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Lymphoma

Integrative Interventions

Caloric Restriction

Caloric restriction (CR), which entails reducing caloric intake while maintaining optimal nutrient density in the diet, is hypothesized to decrease cancer development and progression through a variety of mechanisms (Meynet 2013; Li 2010). An experiment in mice that develop cancers resembling Burkitt’s lymphoma and DLBCL found that a reduced calorie diet (75% of normal intake) combined with a targeted therapy (ABT-737) decreased the number of circulating lymphoma cells. The investigators speculate that the combination of calorie restriction and targeted therapy may have the potential to increase survival (Meynet 2013).

Chronic caloric restriction extends the latency to onset and increases the average lifespan in mice genetically prone to developing cancer (Shields 1991). The influences of caloric restriction on lymphoma development have been inferred from disease pattern surveys of rodents fed semi-purified diets. In this research, the frequency of death due to lymphoma among calorie-restricted mice was lower and maximum life spans were extended. Caloric restriction lowered the incidence and delayed the onset of lymphoma, thus yielding lowered lymphoma mortality and extended lifespan (Saxton 1947). In another mouse study, 4 months of alternate-day fasting significantly reduced the incidence of lymphoma (0% compared to 33% in controls) (Descamps 2005).

A comprehensive overview of caloric restriction and its many benefits is available in the Caloric Restriction protocol.

Selenium

Selenium is an essential trace element and a cofactor of selenium-dependent enzymes such as glutathione peroxidase (a detoxifying enzyme) (Neve 2002). It has an established role in cancer prevention (Gerhauser 2013), and recent evidence also supports its role in lymphoma treatment. Selenium prevents lymphoma cell proliferation, causes lymphoma cell death, and selectively sensitizes lymphoma cells to the antitumor effects of chemotherapy (Goenaga-Infante 2011; Gopee 2004).

Studies indicate that selenium deficiency is implicated in lymphoma development (Sumba 2010). In a study of 20 patients with HL, selenium levels, zinc levels, and glutathione peroxidase activity were found to be significantly lower compared to healthy controls (Güven 2000).

In addition, serum selenium levels at diagnosis are predictive of outcome in lymphoma patients, including those with diffuse large B-cell lymphoma, Hodgkin lymphoma, and follicular lymphoma (as well as acute myeloid leukemia). In this study of 430 patients (156 with Hodgkin lymphoma, 111 with follicular lymphoma, and 163 with acute myeloid leukemia), serum selenium levels measured at diagnosis were found to be lower than normal in 45% of subjects. Hodgkin lymphoma and acute myeloid leukemia patients with low serum selenium had poorer response to anticancer treatment. Furthermore, low selenium levels were linked to a poorer survival in follicular lymphoma patients and a tendency toward a poorer overall survival in acute myeloid leukemia patients (Stevens 2011).

Several studies have evaluated the role of selenium in lymphoma. In one study, the malignant transformation of B lymphocytes stimulated by EBV was significantly inhibited (by 83%) by a selenium-rich rice extract. In laboratory studies, selenium selectively prevents the growth of cancer cells but not normal healthy cells from patients with leukemic lymphoma (Jiang 1992).

The cellular toxicity of several chemotherapy drugs against B-cell lymphomas was increased by up to 2.5-fold when combined with selenium (in the form of methylseleninic acid) (Jüliger 2007). Selenium supplementation directly affects tumor immune response in mice immunized with lymphoma cells, depending on the level of selenium. Mice fed an extremely low selenium diet were unable to elicit normal tumor-specific immune responses, such as tumor killing activities (Hu 1990).

The effectiveness of different forms of selenium, such as sodium selenite, selenocysteine, and selenomethionine were compared in terms of prolongation of survival of lymphoma-bearing mice. Selenomethionine increased the lifespan of lymphoma-bearing mice by almost two-fold through maintenance of high glutathione (GSH) levels and normal glutathione peroxidase activity during the initial phase of tumor growth (Mukhopadhyay-Sardar 2000). In another animal study, lymphoma-bearing mice that were supplemented with selenomethionine had a 143% increase in survival time, indicating that selenium exerts potent activity as an anti-lymphoma agent (Rana 1996).

One clinical study reports that in patients with newly diagnosed NHL, 200 mcg/kg/day of sodium selenite significantly increased overall survival time. In this study patients with newly diagnosed NHL were divided into two groups. Group I received standard chemotherapy alone, whereas group II received chemotherapy together with sodium selenite (200 mcg/kg/day) for 7 days. The selenium-supplemented patients had a significant reduction in swollen lymph nodes, decrease in spleen size and bone marrow infiltration, and a significant increase in lymphoma cell death. Furthermore, these patients did not experience heart injury; that is, there was no reduction in cardiac ejection fraction (CEF) (the capacity of the heart to pump blood to the body) compared to the non-supplemented patients who had a reduction in CEF (Asfour 2006).

Green Tea

Green tea (Camellia sinensis) contains phytonutrients called catechins, which have been shown to possess anticancer properties. Animal studies found that green tea significantly inhibits NHL tumor growth (Bertolini 2000). After the publication of experimental research on green tea and lymphoma, physicians at Mayo Clinic discovered four patients with low-grade lymphomas began consuming over-the-counter green tea products containing EGCG on their own initiative. Subsequently, three of the four patients with low-grade B-cell lymphomas who used EGCG eventually fulfilled the criteria for partial response. The Mayo Clinic doctors stated, “… Several patients presented here had documented steady clinical, laboratory, and/or radiographic evidence of progression immediately prior to initiation of over-the-counter green tea products and then developed objective responses shortly after self-initiating this therapy” (Shanafelt 2006).

Epigallocatechin gallate (EGCG) is the major active component of green tea and has broad spectrum antibacterial and antiviral effects against numerous microorganisms including EBV, hepatitis B and C viruses, HIV, herpes simplex virus type 1, and adenoviruses (Lin 2013; Steinmann 2013).

A 2013 study found that green tea’s polyphenolic catechins may be useful in the prevention and treatment of chronic HCV infection-induced diseases by simultaneously inhibiting viral replication, inflammation, and virus-induced cancer development. The most common type of NHL (DLBCL) is causally related to HCV and green tea catechins protect against both HCV replication and virus-induced inflammation. In addition, EGCG also has antiviral activity against HBV (Lin 2013).

Curcumin

The anticancer activity of curcumin (Curcuma longa L.; Zingiberaceae), extracted from the Indian spice turmeric, has been examined in many published studies and is being further explored in dozens of ongoing studies (Shehzad 2013; Gupta 2012). Laboratory studies have found that curcumin is able to kill human lymphoma cells (Khan 2012; Singh 2011).

Preclinical studies report that curcumin is a radiosensitizer and chemosensitizer for lymphoma, making chemotherapy and radiation therapy work better against the cancer while protecting normal, healthy cells (Goel 2010; Qiao 2013a). In NHL, curcumin enhanced lymphoma cell response to radiation therapy (Qiao 2013b). The researchers (Qiao 2013b) believe that “[this] offers great potential for curcumin to be used in conjunction with radiotherapy for NHL in order to increase the efficiency of the treatment” (Qiao 2013a).

A Hodgkin lymphoma therapeutic research goal is to find new treatments that specifically target deregulated signalling pathways, such as nuclear factor-kappaB (NF-κB) and STAT3, which cause the proliferation of Reed-Sternberg cells and are responsible for the resistance to apoptosis. Laboratory studies show that curcumin is incorporated into Reed-Sternberg cells and then inhibits both NF-κB and STAT3 activation, leading to lymphoma cell death and a significant 80-97% reduction in Reed-Sternberg cell viability (Mackenzie 2008).

Animal studies report that curcumin retards lymphoma growth through several mechanisms. In mice with lymphoma, curcumin reduces oxidative stress in the liver by increasing antioxidant enzyme activities and suppressing reactive oxygen species production, which in turn influences NF-κB activity, leading to a decrease in lymphoma growth (Das 2012). In another animal study, curcumin retarded tumor growth in a mouse bearing T-cell lymphoma by altering parameters of the tumor microenvironment, including hypoxia (low oxygen concentration), pH, and glucose metabolism (Vishvakarma 2011). Curcumin selectively kills cutaneous T-cell lymphoma (CTCL) cells and inhibits the growth of Burkitt's lymphoma cells in animal studies (Cotto 2010; Li 2009; Zhang 2010; Hussain 2008).

Mistletoe Extract

Mistletoe (Viscum album L. extract [eg, Iscador]) has been used either alone or in combination with chemotherapy and/or radiation therapy as an immunomodulator in the treatment of various cancers (Ostermann 2012). Case studies suggest the effectiveness of mistletoe extract in the treatment of follicular B-NHL (Hugo 2005).

In a lab study comparing mistletoe extract with the chemotherapy drug vincristine against human B-cell lymphoma growth, both agents suppressed the proliferation of lymphoma cells to a similar degree and eventually led to the death of the lymphoma cells. The researchers concluded “the effects of [Mistletoe extract] on the B-cell lymphoma cell line [WSU-1] were comparable to those of vincristine in all parameters” (Kovacs 2008). Other laboratory studies found that mistletoe extract stops the growth of lymphoma cells and kills up to 92% of tumor cells in some cases. They found that mistletoe extract was more effective in killing lymphoma cells that have a high proliferation rate than those with a low proliferation rate (Kovacs 2006).

A Swiss study tested the effect of mistletoe treatment on serum levels of the inflammatory marker IL-6 in 27 B-cell NHL patients (Kovacs 2002). Twenty-one of 27 patients had been treated previously with chemotherapy and/or radiation therapy. The patients (45–79 years of age) were divided into two groups – those treated short-term (1–15 months) with mistletoe or long-term (2–14 years). Long-term mistletoe therapy significantly lowered IL-6 levels. Clinical results showed that half of the B-cell lymphoma patients (6/12) receiving long-term mistletoe treatment had a continuous complete remission, whereas only 2/15 patients in the short-term mistletoe treatment group had a complete remission. The doses of mistletoe extract varied from 5–30 mg per subcutaneous injection (Kovacs 2002). Mistletoe extract is generally administered subcutaneously two to three times a week.

A case report of advanced follicular lymphoma (stage IV, diagnosed in a 44-year-old man with bone marrow infiltration) treated with mistletoe extract for 12 years indicates that phases of uninterrupted mistletoe extract treatment resulted in lymphoma regression, while cessation of treatment led to disease progression. Good quality of life was maintained throughout the treatment period (Kuehn 1999).

A 12-year-old girl diagnosed with nodal large cell ALK-1-anaplastic lymphoma (ALCL) was treated with mistletoe alone. Within 1 week after starting mistletoe treatment the skin lesions and lymph node enlargement improved. She continued mistletoe therapy, and 30 months after diagnosis the patient was still in complete remission (Kameda 2011).

The effect of mistletoe on cancer patient survival time was reviewed in a 2012 study. Four studies on mistletoe preparations and patient survival revealed a moderate overall positive effect in favor of mistletoe treatment (Ostermann 2012). A comprehensive review of evidence published in 2008 reports that of 16 trials investigating the efficacy of mistletoe extracts for either improving quality of life, psychological measures, performance index, symptom scales or the reduction of adverse effects of chemotherapy, 14 showed some evidence of a benefit. Mistletoe extracts are usually well tolerated and have few side effects (Horneber 2008).

Melatonin

Disruption of circadian rhythm, which in turn reduces melatonin production, is associated with an increased risk of lymphoma and several other cancers among shift-workers and night-workers (Puligheddu 2012; Parent 2012).

Laboratory studies indicate that melatonin significantly inhibits the propagation of certain human lymphoma cells (Persengiev 1993). In fact, melatonin caused cell death in DLBCL, follicular B-cell NHL, EBV-negative Burkitt’s lymphoma, and acute T cell leukemia cells in a laboratory study (Sánchez-Hidalgo 2012). Melatonin promotes lymphoma growth arrest and causes the death of tumor cells, with molecular indications of cell death being seen as soon as 0.5-1 h after exposure to melatonin (Trubiani 2005; Sánchez-Hidalgo 2012). In mice with lymphoma, melatonin decreases bone marrow and lymphatic toxicity caused by Adriamycin®, which was attributed to its antioxidant properties (Rapozzi 1998).

Low-grade, advanced stage NHLs are considered incurable. Nonetheless, a case of low-grade advanced NHL (stage 4) treated successfully with cyclophosphamide plus somatostatin, bromocriptine, retinoids, and melatonin was reported. The author reports, “After 2 months the patient had a partial response, and after 5 months he achieved a complete response.” Eighteen months after beginning treatment the patient was in complete remission. The patient tolerated the treatment protocol well and was able to perform his normal activities at home (Todisco 2007).

Use of the same treatment protocol, with the inclusion of adrenocorticotropic hormone, in 12 patients with low-grade advanced NHL demonstrated a complete response in 50% and partial response in 50% of patients. Four of these patients were previously untreated and 8 patients had relapsed after chemotherapy and they had a therapy-free period of at least 6 months prior to commencing the protocol using melatonin (Todisco 2001).

High-grade NHL patients who relapse after receiving a transplant of their own stem cells have a poor prognosis; few of these patients can be cured by chemotherapy and generally have severe toxicities. A patient with relapse of high-grade NHL after autologous stem cell transplantation (ASCT) was successfully treated with the aforementioned regimen including melatonin supplementation. After 2 months, this patient had a partial response, and after 5 months he achieved a complete response. The patient was still in complete remission 14 months after beginning treatment (Todisco 2006).

A clinical study using a combination of melatonin plus low-dose interleukin-2 (IL-2) in 12 patients with advanced cancers of the blood (6 with NHL, 2 with HL) that did not respond to standard therapies found that this therapy prolonged survival. Melatonin was given as a 20 mg oral dose every evening. IL-2 was injected subcutaneously at a dose of 3 million IU/day for 6 days per week for 4 weeks. Lymphoma did not progress during the study in 4 out of 8 patients and the treatment was well tolerated (Lissoni 2000).

Devil’s Claw

Devil’s claw (Harpagophytum procumbens) is a member of the sesame family; its name derives from tiny hooks that cover its fruit. It is a traditional medicine in the Kalahari region of southern Africa (Mncwangi 2012).

Laboratory studies show that devil’s claw has antimicrobial, anti-inflammatory, antioxidant, and pain-relieving properties (Mncwangi 2012; Georgiev 2013). Additional evidence indicates that devil’s claw extract inhibits expression of the inflammatory mediators tumor necrosis factor–alpha (TNF-α) and cyclooxygenase-2 (COX-2) (Fiebich 2012).

Two case studies suggest lymphoma regression in two patients with low-grade follicular lymphoma following the use of devil’s claw supplements without chemotherapy. Although these initial reports are compelling, more research is needed to determine the role of devil’s claw in treating lymphoma (Wilson 2009).

Ayurvedic Herbs with Anti-Lymphoma Activity

Herbal research in lymphoma is limited mostly to laboratory and animal studies and not to clinical use. However, an evidence-based review examining the safety and efficacy of herbal medicine use by lymphoma patients found that several herbs are commonly used both during and after lymphoma treatment. This study discovered that lymphoma patients include herbal extracts in their treatment protocols based on positive results of laboratory studies and because historically they have been used in Traditional Chinese Medicine and Ayurvedic medicine to treat lymphoma (Ben-Arye 2010).

Four herbs used in ancient Indian (Ayurvedic) medicine – turmeric (Curcuma longa L.) (CL), guduchi (Tinospora cordifolia [wild]) (TC), holy basil/tulsi (Ocimum sanctum L.) (OS), and Indian Plum (Zizyphus mauritiana Lam.) (ZM) – were tested for their anti-tumor activity in lymphoma-bearing mice. Oral administration of crude herb (with human equivalent dose ranges of 1050-1190 mg CL; 1120-1190 mg TC; 980-1260 mg OS; and 1050-1190 mg ZM) increased the survival time of lymphoma-bearing mice. The most potent anti-lymphoma activity was exhibited by Tinospora cordifolia (followed by Z. mauritiana, curcumin, and O. sanctum, respectively) (Adhvaryu 2008). Tinospora cordifolia is readily available and has an excellent safety profile. It is used in general debility, digestive disturbances, urinary problems, and fever (Kapil 1997).

Tinospora cordifolia. Tinospora cordifolia has anti-cancer, adaptogenic, anti-inflammatory, antipyretic (fever-reducing), antioxidant, and immune system-balancing properties (Jagetia 2006; Adhvaryu 2008). It enhanced some aspects of anti-tumor immunity in mice (Singh 2005). Administration of Tinospora cordifolia whole plant extract to animals increases the recruitment of macrophages in response to lymphoma growth in T cell lymphoma-bearing mice (Singh 2006).

The cytotoxic compounds in Tinospora include alkaloids, glycosides, diterpenoid lactones, steroids, sesquiterpenoid, phenolics and polysaccharides (Jagetia 2006).

Optimizing Vitamin D Levels

A Mayo Clinic study on 983 newly-diagnosed NHL patients found that circulating vitamin D levels predict overall survival. Within 120 days of diagnosis, 44% of patients had vitamin D levels <25 ng/mL. Lymphoma patients with low vitamin D levels were found to have poorer overall survival, whereas higher vitamin D levels were associated with better survival (Drake 2010). In another study, lower vitamin D levels correlated with lymphoma among patients with Sjögren’s syndrome, an autoimmune disease associated with increased lymphoma risk (Agmon-Levin 2012).

Life Extension suggests that most individuals strive to attain a 25-hydroxyvitamin D level of 50 to 80 ng/mL for optimal health.

Preventing Long-Term Complications of Conventional Lymphoma Treatment

Screening for secondary cancers should commence 5–10 years after initial lymphoma treatment, and all lymphoma patients should cease smoking. Patients who receive radiation therapy to the chest/neck area are at a high risk for developing hypothyroidism and should be observed and monitored with periodic measurements of thyroid hormone status (van Dorp 2012; Thompson 2011).

Increasing numbers of survivors of childhood lymphoma treated with anthracyclines (chemotherapeutic antibiotics commonly used to treat lymphoma) will experience cardiac damage and require long-term surveillance and management (von der Weid 2008). Therefore, reducing or preventing cardiotoxicity from anthracycline chemotherapy during lymphoma treatment may benefit lymphoma survivors long-term (Tantawy 2011).

Preventing heart damage (cardiotoxicity). Heart and vascular damage is one of the most common long-term side effects of lymphoma treatment (Straus 2011). Cardiotoxicity occurs in 14-49% of patients who receive treatment with anthracyclines for lymphoma. Among anthracyclines, which are known to increase survival in NHL patients, the most commonly used is doxorubicin (Adriamycin®) (Hershman 2008). The good news is that heart damage caused specifically by Adriamycin® can be prevented with specific natural ingredients, including coenzyme Q10 and resveratrol (Gu 2012; Zhang 2011; Iarussi 1994).

  • Coenzyme Q10. The cardiotoxicity induced by anthracyclines is caused by irreversible damage to heart cells’ mitochondria (energy-generating “cellular powerplants”), leading to death of heart muscle cells. Coenzyme Q10, an essential component of mitochondrial energy production and a potent intracellular antioxidant, prevents damage to the mitochondria of the heart, thus preventing the development of anthracycline-induced cardiomyopathy (Conklin 2005).

    In a review of the literature on cardioprotection against the toxic effects of anthracyclines given to children with hematologic malignancies including lymphoma, one report found that children with lymphoblastic lymphoma or NHL experienced a protective effect of coenzyme Q10 on cardiac function during anthracycline therapy (Bryant 2007).

    A Chinese study investigating the adverse effects of Adriamycin® on cardiotoxicity found approximately 25% of the study group developed some type of abnormal ECG manifestations and of those, 4 developed fatal congestive heart failure. The authors concluded that in order to reduce Adriamycin® cardiotoxicity, “simultaneous […] coenzyme Q10 and vitamin E are indicated” (Wang 1991).

    In a clinical study of 79 cancer patients (55 lymphoma patients) treated with Adriamycin® (or daunorubicin), coenzyme Q10 tended to prevent heart dysfunction, as shown by ECG, and reduced incidence of diarrhea and stomatitis (inflammation of the mouth). In this study, CoQ10 was given intravenously (1 mg/kg/day) the day before, day of, and for another 2 days after chemotherapy (Tsubaki 1984).

  • Resveratrol. Resveratrol has also been shown to reduce the heart cell damage and heart cell death caused by doxorubicin in mice with lymphoma (Gu 2012).

Preventing secondary cancers. Studies suggest that secondary cancers caused by radiation and chemotherapy treatment of lymphoma can be prevented with coenzyme Q10 and other antioxidant supplements. A dietary antioxidant formula containing coenzyme Q10, L-selenomethionine, N-acetyl cysteine, ascorbic acid, α-lipoic acid, and vitamin E succinate markedly suppressed radiation-induced cancer development in mice. These dietary antioxidants prevented early-stage cancer growths from progressing to malignant tumors. Furthermore, animals that underwent radiation treatment but were maintained on dietary antioxidants did not develop any tumors (Kennedy 2011).