chandra et al., 2021; Larionova et al., 2022). Similarly to chemotherapy resistance, this resistance can lead to radiation therapy failure, cancer metastasis, recurrence, and ultimately, a poor prognosis for patients.
Addressing radiation and chemotherapy resistance is crucial to enhancing their effectiveness and achieving better overall treatment. On the other hand, it also highlights the limitations of those treatments and serves as motivation to look for more effective, innovative therapies.
High cost of treatment
A limitation that affects the physiological well-being of patients in conjunction to significantly limiting access to care and its efficacy is the cost of care. Expensive cancer drugs and limited affordable alternative options exacerbate patient’s financial pressures and hinder access to essential treatments. A study done on the financial distress of patients with advanced cancer highlights the concern among oncology providers about the cost barriers to innovative cancer treatments and discusses coping mechanisms for patients facing financial toxicity (Barbaret et al., 2017). It also emphasizes the need for open discussions between providers and patients about the cost and value of cancer treatment and advocates for management strategies to assess and mitigate financial toxicity as part of supportive care in cancer facilities (Carrera et al., 2018).
It was estimated in 2018 that low- and middle-income countries have less than 5% of the global ressources for combating cancer (World Health Organization, 2018). The insufficient accessibility to both new and off-patent essential cancer medicines raises concerns, particularly due to the soaring prices that significantly affect affordability for large populations in low- and middle-income countries (International Agency for Research on Cancer, 2020; World Health Organization, 2018; Goldstein et al., 2017). As an illustration, the cost of a standard treatment course (doxorubicin, cyclophosphamide, docetaxel, trastuzumab) for early-stage human epidermal growth factor receptor 2 positive (HER2+) breast cancer in India and South Africa would amount to approximately 10 years of average annual wages in those countries (International Agency for Research on Cancer, 2020). According to a technical report by the World Health Organization (WHO), countries with lower national incomes experienced reduced accessibility to anti-cancer medicines. In such countries, these medications were either less available or only accessible with higher out-of-pocket patient payments, particularly for higher-cost medicines, including targeted therapies (World Health Organization, 2018). The availability of cancer medicines on the essential medicine list was reported to be 32.0% in lower-middle-income countries and 57.7% in low-income countries. However, these medicines were accessible only to patients who were willing to bear their full costs (World Health Organization, 2018). Hence, in low- and middle-income countries, significant portions of the population face restricted access to medicines. This lack of access can result from either limited availability or the need for patients to cover the costs of their prescriptions. In the absence of government reimbursements, insurance, or exclusive access schemes in these countries, many patients are burdened with the entire cost of their treatment. Consequently, this situation can lead to deprivation, poverty, or premature death for affected individuals. In several studies (Goldstein et al., 2017; Faruqui et al., 2019; Islam et al., 2015; Sarwar et al., 2018), it was found that anticancer medicines are less affordable in low- and middle-income countries when considering individual patients' income levels (Faruqui et al., 2018; Islam et al., 2015; Sarwar et al., 2018) compared to high-income countries based on the country's Gross Domestic Product (GDP) per capita (a measure of economic output per person) (Goldstein et al., 2017).
For example, using international indicators of wealth, such as the monthly GDP per Capita at Purchasing Power Parity (PPP) provided by the International Monetary Fund, one study (Goldstein et al., 2017) revealed that anticancer drug prices in countries like India, China, and South Africa were less affordable than in all high-income countries, including the United States where prices were significantly higher. In other words, cancer medicines are harder to afford for individuals in low- and middle-income countries based on their personal income levels compared to how easy it is for people in high-income countries to afford them based on their country's economic output per person. The issue of poor affordability underscores the importance of developing policies to ensure fair and equitable access to medicines. Hence, various scientists around the world are trying to develop new/alternative therapies, such as plant-based ones, which could potentially be more affordable and thus decrease treatment abandonment in underprivileged individuals.
The following section of the review attempts to introduce various complementary and alternative methods of cancer therapy.
Complementary and alternative medicine (CAM) in cancer
Figure 1. Overview of CAM in cancer treatment
CAM stands for Complementary and Alternative Therapies for cancer. They are increasingly becoming more popular, with reportedly around 40-85 percent of cancer patients trying CAM, depending on the type of cancer (Berretta et al., 2017). A common CAM therapy method is Traditional chinese medicine (TCM) in which quite a few of the plant derived CAM compounds are derived from. Several CHM (Chinese Herbal Medicine)‐derived compounds have exhibited anticancer properties that inhibit the development, proliferation, angiogenesis, and metastasis of human cancer (Xiang et al., 2019). Some other types of CAM also include: spiritual or healing prayer (18.7 percent), herbal medicine (9.6 percent), chiropractic therapy (7.6 percent) (Pérez and Luquis, 2021).
The following section will explore both plant-based and non plant-based methods of CAM.
Plant-based derivatives of CAM
Table 1. Plant-based derivatives of CAM, their structure subclass and the type of cancer it treats
Structure subclass | Compound | Cancer type | References |
Lipophilic diterpenoid | Paclitaxel | Ovarian cancer Breast cancer Small-lung cancer | Kingston (2005) Hartwell (1982) Cuendet and Pezzuto (2004) Mcguire et al. (1989) Sedlacek (2000) |
Synthetic flavone | Flavopiridol | Leukemia Lymphomas | Pinney et al. (2005) Sausville et al. (1999) Sedlacek (2000) Cragg and Newman (2005) Pinto et al. (2020) |
Alkaloid | Nigella Sativa | Lung cancer Colon cancer Skin cancer | Ahmad et al. (2013) Shafiq et al. (2014) Mabrouk et al. (2002) Kumara and Huat (2001) Al-Amri and Bamosa (2009) |
Cytotoxic alkaloid | Camptothecin | Ovarian cancer Small-lung cancer Metastatic Colorectal cancer | Cragg & Newman (2005) Creemers et al. (1996) Fuchs et al. (2006) Nirmala et al. (2011) |
Alkaloid esters of cephalotaxine | Harringtonine Homoharringtonine | Leukemia | Nirmala et al. (2011) Cragg and Newman (2005) Effereth et al. (2007) Jiang et al. (1983) |
Phytochemical | Sulforaphan | Breast cancer Colon cancer | Fimognari (2006) |
Cisplatin toxicity | Resveratrol | Carcinoma | Amri et al. (2011) |
Polyphenol metabolite | Curcumin | Colorectal | Yuening Xiang et al. (2019) |
Acid | Aristolochic | Urothelial cancer | Volker et al. (2002) |
Galactose-specific lectin | Visum album [L.] | Pancreatic cancer Breast cancer | Tröger et al. (2013) Tröger et al. (2012) |
Curcumin
Curcumin is a polyphenolic compound and bioactive metabolite found in Curcuma longa (turmeric). Curcumin works as a coloring agent as well as therapeutic activities. “The discovery of curcumin dates to around two centuries ago when Vogel and Pelletier reported the isolation of ‘yellow coloring-matter’ from the rhizomes of Curcuma longa (turmeric) and named it curcumin” (Gupta et al., 2012). Curcumin is a polyphenol and bioactive metabolite and research shows that 8g of oral curcumin and gemcitabine-based were a safe combination for patients to use daily. Curcumin also “prolong[s] the median survival time of mice bearing esophageal squamous cell carcinoma while exposed to radiation therapy” (Xiang et al., 2019). Limitations of curcumin exist in clinical use such as toxicity, low solubility, low stability, and more. Oral applications “cannot have a direct effect on tumor tissues/cells and its antitumor effect is mostly caused by modulation of the gut microbiota” (Dytrych et al., 2023). Gut microbiota is a densely populated gut with different bacterias.
Resveratrol
Resveratrol is a natural phytochemical, or phytoalexin, found in spermatophytes such as grapevines. “Resveratrol was first isolated in 1939 by Takaoka from Veratrum grandiflorum O. Loes” (Pezzuto, 2018) Dietary resveratrol may “act as an antioxidant, promote nitric oxide production, inhibit platelet aggregation, and increase high-density lipoprotein cholesterol” (Bhat et al.,). Resveratrol improved cisplatin toxicity which is an apoptosis-dependent mechanism. Both resveratrol and berberine enhanced radiosensitivity in nasopharyngeal carcinoma cells. “In a mouse renal tumor model, low dose resveratrol administration was shown to inhibit tumor growth by modulation of CD8(+) T cells'' (Xiang et al., 2019). Resveratrol shows potential therapeutic effects toward cancer as it functions as a cancer chemopreventive agent. TCM treatments had fewer incidences of radiation xerostomia (dry mouth) in head and neck cancer patients during radiotherapy. Limitations of resveratrol include “poor solubility, limited stability, high metabolization and weak bioavailability” (Amri et al., 2011).
Paclitaxel
Paclitaxel is a plant-derived chemotherapeutic agent that was initially found in the bark of Taxus brevifolia (commonly known as Pacific Yew) during the 1960s. (Kingston, 2005). It was identified by the US Department of Agriculture during a collection program for the NCI. It was originally used by Native American tribes as medicine for other diseases (Hartwell, 1982). Paclitaxel took 20-30 years of dedicated research until it was finally proven as an efficient clinical agent and integrated into standard clinical care (Cuendet and Pezzuto, 2004). It is often used to treat ovarian, breast, and small-cell lung cancer as well as non-cancerous diseases such as sclerosis, psoriasis, and rheumatoid arthritis. In phase II trials with patients previously treated with chemotherapy, the response rate in advanced and refractory ovarian cancer was 30% (Mcguire et al., 1989). Limitations to this drug include poor water solubility, allergic reactions, and clinical delay due to the lack of appropriate delivery vehicles (Singla et al., 2001).
Flavopiridol
Flavopiridol is an anti-cancer drug which is entirely synthetic, but finds its basis in a natural product, rohitukine. The plant was derived from the South African “brush willow” in the 1970s as part of a random collection program for the NCI, working in collaboration with the Botanical Research Institute of South Africa (Pinney et al., 2005). Flavopiridol was one of 100 analogs of rohitukine synthesized during structure-activity studies (Sausville et al., 1999). Flavopiridol has been found to possess tyrosine kinase activity (which plays a role in the communication, development and division of cancer cells) and strong growth inhibitory activity against human tumors. Flavopiridol is an attractive drug option as it kills both resting and cycling tumor cells, increasing the efficacy of the treatment (Sedlacek, 2000). It is currently in 18 Phase I and Phase II clinical trials against a wide range of tumors, including leukemias, lymphomas and solid tumors (Cragg and Newman, 2005). A limitation to this study is that it still needs to be further studied because researchers don’t fully understand its clinical validity. More research is needed to prove to hospitals that it delays disease progression and improves the overall patient outcomes (Pinto et al., 2020).
Nigella sativa
Nigella sativa is a seed that has been used around the world to treat different human diseases, as it has many nutritional and medicinal benefits. It is very popular in many traditional medical systems like Unani, Tibb, Ayurveda, and Siddha (Ahmad et al., 2013). Its main bioactive ingredient, thymoquinone, has been proven by many studies to be effective against chronic illnesses. This ingredient has several medicinal properties including anti-cancer, anti-inflammatory, and antioxidant activities. (Shafiq et al., 2014). A supplement with Nigella sativa and honey was shown to have protective effects against lung, colon, and skin cancer. (Mabrouk et al., 2002). A study by Kumara and Huat demonstrated that Nigella sativa exhibited anti-cancer activity against the LL/2 tumor cell line by implanting the drug into mice. The results showed that the plant extract had significant anticancer activity against the lung cancer cell line and inhibited cancer cell proliferation by about 90% (Kumara and Huat, 2001). Limitations to this drug are its mono target capabilities, which limits it to only be able to target one cancer pathway (Al-Amri and Bamosa, 2009).
Camptothecin
Camptothecin, a cytotoxic alkaloid, is mainly isolated from the bark and stem of a Chinese tree called Camptotheca acuminate. Camptothecin showed poor solubility and low toxicity so certain analogues of it were synthesized to overcome these issues which were the initial limitations of Camptothecin. Campothecin, itself, is sodium salt and was advanced to clinical trials by the NCI in the 1970s but it was seen to have extreme bladder toxicity (Cragg & Newman, 2005). So, Camptothecin was later developed into the more effective derivatives, such as Topotecan and Irinotecan through 20-30 years of continued research due to its original inefficacy in clinical trials (Cragg & Newman, 2005). Topotecan is effective for ovarian cancer and small lung cancer as a second line treatment (Creemers et al., 1996). Irinotecan works as a first and second line treatment for metastatic colorectal cancer (Fuchs et al., 2006). They work by inhibiting the DNA Topoisomerase I which plays a big role in DNA function like in replication and transcription. The camptothecin molecule has a S-configured lactone form and carboxylate form which is responsible for the anti-cancer activity (Nirmala et al., 2011). Although the derivatives might help in treating cancer there are side effects which include neutropenia and thrombocytopenia for Topotecan, and neutropenia and diarrhea for Irinotecan (Mathijssen et al., 2002).
Harringtonine and homoharringtonine
Harringtonine and homoharringtonine are two alkaloid esters of cephalotaxine and were originally used in traditional Chinese medicine to cure cancer (Nirmala et al., 2011). These compounds were isolated from the evergreen coniferous shrubs of Cephalotaxus species (Nirmala et al., 2011). Through in vitro testing, homoharringtonine is found to be effective against leukemic cells by inhibiting protein synthesis and causing inhibition of chain elongation during translation (Nirmala et al., 2011). A mixture of the two can be used to treat both acute myeloid leukemia and chronic myeloid leukemia (Cragg and Newman, 2005; Effereth et al., 2007).
A study to compare their antitumor activity against solid tumors tested these compounds on in vitro culture of fresh tumor cells from 23 patients. Significant antitumor activity was noted for harringtonine in ovarian and endometrial carcinoma, but with continuing exposure homoharringtonine was seen to be more potent in terms of its antitumor activity. This was especially seen in sarcoma and breast cancer as well as in ovarian and endometrial carcinoma. These results show that both agents may be of use in solid tumors, and that homoharringtonine has a greater degree of colony inhibition with continued exposure (Jiang et al., 1983). Homoharringtonine and Harringtonine did proceed to clinical trials in which they were later approved for clinical use specifically in China (Xu et al., 2012). Homoharringtonine is then a cancer therapy drug in China and has definite trials in the United States proving its positive effect on leukemia patients, but neither country has recommended its production (Xu et al., 2012).
Sulforaphane
Sulforaphane (SFN) is a phytochemical capable of various biological health benefits for health promotion and disease prevention. Sulforaphane is derived from cruciferous vegetables, such as broccoli, cauliflower, and kale. Sulforaphane is from the family of isothiocyanates. A phytochemical is a medical compound that is produced by plants. It can help cope with side effects of cancer such as headaches, nausea, and fatigue. Studies conducted both in vitro and in living organisms in vivo have shown that SFN can have a significant impact on various stages of cancer development (Eur. J. Oncol. Nurs, 2005). It has been found to regulate the early stages of the carcinogenic process, as well as impact specific events such as apoptosis, cell proliferation, and angiogenesis that are involved in the progression phases of cancer (Fimognari, 2006). Studies have shown that SFN has a variety of activities, including antioxidant, antitumor, anti-angiogenic, and anti-inflammatory properties. SFN is a natural dietary supplement that is safe, well-tolerated, and less toxic, making it a promising option for clinical trials.
Aristolochic acid
Aristolochic acid (AA) is an old herbal drug that is derived from Aristolochia spp. (Aristolochiaceae) commonly used to treat arthritis, gout, rheumatism and present a variety of herbal remedies (Schwetz 2001). It almost entered the market through German pharmaceuticals until it was discovered to be carcinogenic (Kluthe et al., 1982) and naturally inappropriate for treating cancer. Major components of plant extract AA, aristolochic acid I (AAI) and aristolochic acid II (AAII), both nitrophenanthrene carboxylic acids, are genotoxic mutagens forming DNA adducts after metabolic activation through simple reduction of the nitro group. (Volker et al., 2002). This aristolochic acid is related to aristolochic acid nephropathy and urothelial cancer. An experiment on the treatment with aristolochic acid on Wistar rats, an ideal model with spontaneous tumors for studies, was conducted. The sodium salt contained in the acid triggered a high incidence of tumors and led to severe papillomatosis and the development of squamous cell carcinomas in the forestomach. Studies have also found that AA not only develops tumor, but also responsible for “the destructive fibrotic process in the kidney…AA is a powerful nephrotoxic and carcinogenic substance with an extremely short latency period, not only in animals but also in humans'' (Volker et al., 2002). This example reveals the complexities of the various compounds in herbal remedies which may be unknowingly toxic.
Viscum album [L.]
The Viscum album extract (VaL) is a cytotoxic and apoptosis-inducing substance extracted from the mistletoe of oak trees (Bussing et al., 1999). Low dose of VaL reduces melanoma growth in a mouse model (Thies et al., 2008). Intratumoral injections of VaL have demonstrated significant efficacy in animal models using human pancreatic cancer xenografts, resulting in partial and complete remissions (Rostock et al., 2005). Similarly, in patients with inoperable pancreatic carcinoma, VaL injections have shown promising outcomes (Matthes et al., 2007). These studies provided strong evidence for the potential of VaL as a treatment strategy for pancreatic cancer, which led to a 2013 phase III randomized clinical trial comparing the overall survival (OS) of patients receiving an extract of viscum album (VaL) or no antineoplastic therapy (Tröger et al., 2013). They found that the median OS was 4.8 months for VaL and 2.7 months for control patients. Within the ‘good’ prognosis subgroup, median OS was 6.6 months versus 3.2 months, within the ‘poor’ prognosis subgroup, it was 3.4 months versus 2.0 months respectively.
Local side-effects of the VaL injections included erythema and swelling on the injection sites, but no other side-effects (local or global) were attributed to VaL in this study. However, other studies reported common side-effects of VaL being soreness and inflammation at injection site, headache, fever, chills, allergic reactions, and in a few cases, severe anaphylactic shock (Kaegi, 1998; Hutt et al., 2001; Stauder et al., 2002; Steele et al., 2014).
Figure 2. Overall survival of the 220 patients (Dispersed equally in a control and experimental group) using the Kaplan-Meier estimates of 12-month overall survival (Tröger et al., 2013).
Non-plant-based CAM
Table 2. Non plant-based forms of CAM and their classifications.
Classification | CAM | References |
Medication | Vitamin C | Verrax & Calderon (2008) Pathak et al. (2005) |
Therapy | Acupuncture | Han (2003) Wu et al. (1999) Zhao (2008) Roscoe et al. (2003) Morrow et al. (2003) |
| Chiropractic therapy | Eisenberg et al. (1998) Barnes et al. (2008) Post-White et al. (2009) Saxe et al. (2008) Sierpina et al. (2007) McEachrane-Gross et al. (2006) Smith Hamish et al. (2015) Pinheiro et al. (2015) Husereau et al. (2003) Proctor et al. (2001) Balon and Mior (2004) Gross et al. (2004) Ernst (2003) Childs et al. (2004) Fritz et al. (2005) Brennan et al. (2006) |
| Energy medicine | Barrie et al. (2004) Rosa et al. (1998) O'Mathuna (2000) Brown et al. (2002) Segal et al. (2001) Gironell et al. (2002) Weinstein et al. (2001) Pelka et al. (2001) |
| Mind-body interventions | NIH (1996) Sellick et al. (1998) |
Particle | Nanoparticles | Zhang & Gurunathan (2016) Yuan et al. (2018) Bindemann et al. (1991) Bridge et al. (1988) Walker (1999) Vasterling et al. (1993) Morrow et al. (1982) Arakawa et al. (1995) |
Vitamin C
Vitamin C can be used in cancer treatment as it has been reported from preclinical studies that vitamin C may have anti-cancer properties, and that vitamin C increases the efficacy of many chemotherapy drugs and radiation therapy either in vitro or in vivo (Verrax & Calderon, 2008). As to the administration, orally vitamin C seems to have no effect on the outcome of patients undergoing chemotherapeutic regimens, suggesting that vitamin C did not protect cancer cells from oxidant damage induced by chemotherapy (Pathak et al., 2005). But, various case reports have shown that vitamin C administered intravenously has seemingly worked in treating the cancer of various patients, but these cases do not show definitive proof of vitamin C truly working in treatment, so further clinical studies are needed (Verrax & Calderon, 2008). Patients have shown adverse effects to taking vitamin C intravenously such as hemolysis, hyperoxaluria, and urine acidification (Verrax & Calderon, 2008). So, although data has also suggested that vitamin C promotes the activity of anti-cancer treatments, its inclusion in cancer treatment should be contemplated on the basis of the preclinical results (Verrax & Calderon, 2008).
Acupuncture
Research suggests that acupuncture may stimulate the release of endorphins, which are natural pain-relieving chemicals in the body. Current scientific evidence suggests that acupuncture regulates the nervous system and reduces inflammation, which could contribute to its effectiveness in managing cancer-related symptoms (Han, 2003, Wu et al., 1999, Zhao, 2008). New research in acupuncture has shown that it can be beneficial for oncology patients in managing symptoms and providing supportive care. Acupuncture has been found to be very effective in treating a variety of symptoms, including general pain, gastrointestinal side-effects, hot flushes, shortness of breath, fatigue, anxiety, depression, and insomnia. A large multicenter study found that acupressure wrist bands were effective in controlling chemotherapy-induced nausea and vomiting. In a randomized study, 50 patients were made to wear either active or placebo acupuncture bands in addition to their normal medications for five days after chemotherapy. The results showed that patients who wore the active band experienced significantly less nausea and vomiting compared to those who wore the placebo band (Roscoe et al., 2003).
Nanoparticles
Nanoparticles in cancer treatment are needed as they increase the efficiency of treatment through a combination of nanoparticles and anticancer drugs to increase the efficacy of anticancer, reduce unwanted side effects, and improve pharmacokinetics (Zhang & Gurunathan, 2016). To focus on a specific case, combinations of silver nanoparticles with the anti-cancer drug camptothecin can potentially induce cytotoxicity and apoptosis without any undesired cytotoxic effects, increasing the efficacy of the two for cancer treatment (Yuan et al., 2018). This combination may be able to prevent the toxic effects on normal cells whilst also directing the cytotoxic effects on cancer cells and combating resistance (Yuan et al., 2018). One study in particular found that Camptothecin and nanoparticles at lower doses could induce cytotoxicity and apoptosis without the undesired side effects, increasing the efficacy of the two molecules for cancer treatment (Yuan et al., 2018). Although more clinical studies are needed in order to prove that this combination therapy is beneficial, from what has been studied the combination therapy results in a better response and improved survival rate compared to single-agent therapy (Yuan et al., 2018).
Energy medicine
Energy therapies are founded on the theory that the human body possesses energy fields surrounding it. The underlying belief is that modifying these purported energy fields through manual manipulations like Qigong (traditional chinese practice) or therapeutic touch, or through the application of electromagnetic fields, can lead to the elimination of disease. However, it is important to note that the existence of these energy fields has not been scientifically substantiated (Barrie et al., 2004).
Therapeutic touch (TT), despite its name, does not involve direct physical contact with the patient. Instead, practitioners hover their hands a few inches above the patient's body, aiming to eliminate perceived "blockages" in the patient's energy field. However, a study published in the Journal of the American Medical Association demonstrated that experienced TT practitioners were unable to detect the investigator's supposed "energy field" (Rosa et al., 1998). Despite the lack of scientific evidence supporting its fundamental premises, TT is still taught in North American nursing schools and widely practiced by nurses in the U.S. and other countries ( O'Mathuna, 2000). Bioelectromagnetic field therapies encompass the application of pulsed, alternating, or direct current and magnetic fields to address various medical conditions. Clinical trials have been carried out to evaluate the effectiveness of magnetic field therapies in pain management (Brown et al., 2002; Segal et al., 2001), tremor reduction (Gironell et al., 2002), epilepsy treatment (Weinstein et al., 2001), and alleviating migraine headaches (Pelka et al., 2001). None of these clinical trials were conclusive in proving energy medicine to be successful.
Mind-body interventions
Mind-body interventions strive to leverage the interconnectedness of the body and mind in order to aid patients in relaxation, stress reduction, and alleviation of symptoms associated with cancer and its treatments. Conventional practitioners, including clinical psychologists, often employ hypnosis and relaxation techniques for this purpose. Several randomized trials have provided evidence of the efficacy of hypnosis in managing both procedural and malignant pain (NIH, 1996; Sellick et al., 1998), as well as reducing anxiety, depression, and mood disturbances in newly diagnosed cancer patients (Bindemann et al., 1991; LRBridge et al., 1988; Walker, 1999). Moreover, these trials have generally reported positive outcomes of hypnosis and relaxation training in mitigating chemotherapy-induced nausea among adults (Vasterling et al., 1993; Morrow et al., 1982), although certain studies have found no significant differences between experimental and control groups (Arakawa et al., 1995).
Chiropractic therapy
The NIH describes chiropractic therapy as “A type of therapy in which the hands are used to manipulate the spine or other parts of the body. Sometimes, heat and ice, relaxation techniques, exercise, and other treatments are also used.” Chiropractic therapy stands out as the most widely used and extensively regulated alternative therapy among the various CAM treatments. It surpasses all other alternative therapies in terms of its popularity and adoption by individuals seeking complementary healthcare solutions (Eisenberg et al., 1998; Barnes et al., 2008; Post-White et al., 2009). Chiropractic therapy is also popularly used amongst cancer patients (Saxe et al., 2008; Sierpina et al., 2007; McEachrane-Gross et al., 2006). Patients undergoing cancer treatment often face a dual challenge, combating both the psychological impacts of the diagnosis (such as heightened depression and anxiety) and the metabolic effects of therapeutic interventions (resulting in reduced activity levels). These factors, in conjunction, can heighten the risk of musculoskeletal conditions, further burdening the patients (Smith et al., 2015; Pinheiro et al., 2015). As a consequence of these conditions, patients often turn to chiropractic care for relief. No robust scientific evidence supports the positive effects of chiropractic therapy on several commonly proclaimed issues, such as tension type headaches (Fernandez-de-las-Penas et al., 2006), infantile colic (Husereau et al., 2003), primary and secondary dysmenorrhea (Proctor et al., 2001), asthma and allergies (Balon and Mior, 2004), as well as neck problems and pain (Gross et al., 2004; Ernst, 2003). However, some studies have found that a specific subgroup of patients experiencing back pain can potentially benefit from spinal manipulation, while others do not (Childs et al., 2004; Fritz et al., 2005; Brennan et al., 2006; Fritz et al., 2006).
Discussion
The plant-based and non plant-based forms of CAM discussed in this review are examples of promising research towards a better standard of cancer care that allows for more patients to be cured in the best way possible. The current standard of cancer care (chemotherapy, radiotherapy, surgery, and immunotherapy) can be effective for patients, but it has many limitations. These include undesired side effects for patients, unaffordable treatment and drug resistance. Therefore, Complementary and Alternative Medicine (CAM) is an encouraging field to explore as different forms of CAM have shown to be beneficial in cancer treatment. These forms include plant-based derivatives like Paciltaxel, and non plant-based CAM like acupuncture. These findings are especially important as patients experience the aforementioned limitations of current cancer care, so CAM could be helpful to combat these issues and allow for a better, more effective standard of care. Vitamin C, for one, is a promising target because it has shown anticancer properties which makes it beneficial in cancer treatment especially if done intravenously. Although further clinical studies are needed to ensure vitamin C’s safety and efficacy in a high dose intravenous administration as this has appeared to be a route that is worthwhile to investigate (Verrax & Calderon, 2008). Other promising compounds that were discussed in this review such as Paclitaxel and Flavopiridol. These two plant-based compounds are especially important to note as they have both moved forward into clinical trials after their anticancer properties were explored, and seemed to benefit cancer treatment. As more clinical trials and research comes out, it will confirm whether these, the other compounds listed in the review, or other unknown compounds will have the best abilities to treat cancer.
The next section discusses the usage of CAM around the world, revealing insights on the general public dependency on CAM.
Case studies of CAM around the world
Morocco as a case study of CAM usage
In Africa, around 70 to 80 percent of all cancer treatments are classified as CAM. One of the most popular plants used in Morocco for cancer treatment is Aristolochiaceae. It is often sold by many traditional healers all over Morocco and North Africa. However, due to the nature of traditional inheritance (how the plant treatments are passed down, usually through word of mouth by family members, many of these traditional medicines are being lost. In Morocco, around 50 percent of the population lives in rural areas, causing access to modern healthcare to be very limited. Because of these conditions, many people rely on folkloric herbal medicines. Casablanca, a region in Morocco is very well known for these herbal medicines. An ethnobotanical survey researching plant based remedies in Casablanca, Morocco was conducted from December 2018 to April 2018. Many different herbalists and traditional healers specializing in cancer treatment were interviewed. The ethnobotanical survey conducted in the Greater Casablanca region identified only wild species of medicinal herbs used in traditional cancer treatment. The study results indicate that there is a wide variety of plant species used in the region for the treatment of cancer, such as Aristolochia baetica, Aristolochia paucinervis, and Bryonia dioica. (Abouri et al., 2012). As shown in the figure below a majority of the 46 CAM users (66 percent) turn to CAM with the purpose of using it as a complete cure. Although CAM can be extremely effective in alleviating negative side effects and symptoms, there is not enough research done to understand the extent of its effectiveness when it comes to fully treating the disease.
Figure 3. Reasons for usage of CAM from the patient perspective.
Italy as a case study of CAM usage
The use of CAM amongst cancer patients in Italy is evaluated to be around 48,9% (ongoing or recent use) according to a 2017 multicenter survey involving 468 patients (Beretta et al., 2017).The study observes that the use of CAM was higher amongst females (56.9% vs. 44.5%) and amongst patients with a high educational level (74.2% vs. 25.8%). Such results corroborated with findings already observed in previous papers around the world (Marshik et al., 2016; Wyatt et al., 1999; Zhang et al., 2015). They presumed that a high educational level corresponded with easier access to the media, internet and information about medicine. The main CAM utilized by cancer patients were supplements and herbal medications used as adjuvants therapies to reduce the side effects of chemotherapy, rather than direct anticancer treatments. Aloe was the most commonly used CAM, with 75% of patients reporting its usage. The majority (67.7%) of CAM prescriptions were self-prescribed, whereas a significantly lower proportion (11.4%) of cases involved a doctor's prescription for CAM. This has very dangerous implications, considering the risk of toxicities and the potential interaction between CAM and standard/conventional medicine. Moreover, 86% of the patients evaluated did not know about the risk of potential side-effects from CAM use. Nevertheless, the satisfaction rate of CAM in this Italian cohort is quite high, with 87% of patients recommending the use of CAM. According to the results of this survey, the patients who use CAM seem to hold great importance to it, and would most likely keep using it throughout and after their traditional treatment. Therefore, seeing as patients will continue using it,it is on the physicians to encourage discussions about it and pay closer attention to their patients’ usage of alternative or complementary medicine to prevent unwanted side-effects or interaction with the conventional therapy the patient may be on.
New Zealand as a case study of CAM usage
In a 2003 survey, it was discovered that 49% of cancer patients in the examined cohort of 200 individuals from New Zealand used at least one form of CAM therapy (Chrystal et al., 2003). Of this group, 80% used more than one type of therapy, 40% reported using four or more different therapies, and 14% used at least seven different therapies. Amongst the different types of therapies reported, vitamins (68%) and antioxidants (54%), were the most common CAM used.Other frequently-used therapies were (in descending order of frequency of use) spiritual, diets, relaxation, herbal, imagery, naturopathy and massage. Prior to their cancer diagnosis, around 35% (above one-third) of patients began utilizing CAM therapies, and an additional 39% started using them at the time of diagnosis. A considerable percentage of patients (38%) disclosed CAM usage alongside conventional treatment, while 20% of patients started CAM only after undergoing conventional treatment. In this study, it was observed that there were no distinctions between CAM users and non-users concerning gender, ethnicity, employment status, diagnosis, or the type of conventional treatment received. Amongst CAM users, 71% reported experiencing some benefits from these therapies. Amongst those individuals, 32% considered the benefits to be extremely helpful. Conversely, only 6% of users perceived CAM as unhelpful. The predominance of patient satisfaction with the CAM used clashes with the studies that found quality-of-life scores to be lower with CAM users than conventionally treated patients (Cassileth et al., 1991), indicating perceived positive impact to be greater than actual benefits.
Limitations of CAM
Lack of substantive scientific evidence
The main issues with CAM include a lack of scientific evidence to support the effectiveness and the risk of harmful side effects. The research for these natural drugs lacks large, well-designed clinical trials that demonstrate their effectiveness in treating cancer or improving patient outcomes. There is no direct scientific evidence in efficacy and safety for many CAM treatments. CAM therapies cannot be directly categorized without scientific evidence but stays between medicine and nonspecific supportive measures with either therapeutic intents or spiritual purposes, such as acupuncture or yoga. Recent studies suggest that the effects from acupuncture in clinics are “indistinguishable from placebo effects that are highly dependent on practitioner-patient interaction” (Gorski, 2014). “Meta-analyses almost always conclude that there is insufficient clinical evidence to make a determination of efficacy and include studies with a high risk of bias” (Gorski, 2014). The absence of standardized protocols and dosages further complicates the evaluation of CAM therapies, making it difficult to compare results across studies or replicate successful outcomes. There are also no tight controls on the production of the natural compound, for example, there are no standardized regulations for the extraction method or dosage, making it dangerous.
Some CAM modalities postulate nonexistent anatomical structures or abnormalities. Others postulate nonexistent physiological functions, such as craniosacral therapy. When RCTs (randomized controlled trials) testing modalities have low pretest probability, confounding effects are magnified which produces false positives. “Many CAM treatments have prior probabilities based on scientific plausibility that can only be characterized as very close to zero. Therefore, if not zero, clinical trials of CAM are, in essence, identifying the noise in the RCT process” (Gorski, 2014). Here lies the key problem in integrative oncology. “The less ‘alternative’ the intervention, the more it resembles conventional oncology; the more ‘alternative’ the intervention, the more it resembles the quackery from which integrative oncologists rightly distance themselves” (Gorski, 2014). The scientific argument against CAM suggests that the improvements in mortality from cancer and quality of life comes from “the ever-more rigorous application of evidence in a progression from basic science to animal models to RCTs” (Gorski, 2014) rather than the scientific basis of cancer care.
Lack of definition and regulation for CAM
There is no straightforward definition of CAM, besides that they are outside the regular set of treatments. This causes a potential harm because anything can be considered “medical treatment”, whether it’s a simple massage or a drug that has taken decades to perfect, blurring the lines of CAM between medicine and nonspecific supportive measures. It also creates the question of morality because patients are being given medication that might only be used for symptom relief and not as a primary treatment for the cancer itself. These natural drugs don’t have to have specific effects on patients, as long as they are shown to help at least one side effect. This creates confusion in patients because they believe the CAM can help cure cancer on its own, even though it is supposed to work complementary to conventional care. This can cause a delay before people actually seek treatment such as radiation or chemotherapy, which can be life threatening.
Another issue surrounding CAM is the extensive use of natural resources required to create the drug. In order for a drug to be proven efficient, it requires decades of research, sometimes even decades (Cuendet and Pezzuto, 2004). Even once they make it to clinical trials, its efficacy is hard to prove, and can end up wasted away. This creates doubt and questions in the public on whether it is worth the time and resources that are dedicated to creating natural drugs. Many see it as a waste of natural resources and as a negative impact to the environment. Additionally, there is no tight regulation or control on what natural compounds are extracted or the method of extraction. This brings into question the environmental morality of CAM because scientists have little control on what they are allowed to use or explore for natural medicine.
Because CAM has so many different branches, there are little rules to what can or can’t be included in CAM, decreasing the supervision required for making these drugs. Dietary supplements are not regulated as strictly as drugs are with respect to efficacy and testing. Manufacturers are not required to submit clinical efficacy and safety data for their products to the FDA before obtaining marketing approval, thus creating a significant health risk to the public. The Dietary Supplement Health and Education Act (DSHEA) also enacted that natural medicine should be classified as food rather than drugs, regardless of its usage. This means that the medication should be used to “supplement” the diet, instead of treating or curing diseases. Many consumers assume that CAM therapies and dietary supplements are safe because they are described as natural, but they can still cause direct or indirect harm. Some of the potential dangers include toxicity, potential drug interactions, dosage variability, risk to special populations, and economic risks. Although there are many steps currently being taken by organizations such as the FDA to improve the safety of the manufacturing of such products, there is still a lack of control and safety of CAM.
Future Research
Much of the future research on CAM should focus on a continuation of clinical studies on the effects of alternative medicine on cancer patients. This is because although these clinical trials have shown promise for decreasing the growth of cancer cells, the progress of cancer, and the symptoms for patients, the actual usefulness of CAM has not been fully established (Knecht et al., 2020). Therefore, more studies must be conducted that are not only focused on the usage of CAM but also on the mechanism of action of CAM in order to ensure the benefits of alternative medicine work for cancer patients and are real and effective. Also, there are more specific adverse effects that should be addressed such as the pharmacokinetic interaction with drugs as the impact of this is unknown, so this should be yet another important aspect of continued research (Knecht et al., 2020). Another crucial aspect for future research is creating a better understanding of CAM in that researchers should create a standardized protocol to ensure that studies focused on the prevalence of CAM can be better specified to what CAM actually is, and the effects of using it as an alternative or complementary manner in cancer treatment (Ernst, 1998). Standardization of information and data can help to define the differences between these two different uses of CAM which will help to truly understand the benefits and harmful factors of this type of treatment (Ernst, 1998). This information could then allow for a greater knowledge for patients (the true benefactor of CAM treatment) for their expectations, reactions, costs, discussions of CAM with their physicians, clinical outcomes, and the optimal uses of CAM in future cancer care (Ernst, 1998).
A crucial part to this future research is coming from the continued technological developments, for example in next generation sequencing. For instance, such new technologies enable the observation of cancer's molecular alterations, shifting anti-cancer drug discovery from past phenotypic screens to more efficient target-based screens (Huang et al., 2021). Such screens with natural compound libraries that are classified by their compound origins, chemical structures or bio-activities, will improve the efficiency of drug hunting (Huang et al., 2018). Another technological advancement that will benefit future research is artificial intelligence as it is currently being applied to natural product research to discover bioactive natural products and understanding their mechanisms which can help to resolve the complexities of combinations of traditional herbal medicines and plant extracts (Huang et al., 2021; Bajorath et al., 2020; Zhang et al., 2021). All in all, these new technologies have allowed for a better understanding of the complexities of cancer.
Overall, although CAM may not be one of the most secure cancer therapies, due to lack of scientific evidence to support its effectiveness, if we invest more funds into research it could provide a less financially strenuous treatment for some of the more debilitating cancer symptoms, such as fatigue and pain. In addition, CAM can be useful as a complementary treatment option for cancer patients. Many CAM therapies have roots and bases in tradition, and have been used for centuries in different countries around the world, such as Morocco and China. Because of the cultural background of CAM, many countries and continents such as Latin America, some parts of Africa, and Asia use CAM primarily for their health care needs. In fact in Morocco around 50 percent of the population lives in rural areas, which makes conventional cancer treatments such as radiotherapy, chemotherapy, and surgery scarcely accessible (Bourhia, 2019).
Conclusion - Integrative Cancer Therapies
This review provides a comprehensive analysis of CAM in cancer therapy and highlights the key CAM therapy methods commonly used. We have provided a new perspective on the current status of various CAM therapy methods. This review has also taken into account CAM’s usage around the world by referencing case studies from various countries in order to provide an overview of how and where CAM is being used to treat cancer. Multiple fields of CAM, such as acupuncture, chiropractors, and many different plant based derivatives of CAM were discussed. Some of the benefits of CAM are that it provides patient centered care that focuses on addressing certain health concerns that may not normally be targeted by conventional medicine. Additionally, some CAM treatments such as chiropractors and acupuncture have been proven to be effective in treating certain conditions such as chronic pain, anxiety, nausea, and depression linked to cancer. However, there are some limitations to CAM. Some limitations of CAM include a lack of rigorous scientific evidence to support its effectiveness, potential interactions with conventional medications, and the risk of adverse effects. Additionally, some CAM therapies may delay or replace conventional treatments that are actually known and have a higher guarantee to be effective, which could have serious consequences for a patient's health. Turning to CAM instead of conventional treatment could be detrimental. It's important for any individual suffering from cancer that wishes to seek out alternative treatments to be properly informed about the potential risks and benefits of any CAM therapy they are considering. CAM should always be used as a complimentary option, not as a replacement treatment to chemotherapy, radiotherapy, or surgery.
References
Ahmad, A., Husain, A., Mujeeb, M., Khan, S., Najmi, A., Siddique, N., Damanhouri, Z., & Anwar, F. (2013). A review on therapeutic potential of Nigella sativa: A miracle herb. Science Direct, 3(5), 337-352.
Al-Amri, AM., & Bamosa, AO. (2009). Phase I safety and clinical activity study of thymoquinone in patients with advanced refractory malignant disease. Shiraz E-Medical Journal, 10(3), 107–111.
Amri, A., Chaumeil, J. C., Sfar, S., & Charrueau, C. (2012). Administration of resveratrol: what formulation solutions to bioavailability limitations?. Journal of controlled release, 158(2), 182-193.
Andrews, P. L., & Sanger, G. J. (2014). Nausea and the quest for the perfect anti-emetic. European journal of pharmacology, 722, 108–121.
Arakawa, S. (1995). Use of relaxation to reduce side effects of chemotherapy in Japanese patients. Cancer Nursing, 18(1), 60-66.
Arlt, V. M. (2002). Aristolochic acid as a probable human cancer hazard in herbal remedies: a review. Mutagenesis, 17(4), 265–277. doi:10.1093/mutage/17.4.265
Bajorath, J., Kearnes, S., A, M. M., Meanwell, N. A., Georg, G. I., & Wang, S. (2020). Artificial Intelligence in Drug Discovery: Into the Great Wide Open. Journal of Medicinal Chemistry, 63(16), 8651–8652.
Balon, J. W., & Mior, S. (2004). Chiropractic care in asthma and allergy. Annals of Allergy Asthma & Immunology, 93(2), S55–S60.
Barbaret, C., Brosse, C., Rhondali, W., Ruer, M., Monsarrat, L., Michaud, P., Schott, A. M., Delgado-Guay, M., Bruera, E., Sanchez, S., & Filbet, M. (2017). Financial distress in patients with advanced cancer. PloS one, 12(5), e0176470.
Barnes, P. M., Bloom, B., & Nahin, R. L. (2008). Complementary and Alternative medicine use among adults and Children: United States [Dataset]. In PsycEXTRA Dataset.
Baskar, R., Lee, K. A., Yeo, R., & Yeoh, K.-W. (2012). Cancer and radiation therapy: Current advances and Future Directions. International Journal of Medical Sciences, 9(3), 193–199.
Berretta, M., Della, Pepa C., Tralongo, P., Fulvi, A., Martellotta, F., Lleshi, A., Nasti, G., Fisichella, R., Romano, C., De Divitiis, C., Taibi, R., Fiorica, F., Di Francia, R., Di Mari, A., Del Pup, L., Crispo, A., De Paoli, P., Santorelli, A., Quagliariello, V., Iaffaioli, RV., Tirelli, U., & Facchini, G. (2017). Use of Complementary and Alternative Medicine (CAM) in cancer patients: An Italian multicenter survey. Oncotarget, 8(15), 24401-24414.
Bhat, K. P., Kosmeder, J. W., & Pezzuto, J. M. (2001). Biological effects of resveratrol. Antioxidants and redox signaling, 3(6), 1041-1064.
Bindemann, S., Soukop, M., & Kaye, S. B. (1991). Randomised controlled study of relaxation training. European Journal of Cancer and Clinical Oncology, 27(2), 170–174.
Brennan, G., Fritz, J. M., Hunter, S. J., Thackeray, A., Delitto, A., & Erhard, R. E. (2006). Identifying subgroups of patients with Acute/Subacute “Nonspecific” low back pain. Spine, 31(6), 623–631.
Bridge, L. R., Benson, P., Pietroni, P. C., & Priest, R. G. (1988). Relaxation and imagery in the treatment of breast cancer. BMJ, 297(6657), 1169–1172.
Brown, C., Ling, F. W., Wan, J. Y., & Pilla, A. A. (2002). Efficacy of static magnetic field therapy in chronic pelvic pain: A double-blind pilot study. American Journal of Obstetrics and Gynecology, 187(6), 1581–1587.
Büssing, A., Wagner, M., Wagner, B., Gm, S., Schietzel, M., Schaller, G., & Pfüller, U. (1999). Induction of mitochondrial Apo2.7 molecules and generation of reactive oxygen-intermediates in cultured lymphocytes by the toxic proteins from Viscum album L. Cancer Letters.
Carrera, P. M., Kantarjian, H. M., & Blinder, V. S. (2018). The financial burden and distress of patients with cancer: Understanding and stepping-up action on the financial toxicity of cancer treatment. CA: a cancer journal for clinicians, 68(2), 153–165.
Cassileth, B. R., & Deng, G. (2004). Complementary and alternative therapies for cancer. Oncologist, 9(1), 80–89.
Cassileth, B. R., Lusk, E. J., Guerry, D., Blake, A. D., Walsh, W. R., Kascius, L., & Schultz, D. (1991). Survival and quality of life among patients receiving unproven as compared with conventional cancer therapy. The New England Journal of Medicine, 324(17), 1180–1185.
Chandra, RA., Keane, FK., Voncken, FEM., & Thomas Jr, CR. (2021). Contemporary radiotherapy: present and future. Lancet, 398(10295),171–84.
Childs, J. D., Fritz, J. M., Flynn, T. C., Irrgang, J. J., Johnson, K. P., Majkowski, G. R., & Delitto, A. (2004). A Clinical Prediction Rule To Identify Patients with Low Back Pain Most Likely To Benefit from Spinal Manipulation: A Validation Study. Annals of Internal Medicine, 141(12), 920.
Chrystal, K., Allan, S., Forgeson, G., & Isaacs, R. (2003). The use of complementary/alternative medicine by cancer patients in a New Zealand regional cancer treatment centre. PubMed, 116(1168), U296.
Chu, E., & DeVita, V. T. (2017). Physicians’ cancer chemotherapy drug manual 2017. Jones & Bartlett Learning.
Cragg, G. M., & Newman, D. J. (2005). Plants as a source of anti-cancer agents. Journal of Ethnopharmacology, 100(1–2), 72–79.
Creemers, G. J., Bolis, G., Gore, M., Scarfone, G., Lacave, A. J., Guastalla, J. P., Despax, R., Favalli, G., Kreinberg, R., Van Belle, S., Hudson, I., Verweij, J., & Ten Bokkel Huinink, W. W. (1996). Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: Results of a large European Phase II study. Journal of Clinical Oncology, 14(12), 3056–3061.
Cuendet, M., & Pezzuto, J. M. (2003). Antitumor Activity of Bruceantin: An Old Drug with New Promise,. Journal of Natural Products, 67(2), 269–272.
Husereau, D., Clifford, T., Aker, P., Leduc, D., & Mensinkai, S. (2003). Spinal manipulation for infantile colic. Canadian Coordinating Office for Health Technology Assessment, Ottawa.
Dytrych, P., Kejík, Z., Hajduch, J., Kaplánek, R., Veselá, K., Kučnirová, K., Skaličková, M., Venhauerová, A., Hoskovec, D., Martásek, P., & Jakubek, M. (2023). Therapeutic potential and limitations of curcumin as antimetastatic agent. Science Direct, 163, 114758.
Eisenberg, D., Davis, R. J., Ettner, S. L., Appel, S., Wilkey, S., Van Rompay, M. I., & Kessler, R. C. (1998). Trends in alternative medicine use in the United States, 1990-1997. JAMA, 280(18), 1569.
Ernst, E. (1998). The prevalence of complementary/Alternative medicine in cancer. Cancer, 83(4), 777–782.
Ernst, E. (2003). Chiropractic spinal manipulation for neck pain: a systematic review. The Journal of Pain, 4(8), 417–421.
Faruqui, N., Martiniuk, A., Sharma, A., Sharma, C. K., Rathore, B., Arora, R. S., & Joshi, R. (2019). Evaluating access to essential medicines for treating childhood cancers: a medicines availability, price and affordability study in New Delhi, India. BMJ Global Health, 4(2), e001379.
Frémont, L. (2000). Biological effects of resveratrol. Life Sciences, 66(8), 663–673.
Fritz, J. M., Brennan, G., & Leaman, H. (2006). Does the evidence for spinal manipulation translate into better outcomes in routine clinical care for patients with occupational low back pain? A case-control study. The Spine Journal, 6(3), 289–295.
Fritz, J. M., Childs, J. D., & Flynn, T. C. (2005). Pragmatic application of a clinical prediction rule in primary care to identify patients with low back pain with a good prognosis following a brief spinal manipulation intervention. BMC Family Practice, 6(1).
Fuchs, C., Mitchell, E. P., & Hoff, P. M. (2006). Irinotecan in the treatment of colorectal cancer. Cancer Treatment Reviews, 32(7), 491–503.
Gironell, A., Kulisevsky, J., Lorenzo, J. M., Barbanoj, M. J., Pascual-Sedano, B., & Otermin, P. (2002). Transcranial magnetic stimulation of the cerebellum in essential tremor. Archives of Neurology, 59(3), 413.
Glimcher, L. (2016). Why Do Cancer Treatments Stop Working? Overcoming Treatment Resistance. National Cancer Institute.
Goldstein, DA,, Clark, J., Tu, Y., Zhang, J., Fang, F., & Goldstein, R. (2017). A global comparison of the cost of patented cancer Medicines in relation to global differences in wealth. Oncotarget, 8, 71548–55.
Gorski, D. H. (2014). Integrative oncology: really the best of both worlds? Nature Reviews Cancer, 14(10), 692–700.
Gross, A., Miller, J. D., D’Sylva, J., Burnie, S. J., Goldsmith, C. H., Graham, N., Haines, T., Bronfort, G., & Hoving, J. L. (2010). Manipulation or mobilisation for neck pain: A Cochrane Review. Manual Therapy, 15(4), 315–333.
Gupta, S. C., Patchva, S., Koh, W., & Aggarwal, B. B. (2012). Discovery of curcumin, a component of golden spice, and its miraculous biological activities. Clinical and experimental pharmacology & physiology, 39(3), 283–299.
Hall E. J. (2006). Intensity-modulated radiation therapy, protons, and the risk of second cancers. International journal of radiation oncology, biology, physics, 65(1), 1–7.
Hartwell J. L. (1971). Plants used against cancer. A survey. Lloydia, 34(2), 204–255.
Hoppe, R. T., Advani, R. H., Ai, W. Z., Ambinder, R. F., Aoun, P., Bello, C. M., Bierman, P. J., Blum, K. A., Chen, R., Dabaja, B. S., Duron, Y., Forero, A., Gordon, L. I., Hernandez-Ilizaliturri, F. J., Hochberg, E. P., Maloney, D. G., Mansur, D. B., Mauch, P., Metzger, M. L., . . . Sundar, H. (2012). Hodgkin Lymphoma, Version 2.2012 featured updates to the NCCN guidelines. Journal of the National Comprehensive Cancer Network, 10(5), 589–597.
Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., & Sarkar, S. (2014). Drug Resistance in Cancer: An Overview. Cancers, 6(3), 1769–1792.
Huang, M., Lu, J., & Ding, J. (2021). Natural products in cancer therapy: past, present and future. Natural Products and Bioprospecting, 11(1), 5–13.
Huang, M., Zhang, L., Ding, J., & Lu, J. (2018). Anticancer drug discovery from Chinese medicinal herbs. Chinese Medicine, 13(1).
Hutt, N., Kopferschmitt-Kubler, M. C., Cabalion, J., Purohit, A., Alt, M., & Pauli, G. (2001). Anaphylactic reactions after therapeutic injection of mistletoe (Viscum album L.). Allergologia Et Immunopathologia, 29(5), 201–203.
Integration of behavioral and relaxation approaches into the treatment of chronic pain and insomnia. (1996). JAMA, 276(4), 313.
International Agency for Research on Cancer. (2020). Fact sheet: GLOBOCAN. Retrieved from https://gco.iarc.fr/
Islam, A., Akhter, A., & Eden, T. (2015). Cost of treatment for children with acute lymphoblastic leukemia in Bangladesh. Journal of Cancer Policy, 6, 37–43.
Jaffary, D. A., & Gospodarowicz, M. K. (2015). Radiation Therapy for Cancer: Disease Control Priorities (3rd ed.). World Bank Publications.
Jiang, T. L., Liu, R. H., & Salmon, S. E. (1983). Comparative in vitro antitumor activity of homoharringtonine and Harringtonine against clonogenic human tumor cells. Investigational New Drugs, 1(1), 21–25. https://doi.org/10.1007/bf00180188.
Kabakov, A. E., & Yakimova, A. O. (2021). Hypoxia-Induced Cancer Cell Responses Driving Radioresistance of Hypoxic Tumors: Approaches to Targeting and Radiosensitizing. Cancers, 13(5), 1102.
Kaegi, E. (1998). Unconventional therapies for cancer: 3. Iscador. Canadian Medical Association Journal, 158(9), 1157–1159.
Kantarjian, H. M., Talpaz, M., Santini, V., Murgo, A., Cheson, B., & O’Brien, S. M. (2001). Homoharringtonine. Cancer, 92(6), 1591–1605.
Kaur, G., Invally, M., Khan, M. Z. A., & Jadhav, P. A. (2018). A nutraceutical combination of Cinnamomum cassia & Nigella sativa for Type 1 diabetes mellitus. Journal of Ayurveda and Integrative Medicine, 9(1), 27–37.
Kim, W., Youn, H., Kang, C., & Youn, B. (2015). Inflammation-induced radioresistance is mediated by ROS-dependent inactivation of protein phosphatase 1 in non-small cell lung cancer cells. Apoptosis, 20(9), 1242–52.
Kingston, D. G. I. (2005). Taxol and its analogs. In CRC Press eBooks.
Kluthe, R., Vogt, A., & Batsford, S. (1982). Doppelblindstudie zur Beeinflussung der Phagocytosefähigkeit von Granulocyten durch Aristolochiasäure. Drug Res., 32, 443–445.
Knecht, K. T., Kinder, D. H., & Stockert, A. (2020). Biologically-Based Complementary and Alternative Medicine (CAM) use in cancer patients: The good, the bad, the misunderstood. Frontiers in Nutrition, 6.
Kroschinsky, F., Stölzel, F., von Bonin, S., Beutel, G., Kochanek, M., Kiehl, M., & Schellongowski, P. (2017). New Drugs, new toxicities: Severe side effects of modern targeted and immunotherapy of cancer and their management. Critical Care, 21(1).
Kumara, SS., & Huat, BT. (2001). Extraction, isolation and characterisation of antitumor principle, α-hederin, from the seeds of Nigella sativa. Planta medica, 67, 29–32.
Larionova, I., Rakina, M., Ivanyuk, E., Trushchuk, Y., Chernyshova, A., & Denisov, E. (2022). Radiotherapy resistance: identifying universal biomarkers for various human cancers. Journal of Cancer Research and Clinical Oncology, 148(5), 1015–1031.
Lichty, B. D., Breitbach, C. J., Stojdl, D. F., & Bell, J. C. (2014). Going viral with cancer immunotherapy. Nature Reviews. Cancer, 14(8), 559–567.
Łukasiewicz, K., & Fol, M. (2018). Microorganisms in the treatment of cancer: Advantages and limitations. Journal of Immunology Research, 2018, 1–8.
Luo, C. Y., Tang, J. Y., & Wang, Y. P. (2004). Homoharringtonine: A new treatment option for myeloid leukemia. Hematology (Amsterdam, Netherlands), 9(4), 259–270.
Mabrouk, G. M., Moselhy, S. S., Zohny, S. F., Ali, E. M., Helal, T. E., Amin, A. A., & Khalifa, A. A. (2002). Inhibition of methylnitrosourea (MNU) induced oxidative stress and carcinogenesis by orally administered bee honey and Nigella grains in Sprague Dawely rats. Journal of experimental & clinical cancer research : CR, 21(3), 341–346.
Majeed, H., & Gupta, V. (2023). Adverse effects of radiation therapy. StatPearls Publishing.
Marshik, P. L., Kharat, A. A., Jakeman, B., Borrego, M. E., Dodd, M. A., Bachyrycz, A., … Salazar, K. (2016). Complementary and alternative medicine and therapy use in a diverse new Mexican population. Journal of Alternative and Complementary Medicine (New York, N.Y.), 22(1), 45–51.
Mathijssen, R. H., Loos, W. J., Verweij, J., & Sparreboom, A. (2002). Pharmacology of topoisomerase I inhibitors irinotecan (CPT-11) and topotecan. Current Cancer Drug Targets, 2(2), 103–123.
Matthes, H., Buchwald, D., Schad, F., & Jeschke, E. (2007). Intratumorale Applikation von Viscum album L (Mistelgesamtextrakt; Helixor M®) in der Therapie des inoperablen Pankreaskarzinom. Thieme, 45(08).
McEachrane-Gross, F. P., Liebschutz, J. M., & Berlowitz, D. R. (2006). Use of selected complementary and alternative medicine (CAM) treatments in veterans with cancer or chronic pain: a cross-sectional survey. BMC Complementary and Alternative Medicine, 6(1).
Mengs, U., Lang, W., & Poch, J. A. (1982). The carcinogenic action of aristolochic acid in rats. Archives of Toxicology, 51, 107-119.
Mesa-Jiménez, J. A., Lozano-López, C., Angulo, S., Rodríguez-Fernández, Á. L., De-La-Hoz-Aizpurua, J. L., & Fernández-De-Las-Peñas, C. (2015). Multimodal manual therapy vs. pharmacological care for management of tension type headache: A meta-analysis of randomized trials. Cephalalgia, 35(14), 1323–1332.
Morrow, G. R., & Morrell, C. (1982). Behavioral treatment for the anticipatory nausea and vomiting induced by cancer chemotherapy. The New England Journal of Medicine, 307(24), 1476–1480.
Namazi, N., Mahdavi, R., Alizadeh, M., & Farajnia, S. (2015). Oxidative Stress Responses to Nigella sativa Oil Concurrent with a Low-Calorie Diet in Obese Women: A Randomized, Double-Blind Controlled Clinical Trial. Phytotherapy Research, 29(11), 1722–1728.
NCI dictionary of Cancer Terms. (2011, February 2). Retrieved 2 September 2023, from National Cancer Institute website: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/chiropractic-therapy
Nirmala, J. M., Samundeeswari, A., & Sankar, D. P. (2011). Natural plant resources in anti-cancer therapy-A review. Research in plant biology, 1, 2231-5101.
Nurgali, K., Jagoe, R. T., & Abalo, R. (2018). Editorial: Adverse effects of cancer chemotherapy: Anything new to improve tolerance and reduce sequelae? Frontiers in Pharmacology, 9.
Olivares-Urbano, M. A., Griñán-Lisón, C., Marchal, J. A., & Núñez, M. I. (2020). CSC radioresistance: A therapeutic challenge to improve radiotherapy effectiveness in cancer. Cells (Basel, Switzerland), 9(7), 1651.
Ozdemir, N., Kantekin-Erdogan, M. N., Tat, T., & Tekin, A. (2018). Effect of black cumin oil on the oxidative stability and sensory characteristics of mayonnaise. Journal of Food Science and Technology, 55(4), 1562–1568.
Pathak, A. K., Bhutani, M., Guleria, R., Bal, S., Mohan, A., Mohanti, B. K., Sharma, A., Pathak, R., Bhardwaj, N. K., Prasad, K. N., & Kochupillai, V. (2005). Chemotherapy Alonevs.Chemotherapy Plus High Dose Multiple Antioxidants in Patients with Advanced Non Small Cell Lung Cancer. Journal of the American College of Nutrition, 24(1), 16–21.
Pelka, R., Jaenicke, C., & Gruenwald, J. (2001). Impulse magnetic-field therapy for migraine and other headaches: A double-blind, placebo-controlled study. Advances in Therapy, 18(3), 101–109.
Pérez, M. A., & Luquis, R. R. (2021). Cultural competence in Health Education and health promotion. Jossey-Bass.
Pezzuto, J. M. (2019). Resveratrol: Twenty years of growth, development and controversy. Biomolecules & Therapeutics, 27(1), 1–14.
Pinheiro, M., Ferreira, M. L., Refshauge, K. M., Ordoñana, J. R., Machado, G., Prado, L. R., Maher, C. G., & Ferreira, P. H. (2015). Symptoms of Depression and Risk of New Episodes of Low Back Pain: A Systematic Review and Meta-Analysis. Arthritis Care and Research, 67(11), 1591–1603.
Pinto, N., Prokopec, S. D., Ghasemi, F., Meens, J., Ruicci, K. M., Khan, I. M., … Nichols, A. C. (2020). Flavopiridol causes cell cycle inhibition and demonstrates anti-cancer activity in anaplastic thyroid cancer models. PloS One, 15(9), e0239315.
Post-White, J., Fitzgerald, M., Hageness, S. M., & Sencer, S. (2008). Complementary and alternative medicine use in children with cancer and general and specialty pediatrics. Journal of Pediatric Oncology Nursing, 26(1), 7–15.
Proctor, M., Hing, W., Johnson, T. A., Murphy, P. A., & Brown, J. (2006). Spinal manipulation for dysmenorrhoea. The Cochrane Library.
Rabey, H. a. E., Al-Seeni, M. N., & Bakhashwain, A. S. (2017). The Antidiabetic Activity ofNigella sativa and Propolis on Streptozotocin-Induced Diabetes and Diabetic Nephropathy in Male Rats. Evidence-Based Complementary and Alternative Medicine, 2017, 1–14.
Robatel, S., & Schenk, M. (2022). Current limitations and novel perspectives in pancreatic cancer treatment. Cancers, 14(4), 985.
Rosa, L. (1998). A close look at therapeutic touch. JAMA, 279(13), 1005.
Roscoe, J. A., & Matteson, S. E. (2002). Acupressure and acustimulation bands for control of nausea: a brief review. American journal of obstetrics and gynecology, 186(5), S244-S247.
Rosenberg, S. A., Restifo, N. P., Yang, J. C., Morgan, R. A., & Dudley, M. E. (2008). Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nature Reviews. Cancer, 8(4), 299–308.
Rostock, M., Huber, R., Greiner, T., Fritz, P., Scheer, R., Schueler, J., & Fiebig, H. H. (2005). Anticancer activity of a lectin-rich mistletoe extract injected intratumorally into human pancreatic cancer xenografts. PubMed, 25(3B), 1969–1975.
Sarwar, M., Iftikhar, S., & Saqib, A. (2018). Availability of anticancer medicines in public and private sectors, and their affordability by low, middle and high-income class patients in Pakistan. BMC Cancer, 18(1).
Sausville, E. A. (1997). Targeted toxins. Academic Press, San Diego.
Saxe, G. A., Madlensky, L., Kealey, S., Wu, D. T., Freeman, K., & Pierce, J. P. (2008). Disclosure to physicians of CAM use by breast cancer patients: Findings from the Women’s Healthy Eating and Living Study. Integrative Cancer Therapies, 7(3), 122–129.
Schwetz,B.A. (2001). From the Food and Drug Administration. J. Am. Med. Assoc., 285, 2705.
Sedlacek, H.H. (2000). Mechanisms of action of flavopiridol. Science Direct, 38 (2), 139-170.
Segal, N. H., Toda, Y., Huston, J. P., Saeki, Y., Shimizu, M., Fuchs, H. A., Shimaoka, Y., Holcomb, R. W., & McLean, M. (2001). Two configurations of static magnetic fields for treating rheumatoid arthritis of the knee: A double-blind clinical trial. Archives of Physical Medicine and Rehabilitation, 82(10), 1453–1460.
Sellick, S. M., & Zaza, C. (1999). Critical review of 5 nonpharmacologic strategies for managing cancer pain. Complementary Therapies in Medicine, 7(4), 266.
Shafiq, H., Ahmad, A., Masud, T., & Kaleem, M. (2014). Cardio-protective and anti-cancer therapeutic potential of Nigella sativa. Iranian Journal of Basic Medical Sciences, 17(12), 967–979.
Sierpina, V. S., Kreitzer, M. J., Cunningham, A. J., Elder, W. G., & Bruckner, G. (2007). Innovations in integrative healthcare education. Explore (New York, N.Y.), 3(4), 423–425.
Singla, A., Garg, A., & Aggarwal, D. (2001). Paclitaxel and its formulations. Science Direct, 235(1-2), 179-192.
Smith, H. (2015). Depression in cancer patients: Pathogenesis, implications and treatment (Review). Oncology Letters, 9(4), 1509–1514.
Stauder, H., & Kreuser, E. D. (2002). Mistletoe Extracts Standardised in terms of Mistletoe Lectins (ML I) in Oncology: Current State of Clinical Research. Oncology Research and Treatment, 25(4), 374–380.
Steele, M. L., Axtner, J., Happe, A., Kröz, M., Matthes, H., & Schad, F. (2014). Safety of Intravenous Application of Mistletoe (Viscum albumL.) Preparations in Oncology: An Observational Study. Evidence-based Complementary and Alternative Medicine, 2014, 1–10.
Takemura, Y., Ohnuma, T., Chou, T.-C., Okano, T., & Holland, James F. (1985). Biologic and pharmacologic effects of harringtonine on human leukemia-lymphoma cells. Cancer Chemotherapy and Pharmacology, 14(3).
Thies, A., Dautel, P., Meyer, A., Pfüller, U., & Schumacher, U. (2007). Low-dose mistletoe lectin-I reduces melanoma growth and spread in a scid mouse xenograft model. British Journal of Cancer, 98(1), 106–112.
Topalian, S. L., Drake, C. G., & Pardoll, D. M. (2015). Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer cell, 27(4), 450–461.
Tröger, W., Galun, D., Reif, M., Schumann, A., Stankovic, N., & Milicevic, M. (2013). Viscum album [L.] extract therapy in patients with locally advanced or metastatic pancreatic cancer: A randomised clinical trial on overall survival. European Journal of Cancer, 49(18), 3788–3797.
Vasterling, J. J., Jenkins, R. L., Tope, D. M., & Burish, T. G. (1993). Cognitive distraction and relaxation training for the control of side effects due to cancer chemotherapy. Journal of Behavioral Medicine, 16(1), 65–80.
Ventola, C. L. (2010). Current issues regarding complementary and alternative medicine (CAM) in the United States: Part 1: The widespread use of CAM and the need for better-informed health care professionals to provide patient counseling. P & T: A Peer-Reviewed Journal for Formulary Management, 35(8), 461–468.
Verrax, J., & Calderon, P. B. (2008). The controversial place of vitamin C in cancer treatment. Biochemical Pharmacology, 76(12), 1644–1652.
Walker, L. A., Walker, M. B., Ogston, K. N., Heys, S. D., Ah-See, A. K., Miller, I., Hutcheon, A. W., Sarkar, T. K., & Eremin, O. (1999). Psychological, clinical and pathological effects of relaxation training and guided imagery during primary chemotherapy. British Journal of Cancer, 80(1–2), 262–268.
Weinstein, S. J. (2001). The anticonvulsant effect of electrical fields. Current Neurology and Neuroscience Reports, 1(2), 155–161.
World Health Organization. (2018). Technical report: pricing of cancer medicines and its impacts: a comprehensive technical report for the World Health Assembly Resolution 70.12: operative paragraph 2.9 on pricing approaches and their impacts on availability and affordability of medicines for the prevention and treatment of cancer. Retrieved from https://apps.who.int/iris/handle/10665/277190.
Wyatt, G., Friedman, L. L., Given, C. W., Given, B. A., & Beckrow, K. C. (1999). Complementary therapy use among older cancer patients. Cancer Practice, 7(3), 136–144.
Xiang, Y., Guo, Z., Zhu, P., Chen, J., & Huang, Y. (2019). Traditional Chinese medicine as a cancer treatment: modern perspectives of ancient but advanced science. Cancer medicine, 8(5), 1958-1975.
Xu, B., Ding, J., Chen, K.X., Miao, Z.H., Huang, H., Liu, H., & Luo, X.M. (2012). Advances in cancer chemotherapeutic drug research in China. Recent Advances in Cancer Research and Therapy, 287–350.
Yard, B. D., Adams, D. J., Chie, E. K., Tamayo, P., Battaglia, J. S., Gopal, P., … Abazeed, M. E. (2016). A genetic basis for the variation in the vulnerability of cancer to DNA damage. Nature Communications, 7(1).
Yimer, E. M., Tuem, K. B., Karim, A., Ur-Rehman, N., & Anwar, F. (2019). Nigella sativa L. (black cumin): A promising natural remedy for wide range of illnesses. Evidence-Based Complementary and Alternative Medicine: ECAM, 2019, 1–16.
Younus, J., Kligman, L., & Jawaid, D. (2016). The impact of cold therapy on the incidence and severity of paclitaxel induced peripheral neuropathy: A pilot study. Journal of Solid Tumors, 6(2), 43.
Yuan, Y.-G., Zhang, S., Hwang, J.-Y., & Kong, I.-K. (2018). Silver nanoparticles potentiates cytotoxicity and apoptotic potential of camptothecin in human cervical cancer cells. Oxidative Medicine and Cellular Longevity, 2018, 1–21.
Zhang, R., Li, X., Zhang, X., Huayan, Q., & Xiao, W. (2021). Machine learning approaches for elucidating the biological effects of natural products. Natural Product Reports, 38(2), 346–361.
Zhang, X., & Gurunathan, S. (2016). Combination of salinomycin and silver nanoparticles enhances apoptosis and autophagy in human ovarian cancer cells: an effective anticancer therapy. International Journal of Nanomedicine, 11, 3655–3675.
Zhang, Y., Leach, M. J., Hall, H., Sundberg, T., Ward, L., Sibbritt, D., & Adams, J. (2015). Differences between male and female consumers of complementary and alternative medicine in a national US population: A secondary analysis of 2012 NIHS data. Evidence-Based Complementary and Alternative Medicine: ECAM, 2015, 413173.
Zhou, Y.Q., Liu, D.Q., Chen, S.P., Sun, J., Zhou, X.R., Rittner, H., … Ye, D.W. (2018). Reactive oxygen species scavengers ameliorate mechanical allodynia in a rat model of cancer-induced bone pain. Redox Biology, 14, 391–397.
Comentários