Lung Cancer, Chemotherapy, & Antioxidants

In the previous two issues of Avenues, we reported on the use of antioxidants along with chemotherapy as it applies to prostate and breast cancer patients. In this issue, we turn our focus to small cell lung cancer and non-small cell lung cancer.

INTRODUCTION
Chemotherapy is a critical part of care for lung cancer patients. However, there are some notable drawbacks to chemotherapy, such as lung cancer cells becoming resistant to treatment or side effects becoming debilitating and intolerable.

Although not commonly addressed in clinical consultation, scientific evidence suggests that combining certain chemotherapy treatments with specific antioxidants at defined dosages can help improve drug effectiveness, or may reduce side effect severity.

This issue is important because it has long been the opinion of many practicing oncologists that antioxidants should simply not be used concurrently with chemotherapy in the belief that the combination might inhibit chemotherapy effectiveness. This reluctance stems, in part, from the fact that some chemotherapy drugs work by strongly promoting oxidation. This is especially the case for the class of chemotherapy drugs called anthracyclines (Adriamycin and epirubicin), the alkylating agents (chlorambucil, cyclophosphamide, thiotepa, and busulfan), and the platinum drugs (cisplatin and carboplatin). Antioxidants, by definition, inhibit oxidation, so it was believed that antioxidants would prevent these chemotherapy drugs from working properly.

The controversy around using antioxidants together with chemotherapy is based, in part, on some studies of other cancer types and chemotherapy drugs that show how depleting glutathione, which is a natural antioxidant in the body, can enhance the treatment effect of chemotherapy. (Meijer, Mulder et al. 1990; Mans, Schuurhuis et al. 1992; Doyle, Ross et al. 1995; Versantvoort, Broxterman et al. 1995; Zaman, Lankelma et al. 1995; Kurokawa, Nishio et al. 1997; Lee, Park et al. 2004) Although this has led many oncologists to believe that all antioxidants should not be combined with chemotherapy, there are numerous laboratory and human studies showing how combining chemotherapy with antioxidants can indeed be helpful.

In this systematic review in which we searched for every paper on the combination of antioxidants and chemotherapy for lung cancer, we found only two laboratory (and no human) studies demonstrating a harmful combined effect.

Chemotherapy drugs that cause high levels of “oxidative stress” are thought to rely in part on oxidative stress to kill cancer cells, but other effects of that oxidative stress may also be getting in the way of the effectiveness of the chemotherapy. This is because oxidative stress slows cell replication and chemotherapy relies on fast cancer cell replication to be effective because it is during replication that chemotherapy kills cancer cells. (Conklin 2000) One approach to addressing this problem is the addition of certain antioxidants at specific dosages to lessen oxidative stress, thus making the chemotherapy treatment more effective. (Perumal, Shanthi et al. 2005)

The interaction between chemotherapy and antioxidants is more complex, however, than simply promoting and inhibiting oxidative stress. There are several mechanisms by which chemotherapy drugs function and antioxidants also have a number of different effects on the body. Each antioxidant has a different interaction with chemotherapy and this effect can even change based upon the dosage used.

In the end, the question is not whether antioxidants should be used in combination with chemotherapy but rather which should be used and at what dosages.

PURPOSE OF THIS PAPER
In this evidence-based review article, we discuss the results of current research showing how antioxidants may enhance or, in some cases, inhibit the therapeutic action of specific chemotherapy drugs used in the treatment of lung cancer. Some of these antioxidants may also reduce chemotherapy side effects or inhibit chemotherapy resistance in lung cancer cells. Finally, some of these antioxidants have been found to be useful for restoring the natural antioxidants in the body, which are often depleted after the completion of chemotherapy.

HOW NUTRIENT DEPLETION FROM CHEMOTHERAPY CAN OCCUR
Chemotherapy can cause nutrient depletion from two major side effects. One is nausea and vomiting, making it more difficult for the patient to maintain adequate nutrient intake. Another is toxicity to cells in the gastrointestinal tract, making it more difficult for the intestines to adequately absorb nutrients. Antioxidants are not the only nutrients to become depleted; vitamins, minerals, amino acids, and fatty acids may also be compromised, especially in patients who have suffered these side effects for a prolonged amount of time. For example, the following chemotherapy drugs damage the cells in the gastrointestinal system and can cause considerable nausea and vomiting: cisplatin, cyclophosphamide, daunorubicin, doxorubicin, mitomycin, mitoxantrone, paclitaxel, and vinorelbine.

METHODS
We searched for clinical or laboratory data published in peer-reviewed medical journals, conducted by cancer researchers in universities and medical research facilities from around the world, most published in prestigious, peer-reviewed journals. Some of these studies are still in early stages and include only laboratory or animal data, while others have advanced to include human volunteers.

We organized these data into the major categories of specific chemotherapy drugs. Within each section for a specific drug are found the research on combinations of that drug with various antioxidants, grouped by the name of the antioxidant in alphabetical order. We also point out specifically which studies were conducted in a laboratory (i.e. using cancer cell cultures), which were conducted using animals, and which were conducted with human volunteers. As each antioxidant appears in the paper for the first time, we provide some introduction to the antioxidant including what food sources naturally contain it, other common applications in clinical use, and typical dosages. The dosages given are not necessarily appropriate for all patients and should be individualized with practitioner guidance.

RESULTS

Carboplatin (Paraplatin)

MELATONIN
Melatonin is a hormone that is released from the pineal gland in the evening and promotes normal sleep; its secretion diminishes significantly with age. It is known to help maintain cell health and many people take it to improve sleep. It is also known to reduce metastasis in cancer patients. In most published studies, melatonin shows a beneficial effect, although it has been reported that in a small proportion of people, melatonin can paradoxically cause sleep disturbance. In others, there can be residual daytime drowsiness, which is usually resolved by using a lower dose.

» Melatonin: Typical dosages range from 1 mg to 20 mg. If aiming for a high dosage, one should start with 1 mg and increase the dosage slowly by 1 mg every 3 to 7 days. The ideal is to achieve peak blood levels of melatonin at about 2am. To do so, one can take the melatonin at bedtime, ideally between 9pm and 10pm.

Twenty previously untreated patients with inoperable small cell and non-small cell lung cancer were randomized in a double blind study to receive either chemotherapy alone or chemotherapy in combination with melatonin (40 mg per day). Chemotherapy consisted of carboplatin and etoposide. The trial investigated the potential of melatonin to protect against chemotherapy-induced toxicity to the bone marrow, where blood cells are produced. There was no significant difference between the groups in blood counts. (Ghielmini, Pagani et al. 1999)

MULTI-COMPOUND REGIMEN
In the following study, investigators combined the antioxidants vitamin C, vitamin E, and beta-carotene with the chemotherapy drugs paclitaxel and carboplatin.

Vitamin C (Ascorbic Acid)
Vitamin C, also called ascorbic acid, is a nutrient that humans cannot synthesize and must obtain from the diet. Almost all fresh vegetables and fruits are sources of vitamin C. Broccoli, cauliflower, citrus fruits, and tomatoes are examples of food sources particularly high in vitamin C.

» Vitamin C: Typical doses range from 60 mg to 1000 mg a day or up to bowel tolerance.

Vitamin E, Alpha Tocopherol
Vitamin E includes several related compounds: Tocopherols and tocotrienols, each of which have four subtypes of alpha, beta, gamma, and delta. Previously, only alpha-tocopherol was considered important, however each type has unique contributions to health. The best dietary sources of vitamin E are considered to be unrefined, cold-pressed vegetable oils such as wheat germ, sunflower seed, and olive oil as well as raw or sprouted seeds, nuts, and grains.

» Vitamin E: Avoid synthetic vitamin E, such as alpha-tocopherol or succinate. Seek out the mixed tocopherols, including tocopherols and tocotrienols. Typical dosage ranges from 50 IU to 800 IU daily.

Beta-Carotene
Beta-carotene is the most well known carotenoid, producing the red, orange, and yellow pigments in fruits and vegetables. It is a precursor of vitamin A, but also has its own physiological functions. (See “What about Lung Cancer and Beta-Carotene” sidebar at the end of this article.)

» Beta-carotene: Typical supplemental doses range from 5000 to 25,000 IU (3 to 15 mg) daily.

In a human lung squamous cell carcinoma cell line, the antioxidant mixture of vitamin C, vitamin E, and beta-carotene enhanced the treatment effect of paclitaxel and carboplatin. Paclitaxel followed by carboplatin 24 hours later led to an apoptosis (cancer cell killing) rate of 54%. In contrast, the vitamins administered together with paclitaxel and 24 hours later by carboplatin led to a 70% apoptosis rate. This effect was further enhanced to an 89% apoptosis rate by pretreatment with the vitamins 24 hours before paclitaxel, then followed another 24 hours later by carboplatin. (Pathak, Singh et al. 2002)

In a follow up human trial, the same combination of chemotherapy and antioxidants was tested in 136 previously untreated patients with advanced stage IIIB and IV non-small cell lung cancer. Patients were randomized to receive chemotherapy alone (paclitaxel and carboplatin) or chemotherapy in combination with ascorbic acid 6100 mg per day, dl-alpha-tocopherol (vitamin E) 1050 mg per day, and beta-carotene 60 mg per day. The response (tumor size reduction) rate in the chemotherapy-only group was 33%, while in the combination group was 37%. Overall survival (OS) was 32.9% at one year in the chemotherapy-alone group and 39.1% in the combination group. Median survival was 9 months in the chemotherapy-alone group and 11 months in the combination group. Toxicity was similar between the two groups. Although the difference in effectiveness was not statistically significant, it may nevertheless still be clinically significant, offering a modest improvement in treatment response and survival. Furthermore, the result of this study does not support the concern that these high-doses of antioxidants compromise the efficacy of paclitaxel-carboplatin combination chemotherapy. (Pathak, Bhutani et al. 2005)

Cisplatin (Platinol)

ASTRAGALUS
Astragalus is a tonic herb and the roots have been used for over 2000 years in Chinese medicine. It is used in the west for heart disease and to support the immune system.

» Astragalus: Typical dosages of the dried root range from 10 to 15 g daily by decoction, or as an extract 10 to 20 mL daily.

The Pine Street Foundation’s 2006 published meta-analysis has shown that adding Chinese herbal formulas based on the herb Astragalus membranaceus (Huang Qi) to cisplatin-based chemotherapy reduced risk of death at 12 months by 33%, when compared to cisplatin-based chemotherapy alone. The increase in tumor response ranged between 34% and 76% depending on the herbal formula used. (McCulloch, See et al. 2006)

DOCOSAHEXAENOIC ACID (DHA)
Omega-3 fatty acids come from several different sources and in several different forms. Sources include blue-green algae, fish oil, and eggs, from which docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) can be derived. It is used as a supplement in clinical practice for many therapeutic uses, some of which include cancer, heart disease, depression, diabetes, and multiple sclerosis.

» Omega 3 Polyunsaturated Fatty Acids (PUFA, from fish oil including DHA/EPA): Typical dosage range is from 1,000 mg to 10,000 mg daily. When finding a fish oil supplement, it is important to identify brands that can provide assurance that they have tested for heavy metals, such as mercury.

In a laboratory study of human small-cell lung cancer cells that were resistant to cisplatin, supplementing with DHA led to an almost three-fold decrease in the ability of tumor cells to be resistant to chemotherapy. In cancer cells that were not resistant to cisplatin treatment, DHA did not increase the treatment effectiveness of cisplatin. (Timmer-Bosscha, Hospers et al. 1989)

GENISTEIN
Genistein is an isoflavone found in legumes, especially soybeans. Isoflavones are antioxidants that counteract the damaging effects of free radicals in body tissues. Isoflavones, such as genistein, also have anti-angiogenic effects, blocking the formation of new blood vessels needed to support the growth of tumors.

» Genistein: A good product will use organic, non-GMO genistein. To achieve anti-tumor effects, the target daily dose, based on animal studies and calculations for similar human dosage, is between 100 mg and 1100 mg. (Boik 2001) One cup of soy milk will contain, on average, about 45 mg of genistein and the other related isoflavones.

Genistein was used in combination with cisplatin, docetaxel, or doxorubicin in the treatment of non-small cell lung cancer cells in a laboratory study. The treatment effect was significantly greater when genistein was used together with cisplatin, docetaxel, or doxorubicin than any of the chemotherapy agents alone. A smaller dose of chemotherapy was applied in the combined treatment and, despite the smaller dose, the treatment was more effective with genistein. The mechanism was through inactivation of NF-kappaB by genistein. (Li, Ahmed et al. 2005) Activation of NF-kappaB (a type of protein complex) plays a role in drug resistance in cancer cells in some chemotherapy agents, including cisplatin. (Yeh, Chuang et al. 2002)

GINSENOSIDE Rh2
Ginsenosides are an active ingredient derived from ginseng, one of the most widely known herbal medicines in the world and commonly used for its immune stimulating and anti-tumor properties. (Boik 2001)

» White American Ginseng Extract: Commonly used dosage levels of ginseng extract range between 200 and 1000 mg.

In a study using human lung adenocarcinoma, Ginsenoside Rh2 reversed resistance to cisplatin. In cisplatin resistant cells, the addition of Ginsenoside Rh2 decreased by three-fold the amount of cisplatin needed to achieve the same treatment effect of cisplatin alone. (Hu, Hu et al. 2005)

MELATONIN
Researchers from Italy published a study in 2007 about non-small cell lung cancer patients receiving cisplatin and etoposide (58 patients) or cisplatin and gemcitabine (16 patients) with or without melatonin (20 mg per day). The response rate to treatment and disease control was higher in patients treated with chemotherapy and melatonin than in patients treated with chemotherapy alone. This difference was only significant in the patients receiving cisplatin and etoposide but was not significant in the group of patients receiving cisplatin and gemcitabine. (Lissoni 2007)

In a second trial from Italy, 100 metastatic non-small cell lung cancer patients were given cisplatin and etoposide with or without melatonin (20 mg per day). The patients treated with chemotherapy and melatonin had significantly less progressive disease, had better overall tumor regression, and better 5-year survival. Three patients in the melatonin group were alive at five years after beginning treatment with chemotherapy whereas no patients were alive after two years in the chemotherapy only group. Treatment with melatonin also significantly decreased neurotoxicity, thrombocytopenia, weight loss, and asthenia. No difference was observed in alopecia and anemia. (Lissoni, Chilelli et al. 2003)

A third trial from Italy enrolled 104 metastatic non-small cell lung cancer patients who received chemotherapy treatment that consisted of cisplatin and etoposide or gemcitabine alone. Patients were randomized to receive chemotherapy alone or chemotherapy and melatonin at 20 mg per day. The response rate to chemotherapy was higher in patients treated with melatonin, although this difference was only significant in patients receiving cisplatin and etoposide but not gemcitabine. Nevertheless, one year survival was significantly higher in the patients receiving melatonin in both chemotherapy groups. (Lissoni, Barni et al. 1999)

5-METHOXYTRYPTAMINE (5-MTT)
5-methoxytryptamine (5-MTT) is a pineal hormone.

» 5-methoxytryptamine (5-MTT): Typical dosage used for cancer patients is 1 mg per day.

One hundred advanced non-small cell lung cancer patients were enrolled in a trial from Italy published in 2007 who received either chemotherapy (cisplatin and etoposide) alone or with melatonin (20 mg per day) or 5-MTT (1 mg per day). The overall response rate and disease control was significantly higher in both the melatonin and 5-MTT groups. The chemotherapy-related toxicity such as thrombocytopenia, neurotoxicity, and asthenia was significantly reduced in patients receiving chemotherapy and melatonin or 5-MTT. 5-MTT was better than melatonin at preventing anorexia. Therefore, the much lower dose of 5-MTT was as effective as melatonin in the treatment of non-small cell lung cancer. (Lissoni 2007)

In another study, 20 metastatic lung cancer patients were treated with cisplatin and etoposide and were randomized to either receive 5-MTT (1 mg per day) in addition to chemotherapy or to receive chemotherapy treatment alone. The patients treated with chemotherapy and 5-MTT had significantly reduced anemia and significantly less progressive disease in comparison to the patients treated with chemotherapy alone. (Lissoni, Malugani et al. 2003)

MULTI-COMPOUND REGIMEN
In the following study, investigators combined the antioxidants alpha-lipoic acid and N-acetyl cysteine with cisplatin, epirubicin, medroxyprogesterone acetate (a hormonal drug that is a progestin derived from the naturally occurring female hormone, progesterone), and recombinant IL-2.

Alpha-lipoic Acid
Alpha-lipoic acid is an important antioxidant that can regenerate other essential antioxidants such as vitamins C and E, coenzyme Q10, and glutathione. It is also a cofactor for some of the key enzymes (alpha-keto acid dehydrogenases) involved in generating energy. Alpha-lipoic acid comes in two forms: the “R” form is biologically active and is naturally produced by the body while the “S” form is manufactured and is less biologically active. Most alpha-lipoic supplements have a mixture of the “R” and “S” forms. Some manufacturers now make available a supplement containing pure R-dihydro-lipoic acid.

» Alpha-lipoic Acid: Typically used in a dosage range between 200 and 600 mg per day. (Boik 2001) When using the Rdihydro-lipoic acid, half the dose may be used.

N-acetyl Cysteine
N-acetyl cysteine is an efficiently absorbed and used form of the amino acid, L-cysteine. L-cysteine, L-glutamic acid, and glycine are the three amino acids that form glutathione, which is one of the most important and powerful antioxidants in the body.

» N-acetyl Cysteine: Typical dosages range between 600 and 1,800 mg per day.

A phase II clinical trial using a combination regimen including cisplatin, epirubicin, medroxyprogesterone acetate, recombinant IL-2, alpha-lipoic acid (300 mg per day), and N-acetyl cysteine (1.8 g per day) enrolled 33 non-small cell lung cancer patients: 26 with stage IIIB disease and 7 with stage IV disease. Of thirty patients whose results could be measured, the median overall survival was 15 months. The one year survival was 55.8%. The median progression free survival was 10 months. Neutropenia was the most significant symptom of toxicity from treatment; other toxicity was low. (Mantovani, Maccio et al. 2002)

QUERCETIN
Quercetin is the most abundant of the plant-derived flavonoid molecules and is a very active antioxidant. Quercetin is a flavonoid found in capers, apples, tea, onions, red grapes, citrus fruits, leafy green vegetables, cherries, and raspberries. Quercetin has anti-inflammatory activity, inhibiting allergic and inflammatory reactions. Dihydroquercetin is a supplement very similar to quercetin that may be even safer than quercetin and is most notable for its synergistic combination with vitamin C. Dihydroquercetin inhibits the oxidation of vitamin C, helping to maintain the concentration of vitamin C in the body over time. Together, vitamin C and dihydroquercetin inhibit oxidative stress and inflammation, avert complications of diabetes, protect against liver damage and hepatitis, provide immune support, and sooth irritated skin.

» Quercetin: Typical dosages range from 200 mg to 1,200 mg daily.
» Dihydroquercetin: Typical dosage is 10 mg combined with vitamin C (1000 mg).

Quercetin, when combined with cisplatin, was found to increase cell death of human non-small cell lung cancer cells by 30.2% compared to cisplatin alone in a laboratory study. (Kuhar, Sen et al. 2006) A second laboratory study also confirmed that cisplatin had a much stronger treatment effect in lung cancer cells when combined with quercetin. (Borska, Gebarowska et al. 2004)

VITAMIN D
Vitamin D includes a series of compounds exhibiting the activity of calciferol. The two most widely known types of vitamin D are ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D3 has a greater potency and longer duration of action than vitamin D2. (Armas, Hollis et al. 2004) It is a fat-soluble vitamin and a hormone and it can either be absorbed through digestion or synthesized in the skin when exposed to sunlight.

Twenty minutes of sun exposure to the face and arms is sufficient to generate production of 600 to 1000 IU of vitamin D (during spring, summer, and fall, in temperate regions such as the San Francisco Bay Area). In an hour’s time, with sun exposure that produces mild redness of the skin, 10,000 to 20,000 IU may be generated. During spring, summer, and fall, 15 minutes of sun exposure, three times per week in the morning or late afternoon on the arms, face, and hands provides sufficient vitamin D stores to last through the end of winter (in latitudes between 35o and 50o; San Francisco is at about 37o). Sunscreen significantly reduces the synthesis of vitamin D.

Although vitamin D comes primarily from sun exposure, food sources include cod liver oil, butter, egg yolks, and vitamin D fortified milk and orange juice.

» Vitamin D: Therapeutic dosages range between 200 IU to 2000 IU per day, and doses up to 10,000 IU have been tested in clinical trials. Very high doses of vitamin D at 40,000 IU per day have been reported to result in hypercalcemia. (Vieth 1999) Lymphoma and granulomatous disease can cause vitamin D sensitivity and therefore people with these conditions should be more cautious in taking vitamin D supplements. A simple blood test for 25 hydroxy vitamin D can be used to monitor blood levels in people using vitamin D supplements.

In human non-small cell lung carcinoma cells, vitamin D compounds decreased the IC50 of cisplatin in a laboratory study (IC50 is the concentration of drug needed to achieve 50% reduction in cancer cell growth). This means that when vitamin D was added, less cisplatin was needed to achieve the same anti-tumor effect as cisplatin alone. (Pelczynska, Wietrzyk et al. 2005)

VITAMIN K
Vitamin K is a coenzyme involved in synthesis of proteins important for blood clotting and bone metabolism. Vitamin K1 is non-toxic up to 500 times the recommended daily allowance, which is 1 microgram per kilogram of body weight. It is a fat-soluble form that naturally occurs in plants and fish. Vitamin K2 is another fat-soluble form that is synthesized by the healthy bacteria in our intestines. Food sources of vitamin K2 are meat, fermented food products such as cheese, or the Japanese fermented soy product natto.

» Vitamin K: Therapeutic dosages range from 45 to 500 micrograms per day. Because vitamin K affects blood clotting, patients using anticoagulant therapy should monitor vitamin K intake with their doctor.

Vitamin K2 was found to enhance small cell lung cancer cell death caused by cisplatin in a laboratory study. (Yoshida, Miyazawa et al. 2003)

Cyclophosphamide(Cytoxan, Neosar)

BETA-1,3 D-CARBOXYMETHYLGLUCAN (BETA-1,3 D-GLUCAN)
Beta-1,3 D-glucan is derived from yeast and is a macrophage stimulator. Macrophages are an important part of the immune system.

» Beta-1,3 D-glucan: Typical dosages range from 100 to 500 mg per day.

In an animal study, Beta-1,3 D-glucan enhanced the treatment effect of cyclophosphamide in Lewis lung carcinoma. The combination treatment was more effective at inhibiting primary tumor node as well as reducing metastasis. After cyclophosphamide treatment alone, metastasis occurred in 40.9% of animals. With combined treatment, metastasis occurred in 7.5% of animals. (Falameeva, Poteryaeva et al. 2001)

GENISTEIN
In an animal study using mice with Lewis lung cancer, cyclophosphamide alone reduced tumor blood supply by 38%, while the combination of cyclophosphamide and genistein reduced tumor blood supply by 61%. (Wietrzyk, Boratynski et al. 2001)

GINSENOSIDE Rg3
A low dose schedule of cyclophosphamide was enhanced by the angiogenic inhibitor ginsenoside Rg3 in mice with Lewis lung carcinoma. Tumor growth was delayed, side effects were mitigated, survival was increased, and angiogenesis was enhanced in mice receiving combined treatment in contrast to mice receiving cyclophosphamide alone. (Zhang, Kang et al. 2006) Angiogenic inhibitors decrease the blood vessels to the tumor so that the supply of nutrients to the tumor is decreased and thus growth is inhibited.

MULTI-COMPOUND REGIMEN
In the following study, investigators combined the antioxidants vitamin A, retinoic acid, vitamin E, vitamin D, melatonin, and beta-carotene with somatostatin (a hormone that inhibits the release of various growth hormones), cyclophosphamide, and bromocriptine (a dopamine agonist that works by blocking the release of prolactin from the pituitary gland and lowering growth hormone levels).

Vitamin A & Retinoic Acid
Retinoic acid is the acidified form of vitamin A (retinol), the animal form of vitamin A. Retinoic acid is a prescription drug; the generic name is tretinoin and one of the trade names is Vesanoid. Retinol is a fat-soluble, antioxidant vitamin important for bone growth and vision. Retinol is ingested in a precursor form from animal foods and is especially plentiful in cod liver oil. Other good sources include butter and egg yolks as well as whole milk, cream, and yogurt.

» Vitamin A: Typical dosages range from 2500 IU to 25,000 IU.

Twenty-three patients with stage IIIB or IV lung adenocarcinoma whose disease had progressed after standard chemotherapy, and who also had poor quality of life, received a combination of somatostatin, retinoids, melatonin, vitamin D, bromocriptine, and cyclophosphamide. The median overall survival was 95 days and the side effect consisted of grade 1-2 diarrhea, nausea/vomiting, and drowsiness. Fifty percent of patients experienced improved respiratory as well as general symptoms. Most of these were patients that survived longer than 95 days. (Norsa and Martino 2006)

Daunorubicin, Daunomycin (Cerubidine)

GENISTEIN , BIOCHANIN A, APIGENIN, AND QUERCETIN
In Adriamycin resistant small cell lung cancer cells, genistein, biochanin A, apigenin (an antioxidant flavonoid found in plants such as parsley, artichoke, basil, and celery), and quercetin inhibited the flow of daunorubicin out of the cancer cells. The antioxidants were not administered together as a mixture but rather tested separately with daunorubicin. (Versantvoort, Schuurhuis et al. 1993)

Docetaxel (Taxotere)

GENISTEIN
Genistein was used in combination with cisplatin, docetaxel, or doxorubicin in the treatment of non-small cell lung cancer cells in a laboratory study. The treatment effect was significantly greater when genistein was used together with cisplatin, docetaxel, or doxorubicin than any of the chemotherapy agents alone. A smaller dose of chemotherapy was applied in the combined treatment and, despite the smaller dose, the treatment was more effective with genistein. The mechanism was through inactivation of NF-kappaB by genistein. (Li, Ahmed et al. 2005) Activation of NF-kappaB plays a role in drug resistance in cancer cells in some chemotherapy agents including cisplatin. (Yeh, Chuang et al. 2002)

Doxorubicin (Adriamycin)

CURCUMIN
Curcumin is a polyphenol and is an extract of the Indian curry spice plant turmeric. Curcumin is known for its anti-tumor, antioxidant, anti-amyloid, and anti-inflammatory properties. It also promotes healthy bile excretion and healthy platelet function.

» Curcumin: The best supplements contain curcumin at 75% or higher concentration. Typical doses range from 500 mg to 4,000 mg daily. Take with meals as it can cause stomach upset when taken on an empty stomach. Bioavailability and potency are increased when combined with Bioperine, from black pepper.

A laboratory study found that curcumin prevented doxorubicin from flowing out of non-small cell lung cancer cells that were resistant to doxorubicin. Therefore, curcumin may enhance the treatment effect of doxorubicin in doxorubicin-resistant lung cancer cells in vitro. (Pesic, Markovic et al. 2006)

DOCOSAHEXAENOIC ACID (DHA)
Slight to no enhancement of treatment effect (but no decreased effect) was observed after combination treatment using doxorubicin and DHA in a laboratory study using bronchial carcinoma cell lines. Interestingly, that same combined treatment did enhance treatment effectiveness in brain cancer cell lines, underscoring the importance of combining the right antioxidant with the right drug and the appropriate cancer. (Rudra and Krokan 2001) In a second laboratory study, DHA increased the concentration of doxorubicin in small-cell lung cancer cells by 10 to 30%. Despite the increase in concentration of doxorubicin, there was no increase in treatment effect in doxorubicin sensitive cells, however there was a partial reversal of resistance in the doxorubicin resistant cells. (Zijlstra, de Vries et al. 1987)

FISH OIL
An animal study compared mice with lung cancer tumors treated with doxorubicin and a diet rich in either corn oil or fish oil. In mice that received fish oil and doxorubicin, there was significant tumor regression. In mice that received corn oil and doxorubicin, the treatment only halted the growth of the tumor. Thus fish oil was found to enhance the treatment effect of doxorubicin. (Hardman, Moyer et al. 2000)

GENISTEIN
Genistein was used in combination with cisplatin, docetaxel, or doxorubicin in the treatment of non-small cell lung cancer cells in a laboratory study. The treatment effect was significantly greater when genistein was used together with cisplatin, docetaxel, or doxorubicin than any of the chemotherapy agents alone. A smaller dose of chemotherapy was applied in the combined treatment and, despite the smaller dose, the treatment was more effective with genistein. The mechanism was through inactivation of NF-kappaB by genistein. (Li, Ahmed et al. 2005) Activation of NF-kappaB plays a role in drug resistance in cancer cells in some chemotherapy agents including cisplatin. (Yeh, Chuang et al. 2002)

MELATONIN
In a laboratory study, melatonin intensified doxorubicin effectiveness in non-small cell lung cancer cells. (Fic, Podhorska-Okolow et al. 2007)

SELENIUM
Selenium is an essential trace mineral in the body and is found in variable amounts in food depending on the soil content of selenium. Brazil nuts are the single best food source of selenium. One of its roles in the body is as an antioxidant and it is most widely known as a cancer preventive.

» Selenium (mineral): The US Adult Tolerable Upper Intake Level (UL) is 400 micrograms a day and the Lowest Observed Adverse Effects Level (LOAEL) for adults is about 900 micrograms daily. There are several different forms of selenium; Se-Methylselenocysteine is a highly bioavailable form because it is not incorporated within a protein such as the form selenomethionine. We recommend getting selenium either in the organically bound forms, such as of Se-Methylselenocysteine, or a combination of selenium compounds with L-selenomethionine, sodium selenate, selenodiglutathione, and Se-methylselenocysteine.

Selenium in combination with doxorubicin or paclitaxel enhanced the chemotherapeutic effect of doxorubicin and paclitaxel in human squamous lung cancer cells in a laboratory study. (Vadgama, Wu et al. 2000)

In human small cell lung carcinoma cells that had developed resistance to doxorubicin, treatment with selenium caused significant apoptosis. In contrast, the cells that were sensitive to doxorubicin did not respond to treatment with selenium as strongly. It is important to note that this study does not comment on the combination of doxorubicin and selenium as a combined treatment, but rather only selenium treatment of cancer cells that are resistant or sensitive to doxorubicin. (Jonsson-Videsater, Bjorkhem-Bergman et al. 2004)

SILIBININ
Silibinin (also called silybin) is an important active compound found in silymarin, extracted from blessed milk thistle (Silybum marianum) which is a member of the sunflower family (Compositae).

» Silymarin: Typical dosages range from 100 mg to 900 mg daily. An example of a good product is one containing 900 mg, standardized to 80% silymarin (720 mg), 30% Silibinin (270 mg), and 4.5% Isosilybin B complex (40.5mg). Silibinin is the most biologically active constituent found in silymarin and Isosilybin B complex is the most efficient constituent of silymarin in maintaining healthy cell division.

An animal study observed the effects of combined treatment with Silibinin and doxorubicin in mice with non-small cell lung cancer. Silibinin enhanced the treatment effect of doxorubicin. The tumor weight was decreased 76% in mice with combined treatment, and only 61% in mice treated with doxorubicin alone. The combined treatment prevented weight loss that otherwise occurred in mice treated with doxorubicin alone. Microvessel density was inhibited by doxorubicin by 58% whereas in combination treatment, microvessel density inhibition was enhanced significantly to 70%. Microvessel density inhibition means that there is less blood supply to the tumor and this leads to better treatment outcomes. The inhibition of the NF-kappaB pathway was found to play a role in the synergistic combination. (Singh, Mallikarjuna et al. 2004)

VITAMIN D
In human non-small cell lung carcinoma cells, vitamin D compounds decreased the IC50 of doxorubicin in a laboratory study (IC50 is the concentration of drug needed to achieve 50% reduction in cancer cell growth). This means that when vitamin D was added, less doxorubicin was needed to achieve the same anti-tumor effect as doxorubicin alone. (Pelczynska, Wietrzyk et al. 2005)

Epirubicin (Ellence)

MULTI-COMPOUND REGIMEN
A phase II clinical trial using a combination regimen including cisplatin, epirubicin, medroxyprogesterone acetate (a hormonal drug that is a progestin derived from the naturally occurring female hormone, progesterone), recombinant IL-2, alpha-lipoic acid (300mg per day), and N-acetyl cysteine (1.8 g per day) enrolled 33 non-small cell lung cancer patients: 26 with stage IIIB disease and 7 with stage IV disease. Of thirty patients whose results could be measured, the median overall survival was 15 months. The one year survival was 55.8%. The median progression free survival was 10 months. Neutropenia was the most significant symptom of toxicity from treatment, but other toxicities were minimal. (Mantovani, Maccio et al. 2002)

Etoposide (Toposar , Etopophos, VePesid)

MELATONIN
Twenty previously untreated patients with inoperable small cell and non-small cell lung cancer were randomized in a double blind study to receive either chemotherapy alone or chemotherapy in combination with melatonin (40 mg per day). Chemotherapy consisted of carboplatin and etoposide. The trial investigated the potential of melatonin to protect against chemotherapy-induced toxicity to the bone marrow, where blood cells are produced. There was no significant difference between the groups in blood counts. (Ghielmini, Pagani et al. 1999)

Researchers from Italy published a study last year about nonsmall cell lung cancer patients receiving cisplatin and etoposide (58 patients) or cisplatin and gemcitabine (16 patients) with or without melatonin (20 mg per day). The response rate to treatment and disease control was higher in patients treated with chemotherapy and melatonin than in patients treated with chemotherapy alone. This difference was only significant in the patients receiving cisplatin and etoposide but was not significant in the group of patients receiving cisplatin and gemcitabine. (Lissoni 2007)

In a second trial from Italy, 100 metastatic non-small cell lung cancer patients were given cisplatin and etoposide with or without melatonin (20 mg per day). The patients treated with chemotherapy and melatonin had significantly less progressive disease, had better overall tumor regression, and higher 5-year survival. Three patients in the melatonin group were alive at five years after beginning treatment with chemotherapy whereas no patients were alive after two years in the chemotherapy only group. Treatment with melatonin also significantly decreased neurotoxicity, thrombocytopenia, weight loss, and asthenia. No difference was observed in alopecia and anemia. (Lissoni, Chilelli et al. 2003)

A third trial from Italy enrolled 104 metastatic non-small cell lung cancer patients who received chemotherapy treatment that consisted of cisplatin and etoposide or gemcitabine alone. Patients were randomized to receive chemotherapy alone or chemotherapy and melatonin at 20 mg per day. The response rate to chemotherapy was higher in patients treated with melatonin, although this difference was only significant in patients receiving cisplatin and etoposide but not gemcitabine. Nevertheless, one year survival was significantly higher in the patients receiving melatonin in both chemotherapy groups. (Lissoni, Barni et al. 1999)

5-METHOXYTRYPTAMINE (5-MTT)
One hundred advanced non-small cell lung cancer patients were enrolled in a trial from Italy published last year who received either chemotherapy (cisplatin and etoposide) alone or with melatonin (20 mg per day) or 5-MTT (1 mg per day). The overall response rate and disease control was significantly higher in both the melatonin and 5-MTT groups. The chemotherapy-related toxicity such as thrombocytopenia, neurotoxicity, and asthenia was significantly reduced in patients receiving chemotherapy and melatonin or 5-MTT. 5-MTT was better than melatonin at preventing anorexia. Therefore, the much lower dose of 5-MTT was as effective as melatonin in the treatment of non-small cell lung cancer. (Lissoni 2007)

In another study, 20 metastatic lung cancer patients were treated with cisplatin and etoposide and were randomized to either receive 5-MTT (1 mg per day) in addition to chemotherapy or to receive chemotherapy treatment alone. The patients treated with chemotherapy and 5-MTT had significantly reduced anemia and significantly less progressive disease in comparison to the patients treated with chemotherapy alone. (Lissoni, Malugani et al. 2003)

Gemcitabine (Gemzar)

MELATONIN
Researchers from Italy published a study last year about non-small cell lung cancer patients receiving cisplatin and etoposide (58 patients) or cisplatin and gemcitabine (16 patients) with or without melatonin (20 mg per day). The response rate to treatment and disease control was higher in patients treated with chemotherapy and melatonin than in patients treated with chemotherapy alone. This difference was only significant in the patients receiving cisplatin and etoposide but was not significant in the group of patients receiving cisplatin and gemcitabine. (Lissoni 2007)

A second trial from Italy enrolled 104 metastatic nonsmall cell lung cancer patients who received chemotherapy treatment that consisted of cisplatin and etoposide or gemcitabine alone. Patients were randomized to receive chemotherapy alone or chemotherapy and melatonin at 20 mg per day. The response rate to chemotherapy was higher in patients treated with melatonin, although this difference was only significant in patients receiving cisplatin and etoposide but not gemcitabine. Nevertheless, one year survival was significantly higher in the patients receiving melatonin in both chemotherapy groups. (Lissoni, Barni et al. 1999)

Interleukin-2, Aldesleukin (Proleukin)

MELATONIN
Twenty-five lung cancer patients received either melatonin alone, melatonin and interleukin-2, or interleukin-2 alone. Patients treated with melatonin and interleukin-2 did not experience thrombocytopenia and their platelet number was significantly higher than patients receiving interleukin-2 alone, several of whom developed thrombocytopenia. (Bregani, Lissoni et al. 1995)

MULTI-COMPOUND REGIMEN
A phase II clinical trial using a combination regimen including cisplatin, epirubicin, medroxyprogesterone acetate (a hormonal drug that is a progestin derived from the naturally occurring female hormone, progesterone), recombinant IL-2, alpha-lipoic acid (300 mg per day), and N-acetyl cysteine (1.8 g per day) enrolled 33 non-small cell lung cancer patients: 26 with stage IIIB disease, and 7 with stage IV. Of thirty patients whose results could be measured, the median overall survival was 15 months. The one year survival was 55.8%. The median progression free survival was 10 months. Neutropenia was the most significant symptom of toxicity from treatment, other toxicity was low. (Mantovani, Maccio et al. 2002)

Mitomycin C & 5-Fluorouracil

VITAMIN C (ASCORBIC ACID)
In Lewis lung cancer-bearing mice, administering ascorbic acid at 1000 mg per kg twice a week together with mitomycin C and 5-fluorouracilonce once per week was more effective than treatment with mitomycin C and 5-fluorouracil alone. (Nakano, Fujimoto et al. 1988)

COMBINATIONS TO AVOID:
N-ACETYL CYSTEINE, MELATONIN, OR RUTIN

Rutin is a flavonoid obtained from many sources, such as from buckwheat and the buds of the Chinese herb Saphora japonica. It is also found in propolis.

In a laboratory study, mitomycin C-induced small cell lung cancer cell death was inhibited by N-acetylcysteine, melatonin, and rutin. (Lee, Park et al. 2004)

Paclitaxel (Taxol, Onxol, Abraxane)

HYALURONIC ACID
Hyaluronic acid is produced naturally in the body. It is important for healthy joints and skin.

» Hyaluronic Acid: A typical dose is 100 mg and it is often combined with other supplements for joint or skin health, so it is important to read all the ingredients on the label.

Hyaluronic acid in combination with paclitaxel provides an antimetastatic effect in mice with Lewis lung cancer. Paclitaxel alone did not result in inhibition of metastasis as a negative 0.9% inhibition was achieved with paclitaxel alone. However, when hyaluronic acid was added to paclitaxel, a positive 36.3% inhibition of metastasis was achieved. (Yin, Ge et al. 2006)

MULTI-COMPOUND REGIMEN
In a human lung squamous cell carcinoma cell line, the antioxidant mixture of vitamin C, vitamin E, and beta-carotene enhanced the treatment effect of paclitaxel and carboplatin. Paclitaxel followed by carboplatin 24 hours later led to an apoptosis (cancer cell killing) rate of 54%. In contrast, the vitamins administered together with paclitaxel and 24 hours later by carboplatin led to a 70% apoptosis rate. This effect was further enhanced to an 89% apoptosis rate by pretreatment with the vitamins 24 hours before paclitaxel, then followed another 24 hours later by carboplatin. (Pathak, Singh et al. 2002)

In a follow up human trial, the same combination of chemotherapy and antioxidants was tested in 136 previously untreated patients with advanced stage IIIB and IV non-small cell lung cancer. Patients were randomized to receive chemotherapy alone (paclitaxel and carboplatin) or chemotherapy in combination with ascorbic acid 6100 mg per day, dl-alpha-tocopherol (vitamin E) 1050 mg per day, and beta-carotene 60 mg per day. The response (tumor size reduction) rate in the chemotherapy-only group was 33%, while in the combination group it was 37%. The overall survival in the chemotherapy group was 9 months and for the combination group was 11 months. Toxicity was similar between the two groups. Although the difference in effectiveness was not statistically significant, it may nevertheless still be clinically significant, offering a modest improvement in treatment response and survival. Furthermore, the result of this study does not support the concern that these antioxidants compromise the efficacy of paclitaxel-carboplatin combination chemotherapy. (Pathak, Bhutani et al. 2005)

RESERVATROL
Resveratrol is an antioxidant that can be derived from the red pigment of grape skins.

» Resveratrol: Typical doses range from 25 to 250 mg per day.

A laboratory study used three different lung cancer cell lines including lung epithelial carcinoma, non-small cell lung cancer, and giant cell carcinoma of the lung. Pretreatment of cells with resveratrol resulted in significant increase in the treatment effect of paclitaxel. However, simultaneous treatment of resveratrol and paclitaxel did not result in significant change in treatment effect. (Kubota, Uemura et al. 2003)

SELENIUM
Selenium in combination with doxorubicin or paclitaxel enhanced the chemotherapeutic effect of doxorubicin and paclitaxel in human squamous lung cancer cells in a laboratory study. (Vadgama, Wu et al. 2000)

COMBINATIONS TO AVOID:
N-ACETYL CYSTEINE AND GLUTATHIONE

Glutathione is an natural antioxidant produced in the body. Nacetylcysteine and glutathione were found to increase paclitaxel IC50 by four fold in a laboratory study using lung cancer cells. This means that when N-acetylcysteine and glutathione were added, the concentration of paclitaxel had to be four times greater to achieve the same effect as paclitaxel alone. The animal study included in the same paper found that supplementing with N-acetylcysteine in mice with induced lung cancer negated the anticancer treatment effect of paclitaxel. (Alexandre, Batteux et al. 2006)

Vincristine (Oncovin, Vincasar)

VITAMIN C (ASCORBIC ACID)
Two studies found that treatment with L-ascorbic acid of nonsmall cell lung cancer cells that had developed resistance to vincristine increased drug uptake, and partially reversed vincristine resistance. In a study from 1995, the multi-drug resistance inhibitor drug called verapamil had no added effect. (Song, Yang et al. 1995) (Chiang, Song et al. 1994)

Vinorelbine (Navelbine)

CURCUMIN
In a laboratory study, vinorelbine alone caused 37.9% cell death in non-small cell lung cancer cells. However, when pretreated with curcumin 24 hours prior to vinorelbine, the cell death rose to 61.3%, dramatically increasing the treatment effect of vinorelbine. (Sen, Sharma et al. 2005)

PHOSPHATIDYLSERINE
Phosphatidylserine is a phospholipid found in fish, green leafy vegetables, soybeans, and rice and is essential for neural cell membranes. It is best known for use to increase memory.

» Phosphatidylserine: Typical dosages range from 50 to 300 mg per day.

In a laboratory study, combined treatment with vinorelbine and phosphatidylserine significantly delayed growth of non-small cell lung cancer compared to vinorelbine given alone. In an animal study reported in the same paper, adding phosphatidylserine increased growth reduction of tumors by 59% compared to 47% with vinorelbine treatment alone. This effect was dramatically increased to 73% tumor reduction when a unique formulation was created with vinorelbine encapsulated by phosphatidylserine. (Webb, Johnstone et al. 2007)

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WHAT ABOUT LUNG CANCER AND BETA-CAROTENE?

A few studies are specifically worth mentioning here, even though they are not about combining chemotherapy and antioxidants in lung cancer patients: Two large clinical trials testing the ability of synthetic betacarotene to prevent lung cancer and a large cohort study at the Mayo Clinic of vitamin and mineral use in lung cancer patients.

In the two beta-carotene studies, researchers found that supplementing with synthetic beta-carotene resulted in increased risk for developing lung cancer. (Omenn, Goodman et al. 1994) There are two mechanisms that may explain this alarming finding: First, the high-dose synthetic beta-carotene used in these studies may have functioned more as a pro-oxidant and in both studies a high proportion of patients were smokers that had been exposed to asbestos. Second, beta-carotene at high dosages may cause a decrease in other protective carotenes, which may already be low in smokers and people exposed to asbestos. Therefore, high dose betacarotene supplementation is not advised in smokers or those who have been exposed to asbestos. Additionally, when considering the use of beta-carotene, a natural form is preferable to the synthetic form.

In the large cohort study from the Mayo Clinic, researchers analyzed self-selected vitamin and mineral use in 1,129 non-small cell lung cancer patients receiving appropriate medical treatment. They found that median survival was 4.3 years in vitamin and mineral users, verses 2 years for non-users. After adjustment for confounding factors, a significant survival advantage remained. In addition, vitamin and mineral users had better quality of life as measured by the Lung Cancer Symptom Scale (LCSS). (Jatoi, Williams et al. 2005) A second, smaller cohort study from the the Mayo Clinic with 178 small cell lung cancer patients, treated as appropriate, found that there was a smaller but still statistically significant survival advantage in vitamin and mineral users, but no improvement in quality of life. (Jatoi, Williams et al. 2005)
Jatoi, A., B. Williams, et al. (2005). “Is voluntary vitamin and mineral supplementation
associated with better outcome in non-small cell lung cancer patients? Results from
the Mayo Clinic lung cancer cohort.” Lung Cancer 49(1): 77-84.

Jatoi, A., B. A. Williams, et al. (2005). “Exploring vitamin and mineral supplementation
and purported clinical effects in patients with small cell lung cancer: results from the
Mayo Clinic lung cancer cohort.” Nutr Cancer 51(1): 7-12.

Omenn, G. S., G. Goodman, et al. (1994). “The beta-carotene and retinol efficacy trial
(CARET ) for chemoprevention of lung cancer in high risk populations: smokers and
asbestos-exposed workers.” Cancer Res 54(7 Suppl): 2038s-2043s.

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