Lymphoma

Lymphoma

1 Overview

Summary and Quick Facts

  • Lymphoma is cancer of parts of the immune system that fight infection, including white blood cells and the lymphatic system. There are different types of lymphoma, and treatment may differ depending the type.
  • This protocol will help you understand how lymphoma develops and how it is treated. You will also learn about some emerging research on promising new therapies, and what dietary changes and supplements may be good for the lymphatic system.
  • Supplementation with melatonin and curcumin may help keep immune cells healthy.

Lymphomas are a surprisingly diverse group of cancers that arise from cells of the immune system called lymphocytes, which are a type of white blood cell. Lymphomas can be categorized as non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL).

HL has a high cure rate of about 75% overall and up to 90% in young patients. The average 5-year relative survival rate for NHL is about 71%.

For those undergoing active treatment, integrative therapies such as selenium, green tea, and mistletoe extract may improve outcome.

Causes and Risk Factors

  • Immunosuppression is the most well-established risk factor:
    • Autoimmune disease
    • Immunodeficiency syndromes
    • HIV infection
    • Organ or stem cell transplantation
  • Male gender
  • Older age
  • Obesity
  • Diets high in trans-fatty acids, processed meats, and high-fat dairy products were associated with increased NHL risk. Diets high in omega-3 fatty acids and fresh fish and seafood have been associated with reduced NHL risk. A high intake of vegetables lowers the risk of lymphoma by 30%.
  • Men who drink ≥1 serving of soda daily, whether diet or regular (sugar-sweetened) soda, have an increased risk of NHL.

Signs and Symptoms include:

  • Lymphadenopathy (swelling of the lymph nodes)
  • Unexplained fever
  • Night sweats
  • Weight loss

Diagnosis

Diagnosis of lymphoma may involve a number of clinical and laboratory tests, including:

  • Medical history
  • Physical examination
  • Imaging studies
  • Tissue biopsy
  • Blood tests such as complete blood count (CBC), chemistry panel, and erythrocyte sedimentation rate (ESR)
  • Laboratory techniques such as immunohistochemistry
  • Assessment for infection

Conventional Treatment includes:

  • Hodgkin Lymphoma:
    • HL is treated typically with radiation and chemotherapy.
  • Non-Hodgkin Lymphoma:
    • Treatment options for NHL patients range from a "watch and wait" strategy to hematopoietic stem cell transplantation.
  • Rituximab is often administered in conjunction with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The combination of all 5 agents is referred to as “R-CHOP.”

Novel and Emerging Strategies include:

  • Interleukin (IL)-6 inhibitors: Plasma IL-6 levels are significantly lower in patients whose lymphomas are in complete remission as compared to those in partial remission or those having progressive disease.
  • Regular use of aspirin was associated with a considerably reduced risk of HL. Acetaminophen use was actually linked to an increased risk of the disease.
  • In combination with rituximab, pixantrone has been shown to be superior to other single-agent therapies for the treatment of relapsed/refractory aggressive NHL.

Integrative Interventions include:

  • Caloric restriction. An experiment in mice that develop cancers resembling Burkitt’s lymphoma and a form of NHL found that a reduced calorie diet (75% of normal intake) combined with a targeted therapy decreased the number of circulating lymphoma cells.
  • Selenium. One clinical study reported that in patients with newly diagnosed NHL, 200 mcg/kg/day of sodium selenite significantly increased overall survival time. 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.
  • Green tea. Physicians at Mayo Clinic discovered that four patients with low-grade lymphomas began consuming over-the-counter green tea products containing epigallocatechin gallate (EGCG) on their own initiative. Subsequently, three of the four patients with low-grade B-cell lymphomas who used EGCG fulfilled the criteria for partial response.
  • Curcumin. 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.
  • Mistletoe extract. Clinical results showed that half of B-cell lymphoma patients 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.

2 Introduction

Lymphomas are a surprisingly diverse group of cancers that arise from cells of the immune system called lymphocytes, which are a type of white blood cell (Leukemia & Lymphoma Society 2011a). The American Cancer Society estimates that 79 030 new cases of lymphoma will be diagnosed in 2013 and 20 200 people will succumb to this disease (Siegel 2013).

Lymphomas can be broadly categorized as non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL). NHL comprises a diverse group of many different types of lymphoma, which together account for about 90% of all lymphoma cases. HL makes up about 10% of lymphoma cases (Leukemia & Lymphoma Society 2011a; Shankland 2012).

For NHL, chemotherapy and radiation therapy are the primary conventional treatment methods. Immunotherapy, which involves modifying the way the immune system responds to cancer cells, is also approved for some NHL subtypes (Leukemia & Lymphoma Society 2011a). HL has a high cure rate of about 75% overall and up to 90% in young patients. NHL prognosis varies significantly by subtype, with some variants having an excellent prognosis and other subtypes with more guarded long-term mortality estimates; inclusive of the many diverse subtypes of NHL, the average 5-year relative survival rate is about 71% (Leukemia & Lymphoma Society 2011b; Leukemia & Lymphoma Society 2013a).

The incidence of NHL has been increasing in the United States over the past few decades (Siegel 2012) for unclear reasons, though speculation includes impaired immune response to some types of viral infections (eg, with Epstein Barr virus [EBV], hepatitis B and C viruses) as well as enhanced exposure to industrial and/or environmental toxins including hair dyes, pesticides, and chemical solvents (De Falco 2011; Lim 2007; Olsson 1988; Ward 1996; Frankenfeld 2008). In contrast with NHL, the incidence of HL has remained relatively stable in the United States over the past few decades (Fast Stats [SEER] 2013).

An important aspect of lymphoma prevention involves the identification and treatment of infections known to be associated with lymphoma (Portlock 2008). For those undergoing active treatment, the use of readily available off-label drugs, including antiviral therapies, non-steroidal anti-inflammatory drugs (NSAIDs) (eg, diclofenac [Voltaren®]), and interleukin-6 (IL-6) inhibitors (eg, tocilizumab [Actemra®]) or integrative therapies such as mistletoe (eg, Iscador) may improve outcome (Gottfried 2013; Braun 2012; Wilson 2009; Wang 2009; Kovacs 2002; Kanakry 2013; Fields 2012). 

In this protocol you will learn the basics of lymphoma and the fundamentals of lymphoma care. The emerging, intriguing science in support of treating specific infections in lymphoma management will be discussed as well. Several integrative interventions that have been medically studied specifically in the context of lymphoma will be presented and the biological mechanisms by which they may reduce lymphoma progression will be reviewed.

3 Background

“Lymphoma" can refer to one of numerous different lymphoma subtypes (Morton 2013; Clarke 2006). The most common subtypes of NHL include diffuse large B-cell lymphoma (DLBCL), which makes up about 30% of all NHL in the United States, and follicular lymphoma, which accounts for roughly 20% of all NHL (Leukemia & Lymphoma Society 2011a).

Lymphomas are cancers of white blood cells (lymphocytes) within the lymphatic system. Lymphocytes can be B lymphocytes (B cells), T lymphocytes (T cells), or natural killer (NK) cells. B cells fight infection by producing antibodies whereas some T cells directly kill virus-infected or cancer cells; NK cells attack cells infected by a virus without the need for antibodies. About 85% of NHLs are of B cell origin (Leukemia & Lymphoma Society 2011a).

Lymphomas can arise as a consequence of a genetic mutation, eventually leading to the formation of a mass of malignant cells (tumor), often in the lymph nodes and sometimes in other body parts. The specific cells affected may be B cells, T cells, and sometimes natural killer (NK) cells (Kobrinsky 2012; Leukemia & Lymphoma Society 2011a; Leukemia & Lymphoma Society 2011b).

HL is usually differentiated from NHL by the presence of characteristic large cells called Reed-Sternberg cells. These cells typically emerge from B cells. Reed-Sternberg cells are the hallmark of HL; however, rarely, these cells may sometimes be seen in other diseases, such as NHL, as well as infectious mononucleosis (Küppers 2005; Thomas 2004; Khan 1993).

There are five types of HL, four of which – nodular sclerosis, mixed cellularity, lymphocyte depleted, and lymphocyte rich – are known as classic HL. The fifth type is called nodular lymphocyte predominant Hodgkin disease; it presents with peculiar features and is treated differently than the classic types (Lash 2013; Townsend 2012).

There are many types of NHL, several of which are outlined in the following table.

Non-Hodgkin lymphoma subtypes, relative frequencies (%), and characteristics (Abramson 2006; Marcucci 2011; Gajra 2013; Al-Humood 2011; Visco 2006; Leukemia & Lymphoma Society 2011a; Schöllkopf 2008; Armitage 1989; LRF 2012)

NHL types (relative frequencies by %)

Characteristics

A) B-cell lymphoma (80-90% of NHL)

Involves B cells but also includes T cell rich large B-cell lymphoma; associated with hepatitis B and C virus.

Diffuse large B-cell lymphoma (DLBCL) (31%)

Lymphoma can be either primary lymph node disease or at extranodal (outside the lymph node) sites; associated with hepatitis C virus 

Follicular lymphoma (22%)

Lymphoma cells have a follicular growth pattern (ie, the cells tend to grow in a circular pattern in lymph nodes)

MALT lymphoma (mucosa-associated lymphoid tissue) (7.5%)

Extranodal marginal zone lymphoma of mucosa-associated lymphatic tissue; gastric (stomach) in origin but can occur in other areas of the body; associated with Helicobacter pylori (H. pylori) infection

Mantle cell lymphoma (6%)

Originates in the mantle zone of the lymph node; it is usually widespread at the time of diagnosis; associated with Borrelia burgdorferi

Burkitt’s Lymphoma (2.5%)

Rare in adults but accounts for 30% of childhood NHL in the United States. EBV is associated with the development of Burkitt's lymphoma.

B) T- and NK-cell lymphomas (~12% of all NHL)

Several subtypes exist, including Sézary syndrome and mycosis fungoides (cutaneous T-cell lymphoma)

Mature T-cell lymphoma (7.6%)

Lymphoma cells have characteristics similar to T-cells; linked to human T-cell lymphotropic virus type 1; it is the most frequent T-cell lymphoma in the United States

Cutaneous T-cell lymphoma (2-3%)

This type of lymphoma includes mycosis fungoides and Sezary syndrome, and it may wax and wane over the course of several years, a characteristic that makes its diagnosis difficult

C) Immunodeficiency-associated lymphoproliferative disorders (relatively rare)

AIDS-associated lymphoma; posttransplantation lymphoproliferative disorder; and lymphoma associated with a primary immune disorder

The parenthetical percentages are approximate but provide perspective of the relative distribution of NHL subtypes.

4 Causes and Risk Factors

Demographics

At least two-thirds of NHL patients are 60 years or older, and men are more likely to be affected than women (Shankland 2012; Kobrinsky 2012).

Immunosuppression

The most well established risk factor for the development of NHL is immunosuppression. Hence, autoimmune disease, immunodeficiency syndromes, HIV infection, and organ or stem cell transplantation all increase risk.

Inherited. Some inherited (genetic) immunodeficiency syndromes are associated with up to a 10% increased risk of developing lymphoma (Chua 2008; Leechawengwongs 2012). Males are affected more than females by these inherited immunodeficiency syndromes; the resulting lymphomas are often associated with the EBV. Infections or autoimmune deficiency occur initially and lymphoma occurs as a later complication (Leechawengwongs 2012).

Acquired. Lymphomas have been associated with acquired immunodeficiency disorders (eg, AIDS) (Lim 2005), including those acquired due to the use of immunosuppressant medications for autoimmune disorders and for the prevention of transplant rejection (MacKenzie 2010). Posttransplantation lymphomas are generally B cell derived and frequently associated with EBV infection (Trofe 2002; Garfin 2013; Taylor 2005). The incidence and severity of lymphomas have increased with the use of immunosuppressive agents such as cyclosporine (Yamazaki 2013). Indeed, discontinuation of immunosuppressants (eg, cyclosporine, methotrexate, tacrolimus) has been shown to result in a partial or complete remission of lymphoma in some cases (Minauchi 2011; MacKenzie 2010; Yuan 2011; Baird 2002).

Autoimmunity. Autoimmune disorders including systemic lupus erythematosus (SLE), Sjögren’s syndrome, autoimmune thyroid disease, autoimmune hemolytic anemia, and rheumatoid arthritis are associated with an increased incidence of NHL (Caligaris-Cappio 2008; Mellemkjaer 2008). Primary Sjögren’s syndrome is associated with a 16-fold increased risk of NHL (particularly DLBCL and follicular lymphomas) (Solans-Laqué 2011). In one study, a 1000-fold increased risk of parotid gland MALT lymphoma was reported in those with Sjögren’s syndrome (Ekström Smedby 2008). Celiac disease is also associated with an increased risk of lymphoma (Mathus-Vliegen 1995; Catassi 2002). Psoriasis is associated with an increased risk of both NHL and HL (Gelfand 2006).

Diet

Being obese (Skibola 2007; Larsson 2007; Larsson 2011) and/or consuming a high-fat diet, high-calorie diet (particularly sugar and refined grains), or a diet rich in animal protein and meat products containing nitrites increases the risk of developing lymphoma (Aschebrook-Kilfoy 2013; Mozaheb 2012). In a Mayo clinic-based study of 603 lymphoma patients, diets high in trans-fatty acids, processed meats, and high-fat dairy products were associated with increased NHL risk (Charbonneau 2013). Phytanic acid, a saturated fatty acid from ruminant meat and dairy products, may also increase NHL risk (Ollberding, Aschebrook-Kilfoy, Caces, Wright 2013).

By contrast, diets high in omega-3 fatty acids and fresh fish and seafood have been associated with reduced NHL risk (Charbonneau 2013).

Noteworthy, men who drink ≥1 daily serving of soda, whether diet soda containing the artificial sweetener aspartame or regular (sugar-sweetened) soda, have an increased risk of NHL (Schernhammer 2012).

Recent findings suggest that eating vegetables and fruits combined, but not fruits alone, significantly reduces NHL risk. Specifically, a high intake of vegetables lowers the risk of DLBCL and follicular lymphoma by 30% (Chen 2013). Furthermore, one study assessing fruit and vegetable intake in relation to NHL survival in women reported an association between higher intake of fruits and vegetables, particularly green leafy vegetables, one year prior to diagnosis and overall survival in NHL patients (Han 2010).

In addition, nutrients found in fruits and vegetables may prevent lymphoma development. In a study of 35 159 women (55-69 years of age), it was found that vitamin C, alpha-carotene (α-carotene), proanthocyanidins, and dietary manganese reduced the risk of NHL – in particular follicular lymphoma. Greater intake of fruits and vegetables (particularly yellow/orange vegetables, broccoli, and apple juice/cider) were associated with lower NHL risk (Thompson 2010).

Nutrients, specifically vitamins A and C, reduce the risk of NHL, probably by affecting mechanisms that may contribute to lymphoma development. In a study of 154 363 postmenopausal women followed for an average of 11 years, it was found that the higher the intake of vitamins A and C from a combination of both diet and supplements, the lower the risk of lymphoma (Kabat 2012).

In a recent study on 301 newly diagnosed patients with NHL, the frequency and amount of food intake in the year prior to diagnosis was assessed and patients were followed for a median of 8.2 years. Higher intakes of carotene-rich vegetables and α-carotene were associated with better overall survival among those patients who had ever smoked (Ollberding, Aschebrook-Kilfoy, Caces, Smith 2013).

Environment

Living near (within 1/2 mile) of stone, clay, or glass industry facilities increases NHL risk (Linos 1991). Gardeners and farmers also have an increased incidence of lymphoma, most likely due to exposure to chemicals, including organochlorines, benzene, organophosphates, and herbicides (Smedby 2011; Alexander 2007).

Infectious Agents

Infection, whether viral or bacterial, is associated with an increased risk of several types of lymphoma. Several mechanisms by which infectious agents may drive lymphomas have been posited. First, some viruses such as EBV can directly cause malignant transformation of immune cells, but the mechanisms by which this occurs are not thoroughly understood (Cohen 2003). Second, infection with human immunodeficiency virus (HIV) can give rise to aberrant immune cell proliferation as a consequence of dramatic immunodeficiency (Engels 2007). Lastly, some chronic infections, for example with the hepatitis C virus (HCV), contribute to rapid immune cell proliferation and subsequent increased potential for malignant transformation.

Another less well established hypothesis is that some transient infectious agents can inflict sufficient damage to immune cells so as to cause genetic mutations that give rise to lymphoma even after the offending agent has been eradicated from the body (Engels 2007; Vendrame 2011).

Human T-cell leukemia/lymphoma virus. One of the most well established examples of a virus causing lymphoma is that of the human T-cell leukemia/lymphoma virus (HTLV-1), which is known to cause adult T-cell lymphoma (Mahieux 2007). 

Epstein-Barr virus. Epstein-Barr virus (EBV) infection is associated with the development of EBV-positive Hodgkin lymphoma. Additionally, EBV is strongly implicated in Burkitt’s lymphoma and nasal natural killer (NK)-cell and T-cell lymphomas (Hjalgrim 2012; Engels 2007).

Other microorganisms (viruses/bacteria) implicated in the development of lymphoma include (De Falco 2011; Smedby 2011; Schöllkopf 2008; Lin 2010; Kobrinsky 2012; Dalia 2013):

  • Hepatitis B virus (follicular lymphoma)
  • Hepatitis C virus (diffuse large B-cell lymphoma [DLBCL], marginal-zone lymphoma, and lymphoplasmacytic lymphoma)
  • H. pylori (gastric mucosa-associated lymphoid tissue lymphoma [MALT])
  • Borrelia burgdorferi (mantle cell lymphoma)
  • Chlamydia psittaci (ocular adnexal lymphoma)
  • Human herpesvirus-8 (HHV-8) (primary effusion lymphoma)
  • HIV infection (by causing immunodeficiency, HIV infection increases susceptibility for an EBV-induced or HHV-8-induced lymphoma)

The clinical implications of understanding the causative microorganisms implicated in lymphoma are that potential treatments and preventive measures can be targeted to the causative agent, whether viral, bacterial, fungal, or parasitic (Ferreri 2009).  

5 Sign and Symptoms

Since there are many types of NHL, the disease can manifest in a variety of ways. Symptom severity can range from mild to very severe, depending on the aggressiveness of the cancer (Kobrinsky 2012). One common presentation is lymphadenopathy – swelling of the lymph nodes.

Lymphadenopathy also occurs in HL, wherein it is observed in lymph nodes above the diaphragm in a significant majority of cases. Specifically, lymph nodes in the neck and under the arm are frequently affected, but swelling may also occur in lymph nodes in the groin in some cases (Lash 2013).

Lymphoma may also cause systemic symptoms, referred to as “B-symptoms,” which may be indicators of a rapidly developing lymphoma. B-symptoms include (Johansson 2010; Kobrinsky 2012; Portlock 2012; CTCA 2013):

  • unexplained fever (ie, temperature >100.4° F for 3 consecutive days)
  • night sweats
  • weight loss (ie, more than 10% of body weight in preceding 6 months)

Additional symptoms can include:

  • itching
  • pain
  • lack of energy
  • shortness of breath
  • headache

Sometimes lymphoma arises in a site other than a lymph node, such as a bone, in which case symptoms may include bone pain; similarly, rashes or lumps in the skin may indicate lymphoma originating in the skin (Leukemia & Lymphoma Society 2011a). 

6 Diagnosis

If a physician suspects lymphoma based upon initial patient presentation, a more in-depth evaluation can help confirm the diagnosis and identify the type of lymphoma the patient has. A complete history and physical examination are necessary to determine the presence of painless, swollen lymph nodes (which is a prominent feature in many lymphoma cases) and extent of disease (Glass 2008; Sisson 2013).

Achieving an accurate diagnosis is crucial because just as the biological properties of the different subtypes of NHL differ, so do the treatment approaches that are likely to be most successful (Kobrinsky 2012; Leukemia & Lymphoma Society 2011a).

Diagnosis of lymphoma may involve a number of clinical and laboratory tests, including (Kobrinsky 2012; Leukemia & Lymphoma Society 2011a; Even-Sapir 2003):

  • a thorough medical history evaluation
  • physical examination
  • imaging studies (eg, computed tomography [CT] and positron emission tomography [PET] and gallium scans)
  • tissue biopsy
  • blood tests such as complete blood count (CBC), chemistry panel, and erythrocyte sedimentation rate (ESR), serum lactate dehydrogenase, and beta 2-microglobulin
  • laboratory techniques such as immunohistochemistry, flow cytometry, and genetic analysis
  • assessment for infection (eg, H. pylori in suspected gastric MALT lymphoma)

Differentiating a benign (non-cancerous) tumor from a cancerous tumor can be complex because cancerous cells in many lymphomas closely resemble benign cells. Whenever a diagnosis of lymphoma is suspected, a biopsy of the largest and most accessible involved lymph node should be performed (Kobrinksy 2012; Portlock 2012). A biopsy involves taking a sample of the affected lymph node and sending it for microscopic evaluation by a pathologist. This allows molecular techniques to be performed to determine the cell of origin and delineate the best treatment approach (Ramsay 2013; Troxell 2005).

7 Conventional Treatment

Hodgkin Lymphoma

HL is treated typically with radiation and chemotherapy. The types of chemotherapy drugs used depend on the type and stage (I-IV) of the cancer. There are 4 chemotherapy regimens that are usually considered first-line treatments for HL (Townsend 2012; Lash 2013):

  • MOPP (mechlorethamine, vincristine, procarbazine, prednisone)
  • ABVD (Adriamycin® [doxorubicin], bleomycin, vinblastine, dacarbazine)
  • Stanford V (doxorubicin, vinblastine, mustard, bleomycin, vincristine, etoposide, prednisone)
  • BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone)

Unfortunately, HL treatment regimens are associated with considerable long-term side effects in many cases; in fact, for patients who survive more than 10-years following therapy, treatment-related long-term side effects are a major cause of death (Townsend 2012). Therefore, an important treatment consideration is to give the patient enough therapy to control their cancer, but not so much as to increase their risk of long-term side effects (Lash 2013).

Generally, HL has a relatively high cure rate, but the disease does relapse sometimes. In these cases, more powerful, higher-dose treatment regimens may be administered, and hematopoietic stem cell transplantation may be utilized to help rescue the patient’s blood-cell-producing system (Lash 2013; Townsend 2012).

Non-Hodgkin Lymphoma

The treatment of NHL varies greatly and depends on the type and stage of the cancer. Treatment options for patients with lymphoma range from a "watch and wait" strategy to hematopoietic stem cell transplantation (Luminari 2012).

The chemotherapy regimen R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone, plus rituximab) is commonly used to treat NHLs, including DLBCL and follicular lymphomas. The role of radiation therapy for early-stage lymphoma is still a matter of debate among experts in the field (MSKCC 2013; Tomita 2013; Campbell 2013).

There is a very limited role for surgery in the treatment of lymphoma. However, surgery is an effective management option in the treatment of primary cutaneous B-cell lymphoma (PCBCL) (Parbhakar 2011). Surgery no longer plays a role in the treatment of gastric MALT lymphoma except for very rare complications such as perforation or bleeding that cannot be controlled endoscopically (Fischbach 2013; NCI 2013).

Patients whose lymphoma returns despite standard treatment (ie, relapsed disease) typically receive a different treatment regimen (eg, chemotherapy, chemoimmunotherapy, radioimmunotherapy, or participate in an investigative clinical trial) (Nastoupil 2012; Ujjani 2013; Otte 2009).

Rituximab

Rituximab is a drug that makes it easier for the body to destroy cancerous B cells. It works by binding to a specialized protein on the surface of most B cells. When rituximab binds to a B cell, it causes changes in the arrangement of structures on the cell’s surface; these changes make it easier for the immune system to kill cancerous B cells (Rudnicka 2013; Marcus 2007).

Rituximab has become an important part of lymphoma treatment and is often administered in conjunction with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). The combination of all 5 agents is referred to as “R-CHOP.” One comprehensive review found that adding rituximab to CHOP led to a 3-fold higher complete remission rate over CHOP in NHL (Hou 2011). Several studies have shown that treatment with rituximab can prolong remission of follicular and diffuse large B-cell lymphomas (Marcus 2007). Addition of rituximab to chemotherapy has been shown to improve complete response and overall survival among HIV-positive individuals with NHL as well (Castillo 2012). Rituximab has also been shown to confer a survival benefit when administered as maintenance therapy in people with treatment-resistant or relapsed follicular lymphoma (Vidal 2011).

Rituximab weakens the immune system and can increase susceptibility to viral infections such hepatitis B, cytomegalovirus infection, and varicella-zoster virus infection (Aksoy 2007; Sisson 2013).

Hematopoietic Stem Cell Transplantation

Standard chemotherapy and/or radiation therapy regimens sometimes fail to eradicate lymphoma, resulting in refractory or relapsing disease. In these cases, doctors may administer higher dosages of chemotherapy or radiotherapy in an attempt to destroy the cancer. However, an unfortunate side effect of high-dose chemotherapy and radiation is destruction of bone marrow, which is where blood cell production takes place. This leads to insufficient blood cell synthesis (ACS 2013; Holmberg 2011).

An important strategy for overcoming this treatment barrier is hematopoietic stem cell transplantation. This involves infusing the patient with hematopoietic stem cells following chemotherapy or radiotherapy. Hematopoietic stem cells help rebuild the blood-cell-generating system within the bone marrow. This helps ensure that the patient is able to continue generating sufficient numbers of blood cells following cancer treatment (ACS 2013).

Stem cells can either be derived from the patient or from someone else whose tissue characteristics match the patient’s. When stem cells are derived from the patient, the procedure is referred to as autologous stem cell transplantation; when they are derived from someone else, the procedure is called allogeneic stem cell transplantation (ACS 2013).

Not all lymphoma patients will be good candidates for stem cell transplantation, and some types of lymphoma are more amenable to this approach than others. For example, high-dose chemotherapy along with autologous stem cell transplantation is used quite often for refractory diffuse large B cell lymphoma and HL (Rancea 2013; Gavrilina 2013; ACS 2013).

Antimicrobial Treatment: H. pylori Eradication to Treat Gastric MALT

MALT lymphomas are usually not aggressive and have a good long-term outcome in most cases (Alshemmari 2013). Many patients with gastric MALT lymphomas who are infected with H. pylori can achieve remission and symptom improvement with antibiotic therapy to eradicate the pathogen.

In one study, in which MALT lymphoma was treated exclusively by eradicating H. pylori, there was complete remission in 62% of patients, minimal residual disease in 18%, partial remission in 12%, no change in 4%, and progressive disease in only 2% at an average 44- month follow up (Fischbach 2004). Patients with more advanced disease, or those unresponsive to H. pylori antibiotic therapy, may be treated with a single agent (eg, chlorambucil), combination chemotherapy (eg, rituximab with fludarabine), or radiation therapy (Sisson 2013; ACS 2013).

8 Novel and Emerging Strategies

Normalizing Markers of Inflammation

Interleukin-6. Interleukin-6 (IL-6) is a cytokine (cell-signaling molecule) that stimulates the growth and maturation of B cells and T cells; it is also a major driver of inflammation (Wang 2009; Erta 2012; Hirano 2010). IL-6 levels are related to prognosis and survival of DLBCL patients (Giachelia 2012). Elevated serum levels of IL-6 are found with more advanced grade, type, B symptoms, and stage in NHL (Yee 1989; Kurzrock 1993; Giachelia 2012).

Abnormal IL-6 production has been observed during lymphoma progression, whereby the lymphoma cells secrete IL-6 continuously (Freeman 1989; Reynolds 2002). This is thought to lead to lymphoma cell growth mediated by IL-6 receptors (soluble IL-6R [sIL-6R]). Soluble IL-6R expression is augmented in NHL patients relative to healthy individuals (Lavabre-Bertrand 1995). Plasma IL-6 levels are significantly lower in patients whose lymphomas are in complete remission as compared to those in partial remission or those having progressive disease (Wang 2011).

One’s IL-6 level can be monitored with a blood test and some integrative interventions have been shown to suppress it. For example, coenzyme Q10 (CoQ10) at a dosage of 150 mg daily decreased IL-6 in patients with coronary artery disease, and mistletoe extract (eg, Iscador) also has been shown to reduce IL-6 levels (Lee 2012; Kovacs 2002). Non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac and indomethacin also modulate the IL-6 pathway and may benefit lymphoma patients; although more research is needed in this area (Tsuboi 1995; Fiebich 1996; Mahdy 2002).

Aspirin

Aspirin has recently received considerable attention for its emerging role as a chemopreventive agent against a variety of cancers, including lymphoma. It is a powerful inhibitor of inflammation that works in large part by blocking the action of cyclooxygenase enzymes, which normally drive the formation of inflammatory molecules called prostaglandins and thromboxanes. Moreover, aspirin disrupts IL-6 signaling, which is an important mechanism thought to play a role in the anti-cancer action of the drug (Tian 2011; Slattery 2007; Kim 2009).

Several studies have examined the relationship between aspirin use and lymphoma risk. A study published in 2004 showed that regular use of aspirin was associated with a considerably reduced risk of HL (Chang 2004). In this study, 565 HL patients and 679 healthy control subjects reported their average use of acetaminophen, NSAIDs, and aspirin over the previous 5 years. Results revealed a statistically robust 40% reduction in HL risk among aspirin users, but other NSAIDs were not linked to reduced risk; acetaminophen use was actually linked to an increased risk of the disease. In a 2010 study conducted in Denmark, aspirin use was assessed in 478 HL patients and 4780 control subjects. The researchers observed modest evidence for a roughly 30% reduced risk of HL among aspirin users compared to non-users or those who took aspirin only rarely. This study also found that other NSAIDs were not associated with protection against HL (Chang 2010). Another study conducted in Denmark revealed similar results: long-term aspirin use was associated with modestly strong evidence for a 35% reduction in HL risk among 1659 HL patients who were matched to as many as 5 control subjects each. Again, other NSAIDs were not linked to reduced risk (Chang 2011).

It also appears that aspirin may reduce risk of NHL. In a study of 625 people with NHL and 2512 controls, regular aspirin use was associated with an 18% reduced risk for the cancer among men. Interestingly, this study also reported an increased risk for NHL in association with greater acetaminophen use (Baker 2005).

Although there is compelling evidence that aspirin may reduce risk of some lymphomas, certain lymphoma subtypes may respond differently to the drug. For example, one study found that aspirin might enhance the ability of a lymphoma cell line (ie, Molt-4 T lymphoma cells) to evade destruction by chemotherapeutic drugs, although this was under laboratory conditions in an experiment conducted on cells taken from a patient who relapsed after multi-drug therapy (Flescher 2000; CLS 2013).

C-reactive protein. C-reactive protein (CRP) is normally present in minute amounts in the blood, but levels increase with the presence of infection, inflammation, and lymphoma. CRP is produced by liver cells as a response to inflammatory cytokines, especially IL-6, which is increased in the tumor microenvironment (Wang 2009). 

Suppression of serum C-reactive protein levels has become a surrogate marker of IL-6 inhibition in cancer studies (Voorhees 2013). Measurement of serum high-sensitivity CRP (hs-CRP) is simple and readily available via blood testing (Wang 2009).

CRP can be reduced by exercising moderately and regularly. A moderate-intensity exercise intervention reduced CRP for 12 months among 115 obese women (Campbell 2009). In one study, a therapeutic lifestyle modification intervention, including exercise, low-calorie diet, health education and counseling for 6 months, was found to be effective for improving patient inflammatory states and significantly decreased CRP levels in a group of 52 women (Oh 2013). In another clinical study on 652 sedentary individuals, a 20-week exercise training program was found to reduce CRP levels (median reduction of 1.34 mg/L) in individuals with high initial CRP levels (Lakka 2005).

Pixantrone

There is no standard therapy for relapsed or refractory (treatment-resistant) aggressive NHL in patients who have received two prior lines of chemotherapy. On May 10, 2012, the European Commission issued a conditional marketing authorization valid throughout the European Union for pixantrone for the treatment of adult patients with multiply relapsed or refractory aggressive non-Hodgkin B-cell lymphoma (Péan 2013). The FDA granted fast track designation (FDA 2010) for pixantrone in patients who had previously been treated with two or more lines of therapy for relapsed or refractory aggressive NHL (Mukherji 2009).

Pixantrone is a novel anthracycline derivative developed with the aim to retain the efficacy of anthracyclines and be less cardiotoxic. In combination with rituximab, pixantrone has been shown to be superior to other single-agent therapies for the salvage treatment of relapsed/refractory aggressive NHL (Mukherji 2009).

In relapsed aggressive NHL, weekly pixantrone (85 mg/m2) for 3 weeks every 4 weeks was associated with a 27% overall response rate and a 15% complete response rate. When used in combination chemotherapy regimens, overall response rates of 58-74% and complete response rates of 37-57% were achieved (El-Helw 2007).

In a trial of pixantrone for patients with relapsed or refractory aggressive NHL, the rate of confirmed and unconfirmed remissions in patients treated with pixantrone was significantly higher than in those receiving other agents, as was the overall response rate and progression-free survival (Papadatos-Pastos 2013). Pixantrone could be a treatment option for patients whose aggressive NHL has failed to respond to at least two previous chemotherapy regimens (Pettengell 2012).

With single-agent pixantrone, neutropenia (low neutrophils) is the most common dose-limiting toxicity. The most common side effects with pixantrone are bone marrow suppression (neutropenia), nausea, vomiting, and weakness (Pettengell 2012; Péan 2013).

Vaccines

Vaccines aim to prevent lymphoma recurrence after standard treatment, particularly for the incurable, slow-growing, or inactive lymphoma types. They are a form of immunotherapy that can be used alone or in combination with chemotherapy regimens, with a goal of extending overall survival (Thomas 2012; Rezvani 2011; Iurescia 2012).

A 2011 clinical study (phase III trial) has shown that a vaccine targeting a unique molecular structure on certain lymphoma cells improved disease-free survival in follicular lymphoma patients who were already in a minimal residual disease state (ie, had a complete response after 6 to 8 months of combination chemotherapy) (Schuster 2011). Based on the positive results of this study, a next-generation DNA vaccine has been developed using residual patient tumor and blood samples from patients vaccinated in the phase III clinical study. This new vaccine will be tested for the first time in patients with asymptomatic-phase lymphoplasmacytic lymphoma (Thomas 2012; Iurescia 2012).

DNA vaccines are being developed as highly specifically-targeted vaccines aimed at certain lymphoma cell surface markers and use multiple genes to enhance immunity and have lower risk than conventional vaccines. One of the most clinically advanced among therapeutic vaccines, BiovaxID®, is not yet available to the patients who need it – those diagnosed with a slow growing or inactive subtype of B-cell lymphoma. The clinical trials that have examined BiovaxID® indicate that it is clinically effective, but they were not large enough (did not enroll enough patients) to satisfy regulatory approval by the FDA. Therefore, unfortunately, more clinical trials will have to be successfully completed in order to make BiovaxID® available to B-cell lymphoma patients (Villanueva 2011; Iurescia 2012).

Targeting Infectious Agents to Treat Some Lymphomas

H. pylori and gastric mucosa associated lymphoid tissue lymphoma (MALT). There is compelling evidence that infection with the bacterium H. pylori causes gastric mucosa associated lymphoid tissue lymphoma (MALT) and that eradication of the bacteria results in lymphoma remission in many patients (Fischbach 2013).

As eradication of H. pylori infection cures gastric MALT in many cases, it is quite plausible that eradication of known causative infectious agents may cure other lymphomas (Kanakry 2013). This suggests it would be reasonable to test for suspected infectious agents (Grudeva-Popova 2013) and treat the infections (Poullot 2013).

For example, eradication of a suspected causative bacterium of mantle cell lymphoma (Borrelia burgdorferi) could possibly cure this lethal type of lymphoma (Fühler 2010; Schöllkopf 2008).

Borrelia burgdorferi and cutaneous B-cell lymphoma (CBCL). Borrelia burgdorferi (B. burgdorferi) is well known as the bacterium that causes Lyme disease. Lyme disease diagnosed early is generally successfully treated with antibiotics (eg, doxycycline, amoxicillin, cefuroxime) for 14 days (Wormser 2006). However, for complicated infections, intravenous antibiotics are often used (Klempner 2001; Pfister 1991). B. burgdorferi DNA has been detected in patients with cutaneous B-cell lymphoma (CBCL) and a response of CBCL to antibiotics has been observed. Physicians in Germany treated a patient with marginal zone lymphoma and B. burgdorferi infection with the antibiotic ceftriaxone, which resulted in lymphoma regression (Fühler 2010).

Therefore, patients with mantle cell lymphoma, CBCL, or marginal zone lymphoma who have been newly diagnosed (and have B. burgdorferi infection) or who have exhausted all other available treatment options, may wish to try the typical course of antibiotics used to treat Lyme disease (Fühler 2010; Hofbauer 2001).

Hepatitis C and Hodgkin lymphoma. In 2012 a documented case of a HL patient with HCV infection who experienced lymphoma regression following interferon-based antiviral therapy was reported. The authors state that “[t]his unique case […] confirms the efficacy of antiviral therapy for [Hodgkin lymphoma].” This case highlights the extent of the involvement of HCV in causing HL and moreover, the power of antiviral therapy in eliminating the causative virus (HCV) and hence the lymphoma itself (Takahashi 2012).

Other evidence suggests that HCV-positive lymphoma (marginal zone lymphoma) may respond to antiviral therapy with interferon and ribavirin (Ignatova 2012; Kelaidi 2004; Hermine 2002). Two cases of large granular lymphocyte (LGL) leukemia associated with B-cell lymphoma (B-NHL) and HCV infection that were successfully treated with antiviral therapy were reported. The researchers state, “HCV screening should be performed in all cases of LGL leukemia or B-NHL at diagnosis. Antiviral therapy may be attempted as first-line treatment for HCV-infected patients with indolent [inactive] B-NHL or LGL leukemia to prevent the side effects of chemotherapy or immunosuppressive treatment” (Poullot 2013).

"Antivirals" in the treatment of adult T cell leukemia/lymphoma. Adult T cell leukemia/lymphoma (ATLL) is a T cell lymphoma caused by infection with the human T-lymphotropic virus type 1 (HTLV-1). Aggressive subtypes of ATLL have a poor survival rate partly due to chemotherapy resistance (Fields 2012).

In a study of 254 lymphoma (and leukemia) patients, the 5-year overall survival rate was 46% for patients who received antiviral therapy alone, 14% for those who never received antiviral therapy, and 12% for those who received chemotherapy followed by antiviral therapy. Consequently, patients who received antiviral therapy in their initial treatment had a better overall survival rate. Moreover, patients with chronic or smoldering (slow-growing) ATLL significantly benefited from antiviral therapy, with a 100% 5-year overall survival rate in contrast to a 42% 5-year survival in those treated with chemotherapy alone (Fields 2012).

Epigenetic Therapy of Lymphoma using Histone Deacetylase Inhibitors (HDACIs)

One group of compounds receiving considerable attention in cancer research are called histone deacetylase inhibitors or HDACIs. These compounds modify gene expression without directly affecting the DNA sequence (Riddihough 2010; Bell 2011). Epigenetic modification by HDACIs has recently been proposed as a potential new therapy for lymphoma and leukemia.

Clinical trials indicate that HDACIs have specific anticancer effects on cutaneous T-cell lymphoma (CTCL), Hodgkin lymphoma, and myeloid tumors (Wada 2012; Mercurio 2010). Pharmacologic HDACIs (vorinostat and romidepsin) have been FDA-approved for the treatment of CTCL and peripheral T-cell lymphoma (Guo 2012; Howman 2011).

Hodgkin lymphoma is often curable with a 5-year survival rate of over 80% (Aleman 2007; Leukemia & Lymphoma Society 2013b). However, patients who relapse and become non-responsive to first- or second-line treatments (refractory) generally have a poor prognosis and early death. Recent clinical trials have shown that HDACIs have promising effects on refractory Hodgkin lymphoma (Buglio 2010).

In addition, it is worth noting that curcumin and resveratrol, both natural compounds, can exert epigenetic influences and are being investigated as cancer therapeutics (Cotto 2010; Frazzi 2013; Howells 2011; Kanai 2013).

Valproic acid. Valproic acid (VPA) was first used in 1963 to treat seizures, acute mania (Emrich 1981), bipolar disorder, and migraine headaches (Terbach 2009). Recent laboratory and animal studies show that VPA also functions as an HDACI, causing cell growth arrest and inducing differentiation in cancer cells. Preclinical studies show that VPA initiates cancer cell death by triggering apoptotic (programmed cell death) pathways in chronic lymphocytic leukaemia (CLL) (Bokelmann 2008). VPA is undergoing evaluation in India as a therapy for CLL (Szwajcer 2011).

The standard treatment for DLBCL patients is the CHOP chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine and prednisone), often combined with rituximab (R-CHOP). However, this chemotherapy regimen achieves a long-term cure in only 50-60% of patients. A 2013 Swedish study reports that VPA sensitizes DLBCL lines to CHOP-induced cell death. VPA alone or in combination with CHOP decreased lymphoma cell proliferation and survival. Therefore, VPA may be a promising novel treatment that can be used in combination with R-CHOP for patients with DLBCL to increase response rate and improve long-term patient outcomes (Ageberg 2013).

Targeting B-Cell Lymphomas with Engineered T Cells

Researchers on the cutting edge of immunological science have developed a method for modifying the immune system that allows for targeted eradication of B cells. This approach involves isolating patients’ T cells and inserting genetic information into them using a virus (viral vector). This new genetic information causes the T cells to target a specialized protein called CD19 on the surface of B cells. Once the engineered T cells are reintroduced into the patient, they seek out and destroy B cells, including those affected by B-cell lymphomas (Gill 2014; Kochenderfer, Rosenberg 2013). Results obtained using this approach have been very intriguing. In December 2013, scientists at the 55th annual meeting of the American Society of Hematology reported that of 14 patients with chemotherapy-refractory diffuse large B-cell lymphoma treated with this new procedure, 5 achieved complete remission and 6 achieved partial remission (Kochenderfer, Dudley 2013). Amazingly, one patient who had previously undergone 3 different chemotherapy treatment regimens but still had relapsing primary mediastinal B-cell lymphoma achieved a complete remission in response to the engineered T cell treatment.

This approach appears very promising as side effects seem to be generally manageable and the intervention is typically well tolerated by patients. Research is ongoing to determine ways to maximize the benefits of these engineered T cells, but few other B-cell lymphoma treatment strategies are garnering as much attention among oncologists and hematologists (Xu 2013).

9 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).

Disclaimer and Safety Information

This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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