Integrative Oncology

1. Breast Cancer Estrogen Metabolism DNA Adducts- PPT - Download PowerPoint Presentation - mg.slrmc.org made the following annotations.
2. Thomas Jefferson  Hospital Integrative Medicine - read more
3. (Society for Integrative Oncology) - (Click here to find a consensus statement on the use of integrative medicine alongside chemotherapy and/or radiation therapy.)
4. MD AndersonIntegrative Oncology - read more
5. Sloan-Kettering Integrative Oncology - read more
   
6. Integrative Cancer Therapies Journal - read more
7. CancerGuides - read more
8. Ovarian Cancer - read more
9. Cancer, Supplements, and Food - (PowerPoint Presentation)
10. Cancer, Chemo, Radiation, and Concurrent Supplements - (PowerPoint Presentation)
11. Pediatric Integrative Oncology - download PDF
12. Pancreatic Cancer - download PDF
    

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On the Issue of Using Supplements and Integrative Medicine alongside Chemotherapy/Radiation Therapy
Tom Archie, MD

Little else in my integrative medicine experience arouses the emotions of physicians and patients alike so much as the issue of whether to use supplements and dietary or other lifestyle changes during chemotherapy or radiation therapy for cancer. There are definitely two sides to this fence separating two very different dogmas, and I sit right on top of that fence with a foot in both camps. I have several years’ experience prescribing supplements, dietary changes, acupuncture, Chinese herbal medicine, and mind-body medicine (including referrals for meditation, yoga, healing touch, guided imagery, and psychotherapy) alongside chemotherapy and radiation therapy. I have clearly seen improvements in quality of life and in tolerance of these conventional treatments. My oncology colleagues in my previous practice have noticed this, as well.

In the professions of medical and radiation oncology, there remains a somewhat dogmatic belief that supplements (especially antioxidants) are harmful when used alongside chemotherapy and radiation therapy. The premise of this belief is rooted in the logical argument that, because chemo/radiotherapy work by way of causing oxidative damage to tumor cells, it stands to reason that consuming supplements or foods that have antioxidant qualities (and reduce oxidative damage) might protect tumors from chemo/radiotherapy, thereby decreasing the effectiveness of the chemo/radiotherapy. Furthermore, the argument goes, if we can’t reference placebo-controlled randomized trials, then we should not take a chance on possibly interfering in the effectiveness of chemo/radiotherapy. In my opinion, “do no harm” works both ways – as a physician, you either recommend for or against something and make your best recommendation based on the knowledge available to you.

It turns out that medical science continues to churn out a literature base that refutes this idea that antioxidants might protect tumors from chemotherapy. With some exceptions, the majority of studies on human tissue, animal trials, and some small human clinical trials show a beneficial effect at best (and a neutral effect at worst). While I join my colleagues in calling for larger randomized human trials, the truth remains that funding for un-patentable food supplements will forever lag far behind funding for patentable pharmaceutical “new-to-nature molecules.”

In the end I am left with the responsibility and willingness to delve into and share the medical literature (such as it is) and mechanistic rationale regarding the concurrent use of “nutraceutical” supplements alongside chemo/radiotherapy and ultimately to support my patients’ choices. In the words of my favorite band, Widespread Panic, “Will we ever know the truth?”

Breast Cancer

Adjunctive Integrative Medicine Therapy for Breast Cancer Management
Tom Archie, MD

*This is a list from which Dr. Archie will select certain supplements in an individualized, case-by-case manner. It is not a substitute for communication with an experienced physician.*

Soy, Estrogen, and Breast Cancer

• Article - Follow this link to an excellent National Cancer Institute article on this subject
• Breast Cancer, Estrogen Metabolism, and DNA Adducts - View Power Point Presentaion
  

Antioxidant support

1. Plantioxidant (Thorne – Bilberry 20mg, Milk Thistle 50mg, Grape Seed Extract 20mg, Green Tea Extract 50mg, Quercetin 50mg per capsule) 2 capsules twice per day
2. White/Green Tea 4 cups per day

Oxidative Stress/Inflammation Reduction

1. CoQ-10 100mg 1-4 per day (use higher dose with doxyrubicin, lower dose if no doxyrubicin but if postmenopausal)
2. EPA:DHA 720mg (Metagenics) 2 twice per day (take with food to decrease fishy aftertaste)

Other

1. Hematologic and sleep support: Melatonin 3mg (Thorne – Melaton 3) Start 1 at bedtime for 1 week. Increase to 2 at bedtime for week2 and if tolerating it, increase to 3 capsules at bedtime on week 3 and continue.
2. GI Lining Support: Glutagenics (Metagenics - L-glutamine 3 grams, DGL 200mg, Aloe 50mg per tsp) 2 teaspoons by mouth in water twice per day
3. Probiotic: Ultra Flora Plus DF Powder (Metagenics - Lactobacillus species and Bifidobacteria 60 billion units total per tsp ) 1/2 tsp in water, juice, or milk by mouth twice daily on empty stomach.

Methylation Support (**Use depends on results of Estrogen Metabolism Plus test)

1. Vessel Care (Metagenics – 1 tablet contains: Riboflavin 5 mg, Vitamin B6 25 mg, Folate (as folic acid and L-5-methyl tetrahydrofolate) 800 mcg, Vitamin B12 (as cyanocobalamin) 500 mcg, Zinc 5 mg, Trimethylglycine 500 mg, Choline 100 mg, Intrinsic Factor 20mg
2. SAMe (Health Concerns 200mg) 2 tablets (400mg) twice per day - important for methylation via COMT – but will increase homocysteine, so be sure to add B6, B12, L5MTHFolate (in Vessel Care formula above). Take last dose by 2pm as may cause insomnia.

Estrogen Metabolism Support (Use depends on results of Estrogen Metabolism Plus test)

1. Breast Health Complete (Pure Encapsulations – 3 capsules contain: Vitamin D3 400iu, folic acid 400mcg, selenium 100mcg, flax seed 1250mg, 7-hydroxymatairesinol (Norway Spruce) 10mg, diindolylmethane 125 mg, green tea 100mg (standardized to contain 65% total tea catechins, 23% epigallocatechin gallate (EGCG) and 7% caffeine), tumeric 250mg (standardized to contain 95% curcuminoids), broccoli sprout concentrate 20:1 (whole plant) 200mg (standardized to contain sulforaphane 800mcg), Vitamin C 30mg) 3 capsules per day.
2. Garlic, Curcumin, Broccoli (along with other cruciferous vegetables)

Medicinal Mushrooms

1. Fu Zheng Support (MycoHerb via Kan Herbs) 60 drops twice per day
2. Himematsutake (MycoHerb via Kan Herbs) 60 drops twice per day
3. Coriolous Versicolor (MycoHerb via Kan Herbs - aka Trancetes versicolor, aka Turkey Tail Mushroom) 60 drops twice per day

Chinese Herbs

1. Enhance (Health Concerns) 5 tablets twice a day (increase to 4 times per day if severely fatigued)
2. Chemo Support (Three Treasures via Kan Herbs) – For Chemotherapy patients only - 2-3 tablets three times per day starting 2 days before and continuing 5 days after Chemo. 2 twice per day otherwise.
3. Radio Support (Three Treasures via Kan Herbs) – For Radiation therapy patients only - 2-3 tablets three times per day while undergoing radiation and for one month afterwards.
4. Spring Wind Red Ointment (Spring Wind Pharmacy) – use topically for mildly inflamed skin due to radiation exposure.
5. Spring Wind Yellow Ointment (Spring Wind Pharmacy) – use topically for inflamed red or cracked skin 3-4 times per day. Stop if irritating.

Exercise:
Daily 30 minutes if possible. In the recovery phase following mastectomy, published literature supports the use of ski poles while walking in order to increase recovery of shoulder range of motion and upper body strength.

Dietary:

1. Lacto-ovo-peche Vegetarian”diet – low or no red, some eggs OK, fish is good
   (but limit fish to 12 oz per week), beans, nuts, olive oil
2. Low Glycemic Whole Foods Diet (avoid high blood sugars which drive insulin levels up and upregulate insulin signaling pathways – over time these
   lead to increased inflammation, which increases future cancer risk.)
   a. Minimize any foods that are processed (jarred, canned, or boxed)
   b. Avoid partially hydrodgenated oils (trans-fats)
   c. Avoid high fructose corn syrup
3. Avoid Bis-Phenol A (BPA)
   a. Plastic found in commonly available hard plastic water bottles labeled with a recycling #7 symbol. Also found in about 70% of canned foods (in the interior plastic lining designed to prevent rust formation).
   b. Has “xenobiotic” properties that are associated with increase risk of breast cancer, prostate cancer, and metabolic syndrome (pre-diabetes).

Healing Retreat Specific to Cancer: - www.commonweal.org

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Radiation, Head and Neck Cancer, and Supplements
Tom Archie, MD

July 2008

I have compiled a list of supplements which I believe to be useful during radiation treatments for cancers of various forms. Following that list is a summary of the literature from which I form my rationale. Undoubtedly there are more substances that may also be of benefit. I believe that the cumulative effect of their use will be to decrease the rate of adverse events caused by radiotherapy, to thereby improve patient safety, and to enhance survival outcomes.

There are three issues here. One issue is the impact of such supplements on survival outcomes from the use of radiation therapy. The second issue is the potential to reduce adverse effects of radiation therapy and thereby improve patient well-being. The third issue has to do with prevention or delay of cancer recurrence. There has been much speculation about the possibility that certain supplements (namely antioxidants) may impair the effectiveness of radiation therapy; however the growing weight of scientific literature suggests strongly that this is not the case and that, in certain studies, the effectiveness of radiation therapy is actually improved. The reduction of adverse effects of radiation is supported in the literature. The prevention of various cancers with certain dietary and lifestyle modifications and certain supplements is also supported.

To the extent possible, the following literature pertains to head and neck cancer; however for the purpose of describing a rationale for use, some of the literature pertains to cancers not found in the head or neck but instead are included in order to describe an effect in the setting of radiotherapy. While some of this literature involves studies of humans undergoing radiation treatments for cancer, much of it is focused on tissue culture media or on animal models commonly used to ascertain information about the effect in humans. These are quite helpful in predicting a human effect, but are not always so easily predictive.

Disclaimers:

1. Some of the information below includes excerpts of others’ writing and is not intended to be representative of flagrant plagiarism. Citations are given.
2. I do not have any financial incentive for prescribing supplements. While I do insist that certain supplements come from a small list of specific manufacturers for quality control issues, one of our local pharmacies handles these accounts. I write supplement prescriptions – they are not covered by insurance but can be paid for with health savings accounts provided that a physicians’ prescription is obtained.
3. It is vitally important that patients dialogue with their medical and radiation oncologists and with their primary care physicians. The relationship between patient and physician is very important, and encouragement of open communication about supplement use is vital. This article does not substitute for such communication but, rather, should be use as a vehicle for facilitating dialogue.

Suggested Supplement Regimen:

• Coriolus (MycoHerb) 60 drops twice per day, #2oz
• Myco Protect (MycoHerb Maitake and Shitake) 60 drops twice per day, #2oz
• Himematsutake (MycoHerb) 60 drops twice per day #2oz
• Vitamin D (Pure Encapsultations) 1000iu 2 per day, #120
• EPA-DHA 720 (Metagenics EPA+DHA 720mg/capsule) 2 twice per day with food, #90
• Spectrasoy (Metagenics – Soy Isoflavones 45mg per tablet) 1 per day, #90
• Co-Q100 (Thorne CoQ10 100mg/capsule) 2 twice per day, #90
• Melatonin (Thorne 3mg) 1-7 per day as tolerated, #60
• Silymarin (Milk Thistle) 300mg per day

If diarrhea, mucositis, or neuropathy occur - Glutagenics (Metagenics – 1 tsp contains L-glutamine 3.5 grams, Aloe, and DGL) 1 tsp twice per day. Double or Triple dose if diarrhea occurs.

Mushrooms – Beta Glucan

Medicinal mushrooms – more specifically the mycelium of various mushrooms – have been used for centuries to treat a variety of ailments of the immunological system. It is thought that the large polysaccharides called beta glucans are the “active ingredients” in these mushrooms. The most studied included coriolus (trancetes vercicolor, or turkey tail mushroom), shitake (lentinula) , reishi (ganoderma), maitake (grifola), himematsutake (Agaricus blazei), cordyceps , flammulina, and chaga. Other sources of beta-glucan include isolates from yeast or barley. In the setting of cancer, I rely mostly on coriolus, shitake, maitake, and himematsutake.

Coriolus (aka: PSP or PSK) does not interact with CYP 3A4, which is important, since over 60% of all pharmaceuticals are metabolized by this pathway. “A clinical study was to investigate the ability of PSP to inhibit or induce the drug metabolism of CYP450 3A 4 in healthy adult human subjects by using a diagnostic CYP450 3A4 specific assay, the erythromycin breath test (EBT). The 14-day course of PSP in 12 healthy subjects (eight women and four men) was not associated with any clinically significant CYP450 3A4 inhibition or induction. This suggests that administration of PSP with other medications and dietary supplements which are primarily metabolized by the CYP450 3A4 pathway is not expected to be associated with significant herb-drug interactions.”

Nicandro, J.P. et al. In vivo effect of I'm-Yunity TM on hepatic cytochrome P450 3A4. J. Herb. Pharmacother .7, 39-56 (2007).

Coriolus has antitumor properties versus lymphoma and leukemia cells.

Coriolus versicolor (CV), also known as Yunzhi, is one of the commonly used Chinese medicinal herbs. Although recent studies have demonstrated its antitumour activities on cancer cells in vitro and in vivo, the exact mechanism is not fully elucidated. Hence, the objective of this study was to examine the in vitro cytotoxic activities of a standardized aqueous ethanol extract prepared from Coriolus versicolor on a B-cell lymphoma (Raji) and two human promyelocytic leukemia (HL-60, NB-4) cell lines using a MTT cytotoxicity assay, and to test whether the mechanism involves induction of apoptosis. Cell death ELISA was employed to quantify the nucleosome production resulting from nuclear DNA fragmentation during apoptosis. The present results demonstrated that CV extract at 50 to 800 μg/ml dose-dependently suppressed the proliferation of Raji, NB-4, and HL-60 cells by more than 90% (p < 0.01), with ascending order of IC50 values: HL-60 (147.3 ± 15.2 μg/ml), Raji (253.8 ± 60.7 μg/ml) and NB-4 (269.3 ± 12.4 μg/ml). The extract however did not exert any significant cytotoxic effect on normal liver cell line WRL (IC50 > 800 μg/ml) when compared with a chemotherapeutic anticancer drug, mitomycin C (MMC), confirming the tumour-selective cytotoxicity. Nucleosome productions in HL-60, NB-4 and Raji cells were significantly increased by 3.6-, 3.6- and 5.6-fold respectively upon the treatment of CV extract, while no significant nucleosome production was detected in extract-treated WRL cells. The CV extract was found to selectively and dose-dependently inhibit the proliferation of lymphoma and leukemic cells possibly via an apoptosis-dependent pathway.

Lau C et al. Cytotoxic activities of Coriolus versicolor (Yunzhi) extract on human leukemia and lymphoma cells by induction of apoptosis. Life Sciences. 2004 July; 25(7): 797-808

Coriolus corrects cyclophosphamide-induced immunosuppression.
Effects of PSP (Coriolus) on cyclophosphamide-induced immunosuppression were investigated by determining lymphocyte proliferation, natural killer cell function, IgG and IL-2 concentration. The results showed that PSP could restore cyclophosphamide-induced immunosuppression in male Wistar rats by stabilizing lymphocyte proliferation, NK cell function, white blood cell count, IgG and IL-2 secretion.

Qian, Z.M. et al. Polysaccharide peptide (PSP) restores immunosuppression induced by cyclophosphamide in rats. Am. J. Chin. Med. 1997; 25:27-35.

We have studied the effect of polysaccharide K (PSK) in the in vitro recognition of ex vivo carcinoma, sarcoma and lymphoma cells by the autologous blood lymphocytes. In 4/25 experiments PSK treatment activated the lymphocytes for auto-tumour lysis. Tumour cells alone generated lytic activity both in short- (16 h) and in longterm (6 days) mixed lymphocyte/tumour cell cultures (MLTC), in 2/12 and 3/13 cases respectively. The tumours that activated the lymphocytes expressed high levels of major histocompatibility complex (MHC) class I molecules. In vitro cytokine (interferon gamma and tumour necrosis factor alpha) treatment of the tumour cells elevated the amounts of class I antigens and the treated cells acquired stimulatory potential. When PSK was added to the MLTC, in which untreated tumour cells were used, lytic potential was induced in 9/13 short-term and in 11/12 long-term cultures. It is noteworthy that in the presence of PSK the untreated, negative or low-class-I-expressor tumours also activated the cytotoxic function of the lymphocytes in 4/5 long-term and in 6/7 short-term cultures. Even in the case of those lymphocytes that could be activated by PSK or tumour cells alone, the simultaneous exposure was more efficient. The effect of PSK was dose-dependent, being optimal at 1 µg/ml and 10 µg/ml. The presence of EDTA and/or cytochalasin B in the cytotoxic test performed with the activated effectors abrogated the lysis, indicating the requirement of contacts with the effector cells.

Vanky F et al. The polysaccharide K (PSK) potentiates in vitro activation of the cytotoxic function in human blood lymphocytes by autologous tumour cells. Cancer Immunology, Immunotherapy. 1992;35(3).

Reishi (ganoderma) has antitumor efficacy in leukemia, lymphoma, and multiple myleoma via induction of apoptosis of tumor cells.
Over many centuries, herbal remedies have treated a variety of ailments. This empiric observational approach has produced a number of leads for formulated medicines. Ganoderma lucidum extract was screened for its anti-proliferative activity using a panel of 26 human cancer cell lines. The six most sensitive hematologic cell lines were: HL-60 (ED50 26 microg/ml), U937 (63 microg/ml), K562 (50 microg/ml), Blin-1 (38 microg/ml), Nalm-6 (30 microg/ml) and RPMI8226 (40 microg/ml). Cell cycle analyses revealed a G2/M arrest, most prominently in HL-60 cells. Four hematopoietic cell lines (HL-60, Blin-1, U937, RPMI8226) were examined for apoptosis, which ranged between 21 and 92%. After exposure to G. lucidum extract, HL-60 cells became multinucleated with an increased DNA content. These results indicate that G. lucidum extract has a profound activity against leukemia, lymphoma and multiple myeloma cells and may be a novel adjunctive therapy for the treatment of hematologic malignancies.

Muller CI et al. Ganoderma lucidum causes apoptosis in leukemia, lymphoma and multiple myeloma cells. Leuk Res. 2006 Jul;30(7):841-8.

This next study at the Department of Pediatrics at Memorial Sloan-Kettering Cancer Center concluded that beta-glucan enhanced the efficacy of monoclonal antibodies (such as Rituximab) in mice with neuroblastoma, melanoma, lymphoma, epidermoid carcinoma or breast carcinoma and warrants further study (human Phase II trial currently underway for Chronic Lymphocytic Leukemia and a human Phase I trial is underway for pediatric patients with relapsed or progressive CD20-positive lymphoma or leukemia or post-allogeneic stem cell transplant-related lymphoproliferative disorder).

Beta-Glucan primes leukocyte CR3 for enhanced cytotoxicity and synergizes with anti-tumor monoclonal antibodies (mAb). We studied readily available (1-->3)-beta- D-glucan using the immune deficient xenograft tumor models, and examined the relationship of its anti- tumor effect an physico-chemical properties. Established subcutaneous (s.c.) human xenografts were treated for 29 days orally with daily beta-glucan by intragastric injection and mAb intravenously (i.v.) twice weekly. Control mice received either mAb alone or beta-glucan alone. Tumor sizes were monitored over time. beta-Glucans were studied by carbohydrate linkage analysis, and high performance size-exclusion chromatography with multiple angle laser scattering detection. Orally administered beta- D-glucan greatly enhanced the anti-tumor effects of mAb against established tumors in mice. We observed this beta-glucan effect irrespective of antigen (GD2, GD3, CD20, epidermal growth factor-receptor, HER-2), human tumor type (neuroblastoma, melanoma, lymphoma, epidermoid carcinoma and breast carcinoma) or tumor sites (s.c. versus systemic). This effect correlated with the molecular size of the (1-->3),(1-->4)-beta- D-glucan. Orally administered (1-->3),(1-->6)-beta- D-glucans also synergized with mAb, although the effect was generally less marked. Given the favorable efficacy and toxicity profile of oral beta- D- glucan treatment, the role of natural products that contain beta- glucan in cancer treatment as an enhancer of the effect of mAb therapy deserves further study.

Cheung NK et al. , Orally administered beta-glucans enhance anti-tumor effects of monoclonal antibodies. Cancer Immunol Immunother 2002 Nov;51(10):557-64

This next paper concluded that non-Hodgkin’s Lymphoma and Hodgkin’s Lymphoma tumors implanted into mice were treated more successfully with rituximab plus beta-glucan versus with rituximab alone.

By activating complement, antitumor monoclonal antibodies coat tumor cells with iC3b. β-glucans, naturally occurring glucose polymers, bind to the lectin domain of the leukocyte receptor CR3, prime it for binding to iC3b, and trigger cytotoxicity of iC3b-coated tumor cells. We studied the combination of the complement-activating antibody rituximab with barley-derived (1→3),(1→4)-β-d-glucan (BG) against CD-20 positive lymphoma xenografts in SCID mice. Growth of established subcutaneous non-Hodgkin's lymphoma (NHL) (Daudi and EBV-derived B-NHL) or Hodgkin's disease (Hs445 and RPMI6666) was significantly suppressed in mice treated with a combination of intravenous rituximab and oral BG, when compared to mice treated with rituximab or BG alone. Survival of mice with disseminated lymphoma was significantly increased in the combination group as compared to other treatment groups. No clinical toxicity was observed. The therapeutic efficacy and lack of toxicity of this combination supports further investigation into its clinical utility.

Modak S et al. Rituximab therapy of lymphoma is enhanced by orally administered (1→3),(1→4)--β-glucan . Leukemia Research , Volume 29 , Issue 6 , Pages 679 – 683

This paper discusses the mechanism by which beta-glucan enhances the efficacy of monoclonal antibodies. Antitumor mAb bind to tumors and activate complement, coating tumors with iC3b. Intravenously administered yeast Your browser may not support display of this image.-1,3;1,6-glucan functions as an adjuvant for antitumor mAb by priming the inactivated C3b (iC3b) receptors (CR3; CD11b/CD18) of circulating granulocytes, enabling CR3 to trigger cytotoxicity of iC3b-coated tumors. Recent data indicated that barley Your browser may not support display of this image.-1,3;1,4-glucan given orally similarly potentiated the activity of antitumor mAb, leading to enhanced tumor regression and survival. This investigation showed that orally administered yeast Your browser may not support display of this image.-1,3;1,6-glucan functioned similarly to barley Your browser may not support display of this image.-1,3;1,4-glucan with antitumor mAb. With both oral Your browser may not support display of this image.-1,3-glucans, a requirement for iC3b on tumors and CR3 on granulocytes was confirmed by demonstrating therapeutic failures in mice deficient in C3 or CR3. Barley and yeast Your browser may not support display of this image.-1,3-glucan were labeled with fluorescein to track their oral uptake and processing in vivo. Orally administered Your browser may not support display of this image.-1,3-glucans were taken up by macrophages that transported them to spleen, lymph nodes, and bone marrow. Within the bone marrow, the macrophages degraded the large Your browser may not support display of this image.-1,3-glucans into smaller soluble Your browser may not support display of this image.-1,3-glucan fragments that were taken up by the CR3 of marginated granulocytes. These granulocytes with CR3-bound Your browser may not support display of this image.-1,3-glucan-fluorescein were shown to kill iC3b-opsonized tumor cells following their recruitment to a site of complement activation resembling a tumor coated with mAb.

Hong F et al. Mechanism by Which Orally Administered beta-1,3-Glucans Enhance the Tumoricidal Activity of Antitumor Monoclonal Antibodies in Murine Tumor Models. J Immunology. 2004; 173: 797-806.

This paper concludes that beta-glucan synergistic with Bevacizumab in ovarian cancer in vitro and in vivo.

Purpose: Bevacizumab is a recombinant IgG1 humanized monoclonal antibody against vascular endothelial growth factor (VEGF). Its proposed mechanism of action is independent of immune effector functions. Many human carcinomas not only secrete VEGF but also express membrane-bound VEGF. In addition, VEGF receptors are expressed on tumor cells. It is hypothesized that bevacizumab could bind membrane-bound VEGF or VEGF-VEGF receptor complexes on tumors, thereby initiating potential immunologic consequences. We previously showed that yeast-derived β-glucan functions with antitumor antibodies that activate complement to recruit complement receptor 3–expressing leukocytes capable of mediating complement receptor 3–dependent cellular cytotoxicity of tumors opsonized with iC3b. In the current study, the therapeutic efficacy mediated by combining bevacizumab with yeast-derived β-glucan was studied in human carcinoma xenograft models.

Experimental Design: Human tumor cell lines were screened for membrane-bound VEGF expression both in vitro and in vivo. Complement activation mediated by bevacizumab was examined. Tumor cell lines positive or negative for membrane-bound VEGF expression were implanted in severe combined immunodeficient mice to establish xenograft models. Tumor-bearing mice were treated with different regimens. Tumor regression and long-term survival were recorded.

Results: Human ovarian carcinoma SKOV-3 cells expressed membrane-bound VEGF both in vitro and in vivo. Bevacizumab was bound to membrane-bound VEGF, activated complement, and synergized with β-glucan to elicit cellular cytotoxicity in vitro. In vivo study showed that β-glucan could significantly augment the therapeutic efficacy mediated by bevacizumab.

Conclusions: Yeast-derived β-glucan can synergize with anti-VEGF monoclonal antibody bevacizumab for the treatment of cancer with membrane-bound VEGF expression.

Salvador C et al. Yeast-Derived β-Glucan Augments the Therapeutic Efficacy Mediated by Anti–Vascular Endothelial Growth Factor Monoclonal Antibody in Human Carcinoma Xenograft Models Clinical Cancer Research 2008; 14: 1239-1247.

Vitamin D has established prevention role in a variety of cancers, and indirect evidence suggests Vitamin D status as a prognostic factor for lymphoma.

While the role of Vitamin D in cancer prevention is well established, its role in cancer treatment is not yet well studied. There is indirect evidence that higher Vitamin D levels will improve prognosis. Season of diagnosis is implicated in prognosis. Patients with colon, breast, or prostate cancer or with Hodgkin’s Lymphoma who are diagnosed in late summer or autumn (time of greatest Vitamin D levels due to increased sunshine exposure intensity and duration) have a 21-60% prognostic advantage over those diagnosed in winter. This suggests that Vitamin D level during the time of treatment plays an important role in survival. I anticipate randomized studies in the future. It is a reasonable suggestion to use Vitamin D 2000iu.

Porojnicu A et al. Season of diagnosis is a prognostic factor in Hodgkin's lymphoma: a possible role of sun-induced vitamin D. Br J Cancer. 2005 Sep 5;93(5):571-4

Porojnicu A et al. Season of diagnosis is a predictor of cancer survival. Sun-induced vitamin D may be involved: a possible role of sun-induced Vitamin D. Steroid Biochem Mol Biol. 2007;103(3-5):675-8.

The following is included but is not specific to lymphoma. Vitamin D has the following known actions: antiproliferative, antiangiogenic, antimetastatic, proapoptotic, prooxidant, immunomodulatory, prodifferentiating. Vit D has synergistic effects with doxorubicin, carboplatin, and cisplatin and additive effects with dtoposide, tamoxifien, 5FU, and busulfan, taxotere

Wigington DP et al. Anticancer Res 2004;23(5A):2905.

Pelczynska M et al. Anticancer Res 2006;26(4A):2701

Fish Oil is associated with increased survival in dogs with non-Hodgkin’s Lymphoma, is associated with an overall decreased risk of developing lymphoma in the first place, appears to enhance the effect of doxorubicin in vitro,

A diet supplemented with fish oil and the amino acid arginine appears to increase survival time in dogs with lymphoma considered similar to non-Hodgkin's lymphoma in humans. This double-blind, randomized study of 32 dogs was designed to evaluate the hypothesis that polyunsaturated n-3 fatty acids can improve metabolic parameters, decrease chemical indices of inflammation, enhance quality of life, and extend disease free interval and survival time for dogs treated for lymphoblastic lymphoma with doxorubicin chemotherapy. Dogs fed the experimental diet had significantly (P < 0.05) higher mean serum levels of the n-3 fatty acids docosahexaenoic acid (C22:6) and eicosapentaenoic acid (C20:5) compared with controls. Higher serum levels of C22:6 and C20:5 were associated with lesser (P < 0.05) plasma lactic acid responses to intravenous glucose and diet tolerance testing. Increasing C22:6 levels were significantly (P < 0.05) associated with longer disease-free interval and survival time for dogs with Stage III lymphoma fed the experimental diet.

Ogilvie GK et al. Cancer. 2000 Apr 15;88(8):1916-28.

Between 2000 and 2002, 591 non-Hodgkin’s Lymphoma (NHL) cases and 460 population-based controls in Sweden completed a semiquantitative food frequency questionnaire. Dietary intake of most macronutrients was not associated with risk of NHL or its common subtypes. However, consumption of omega-3 or marine fatty acids was associated with decreased risk of NHL (40% lower risk) and chronic lymphocytic lymphoma, and dietary fiber was associated with 50% lower risk of all subtypes examined. Dietary consumption of beta-carotene or alpha-tocopherol was associated with lower NHL risk, whereas intake of calcium or retinol was associated with increased NHL risk.

Chang ET et al. Nutrient Intake and Risk of Non-Hodgkin's Lymphoma. American Journal of Epidemiology 2006 164(12):1222-1232

Modification of cultured lymphoma cells (L5178Y) with individual unsaturated fatty acids [oleic acid (OA), linoleic acid (LA), alpha-linolenic acid (alpha-LNA), arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)] influenced cell growth and the responses of the cells to the chemotherapeutic agents doxorubicin (DRN), dexamethasone (DEX) and mitomycin-C (MTC). Cell proliferation generally decreased following modification with highly unsaturated fatty acids (> 10 microM). The effects of drugs on growth varied with the type of fatty acid. Preincubation with alpha-LNA enhanced survival of L5178Y cells exposed to DRN. Modification with AA, EPA or DHA (> 10 microM) reduced cell proliferation, particularly when cells were subsequently exposed to 50 or 100 nM DRN. There was no consistent relationship between fatty acid chain length, degree of unsaturation, and survival of cells when exposed to DEX or MTC. The data showed that modification of cultured L5178Y cells with highly unsaturated fatty acids, particularly DHA, enhances the toxic action of chemotherapeutic agents.

Kinsella JE, Black JM. Effects of polyunsaturated fatty acids on the efficacy of antineoplastic agents toward L5178Y lymphoma cells. Biochem Pharmacol. 1993 May 5;45(9):1881-7.

Soy Isoflavone – Genistein - enhances in vivo (murine) and in vitro efficacy of CHOP for non-Hodgkin’s Lymphoma but has not been studied in human clinical trials yet.

Diffuse large cell lymphoma (DLCL) is the most common subtype of NHL. These cells are notable for the high expression of the transcription factor nuclear factor kappa beta (NF-Your browser may not support display of this image.B), raising the possibility that constitutive activation of the NF-Your browser may not support display of this image.B pathway may contribute to the poor prognosis of DLCL patients. Soy isoflavone genistein promotes apoptosis by decreasing NF-Your browser may not support display of this image.B activity. The WSU-DLCL2 cell line and its severe combined immunodeficient (SCID) xenograft have constitutively active NF-Your browser may not support display of this image.B which provides us with an excellent model in which to study NF-Your browser may not support display of this image.B modulation and CHOP sensitization by genistein. The antitumor activity of CHOP with or without a genistein was evaluated in our WSU-DLCL2 model. In vivo, WSU-DLCL2-bearing SCID mice received genistein alone (800 µg kg-1 day-1, p.o. as gavages for 5 days), CHOP alone ("C", 40 mg/kg, i.v.; "H", 3.3 mg/kg, i.v.; "O", 0.5 mg/kg, i.v.; and "P", 0.2 mg/kg, every day for 5 days, p.o.), or genistein for 5 days followed by CHOP. Tumor growth inhibition (T/C), tumor growth delay (T - C), and log10 kill for genistein, CHOP, and genistein followed by CHOP were 33.6%, 19.2%, and 5.2%; 7, 8, and 17 days; and 1.0, 1.2, and 2.6, respectively. To begin elucidating the mechanism of genistein-induced sensitization of WSU-DLCL2 cells to CHOP chemotherapy in this xenograft mouse model, we studied the in vitro effect of genistein on WSU-DLCL2 growth inhibition, cell cycle, Bax:Bcl-2 ratio, NF-Your browser may not support display of this image.B DNA binding, and apoptosis in vitro. At 30 µM, genistein inhibited the growth significantly, induced G2-M arrest, increased Bax:Bcl-2 ratio, decreased NF-Your browser may not support display of this image.B DNA binding, and induced apoptosis. Genistein also inhibited NF-Your browser may not support display of this image.B DNA binding in vivo, whereas CHOP enhanced it. Our results show that genistein has growth modulatory effects on WSU-DLCL2 cells and enhances the antitumor activity of CHOP. Because soy isoflavone genistein is a widely available nutritional supplement, its use in combination with CHOP chemotherapy should be further explored in a clinical trial in patients with NHL.

Ramzi et al. Genistein sensitizes diffuse large cell lymphoma to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. Mol Cancer Ther. 2003 Dec ;2 (12):1361-8

CoQ10 does not interfere with CHOP protocol, enhances the efficacy of doxorubicin in mice with leukemia, and is associated with cardiac protection from doxorubicin in some randomized human clinical studies.

CoEnzyme Q10 does not interfere with antitumor activity (nor myelosuppresion) in patients treated with doxorubicin, vincristine, and cyclophosphamide every 4 weeks. In this same study of 18 patients, 80% of the non-CoQ10 patients developed decreased left ventricular function compared to 25% of those receiving CoQ10. This suggests more than a 3-fold reduction in the risk of doxorubicin cardiomyopathy in patients taking CoQ10 concurrently.

Cortes EP et al. Cancer Treat Rep. 1978;62:887-891.

Survival of leukemic mice is increased 70% with doxorubicin plus administration of CoQ10 compared to doxorubicin alone.

Yamanaka N et al. Biomedical and Clinical Aspects of Coenzyme Q. Vol 2. Amsterdam, the Netherlands: Elsevier/North-Holland Biomedical Press; 1980:213-224.

CoQ10 protects lung cancer patients from doxorubicin cardiotoxicity. 14 patients with lung cancer received doxorubicin with or without CoQ10 100mg/day starting 3-5 days before the first dose of doxorubicin and continuing until the end of treatments. After a cumulative doxorubicin dose of 600mg/m2, those without CoQ10 developed increased heart rate, decreased ejection fraction/stroke index/cardiac index. Those with CoQ10 did not have any cardiac changes. After a cumulative dose of 900mg/m2, (the dose at which 50% of patients are expected to develop CHF), those patients taking CoQ10 only had increased heart rate but still had normal ejection fraction/stroke index/cardiac index.

Judy WV et al. Coenzyme Q10 reduction of Adriamycin cardiotoxicity. In: Folkers K, Yamamura Y, eds. Biomedical and Clinical Aspects of Coenzyme Q. Vol 4. Amsterdam, the Netherlands: Elsevier/North-Holland Biomedical Press; 1984:231-241.

A randomized trial of 80 patients with various types of malignancies compared doxorubicin to doxorubin plus CoQ10 90mg per day and concluded that CoQ10 protects from cardiotoxicity of doxorubicin (measurements were QRS voltage depression and QT prolongation).

Okuma K. . In: Folkers K, Yamamura Y, eds. Biomedical and Clinical Aspects of Coenzyme Q. Vol 5. Amsterdam, the Netherlands: Elsevier/North-Holland Biomedical Press; 1986:247-256.

Children with hematologic malignancies were treated with doxorubicin/danorubicin with or without CoQ10 100mg twice per day. Echocardiograms were performed prior to, after a cumulative dose o 180mg/m2, and after completion of treatments. Those receiving CoQ10 at later development of and lesser degree of left ventricular dysfunction. Only those not receiving CoQ10 developed depressed interventricular septal wall thickening.

This suggested a reduction in anthracycline induced cardiotoxicity by CoQ10.

Iarussi et al. Mol Aspects Med. 1994;15:s207-s212.

Melatonin

Melatonin does not decrease the efficacy of chemotherapy treatments in any published medical literature. It decreases the toxicity of doxorubicin in kidney, brain, heart, breast, and bone marrow (Granzotto et al, 2001), and is shown in some studies (and not in others) to protect against neutropenia, lymphocytopenia, and thrombocytopenia. Some of the literature is from animal studies and some from human studies. Conclusion of enhancement of treatment is not able to be drawn, but there is no evidence of harm, there may be benefit, cost is minimal, and sleep is enhanced. The balance of evidence suggests that this is a reasonable suggestion. The dose is up to 20mg at bedtime (less if not tolerated – morning drowsiness, vivid dreams).

In this Phase II trial of twenty patients with low-grade non-Hodgkin's lymphomas (NHL), a combined treatment with cyclophosphamide, somatostatin, bromocriptin, retinoids, melatonin and ACTH showed minimal toxicity (the most common side effects being drowsiness, diarrhea and hyperglycemia) and good efficacy. Treatment for one month in all patients, three months in patients with stable or responding disease, and six or more months in responding patients led to the following initial response rates: 70% (14 of 20 patients; 95% confidence interval [CI], 50% to 90%) had a partial response; 20% (4 of 20) had stable disease, and 10% (2 of 20) showed disease progression on therapy. Of the 70% with partial response, none had any disease progression over the average followup time of 21 months, and 50% of those patients had a complete response (35% of the original twenty patients in the study).

Todisco M et al. Cyclophosphamide plus somatostatin, bromocriptin, retinoids, melatonin and ACTH in the treatment of low-grade non-hodgkin's lymphomas at advanced stage: results of a phase II trial. Cancer Biotherapy & Radiopharmaceuticals 2001. 16(2):171-177.

Subcutaneous administration of 10 mg/kg melatonin reduced mortality caused by doxorubicin and prevented oxidative damage from it in mice with transplanted lymphoma cells. The antitumor activity of doxorubicin was not reduced by melatonin treatment.

Rapozzi V, Zorzet S, Comelli M, et al. Melatonin decreases bone marrow and lymphatic toxicity of adriamycin in mice bearing TLX5 lymphoma. Life Sci 1998; 63(19):1701–13.

This randomized study of CHOP chemotherapy with or without melatonin in 112 patients with favorable prognosis large B-cell lymphoma showed no decrease in the incidence of neutropenia after cycle 1 and that there was no improvement in neutrophil nadir, complete response rate, infection rate, or hemoglobin or platelet counts with the addition of melatonin.

Sarma A et al. A randomized trial of CHOP chemotherapy with or without melatonin in patients with favorable prognosis large B-cell lymphoma. Journal of Clinical Oncology 2004;22(14S):8066.

In a small Phase II trial, the use of IL-2 plus melatonin appeared to stop the progression of disease and to prolong the survival time in 8 of 12 patients (67%) who were previously unresponsive to standard treatment for advanced hematologic malignancies, including non-Hodgkin's lymphoma, Hodgkin's disease, acute myelogenous leukemia, multiple myeloma, and chronic myelomonocytic leukemia. IL-2 was given 6 days a week for 4 weeks, along with oral melatonin (20 mg a day). Average followup was 21 months. The melatonin/IL-2 therapy was well-tolerated.

Lissoni et al. A phase II study of neuroimmunotherapy with subcutaneous low-dose IL-2 plus the pineal hormone melatonin in untreatable advanced hematologic malignancies. Anticancer Res. 2000 May-Jun;20(3B):2103-5

Silymarin (Milk Thistle) for protection against toxicity to the liver, kidneys, and heart. Greenlee et al. Applications of Silybum marianum in Oncology. Int Cancer Ther. 2007;6(2):158-165

Only one randomized, double-blind trial has reported on the effects of concurrent use of silymarin on chemotherapy-induced hepatotoxicity. Fifty children with acute lymphocytic leukemia (ALL) with grade > 2 hepatotoxicity were randomized to receive silymarin 5.1mg/kg/day or placebo for 4 weeks. The treatment group saw greater reductions in AST than the control group (p<0.05). More children in the silymarin group saw a >50% reduction in total bilirubin at day 28 compared to placebo (p=0.0069).

Ladas EJ et al. Milk thistle is associated with reductions in liver function tests (LFTs) in children undergoing therapy for acute lympohblastic leukemia (ALL). Paper presented at: 3rd International Conference of the Society for Integrative Oncology; Novebmer 11, 2006; Boston, MA

No human randomized studies exist to report on the effect of concurrent use of silymarin on chemotherapy-induced nephrotoxicity, but animal studies demonstrate this use to be effective in the setting of cisplatin and vincristine.

Sonnenbichler J et al. Stimulatory effects of silibinin and silicristin from the mild thistle Silybum marianum on kidney cells. J Pharmacol Exp Ther. 1999;290:1375-1383.

Bokemeyer C et al. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumor activity. Br J Cancer. 1996; 74:2036-2041.

Graedeke J et al. Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant. 1996;11:55-62.

Sonnenbichler J et al. Influence of Flavonolignan Silibinin of Milk Thistle on Hepatocytes and Kidney Cells. Washington, DC: American Cehmical Society; 1998.

This animal model study showed that oral silymarin administered before gamma radiation exposure exerted protective effects on serum BUN and creatinine levels.

Ramadan LA et al. Protective role of silymarin against gamma radiation effects of lipids, urea, and creatinine serum levels. Acta Pharm. 2002;52:161-170

No human randomized studies exist to report on the effect of concurrent use of silymarin on chemotherapy-induced cardiotoxicity, but one animal study demonstrated protection of cardiac microsomes and mitochondria against doxorubicin-induced lipid peroxidation, meaning that doxorubicin-induced cardiomyocyte inflammation was prevented.

Psotova J et al. Phytother Res 2002;16(suppl 1):S63-S67.

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