Lymphoma-2

New and Upcoming Therapies for Lymphoma
New treatments for lymphomas largely involve the use of established chemotherapy and radiotherapy agents in combination with methods that capitalize on innate features of the immune system. Successful treatment of lymphoma must take into account the patient’s age and the role of nutrition in helping the body tolerate and recover from cytotoxic treatments.

Immunotherapy (e.g., Rituxan® [Rituximab]). B-cells, and therefore all lymphomas of B-cell origin, have a molecule on their surface known as CD20 (Maloney DG 2005). Rituxan® is an antibody designed to bind to CD20 on lymphoma cells (Plosker GL et al 2003). Upon the binding of Rituxan®, a process known as antibody-dependent cell cytotoxicity (ADCC) is initiated; this causes the immune system to destroy the lymphoma cell. Because normal B-cells also have CD20 on their cell surface, use of Rituxan® also leads to their destruction, and patients suffer from low B-cell numbers for approximately six months; however, these numbers return to normal 9 to 12 months after treatment (Plosker GL et al 2003).

In the US, Rituxan® is already available for the treatment of low-grade or follicular, relapsed NHL (Plosker GL et al 2003). Recent studies suggest that Rituxan® is also effective against diffuse large B-cell lymphoma (Nakai S et al 2005).

Chemoimmunotherapy (e.g., Rituxan® and CHOP). Recent studies have shown the use of Rituxan® in combination with CHOP chemotherapy to be more effective than CHOP chemotherapy alone in elderly patients with diffuse large B-cell lymphoma (Feugier P et al 2005). This therapy is also effective in previously untreated mantle cell lymphoma and aggressive recurrent pediatric B-cell large-cell NHL (Jetsrisuparb A et al 2005; Lenz G et al 2005). Although Rituxan® in combination with CHOP is approved in Europe for the treatment of diffuse large B-cell lymphoma (the most common aggressive form of NHL), it is yet to be approved for this use in the US (Plosker GL et al 2003).

Radioimmunotherapy. Radioimmunotherapy is the use of antibodies that target the CD20 molecule on lymphoma cells to specifically deliver the radiation required to destroy the cancer cell (DeNardo GL 2005). Two such radio-labeled antibodies to CD20 (iodine-131 tositumomab and yttrium-90 [90Y] ibritumomab tiuxetan) have been tested against NHL (Dillman RO 2003). In 2002, 90Y ibritumomab tiuxetan was approved in the US for the treatment of relapsed or refractory low-grade, follicular, or transformed lymphoma; it is commercially available as Zevalin® (Dillman RO 2003; Forero A et al 2003; Grillo-Lopez AJ 2005; Lewington V 2005; Wiseman GA et al 2005). The second radioimmunotherapy agent, I-131 tositumomab, has also been approved in the US and is commercially available as Bexxar® (Lewington V 2005).

(Additional information to Radioimmunotherapy section - added 7/24/2007) According to a recent New York Times report, two potentially lifesaving drugs are languishing in obscurity, largely due to market forces. The drugs, Zevalin and Bexxar, have been approved by the Food and Drug Administration for the treatment of lymphoma, including non-Hodgkins lympohoma; the fifth most common cancer in the United States. But only about 10 percent of eligible patients are receiving the drugs, despite some remarkable results among those few who have been treated with them. Although patients are more likely to respond to Zevalin or Bexxar than to older, more commonly-used lymphoma treatments -- and the newer drugs are better tolerated, with fewer side effects (Riley MB 2004) -- oncologists have been slow to embrace them.

Part of the problem stems from the fact that the drugs are the first members of a promising new class of treatments, known as radioimmunotherapies. These drugs utilize cutting-edge monoclonal antibody technology to deliver radioactive particles directly to tumor cells. But, while radioactivity is the key to their effectiveness, it is also a stumbling block that has rendered many oncologists reluctant to prescribe them. Due to their radioactivity, they must be administered in a hospital setting. As a result, oncologists must abandon financial incentives they might otherwise reap for prescribing older chemotherapy drugs, and they must coordinate their efforts with additional clinicians. Patients taking the new drugs must also be monitored for changes in blood cell counts.

A single treatment may cost about $25,000. But one treatment is often all that is required to effect remission. The more common alternative -- treatment with months of chemotherapy, followed by a commonly prescribed drug, Rituxan -- costs about the same.

But Bexxar or Zevalin are often more effective at stopping the deadly disease. A recent study found the drugs offer “…impressive clinical outcomes (approximately 20%-40% complete response rates and 60%-80% overall response rates for patients with [non-Hodgkins lymphoma].” (Macklis RM 2007) Another study reported similar results. (Witzig TE et al 2007) An older study compared the newer drugs to Rituxan and found an overall response rate of “…80% for the [Zevalin] group versus 56% for the [Rituxan] group.” The same study found that 30% of Zevalin patients experienced complete remission, as opposed to 16% of patients receiving Rituxan (Witzig TE et al 2002).

Advocates worry the drugs’ makers may abandon production if physicians don’t overcome their reluctance to use them soon. They hope the as-yet-unreleased results of ongoing clinical trials, designed to assess the efficacy of the drugs among large groups of patients, may finally convince oncologists to embrace their use. According to the New York Times, some lymphoma patients have been forced to take matters into their own hands, demanding access to the drugs, often with remarkable results.

Vaccine Therapy. The use of vaccination as a treatment for lymphoma is also being investigated. Further details on vaccine therapy for lymphoma can be found in the Experimental & Investigational Therapies protocol.

Nutritional Therapy
Nutritional supplements with demonstrated activity against lymphoma cells include:

a)Curcumin

b)Soy extract

c)Vitamins A, C, D, and E

d)Green tea

e)Resveratrol

f)Ginger

g)Fish oils

h)Garlic.

Curcumin. Curcumin, an extract from the spice turmeric, blocks the growth of various types of lymphoma cells, including Burkitt’s lymphoma and EBV B-cell lymphomas (Han SS et al 1999; Ranjan D et al 1999; Wu Y et al 2002b). In addition to arresting the growth of lymphoma cells, curcumin also causes lymphoma cell death by reducing the levels of some genes (c-myc, bcl-2) and mutant p53 proteins (Han SS et al 1999; Ranjan D et al 1999; Wu Y et al 2002c). Curcumin has an additional benefit in that it blocks the production of growth factors that cancer cells require to invade other organs (Dulak J 2005). Clinical studies have shown curcumin supplements to be safe in doses of up to 3.6 grams a day (Gescher A 2004).

Soy Extract. Genistein, found in soy extracts, induces cell death in lymphoma cells (Baxa DM et al 2003; Buckley AR et al 1993). It increases the effectiveness of chemotherapy for lymphoma by making cells more susceptible to agents that cause lymphoma cell death (Mohammad RM et al 2003). Genistein also reduces the ability of cancer cell spread (angiogenesis) by blocking the production of proteins (angiogenesis growth factors) that cancer cells need to form new blood vessels (Dulak J 2005).

Vitamins A and D3. Natural and synthetic vitamin A (also known as retinoids) promote normal cell differentiation and have been used to treat T-cell lymphomas (Kempf W et al 2003; Mahrle G et al 1987; Zhang C et al 2003). Vitamin D3 blocks the growth of lymphoma cells (Mathiasen IS et al 1993).

Green Tea. Green tea, which contains epigallocatechin gallate (EGCG), triggers lymphoma cell death (Bertolini F et al 2000; Katsuno Y et al 2001). In addition, EGCG from green tea reduces the ability of lymphoma cells to invade other organs by blocking the production of growth factors, such as vascular endothelial growth factor (VEGF) and the glycoprotein messenger interleukin-8 (IL-8), which lymphoma cells need to spread (Dulak J 2005).

Vitamins C and E. In experimental studies, vitamin C has improved the effectiveness of chemotherapy in inducing lymphoma cell death (Chen Q et al 2005; Nagy B et al 2003; Prasad SB et al 1992). Vitamin E supplements boost the function of immune cells capable of killing lymphoma cells (Ashfaq MK et al 2000; Dalen H et al 2003b; Dasgupta J et al 1993). Alpha-tocopheryl succinate, a semisynthetic analogue of vitamin E, is a potential adjuvant in cancer treatment (Dalen H et al 2003a).

Resveratrol. Resveratrol, a naturally occurring substance found in grapes, blocks the growth of lymphoma cells and also increases their rate of cell death (Bruno R et al 2003; Park JW et al 2001). Resveratrol sensitizes chemotherapy-resistant lymphoma cells to treatment with paclitaxel-based chemotherapy (Jazirehi AR et al 2004). Resveratrol also reduces the production of growth factors such as VEGF and IL-8, and theoretically should be beneficial in reducing the ability of lymphoma cells to spread to other organs (Dulak J 2005).

Ginger. Extracts from ginger, known as galanals A and B, induce cell death in human lymphoma cells (Miyoshi N et al 2003).

Fish Oil. Eicosapentaenoic acid (EPA) found in fish oil induces cell death in lymphoma cells (Heimli H et al 2001, 2002, 2003). Omega-3 fatty acids in fish oil normalized elevated blood lactic acid in a dose-dependent manner, increasing disease-free survival and survival time for dogs with Stage III lymphoma (Ogilvie GK et al 2000).

Garlic. Garlic extracts can induce death in lymphoma cells (Arditti FD et al 2005; Scharfenberg K et al 1990). Indeed, in a recent study, conjugation of a garlic extract to the antibody rituximab (which targets lymphoma cells) led to the death of these cells (Arditti FD et al 2005).

Blood Tests
Patients are advised to consult their physicians about the following blood tests that can be used to monitor the effectiveness of conventional medical treatment and nutritional supplements for lymphoma.

Cancer cell markers: Several nutritional supplements, including curcumin and ginger extracts, work by reducing the production of proteins such as p53 and bcl-2. Production of these proteins could be monitored to assess the continued effectiveness of therapy (Han SS et al 1999; Miyoshi N et al 2003; Ranjan D et al 1999; Wu Y et al 2002d; Wu Y et al 2002a).

Angiogenesis markers: Supplements of green tea, curcumin, resveratrol, and genistein work in part by blocking the production of growth factors, such as VEGF and interleukin-8 (IL-8), that cancer cells need to spread to other organs (Dulak J 2005). Patients using these nutritional supplements could routinely monitor these growth factors in their blood samples to assess the effectiveness of their therapy and check for disease progression. Reductions in VEGF levels have been linked to treatment response in lymphoma patients (Pedersen LM et al 2005).

IL-6: Patients could also monitor levels of the cytokine (messenger) IL-6, as reductions in its levels have been linked with treatment response and can be used to forecast survival (Pedersen LM et al 2005).

Beta-2-microglobulin: Levels of this protein are elevated in lymphoma patients, and monitoring it can be used to assess treatment response and disease progression; levels less than 3.0 mg/L are associated with remission (Escalon MP et al 2005; Litam P et al 1991).

Lactate dehydrogenase (LDH): Levels of this enzyme are elevated in lymphoma patients before treatment, and monitoring it can be used to assess response to treatment and to forecast survival (Escalon MP et al 2005; Schneider RJ et al 1980).

Molecular monitoring :Lymphoma cells can be detected in samples of blood and bone marrow. However, when these cells are present in very low numbers, molecular monitoring using a technique known as polymerase chain reaction (PCR) is recommended to determine response to treatment and check for remission (Martin S et al 2005).

Calcium levels: Patients using vitamin D supplements should be monitored for vitamin D toxicity, which can result in abnormally high calcium levels in the blood (Lagman R et al 2003).

Physical examination and X-ray scans can detect disease progression by monitoring the body, body weight, and size of lymph nodes.

For More Information

Lymphoma patients may wish to consult the following protocols and design a program that addresses the full range of their cancer problems:

Leukemia
Cancer Radiation
Cancer Chemotherapy
Anemia, Leukopenia, and Thrombocytopenia
Experimental & Investigational Therapies.


Life Extension Foundation Recommendations

Lymphoma patients should consult their physicians before using any nutritional supplements while receiving conventional medical treatment. In addition, lymphoma patients using nutritional supplements should enlist their physicians in ensuring the use of blood tests and diagnostic procedures that are essential in monitoring the effectiveness of any adjuvant therapy for lymphoma.

The Life Extension Foundation suggests:

a)Curcumin—up to 3.2 grams (g) daily (Gescher A 2004)

b)Soy extract (containing up to 60 milligrams (mg) of isoflavones): twice daily (Anderson GD et al 2003)

c)Vitamin A—40,000 to 50,000 international units (IU) daily (Kakizoe T 2003; Meyskens FL, Jr. et al 1995)

d)Vitamin D3—16,000 IU three times weekly (Mellibovsky L et al 1993)

e)Green tea—725 mg three times daily, or 10 cups of Japanese green tea (Laurie SA et al 2005; Pisters KM et al 2001)

f)Vitamin C—2000 mg daily (Kakizoe T 2003)

g)Vitamin E—400 IU daily (Kakizoe T 2003)

h)Resveratrol—20 to 40 mg daily (Walle T et al 2004)

i)Ginger—up to 6 g daily (Betz O et al 2005)

j)Fish oil—4.8 g of EPA/DHA daily (Buckley R et al 2004)

k)Garlic—600 mg of aged garlic extract twice daily.


Lymphoma Safety Caveats

An aggressive program of dietary supplementation should not be launched without the supervision of a qualified physician. Several of the nutrients suggested in this protocol may have adverse effects. These include:

Curcumin
Do not take curcumin if you have a bile duct obstruction or a history of gallstones. Taking curcumin can stimulate bile production.
Consult your doctor before taking curcumin if you have gastroesophageal reflux disease (GERD) or a history of peptic ulcer disease.
Consult your doctor before taking curcumin if you take warfarin or antiplatelet drugs. Curcumin can have antithrombotic activity.
Always take curcumin with food. Curcumin may cause gastric irritation, ulceration, gastritis, and peptic ulcer disease if taken on an empty stomach.
Curcumin can cause gastrointestinal symptoms such as nausea and diarrhea.

Daidzein

Consult your doctor before taking daidzein/daidzin if you have prostate cancer.
Do not use daidzein/daidzin if you have estrogen receptor–positive tumors.
Daidzein/daidzin can cause hypothyroidism in some people.

EPA/DHA
Consult your doctor before taking EPA/DHA if you take warfarin (Coumadin). Taking EPA/DHA with warfarin may increase the risk of bleeding.
Discontinue using EPA/DHA 2 weeks before any surgical procedure.

Garlic

Garlic has blood-thinning, anticlotting properties.
Discontinue using garlic before any surgical procedure.
Garlic can cause headache, muscle pain, fatigue, vertigo, watery eyes, asthma, and gastrointestinal symptoms such as nausea and diarrhea.
Ingesting large amounts of garlic can cause bad breath and body odor.

Genistein

Consult your doctor before taking genistein/genistin if you have prostate cancer.
Do not take genistein/genistin if you have estrogen receptor–positive tumors.
Genistein/genistin can cause hypothyroidism in some people.

Green Tea

a)Consult your doctor before taking green tea extract if you take aspirin or warfarin (Coumadin). Taking green tea extract and aspirin or warfarin can increase the risk of bleeding.

b)Discontinue using green tea extract 2 weeks before any surgical procedure. Green tea extract may decrease platelet aggregation.

c)Green tea extract contains caffeine, which may produce a variety of symptoms including restlessness, nausea, headache, muscle tension, sleep disturbances, and rapid heartbeat.

Vitamin A

a)Do not take vitamin A if you have hypervitaminosis A.

b)Do not take vitamin A if you take retinoids or retinoid analogues (such as acitretin, all-trans-retinoic acid, bexarotene, etretinate, and isotretinoin). Vitamin A can add to the toxicity of these drugs.

c)Do not take large amounts of vitamin A. Taking large amounts of vitamin A may cause acute or chronic toxicity. Early signs and symptoms of chronic toxicity include dry, rough skin; cracked lips; sparse, coarse hair; and loss of hair from the eyebrows. Later signs and symptoms of toxicity include irritability, headache, pseudotumor cerebri (benign intracranial hypertension), elevated serum liver enzymes, reversible noncirrhotic portal high blood pressure, fibrosis and cirrhosis of the liver, and death from liver failure.

Vitamin C

a)Do not take vitamin C if you have a history of kidney stones or of kidney insufficiency (defined as having a serum creatine level greater than 2 milligrams per deciliter and/or a creatinine clearance less than 30 milliliters per minute.

b)Consult your doctor before taking large amounts of vitamin C if you have hemochromatosis, thalassemia, sideroblastic anemia, sickle cell anemia, or erythrocyte glucose-6-phosphate dehydrogenase (G6PD) deficiency. You can experience iron overload if you have one of these conditions and use large amounts of vitamin C.

Vitamin D
a)Do not take vitamin D if you have hypercalcemia.

b)Consult your doctor before taking vitamin D if you are taking digoxin or any cardiac glycoside.

c)Only take large doses of vitamin D (2000 international units or 50 micrograms or more daily) if prescribed by your doctor.

d)See your doctor frequently if you take vitamin D and thiazides or if you take large doses of vitamin D. You may develop hypercalcemia.

e)Chronic large doses (95 micrograms or 3800 international units or more daily) of vitamin D can cause hypercalcemia.

Vitamin E
a)Consult your doctor before taking vitamin E if you take warfarin (Coumadin).

b)Consult your doctor before taking high doses of vitamin E if you have a vitamin K

c)deficiency or a history of liver failure.

d)Consult your doctor before taking vitamin E if you have a history of any bleeding disorder such as peptic ulcers, hemorrhagic stroke, or hemophilia.

e)Discontinue using vitamin E 1 month before any surgical procedure.