CYCLOPHOSPHAMIDE

Safetychecker Summary for Cyclophosphamide
(for details about the summarized interactions, read the full article)

May be Beneficial: Side effect reduction/prevention—Taking these supplements may help reduce the likelihood and/or severity of a potential side effect caused by the medication.	Antioxidants* (vitamin A, vitamin C, vitamin E) Beta-carotene* (mouth sores) Chamomile* (mouth sores) Eleuthero* (see text) Ginger* (nausea) Glutamine* (mouth sores) Glutathione* (i.v. only) Melatonin* (see text) N-acetyl cysteine* (NAC) Spleen peptide extract (see text) Thymus peptides* (see text) Vitamin E*, topical (mouth sores) Zinc(taste alterations)
Check: Other—Before taking any of these supplements or eating any of these foods with your medication, read this article in full for details.	Echinacea* Multivitamin-mineral* Vitamin A* Vitamin C*
Depletion or interference	None known
Supportive interaction	None known
Reduced drug absorption/bioavailability	None known
Adverse interaction	None known

Interactions with Dietary Supplements

Antioxidants
Cyclophosphamide requires activation by the liver through a process called oxidation. In theory, antioxidant nutrients (vitamin A, vitamin E, beta-carotene and others) might interfere with the activation of cyclophosphamide. There is no published research linking antioxidant vitamins to reduced cyclophosphamide effectiveness in cancer treatment. In a study of mice with vitamin A deficiency, vitamin A supplementation enhanced the anticancer action of cyclophosphamide.¹ Another animal research report indicated that vitamin C may increase the effectiveness of cyclophosphamide without producing new side effects.² Preliminary human research found that adding antioxidants (beta-carotene, vitamin A, and vitamin E) to cyclophosphamide therapy increased the survival of people with small-cell lung cancer treated with cyclophosphamide.³ It is too early to know if adding antioxidants to cyclophosphamide for cancer treatment is better than cyclophosphamide alone. Vitamin A can be toxic in high amounts.

Intravenous injections of the antioxidant, glutathione, may protect the bladder from damage caused by cyclophosphamide. Preliminary evidence suggests, but cannot confirm, a protective action of glutathione in the bladders of people on cyclophosphamide therapy.⁴ There is no evidence that glutathione taken by mouth has the same benefits.

Glutamine
Though cancer cells use glutamine as a fuel source, studies in humans have not found that glutamine stimulates growth of cancers in people taking chemotherapy.^{5 6} In fact, animal studies show that glutamine may actually decrease tumor growth while increasing susceptibility of cancer cells to radiation and chemotherapy,^{7 8} though such effects have not yet been studied in humans.

Glutamine has successfully reduced chemotherapy-induced mouth sores. In one trial, people were given 4 grams of glutamine in an oral rinse, which was swished around the mouth and then swallowed twice per day.⁹ Thirteen of fourteen people in the study had fewer days with mouth sores as a result. These excellent results have been duplicated in some,¹⁰ but not all¹¹ double-blind research. In another study, patients receiving high-dose paclitaxel and melphalan had significantly fewer episodes of oral ulcers and bleeding when they took 6 grams of glutamine four times daily along with the chemotherapy.¹²

One double-blind trial suggested that 6 grams of glutamine taken three times per day can decrease diarrhea caused by chemotherapy.¹³ However, other studies using higher amounts or intravenous glutamine have not reported this effect.^{14 15}

Intravenous use of glutamine in people undergoing bone marrow transplants, a procedure sometimes used to allow very high amounts of chemotherapy to be used, has led to reduced hospital stays, leading to a savings of over $21,000 for each patient given glutamine.¹⁶

Melatonin
High amounts of melatonin have been combined with a variety of chemotherapy drugs to reduce their side effects or improve drug efficacy. One study gave melatonin at night in combination with the drug triptorelin to men with metastatic prostate cancer.¹⁷ All of these men had previously become unresponsive to triptorelin. The combination decreased PSA levels—a marker of prostate cancer progression—in eight of fourteen patients, decreased some side effects of triptorelin, and helped nine of fourteen to live longer than one year. The outcome of this preliminary study suggests that melatonin may improve the efficacy of triptorelin even after the drug has apparently lost effectiveness.

N-acetyl cysteine (NAC)
NAC, an amino acid–like supplement that possesses antioxidant activity, has been used in four human studies to decrease the kidney and bladder toxicity of the chemotherapy drug ifosfamide.^{18 19 20 21} These studies used 1–2 grams NAC four times per day. There was no sign that NAC interfered with the efficacy of ifosfamide in any of these studies. Intakes of NAC over 4 grams per day may cause nausea and vomiting.

The newer anti-nausea drugs prescribed for people taking chemotherapy lead to greatly reduced nausea and vomiting for most people. Nonetheless, these drugs often do not totally eliminate all nausea. Natural substances used to reduce nausea should not be used instead of prescription anti-nausea drugs. Rather, under the guidance of a doctor, they should be added to those drugs if needed. At least one trial suggests that NAC, at 1,800 mg per day may reduce nausea and vomiting caused by chemotherapy.²²

Spleen Extract
Patients with inoperable head and neck cancer were treated with a spleen peptide preparation (Polyerga®) in a double-blind trial during chemotherapy with cisplatin and 5-FU.²³ The spleen preparation had a significant stabilizing effect on certain white blood cells. People taking it also experienced stabilized body weight and a reduction in the fatigue and inertia that usually accompany this combination of chemotherapy agents.

Beta-carotene and Vitamin E
Chemotherapy frequently causes mouth sores. In one trial, people were given approximately 400,000 IU of beta-carotene per day for three weeks and then 125,000 IU per day for an additional four weeks.²⁴ Those taking beta-carotene still suffered mouth sores, but the mouth sores developed later and tended to be less severe than mouth sores that formed in people receiving the same chemotherapy without beta-carotene.

In a study of chemotherapy-induced mouth sores, six of nine patients who applied vitamin E directly to their mouth sores had complete resolution of the sores compared with one of nine patients who applied placebo.²⁵ Others have confirmed the potential for vitamin E to help people with chemotherapy-induced mouth sores.²⁶ Applying vitamin E only once per day was helpful to only some groups of patients in another trial,²⁷ and not all studies have found vitamin E to be effective.²⁸ Until more is known, if vitamin E is used in an attempt to reduce chemotherapy-induced mouth sores, it should be applied topically twice per day and should probably be in the tocopherol (versus tocopheryl) form.

Vitamin A
A controlled French trial reported that when postmenopausal late-stage breast cancer patients were given very large amounts of vitamin A (350,000–500,000 IU per day) along with chemotherapy, remission rates were significantly better than when the chemotherapy was not accompanied by vitamin A.²⁹ Similar results were not found in premenopausal women. The large amounts of vitamin A used in the study are toxic and require clinical supervision.

Zinc
Irradiation treatment, especially of head and neck cancers, frequently results in changes to normal taste sensation.^{30 31} Zinc supplementation may be protective against taste alterations caused or exacerbated by irradiation. A double-blind trial found that 45 mg of zinc sulfate three times daily reduced the alteration of taste sensation during radiation treatment and led to significantly greater recovery of taste sensation after treatment was concluded.³²

Multivitamin-mineral
Many chemotherapy drugs can cause diarrhea, lack of appetite, vomiting, and damage to the gastrointestinal tract. Recent anti-nausea prescription medications are often effective. Nonetheless, nutritional deficiencies still occur.³³ It makes sense for people undergoing chemotherapy to take a high-potency multivitamin-mineral to protect against deficiencies.

Taurine
Taurine has been shown to be depleted in people taking chemotherapy.³⁴ It remains unclear how important this effect is or if people taking chemotherapy should take taurine supplements.

Thymus peptides
Peptides or short proteins derived from the thymus gland, an important immune organ, have been used in conjunction with chemotherapy drugs for people with cancer. One study using thymosin fraction V in combination with chemotherapy, compared with chemotherapy alone, found significantly longer survival times in the thymosin fraction V group.³⁵ A related substance, thymostimulin, decreased some side effects of chemotherapy and increased survival time compared with chemotherapy alone.³⁶ A third product, thymic extract TP1, was shown to improve immune function in people treated with chemotherapy compared with effects of chemotherapy alone.³⁷ Thymic peptides need to be administered by injection. People interested in their combined use with chemotherapy should consult a doctor.

Interactions with Herbs

Echinacea (Echinacea purpurea, Echinacea angustifolia)
Echinacea is a popular immune-boosting herb that has been investigated for use with chemotherapy. One study investigated the actions of cyclophosphamide, echinacea, and thymus gland extracts to treat advanced cancer patients. Although small and uncontrolled, this trial suggested that the combination modestly extended the life span of some patients with inoperable cancers.³⁸ Signs of restoration of immune function were seen in these patients.

Eleuthero (Eleutherococcus senticosus)
Russian research has looked at using eleuthero with chemotherapy. One study of patients with melanoma found that chemotherapy was less toxic when eleuthero was given simultaneously. Similarly, women with inoperable breast cancer given eleuthero were reported to tolerate more chemotherapy.³⁹ Eleuthero treatment was also associated with improved immune function in women with breast cancer treated with chemotherapy and radiation.⁴⁰

Milk thistle (Silybum marianum)
Milk thistle’s major flavonoids, known collectively as silymarin, have shown synergistic actions with the chemotherapy drugs cisplatin and doxorubicin (Adriamycin®) in test tubes.⁴¹ Silymarin also offsets the kidney toxicity of cisplatin in animals.⁴² Silymarin has not yet been studied in humans treated with cisplatin. There is some evidence that silymarin may not interfere with some chemotherapy in humans with cancer.⁴³

Ginger  (Zingiber officinale)
Ginger can be helpful in alleviating nausea and vomiting caused by chemotherapy.^{44 45} Ginger, as tablets, capsules, or liquid herbal extracts, can be taken in 500 mg amounts every two or three hours, for a total of 1 gram per day.

German chamomile (Matricaria recutita)
A liquid preparation of German chamomile has been shown to reduce the incidence of mouth sores in people receiving radiation and systemic chemotherapy treatment in an uncontrolled study. ⁴⁶

PSK (Coriolus versicolor)
The mushroom Coriolus versicolor contains an immune-stimulating substance called polysaccharide krestin, or PSK. PSK has been shown in several studies to help cancer patients undergoing chemotherapy. One study involved women with estrogen receptor-negative breast cancer. PSK combined with chemotherapy significantly prolonged survival time compared with chemotherapy alone.⁴⁷ Another study followed women with breast cancer who were given chemotherapy with or without PSK. The PSK-plus-chemotherapy group had a 25% better chance of survival after ten years compared with those taking chemotherapy without PSK.⁴⁸ Another study investigated people who had surgically removed colon cancer. They were given chemotherapy with or without PSK. Those given PSK had a longer disease-free period and longer survival time.⁴⁹ Three grams of PSK were taken orally each day in these studies.

Although PSK is rarely available in the United States, hot-water extract products made from Coriolus versicolor mushrooms are available. These products may have activity related to that of PSK, but their use with chemotherapy has not been studied.

Interactions with Foods and Other Compounds

Food
It is recommended to take cyclophosphamide on an empty stomach. If this causes severe gastrointestinal (GI) upset, cyclophosphamide may be taken with food.⁵⁰ People with questions should ask their prescribing doctor or pharmacist.

Fruit drinks
Often, people who undergo chemotherapy develop aversions to certain foods, sometimes making it permanently difficult to eat those foods. Exposing people to what researchers have called a “scapegoat stimulus” just before the administration of chemotherapy can direct the food aversion to the “scapegoat” food instead of more important parts of the diet. In one trial, fruit drinks administered just before chemotherapy were most effective in protecting against aversions to other foods.⁵¹

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4. Nobile MT, Vidili MG, Benasso M, et al. A preliminary clinical study of cyclophosphamide with reduced glutathione as uroprotector. Tumori 1989;75:257–8.

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12. Cockerham MB, Weinberger BB, Lerchie SB. Oral glutamine for the prevention of oral mucositis associated with high-dose paclitaxel and melphalan for autologous bone marrow transplantation. Ann Pharmacother 2000;34:300–3.

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16. MacBurney M, Young LS, Ziegler TR, Wilmore DW. A cost-evaluation of Glutamine-supplemented parenteral nutrition in adult bone marrow transplant patients. J Am Diet Assoc 1994;94:1263–6.

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18. Holoya PY, Duelge J, Hansen RM, et al. Prophylaxis of ifosfamide toxicity with oral acetylcysteine. Sem Oncol 1983;10(suppl 1):66–71.

19. Slavik M, Saiers JH. Phase I clinical study of acetylcysteine’s preventing ifosfamide-induced hematuria. Sem Oncol 1983;10(suppl 1):62–5.

20. Loehrer PJ, Williams SD, Einhorn LH. N-Acetylcysteine and ifosfamide in the treatment of unresectable pancreatic adenocarcinoma and refractory testicular cancer. Sem Oncol 1983;10(suppl 1):72–5.

21. Morgan LR, Donley PJ, Harrison EF. The control of ifosfamide induced hematuria with N-acetylcysteine. Proc Am Assoc Cancer Res 1981;22:190.

22. De Blasio F et al. N-acetyl cysteine (NAC) in preventing nausea and vomiting induced by chemotherapy in patients suffering from inoperable non small cell lung cancer (NSCLC). Chest 1996;110(4, Suppl):103S.

23. Borghardt J, Rosien B, Gortelmeyer R, et al. Effects of a spleen peptide preparation as supportive therapy in inoperable head and neck cancer patients. Arzneimittelforschung 2000;50:178–84.

24. Mills EED. The modifying effect of beta-carotene on radiation and chemotherapy induced oral mucositis. Br J Cancer 1988;57:416–7.

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29. Israel L, Hajji O, Grefft-Alami A, et al. Agumentation par la vitamine A des effets de la chimiotherapie dans les cancers du sein metastases apres la menopause. Ann Med Interne 1985;136:551–4.

30. Henkin RI. Prevention and treatment of hypogeusia due to head and neck irradiation. JAMA 1972;220:870–1.

31. Mossman KL, Henkin RI. Radiation-induced changes in taste acuity in cancer patients. Int J Radiat Oncol Biol Phys 1978;4:663–70.

32. Ripamonti C, Zecca E, Brunelli C, et al. A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 1998;82:1938–45.

33. Dreizen S et al. Nutritional deficiencies in patients receiving cancer chemotherapy. Postgrad Med 1990;87(1):163–70.

34. Desai TK, Maliakkal J, Kinzie JL, et al. Taurine deficiency after intensive chemotherapy and/or radiation. Am J Clin Nutr 1992;55:708–11.

35. Cohen MH, Chretien PB, Ihde DC, et al. Thymosin fraction V and intensive combination chemotherapy. Prolonging the survival of patients with small-cell lung cancer. JAMA 1979;241:1813–5.

36. Macchiarini P, Danesi R, Del Tacca M, Angeletti CA. Effects of thymostimulin on chemotherapy-induced toxicity and long-term survival in small cell lung cancer patients. Anticancer Res 1989;9:193–6.

37. Shoham J, Theodor E, Brenner HJ, et al. Enhancement of the immune system of chemotherapy-treated cancer patients by simultaneous treatment with thymic extract, TP-1. Cancer Immunol Immunother 1980;9:173–80.

38. Lersch C, Zeuner M, Bauer A, et al. Nonspecific immunostimulation with low doses of cyclophosphamide (LDCY), thymostimulin, and Echinacea purpurea extracts (Echinacin) in patients with far advanced colorectal cancers: Preliminary results. Cancer Invest 1992;10:343–8.

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41. Scambia G, De Vincenzo R, Ranelletti FO, et al. Antiproliferative effect of silybin on gynaecological malignancies: Synergism with cisplatin and doxorubicin. Eur J Cancer 1996;32A:877–82.

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45. Pace JC. Oral ingestion of encapsulated ginger and reported self care actions for the relief of chemotherapy-associated nausea and vomiting. Dissertation Abstr Int 1987;8:3297.

46. Carl W, Emrich LS. Management of oral mucositis during local radiation and systemic chemotherapy: A study of 98 patients. J Prosthet Dent 1991;66:361–9.

47. Toi M, Hattori T, Akagi M, et al. Randomized adjuvant trial to evaluate the addition of tamoxifen and PSK to chemotherapy in patients with primary breast cancer. Cancer 1992;70:2475–83.

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49. Mitomi T, Tsuchiya S, Iijima N, et al. Randomized, controlled study on adjuvant immunochemotherapy with PSK in curatively resected colorectal cancer. The Cooperative Study Group of Surgical Adjuvant Immunochemotherapy for Cancer of Colon and Rectum (Kanagawa). Dis Colon Rectum 1992;35:123–30.

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Copyright © 2002 Healthnotes, Inc.  All rights reserved. www.healthnotes.com

Please read the disclaimer about the limitations of the information provided here. Do NOT rely solely on the information in this article.

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The information presented in Healthnotes is for informational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, or traditional usage as cited in each article. The results reported may not necessarily occur in all individuals. For many of the conditions discussed, treatment with prescription or over-the-counter medication is also available. Consult your doctor, practitioner, and/or pharmacist for any health problem and before using any supplements or before making any changes in prescribed medications. Information expires December 2003.

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