Condition Monogram: Melanoma

Definition of Condition

Melanoma is a rare, highly malignant form of skin cancer. It is notoriously unpredictable and the leading cause of death from skin disease.6 Melanoma is associated with a 5 year survival rate of less than 20% if metastasized. The National Cancer Institute estimated 73,870 new cases were diagnosed in 2015 in the United States with estimated mortality of 9,180 people in 2014.34  

Melanoma is a disease of skin pigmentation, so individuals with fair skin are more susceptible as the ratio per 100,000 people is 1 in black population, 4 in Hispanic and 25 in non-Hispanic whites annually.34  A recent April, 2016 meta-analysis and review reported patients with chronic lymphocytic leukemia (CLL) have a 4 fold increased risk of developing melanoma.28  Long term survivors of CLL had a 36 percent risk of developing other cancers, 72% of those treated for CLL and 28% for those untreated.

Body System Affected

Melanoma originates in the melanocytes of the skin and has a high rate of malignancy.  If the melanoma metastasizes, it can affect any organ of the body.  The prognosis is based on size, depth, invasiveness of the tumor, and the presence of metastasis.6

Etiology and Pathophysiology

Etiology for high risk of developing skin cancer includes; excessive exposure to sunlight for individuals with fair skin, exposure to toxic chemicals, recurrent trauma, family history, and irradiation. 6  Melanoma risk after CLL increases significantly among patients receiving fludarabine chemotherapy and significantly elevated risks with T-cell activated autoimmune disease.21  Pesticides have been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MML).2 Many genes involved in melanocyte development have also been implicated.33 

Malignant cancer cells form in melanocytes, the cells that produce melanin in the epidermis.  It is still unclear how melanocytes become melanoma cells.33 Transformed melanocytes that develop into melanomas show abnormal proliferation and begin to grow radially in the skin. Vertical growth can follow, leading to penetration of the basement membrane of the dermis and metastasis to the blood and or lymphatic systems affecting other organs of the body.33 Metastatic melanoma has a high mortality rate due to resistance of many tumors to radiotherapy, chemotherapy. 33 and a hypoxic microenvironment.30

Allopathic Diagnosis and Treatment

Symptoms

Examination of  lumps or moles that increase rapidly in size, change color, ulcerate or bleed should be evaluated.6  Common sites are those most exposed to the sun including the head, face and neck.

Early Detection and Diagnosis

Early detection of melanoma is clinically imperative due to the propensity to metastasize and lack of effective treatment therapies.13 Computer aided diagnosis (CAD) systems increase the specificity and sensitivity of melanoma detection. New research on CAD is working toward an algorithm that can classify different melanocytic lesions. In Poland, one such CAD was tested on 300 dermoscopic images achieving 92 % accuracy.13   Development of a CAD that can diagnose the type of skin mole will reduce the amount of biopsies and morbidity related to skin lesion excision.13

Trained expert pathologists are currently using newer cytogenetic testing technologies, fluorescence in situ hybridization (FISH) and/or comparative genomic hybridization (CGH) to interpret melanocytic lesions.41

Treatment

Treatment of advanced melanoma remains challenging as it is classified as a highly complex heterogeneous disease comprised of several subpopulations of tumor cells.33   The NCI stage classification defines treatment options.  Stage 0 to I treatment is surgical excision which has low risk of recurrence.33 Stage II and III resectable melanoma is managed with excision and lymph node resection if involved, and unresectable stage III and IV melanoma are treated with targeted therapy, chemotherapy and immunotherapy.33  Metastatic melanoma remains challenging.33 

Immunotherapy is a gene-editing treatment which utilizes the body’s immune system to attach and kill cancer.40  Geneticists are reprograming T cells to only attack and kill cancer cells which display a specific protein  and viruses which are also genetically altered to kill melanoma cells.

Targeted therapies and immune checkpoint inhibitors shows promise in clinical trials for advanced melanoma. FDA approved therapeutic drugs vermurafenib, trametinib and dabrafenib target the mitogen-activated protein kinase (MAPK) pathway.34 Immunotherapeutic drugs ipilimumab, nivolumab and pembrolizumab block immune checkpoint receptors on T lymphocytes.33 Pembrolizumab is an anti-PD 1 immunotherapy drug approved by the FDA in 2014 that blocks the protein PD-L1 found on the surface of Melanoma cells.32 PD-L1 protects the melanoma cell from detection and destruction by the immune system.32  

Oncolytic virotherapy is a form of immunotherapy which utilizes viruses including FDA approved Coxsackie and Herpes simplex virus 1, which are showing great promise in clinical trials.  Coxsackievirus (CVA21) is an RNA virus shown to possess oncolytic activity against cultured malignant melanoma cells and melanoma xenografts resulting in significant tumor volume reduction.4 Anti–CVA21 antibodies can exist in some patients.4   

Oncolytic virotherapy of the Herpes virus 1 (HSV-1) was recently FDA approved for melanoma treatment.38.  HSV-1 is genetically modified to not harm host healthy cells and to replicate in malignant cancer cells.40  Talimogene laherparepvec (T-Vec), FDA approved in February, 2016 is the first genetically modified oncolytic virus shown in phase II and III, clinical trials to demonstrate  benefit to melanoma patients.20  In a phase II clinical trial, T-VEC showed an objective response rate of 26% in advanced melanoma patients.16  In a phase II clinical trial of 50 patients with stage IIC or IV melanoma, direct injection of T-VAC into the tumor resulted in a  67.2 % decrease in tumor size by 30% and 46.1% of tumors completely resolved.16  The mechanism of action of T-VEC is not completely understood.  Tumor cell replication may be dependent on low levels of protein kinase R (PKR) and dysfunctional type I IFN signaling.20

When to Refer

Suspicious cutaneous lesions of the skin should be seen by a dermatologist as soon as possible.  Prompt treatment of melanoma is essential for prevention of metastasis.

Integrative Perspective of Causes

Environmental and medically induced toxicity, comorbidity with non-Hodgkin lymphoma (NHL) and hypoxia (low tissue oxygen) 10 have only recently (2013-2016) been implicated as risk factors to melanoma.  The combination of occupational sun exposure with environmental toxicity appears to increase the risk of developing melanoma.  Pesticide exposure to herbicides (glyphosate) and fungicides (mancozeb, maneb) showed an augmented risk of cutaneous melanoma, especially by subjects exposed to both pesticides and occupational sun exposure.9 

Survivors of NHL have an increased risk of developing cutaneous melanoma.21 A  large 44,870 population report found  melanoma risks were higher among male, non-Hispanics residing is southern regions and survivors of CLL SLL with lesions occurring on high sun exposed areas of the face, head and neck.21 

Drug resistance to melanoma treatment was recently shown to be associated with hypoxia.30  Vemurafenib improves melanoma survival yet resistance occurs under hypoxic conditions as shown through enhanced cell proliferation rate and migratory capacity in hypoxia treated cells.30 Cancer thrives in oxygen depleted hypoxic environments, strategies to increase tissue oxygen may show to be of paramount importance.   

Specialized Integrative Analysis

Functional range blood chemistry is used to assess the risk of disease before the disease develops allowing for preventive and proactive adjustments to diet, nutrition and medical interactions.

Urinary pH analysis is a screening tool used by the patient and practitioners to monitor the acid base system of bodily fluids.  The patient tests the fasting urine pH twice daily first morning after 5 am, and fasting evening before dinner.  The ideal range is 6.4-7.0.   Urinary pH supports the microenvironment and protects against acidic conditions which lead to tissue hypoxia.  At a blood pH of 7.4 the mitochondria produce 32-36 molecules of ATP per molecule of glucose optimizing cellular oxygen.24 

Kinesiology Biofeedback- Quantum Reflex Analysis (QRA) is a diagnostic method that uses kinesiology and the acupuncture meridian system to assess the health of the bodily systems.12 It can be used manually by trained practitioners or with a machine such as Zyto.  Biofeedback uses the galvanic skin response to measure key biochemical sensitivities along meridians of the body.  It is accurate, inexpensive and an effective diagnostic tool.

Integrative Support Protocols

Increase Tissue Oxygen  Treatments to increase tissue oxygen levels to improve or prevent the development of hypoxia focus on dietary, mineral support and pH balance. Mineral supplementation with vitamin K and vitamin D are essential to optimize tissue oxygen levels and prevent a hypoxic environment suited for melanoma proliferation.  Tissue oxygen can be easily monitored by pH of urine (fasting morning and evening 6.4-7.0). Blood chemistry markers that also correlate with acid base conditions and hypoxia include CO2, total protein, calcium, hemoglobin, signs of anemia (elevated MCV, MCH, MCHC and RDW), and kidney function (BUN, creatine, sodium, potassium). Educating the patient on diet and teaching them how to monitor the first morning urine pH is highly recommended, inexpensive, and encourages patient self-care. 

Immune System Support

Support for the immune system is essential in cancer treatment. The first priority is achieving healthy function of the gastrointestinal system (GI).  Seventy percent of the immune system resides in the GI so supporting healthy GI function is an essential CAM protocol.  Identifying risk factors include low HCL, insufficient digestive enzymes, food intolerances (gluten, dairy, white flour), liver and or gallbladder dysfunction, constipation or diarrhea and malabsorption.

Detoxification

Environmental toxicity including exposure to pesticides, occupational carcinogens, tobacco smoke, poor nutrition and physical inactivity are estimated to be responsible for 75 to 80 percent of cancer deaths in the U.S.24   Systemic chelation of toxins with  internal and external phytonutrients and minerals are an essential CAM protocol for cancer prevention and treatment.  Colonic hydrotherapy, internal bentonite and zeolite clay therapy, lymphatic drainage and blood cleanses are case specific CAM protocols for cancer.  Once the colon is cleaned with either water or salt, hydrotherapy with coffee enemas will detoxify and strengthen liver function.24    Organic low roasted coffee is high in antioxidants, alkalinizes the intestinal tract and contains palmitic acid which the liver uses to produce the enzyme glutathione transferase.  Glutathione transferase is the most powerful detoxifying agent in the human body. 35  

Peat and other clays are used externally with both baneotherapy (water) and hyperthermia (heat) therapy.11  Hyperthermia applications of whole body or localized infrared applications with peat are used extensively in cancer treatments globally. Cancer is heat intolerant and whole body hyperthermia stimulates T cell activation, granulocyte mobility, phagocytosis, and activation of apoptosis.11  

Lifestyle Modifications

Nutrition is essential to nourish and alkaline the system. Dietary considerations are to increase leafy greens and vegetables with low glycemic fruits while eliminating acidifying foods such as coffee, pastries, sugar, white flour and excessive  animal protein  Glucose fuels cancer, so elimination of sugar is essential.  A mediteranean diet is recommended.  Exercise, a minimum of 20 minutes daily will oxygenate and detoxify the system and is  valuable for stress reduction.

Herbal Protocols

Cannabinoids Naturally occurring quinone compounds are the second largest class of anticancer agents in use 29  The parachinone cannabinol HU-331 represents the newest class of promising antineoplastic quinone agents 29 and is far  less cardiotoxic when compared to other quinones.18  The parachinone cannabinol HU-331 from cannabis sativa exhibits potent and selective cytotoxic activity on many tumors including melanoma.29  HU-331 exhibits both apoptotic and antiangiogenic properties and was shown in mice hearts not to generate reactive oxygen species.19  The apoptotic mechanism of action is activation of the CBD 1 and CBD 2 receptors which turn off tumor cell proliferation resulting in apoptosis, cancer cell death without changing the expression of pro and antiangiogenic cytokines and their receptors while reducing tumor size.19  The antiangiogenic properties show HU-331 cannabinols interfere and destroy substances within the fine network of blood vessels needed by tumors to grow and metastasize.29 

Agaricus blazei Murill (AbM)AbM is a  medicinal mushroom shown in-vivo and in-vitro animal experiments to possess anti-metastatic effects in melanoma.26  AbM was tested in-vivo with severe immunodeficient mice with melanoma lung metastasis and shown to increase the survival rate by 0% to 50 % in a dose dependent study indicating  reduction in lung metastasis.37 

Cordyceps  – The anti-cancer benefits of Cordyceps mushroom varieties against melanoma  metastasis, angiogenesis and apoptosis are well documented in in-vivo and in-vitro animal studies,  and clinical trials are needed.  The mechanism of action showed that Cordyceps sinensis (Cs) inhibited matrix metalloproteinases expression through either NF-kB or extracellular signal regulated kinase and p38 mitogen-activated protein kinases (MAPK), inhibiting melanoma cell migration.14 Inhibition of MAPK signaling may play an important role in treatment for melanoma.  Cs targets miRNA suppressing tumor metastasis by binding to HMGA2, Twist1 and ZEB1 3’ UTR and suppressing their expression.39 Cordyceps taii inhibited lung metastasis of melanoma in mice.23  The anti-angiogenesis and apoptosis effects of Cordyceps militaris (Cm) in melanoma cells are suppression of tumor growth through apoptosis and down regulation of vascular endothelial growth factor receptors.31

Resveratrol is a plant polyphenol with diverse biological properties suitable for cancer including antioxidant, anti-inflammatory, proapoptotic, chemopreventive, antiproliferative,17 suppressing of tumor growth and angiogenesis.  Resveratrol is being studied with cancer drugs to test viability.  Co treatment with chemotherapeutic drug Fluorouracil inhibited B16 murine melanoma cell proliferation, reduced tumor growth and reduced the number of microvascular vessels.22   In another report, choloroquin  ursolic acid  and resveratrol were combined and shown to reduce the viability of murine and human melanoma cells.15  Methylation of Resveratrol cis-(Z)-isomer resulted in more potent anti-cancer properties through inhibition of phenotype metastatic and non-metastatic murine melanoma cells.25

Phytonutrient and Mineral Support

MineralsMinerals to support pH and prevent hypoxia include calcium, magnesium, phosphorus, and iron.

Fatty Acids – Essential fatty acids include vitamin K, vitamin D and DHA.

Immune Support – Supplementation with Colostrum IgG, Green tea,  Olive Leaf (Olea europaea), Turmeric (Curcuma longa), Cordyceps (Cordyceps sinensis), Vitamin C and Resveratrol from Giant Knotweed (Polygonum cuspidatum)  support the immune system.

Detoxification Support – Chemical detox support with Modified Citrus Pectin, Noni (Morinda citrifolia), Protease, Amylase, Diastase, Apple Cider vinegar, Pepsin, Lipase, Lactase Invertase.

Pesticide detox support with Calcium Bentonite.  Heavy Metal support with Organic Chlorella (Chlorella sorokiniana).

References

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