Riordan Clinic IVC Academy 7 · Vitamin C - Use With Chemotherapy Stoute, Judith A. The use of vitamin C with chemotherapy in cancer treatment: an annotated bibliography. (44 studies

O

7The Riordan IVC Protocol

Slides 61 - 120

© Riordan Clinic 2018

Riordan Clinic IVC Academy

AA

AA

2e-Fe3+

Fe2+

2O2e-

H2O22O2

Fe3+

Fe2+

e-

+2H+

O2+

The Pro-oxidant Effect of Vitamin C in the Presence of Iron and Oxygen


National Institutes of Health May 14, 2007

Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivoProceedings of National Academy of ScienceChen, Espey, Krishna, Mitchell, Corpe, Buettner, Shacter, Levine

May 14, 2007 | vol. 104 | no. 21 | 8749-8754


PNAS | May 14, 2007 | vol. 104 | no. 21 | 8749-8754


Fenton’s Reaction Ferrous Iron is Oxidized Back to Ferric State

Fe

FeH2O2

OHe-+ OH

3+

2+

Hydroxyl Radical


AA

DHA

2e-

kidneys

Fe3+

Fe2+

OHe-+OH

H2O2

Fe3+

Fe2+


Water Wheel Analogy – Vitamin C Generating an Oxidant

AA

DHA

OHRedox Cycling

requiresOrtho-dosingof Vitamin C

HydroxylRadical


Less Mitochondrial

Oxidative Stress

Cellular Hypoxia is relieved by

IVC

Improved OXIDATION of NADH to NAD

Enhanced Krebs cycle:increasing ATP !!

Better production of antioxidant enzymes

Decreasedmitochondrial

injury

Cell shifts back to AEROBIC

p53 functional again

IVC - redox cycling

OH


The Microevolutionary ModelConventional cancer treatments kill cancer cells

by increasing oxidationinducing apoptosis

Damaged apoptosis control mechanisms

such as p53 genetic control

allow therapy-resistant cells to emerge and multiply (progression of tumor)


The Microevolutionary Model

The ideal redox therapy would serve as BOTHanti-oxidant

CONTROLS extracellular oxidative stressREPAIRS apoptosis controls

pro-oxidantSIGNALS initiation of apoptosis in damaged cancer cells OXIDIZES NADH to NAD to restore aerobic function

High Dose IV Ascorbate is a bi-oxidant functioning in the cellular redox milieu


Bi-Oxidant Properties of High Dose IVC:High dose intravenous Vitamin C is, biologically, a very powerful anti-oxidant:

Mops up large numbers of free radicalsModulates cytokine-controlled inflammationPromotes formation of healthy collagen (walls off tumor)

High dose IVC is also, pharmacologically, a pro-oxidant “drug” that generates hydroxyl radicals

Healthy cells neutralize peroxide with adequate catalaseCancer cells lack adequate catalase IVC apoptosis


Seven Steps Leading to Cancer1) Oxidative stress/injury and oxygen under-utilization cause progressive anaerobic shift

2) Sustained cellular injury leads to excessive inflammatory cytokines which eventually change cellular behavior

3) Damaged cells (that sustain aerobic metabolism) normally respond to the oxidative signal

with mitochondria-coordinated apoptosis

4) Excessive DNA damage and mutation, with shift to glycolytic metabolism, results in loss

of p53 control of apoptosis

5) Oxidation/Inflammation promotes uncontrolled cellular proliferation

6) Injured multi-cellular tissues undergo malignant transformation and regress back to the

“selfish cell” – single-cell survival behaviors

7) Cancer “stabilizes” in anaerobic metabolism, angiogenesis, with aggressive cellular

proliferation, metastases, and body wasting


The Riordan IVC Cancer Protocol

IVC re-balances redox (bi-oxidant properties)

IVC detoxifies and removes disruptions

IVC treats with hydroxyl generationselective cytotoxicity (may augment conventional therapy)

oxidation of NADH to NAD aerobic restoration of the mitochondria

IVC controls inflammatory cytokinesshifts cytokine activity towards “normal”

IVC promotes whole cell energy restorationhelps to restore aerobic mitochondrial function


3. Inclusion criteria and candidates:

The Riordan IVC Protocol

“Science is build up of facts, as a house is with stones. But a collection of facts is no more a

science than a heap of stones is a house.”- Henri Poincare’

Five Categories of IVC Candidates1. Patients who have failed standard treatment regimens

2. Patients seeking to improve the effectiveness of their standard cancer therapy

3. Patients who want to decrease the severity and carcinogenicity of side effects from standard therapy

4. Patients attempting to prolong their remission with health-enhancing strategies

5. Patients who have refused standard treatment, yet wish to pursue primary, alternative treatment.


ContraindicationsThose unwilling to sign a consent-to-treat form for IVC treatments

Significant psychiatric illness that would preclude cooperation with IVC treatments

Severe congestive heart failure or other conditions characterized by fluid overload

Significant renal insufficiency or failure

G6PD Deficiency (can result in hemolysis)

Any uncontrolled co-morbid medical condition (for example – hemachromatosis)


Prior To Beginning IVC Therapy1. Appropriate laboratory baselines

Chemistry profile, CBC, G6PD, UA, vital signs, and weight

2. Complete medical history and physical exam

3. Tumor type and stagingOperative reports, pathology reports, special procedure reports Consider re-staging if relapse and symptom progression has

occurred since diagnosis.

4. Appropriate tumor markers, CT, MRI, PET scans, bone scans and x-ray imaging.

5. Prior cancer treatments, the patient’s response to each treatment type, including side effects.


4. Precautions and side effects:


“We are usually convinced more easily by reasons we have found ourselves than by those

which have occurred to others.”- Blaise Pascal

IVC Side Effects Are RareIn our 30+ years of clinical experience

Giving over 120,000 onsite IVC treatments

The side-effects of high-dose IVC are rare

When side-effects do occur, they are generally very mild and easily managed


What To Watch For:Type 1 Diabetics who use glucometers:

Falsely high readings leading to unwarranted increases in insulin dosing and hypoglycemia

Venous blood run in a laboratory using the hexokinase serum glucose method is not affected

Minor complaints: vein irritation, infiltration, shakiness –

SLOW THE RATE OF INFUSION!

Osmolality issues: infusion concentrations less than 1200 mOsm/kg H2O are well tolerated

Rapid tumor necrosis was report by Pauling and Cameron, but has been rarely observed


Riordan IVC Standard Infusion Protocol Developed and Typically Used at Center

Vitamin C (A.A.)# Grams (# cc)

DiluentType

MgClAdded

Infusion Time(~0.5 gram/minute)

Osmolality (calculated)

15 grams (30cc) 250cc Ringer's Lactate 1cc ~30 minutes* 827 mOsm/L

25 grams (50cc) 250cc Sterile Water 1cc ~50 minutes 800 mOsm/L




The Riordan IVC Protocol dosing schedule depicted above has served as a “safe start” for cancer patients new to IVC. The Center for the Improvement

of Human Functioning International in Wichita, Kansas, since 1990, has administered over 75,000 onsite IVC infusions according to this protocol. Zero fatalities and rare side effects a testament to its remarkable safety.


U. of Nebraska Phase 1 Study• 24 cancer patients

• Continuous IVC (10-50 grams per day)

• 8 weeks (50 gr/d = 710 mg/kg/d)

• CBC and Chemistry Profiles done• BUN and creatinine, glucose, uric acid were stable – no renal distress

• WBC counts – no decrease during the trial

• RBC stayed stable

• No toxicity…no side effects

• Plasma levels increased to 20 mg/dl

• Prior to starting IVC, more than half had no detectable vitamin C in plasma

• This demonstrated vitamin C depletion that is typical in cancer patients


5. Administration of IVC:


“For a successful technology, reality must take precedence over public relations, for Nature cannot be fooled.”

- Richard Feynman

Beginning IVC TherapyBegin with a series of three consecutive IVC infusions at the 15, 25, and 50 gram dosages

Follow each infusion with a “post IVC saturation level”

(a plasma C level after IVC)

This will help the administering physician to determine the patient’s

oxidative stress burden

These three levels will help to determine the optimal dosage for subsequent IVC’s


The Post-IVC Saturation LevelDrawn immediately upon completion of IVC

Drawn from a vein in the opposite arm

Use proper specimen handling and shipping!

Send to a lab familiar with doing dilutional vitamin C levels

Dr. John Hoffer has developed a simplified way to do this

The Post-IVC result can be correlated with tumor burden,

staging, and concurrent treatment to plan IVC dose


0

20

40

60

80

100

120

140

160

180

Healthy Local Regional Distant

Healthy Local

Regional Distant

Post 15 gram IVC Serum Ascorbate Levels in Healthy vs. Cancer Patients by Stage

n = 12n = 3

n = 7

n = 8


What Is a “Typical” IVC Protocol?

Twice a week first 6 months

Weekly to complete 12 months

Twice a month for year two

Monthly thereafter


Cancer Patients Post IVC Summary

24.90

58.2174.38

186.62

115.27

192.84

305.79

408.55

205.64

327.46

537.19

630.48

0

100

200

300

400

500

600

700

15 grams 25-45 gm 50 grams 60+ grams

mg/

dL

Count Sum Average Stdev -2 Mean +215 grams 226 26051 115.27 45.18 24.90 115.27 205.6425-45 gm 288 55537 192.84 67.31 58.21 192.84 327.4650 grams 352 107637 305.79 115.70 74.38 305.79 537.1960+ grams 49 20019 408.55 110.96 186.62 408.55 630.48


6. Concurrent Therapy:


“The greater the ignorance, the greater the dogmatism.”

- Sir William Osler

Vitamin C - Use With ChemotherapyStoute, Judith A. The use of vitamin C with chemotherapy in cancer

treatment: an annotated bibliography. (44 studies reviewed)J of Orthomolecular Medicine. 2004;19(4):198-245.

“…antioxidants [including vitamin C] do not protect cancer cells against free radical and growth-inhibitory effects of standard therapy. On the contrary, they enhance its growth-inhibitory effects on tumor cells, but protect normal cells against its adverse effects.”


Charles B. Simone, M.D.The Truth About Breast Health, Breast CancerAntioxidants enhance treatment kill rate and reduce treatment side effects

Cellular studies: 145Animal studies: 135Human studies: 508500 patients…5000 took antioxidants

4700 of the 5000 showed increased survival

Antioxidants reduce oxidative stress and may help to restore aerobic metabolism (Krebs Cycle)


Predicted plasma vitamin C in healthy persons after oral

or intravenous (IV) administration of vitamin C

Padayatty et al. 2004 Annals of Internal Medicine, 140, 7: 533

High plasma concentrations of vitamin C can only be achieved if ascorbate is administered IV as the rate of absorption from the gut is limited with oral administration.


7. Conclusions:


“All truth passes through three stages:First, it is ridiculed;

Second, it is violently opposed;Third, it is accepted as being self-evident.”

- Arthur Schopenhauer

Survival time in Phase I/II studies

Stage IV pancreatic cancer treated with gemcitabine and with addition of IVC therapy (Welsh et al).

Historic median survival for gemcitabine-treated patients is 5.65 months. The mean survival in Welsh study was 12 months.

Better than expected survival time for the patient population (Monti et al).

IVC in patients with advanced ovarian cancer showed a trend toward longer time to relapse (Ma et al).

IVC with chemotherapy may enhance tumor response in advanced stage cancer patients (specifically pancreatic cancer) and increase survival.

Welsh et al. Cancer Chemother Pharmacol. 2013; 71(3): 765–775. Monti et al. PLoS ONE 7:e29794 (2014)


IVC Quality of Life •Several recent studies have indicated that intravenous

(IV) vitamin C alleviates a number of cancer and chemotherapy-related symptoms• fatigue, insomnia, loss of appetite, nausea, pain.

•Improvements in physical, cognitive, emotional, and social functioning, as well as an improvement in overall health, were also observed.


IVC Quality of Life Studies1. Riordan et al found that IV ascorbic acid to be relatively safe, provided the patient does not have a history of kidney stone formation.

P R Health Sci J 2005; 24:269–276

2. Stephenson et al found that quality of life as measured by the EORTC-QLQ C30 questionnaire was improved at weeks 3 and 4, QOL

Cancer Chemother Pharmacol (2013) 72:139–146

3. Hoffer et al found that those patients who received 42g/70kg or more had stabilization of their physical function as measured by the FACT-G questionnaire.

Ann Oncol 2008; 19 (11): 1969–74

4. Yeom et al found for stage IV cancer patients 10g IVC resulted in improvements in health score, physical, role, emotional, and cognitive function, and improvements of symptoms: fatigue, nausea/ vomiting, pain, and loss of appetite.

J Korean Med Sci 2007; 22 (1):7–11


IVC / Chemotherapy-related Quality of LifePROSPECTIVE Patients Intervention Other therapies Outcomes

Ma et al.

25 Ovarian cancer (stage III–IV)

13 Chemo + vit C

12 Chemo group

IV vitamin C

75–100g

2x/week

12 months

Chemotherapy

(paclitaxel, carboplatin)

6 months

Grade 1 and 2 toxicities

Stephenson et al

17 Refractory advanced solid

tumors(stage III–IV; colon,

pancreas, breast, etc.)

IV vitamin C

0.8–3 g/kg

4x/week

1–4weeks

None

Fatigue, Pain

Nausea/vomiting

Insomnia

Appetite loss

Takahashi et al.60 Advanced cancer(lung,

breast, stomach, colon, etc)

IV vitamin C

25–100g

2x/week

4weeks

Chemotherapy

Fatigue, Pain

Insomnia

Constipation

Yeom et al.

39 Terminal cancer (stomach,

colorectal, lung, breast, biliary,

etc.)

IV vitamin C

10g2x/week

4 g oral daily

1week

None

Fatigue, Pain

Nausea/vomiting

Insomnia

Appetite loss

Carr A. Frontiers in oncology, 2014, 4© Riordan Clinic 2018

The effect of intravenous vitamin C on cancer- and chemotherapy-related fatigue and quality of life

125 Breast cancer(stage IIa–IIIb)53 Treatment group72 Control group

IVC 7.5g 1x/week during 4weeksChemotherapy (epirubicin, cyclophosphamide, methotrexate, fluorouracil) + RadiotherapyImprovements in Fatigue, Depression, Nausea, Sleep disturbance, Appetite loss, Dizziness

Vollbracht C. in vivo 25: 983-990 (2011)


Intravenous Vitamin C Administration Improves Quality of Life in Breast Cancer Patients during Chemo-/Radiotherapy

Vollbracht C. in vivo 25: 983-990 (2011)

Intensity score of symptoms during adjuvant therapy and aftercare was nearly twice lower than in the control group.


Means of overall intensity of complaints during adjuvant therapy with/without chemotherapy and with/without radiotherapy.


Reduction of toxicity in ovarian cancer patients after adding ascorbate to chemotherapy

Ascorbate treatment did not increase the rateof grade 3 or 4 toxicity. Grade 1 and 2 toxicities were decreasedin the Carboplatin + Paclitaxel+ AA group versus the Cp+ Paxgroup. Median time for disease progression/relapse was 8.75 months longer in the AA group.

Ma Y et al. Sci Transl Med 6, 222ra18 (2014); © Riordan Clinic 2018

IV Vitamin C1. IVC can reduce the severity of cancer symptoms and the unpleasant side-effects of chemotherapy and radiotherapy.

2. IVC can enhance the effectiveness of conventional cancer treatment such as chemotherapy and radiotherapy.


SYNERGY of chemotherapeutics and ascorbate

In vitro analyses of the effect of pretreatment of tumor cells with ascorbate and addition of several chemotherapeutics on cell viability.

Synergistic action of ascorbate with chemotherapeutics in animal models.

Clinical studies of chemotherapy with vitamin C.


Studies of chemotherapy with vitamin C (in vitro)Cervical cancer

(Reddy et al)

0.1 μM to 10 mM Cisplatin, Etoposide, Adriamycin, Bleomycin

Potentiate. Down regulates AP-1 and stabilizes p53

Neuroblastoma

(Prasad et al)

L-ascorbic acid at 500 μg/mL (2.53 mM) and sodium d-isoascorbate

5-Fluorouracil 5FU), X-irradiation, Bleomycin, Prostaglandin E1, Sodium butyrate

Potentiate. Inhibition of catalase leading to accumulation of H202 and subsequent cell death

Esophageal cancer

(Abdel-Latif et al)

20 mM Cisplatin5FU

Potentiate. Inhibit translocation of NF-κB and AP-1 (activator protein 1)

Breast cancerColon fibroblastMelanomaPancreatic cancerSkin fibroblast

(Casciari et al)

Ascorbic acid 10 mM for 2 days

Doxorubicin Potentiate cell death at high levels. Additive effect at high levels with doxorubicin may not be clinically feasible.


Pharmacological concentrations of AA reinforce activity of drugs

Verrax et al. Free radical biology and medicine. 2009, 47: 32-40

The combination of ascorbate and chemotherapy was more effective in killing MCF7 cells than either chemotherapy or ascorbate alone.


Studies of chemotherapy with vitamin C (mouse model)

BladderBreastCervixHepatocarcinomaProstate

(Verrax and Calderon)

Ascorbate concentration50 μM to 33mM

EtoposideCisplatin5FUDoxorubicinPaclitaxel

Potentiate in combination. H202-mediated cytotoxicity

Pancreatic

Espey et al.

Vitamin C 4 g/kg

Gemcitabine Potentiates in combination with activity alone, through H202 production.


Gemcitabine–ascorbate combinations administered to mice enhanced inhibition of growth compared to gemcitabine alone, produced 50% growth inhibition in a tumor type not responsive to gemcitabine.

Espey et al. Free RadicBiol Med. 2011, 50: 1610–1619

Study of chemotherapy with ascorbate (animal study)


Effects of ascorbate alone and in combination with chemotherapy in an ovarian cancer (animal model)

Ascorbate and carboplatin combination treatment was more effective compared to either ascorbate or carboplatin alone. Similar potentiation was seen with an ascorbate and paclitaxel combination

Ma Y. Sci Transl Med 6, 222ra18 (2014)© Riordan Clinic 2018

Existing evidence suggests safety of IVC when given alongside most chemotherapy agents, with possible synergistic effects

Ma et al evaluated high dose IVC in ovarian cancer patients receiving paclitaxel and carboplatin, and found that there was a reduction in chemotherapy related side effects, as well as a trend toward longer time to relapse compared to chemotherapy alone. Monti and Welsh evaluated high dose IVC in combination with gemcitabine and/ or

erlotinib and found reductions in tumor mass and possible improvements in survival in stage IV pancreatic cancer patients, and no evidence of increased toxicity.Vollbracht et al investigated 7.5g IVC alongside standard therapies in early stage

breast cancer patients. IVC significantly reduced side effects without any evidence of increased toxicity compared to patients receiving standard therapies alone.


Phase I Evaluation of Intravenous Ascorbic Acid in Combination with Gemcitabine and Erlotinib in Patients with Metastatic Pancreatic Cancer

Gemcitabine was administered intravenously at a dose of 1000 mg/m2 once wk x 7 wk. Erlotinib was given

orally in a single dose of 100 mg per day x8wk. IVC 50-100 g 3 days/wk x8wk. 7 patients had stable disease and 2 patients had progressive disease (non-responders).

Monti et al. PLoS One 7: e29794, 2012.

Tumor size initially and after 8 weeks of treatmentwith ascorbic acid, gemcitabine, and erlotinib for each of the patients who completed the study.


Kaplan-Meier curves of overall survival at 60 months after diagnosis.

High-Dose Ascorbate Enhanced Chemosensitivity of Ovarian Cancer

Ma Y. Sci Transl Med 6, 222ra18 (2014)

Chemotherapeutic agents: carboplatin and paclitaxel.


Summary of case reports13 case reports detailed the effectiveness of high dose IVC in a population consisting of 68 patients with the following cancer types:

colorectal (n=10), breast (n=8), bladder (n=7), kidney (n=7), lung (n=8), lymphomas (n=8), ovarian (n=5), stomach (n=5), pancreatic (n=3), gallbladder (n=2),brain (n=1), melanoma (n=1), others (n=3).


Summary of case reports Collectively, the case reports documented one or more of the following outcomes:

cancer remission and long term cancer-free survival;

survival considerably beyond life expectancy;

initial disease stabilization but recurrence or death after IVC was decreased or stopped;

tumor stabilization and/ or regression based on circulating tumor markers, CT scans, x-ray, bone scans, or other imaging techniques;

improvements in pain related to bone metastasis, and a reduction in the need for pain medication.


Dr. Riordan’s first cancer patient• George Williams - Clinic’s first cancer patient

– J Orthomol Med 1990;5:5-7• 1990 – Adenocarcinoma of right kidney• Underwent nephrectomy • After surgery, lung and liver mets discovered• IVC 30 grams twice weekly…felt well• After 15 months of therapy, mets were gone• 14 yrs later, at age 84, George died of CHF


Dr. Riordan’s case reportsRenal Cell Ca (n=2), Colon Ca (n=1), pancreatic (n=1), non- Hodgkin’s lymphoma (n=2), breast cancer (n=1)IVC treatment - 30-100g 2x/wk1. RCC #1: lived cancer free x 14 years and died of CHF at age 842. RCC #2: objective remission at 4 years3. Colon Ca: clear of mets and primary at 1.5 years (CT scan)4. Pancreatic: “surpassed life expectancy”; 5. Non Hodgkin’s lymphoma #1 remained cancer free at 2 years6. Non Hodgkin’s lymphoma #2 CT scan clear, “complete remission”

per oncologist at 11 months7. Breast cancer (w bone mets): 100 gr x5d in hospital

bone scan showed resolution of some skull mets at 3 months


3 Case reports of IVC use in cancer patientsNational Cancer Institute (NCI) Best Case Series guidelines

• IVC - 15, 30, 65g 2x/wk for first months • Then IVC variable (1-2x/wk or monthly) for several months• Unexpectedly long survival and objective tumor regression.• Renal Cell Ca with mets: declined conventional therapy: complete tumor

regression with IVC at 1y. Recurrence of second primary tumor at 6y followed by death at 7y.

• Bladder cancer: local resection, declined chemo: healthy and without recurrence at 9y.

• Diffuse large B-cell lymphoma: local radiation only: complete regression of tumor at 1y, no recurrence at 10y.

Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M. Intravenously administered vitamin C as cancer therapy: three cases. CMAJ Canadian Medical Association Journal. 174.(7):937-42. 2006.


A Rational Adjunctive Treatment for Cancer…

Health – re-balances redox

Injury – removes disruptions

Signal – treats with oxidation

Repair – controls inflammation

Healing – whole cell aerobic restoration


The Riordan IVC Cancer Protocol

IVC re-balances redox IVC detoxifies and removes disruptionsIVC treats with hydroxyl radicalIVC controls inflammatory cytokinesIVC promotes whole cell restoration


The Riordan IVC Protocol Addresses Cancer in a Comprehensive Way

1. Boosts immunity (to prevent secondary infections)

2. Stimulates collagen formation (to wall off tumor)

3. Inhibits hyaluronidase (to retard metastasis)

4. Relieves cellular hypoxia/restores aerobic metabolism

5. Restores mitochondrial functioning, including apoptosis

6. Inhibits angiogenesis and reduces tumor nutrient supply

7. Corrects scurvy in cancer patients (less fatigue)

8. Is Immune Activating (fights underlying infections)

9. Supports detoxification systems in the body

10. Relieves pain and promotes well-being

11. Potentiates chemotherapy and radiation

12. Reduces side effects & toxicity of conventional therapy

13. Plausible oncologic adjunct in cancer patient care© Riordan Clinic 2018

IVC is a

PREMIERONCOLOGIC ADJUNCT

in cancer patient care!

Vitamin C: Nature’s AdaptogenAll animals make their own vitamin C, except humans, primates, guinea pigs, and some bats

Vitamin C production in wild animals markedly increases with illness, injury, & infection (stress)

Cancer is man’s most challenging chronic illness

IVC can restore to humans, nature’s universal response to stress…high dose vitamin CTogether with optimal nutrition and sound medical care, The Riordan IVC Protocol can greatly assist in the optimal care of the distressed cancer patient


Documents

Riordan Clinic IVC Academy 7 · Vitamin C - Use With Chemotherapy Stoute, Judith A. The use of vitamin C with chemotherapy in cancer treatment: an annotated bibliography. (44 studies