INTEGRATIVE TREATMENTS IN CANCER PATIENTS: CASE STUDIES

MASSIMO BONUCCI M.D.

FIRST ISS-ARTOI CONFERENCE ON INTEGRATIVE ONCOLOGY NOVEMBER 6/7 - 2013 ROME

PRESIDENT A.R.T.O.I.CHIEF OF SURGICAL PATHOLOGY DEPARTMENT

AND ONCOLOGY OUTPATIENTSAN FELICIANO HOSPITAL - ROME

Dr. Massimo BONUCCI

Dr. Giuseppe DI FEDE

Dr. Carlo PASTORE

ONCOLOGY

CLINICAL MEDICINE -CARDIOLOGY

Prof.ssa Vezia MEI

CHEMICAL PHARMACEUTIC

Dr. Vincenzo FERRERA

Dr. Enrico RESTINI

SURGERY

Dr. Giovanni OCCHIONERO

RADIOLOGY

Dr. Gianluca PAZZAGLIA

Felice BONUCCI

Piero BIZZARRI

MENAGER

Mario BONUCCI

Association Research Theraphy Oncological Integrative

www. artoi.it

Prof. Massimo FIORANELLI

SOCI ORDINARI E SOSTENITORI

Dr.ssa Ferlante; Dr. Martin; Dr. Evangelista; Dr. Ottavio; Dr. La Cagnina; Dr. Cavallino; Dr. Storace; Dr. Del Buono; Dr. D’Orta; Dr. Farinelli; Dr.ssa Aimati; Dr. Episodio; Dr. Torchia; Dr.ssa Capurso; Dr. Allegrini; Dr. Catucci; Dr. Romiti; Dr. Mastrodonato; Dr. Paoluzzi; Dr.ssa Marino; Dr. Dardes; Dr.ssa Moscatelli; Dr.ssa Di Lupo; Dr. Luperi; Dr. Ravagnan; Dr.Giavolucci; Dr. Proietti; Dr. Strangis; Dr. Turchetti; Sig.ra Manicardi; Dr. Mattia; Sig.ra Mosti; Dr,. Caldarini; Dr.ssa Borghi;Dr. Bolognino; Dr.ssa Maruti; Dr.ssa Boccardi

SOCI FONDATORI

Integrative Oncology in Italy : A.R.T.O.I.

The spreading of scientific knowledge The scientific researc To integrate terapies and methodologies

(Hyperthermia) To develop a personalized therapy (Pharmaco and

Nutrigenomic) To improve results and quality of live Prevention

1- reduction of adverse effects from CT and RT with particular reference to nausea and vomiting

2- management of pain3- reduction of adverse effects due to iatrogenic menopause4- improvement in QoL5- resolution anxiety, depression, fatigue, supportive treatment CT and

RT, perioperative noise reduction6- gastrointestinal disorders, sleep disorders7- prevention of relapse8- reduction of muscle disorders, palliative care, reduction of

neuropathy

The main clinical indications for which is used in Integrative Oncology IN ITALIAN CENTRES are in order of frequency

Efficacy/EfficiencyTraditional use ? Extract ? Which? Single constituent or phytocomplex ? Single plant or multi-medicinal plants ? Pre-clinical/epidemiological studies Phase I / II Quality of clinical research Number of patients Herb-drug interactions

ABSORPTION: ALTERATION OF ORAL BIOAVAILABILITY

DISTRIBUTION : ALTERATION OF PROTEIN TRANSPORT Phase IMETABOLISM: INTERATION METABOLISM Phase II

EXCRETION: ALTERATION EXCRETION URINARY/LIVER

INTERACTION OF PHARMAKOCYNETICS

Induction Rapid metabolis short time/plasma concentration REDUCED EFFECT

Inhibition Reduced metabolis More time/plasma concentration

INCREASE ACTION INCREASE TOXIC EFFECTS

FACTORS: INDUCTORS - INHIBITORS

CYP 1A1-2CYP 2 B6CYP 2 C8-9-19CYP 2D6CYP 2E1CYP 3A4 35 % OXIDATION

EsterasiUGT

CYP Family

Anastrozole CYP2C9/ CYP 3A4

Bleomycin N/A

Busulfan CYP 3A4

Capecitabine Carbossilesterasi/Citidinesterasi

Cisplatin OCT2/ABCC2Cyclofosfamide CYP2B6/CYP2C9/ CYP3A4

Docetaxel CYP 3A4/5 – ABCB1Doxorubicine CYP 3A4 /CYP2D6- ABCB1

Epirubicine CYP 3A4

Erlotinib CYP3A4 /CYP1A2

Etoposide CYP3A4 /ABCB1/ABCC1-2

Fluorouracile Diidropirimidin deidrogenasi

Gefitinib CYP3A4 /ABCG2

Gemcitabine Deamminasi

Ifosfamide CYP2B6/ CYP3A4

Imatinib CYP2C9/ CYP 3A4 Irinotecan CYP 3A4 /UGT1A1 Methotrexate ABCC1/ABCG2 Mytomicine C N/A Oxaliplatin OTC2 Paclitaxel CYP 3A4 /CYP2C8 Tamoxifene CYP2D6/ CYP 3A4 Teniposide CYP 3A4 – ABCB1 Topotecan CYP 3A4 - ABCB2 Vimblastine CYP 3A4 – ABCB1 Vincristine CYP 3A4/5 - ABCB1 Vinorelbine CYP 3A4

• Panax ginseng Inhib. CYP2D6/CYP3A4 •Citrus aurantium no az. CYP2D6/CYP3A4

• Black pepper Inhib. CYP3A4/ABCB1

• Scutellaria Inib. CYP3A4/ABCB1

• Echinacea Induct. CYP3A4

• Garlic Inhib CYP3A4/CYP2E1

• Ginger no act CYP2C9

• Grapefruit strong inhib. CYP3A4

• Ginkgo strong induct. CYP2C19 Inhib CYP3A4

• Vitis Vinifera induct. CYP3A4

• Tea no act CYP2D6/CYP3A4 Green Induct. CYP1A2

• Kava Kava strong inhib. CYP2E1

• Licorice inhib. CYP3A4

• Silibum mariano no act CYP1A2/CYP2D6 /CYP3A4

• Peppermit Inhib. CYP3A4

• Panax quinq no az CYP2D6/CYP3A4

• S. Jont W strong induct. CYP1A2/CYP2C8 CYP2C9/CYP2E1/CYP3A4

• Turmeric no act CYP3A4

• Valerian no act CYP1A2/CYP2D6 /CYP3A4• Alfa glucan no act CYP1A2/CYP2D6 /CYP3A4

- ECHINACEA Attention with Camptothecins,Cyclophosphamide TK inhibitors,Epipodophyllotoxin,Taxans,Vinca (inductor CYP3A4)- GINKGO Attention with Camptothecins,Cyclophosphamide Taxans,Vinca(inhibitor CYP3A4/CYP2C19) Discourage Alkylanting agents,Cancer Antibiotics, platinum derivates (scavenger with free radicals)- GINSENG Discourage Estrogen receptor positive breast and endometrial (stimulus to growth)- GREEN TEA Discourage with Erlotinib ( CYP1A2 inductor)- SOY Avoid withTamoxifen (antagonist in inhibiting

growth), Estrogen receptor positive, breast- endometrium (stimulus to growth)

- S.JHON W Avoid with all drugs (inductor all CYP)- VALERIAN Attention withTamoxifen,Cyclophosphamide,Teniposide (CYP2C19 inhibitor)- VITIS VINIFERA Attention with Camptothecins,Cyclophosphamide TK inhibitors,Epipodophyllotoxins,Taxans,Vinca,Platinum (inductor CYP3A4 e scavenger with free radicals)

- Cisplatin Quercitin Coriolus versicolor Astragalo mebr. Silibum mariano AHCC AHCC Aloe vera Ginkgo biloba- Cyclophosphamide Astragalo membr. AHCC Withania Somnif. Coriolous Versic.- Adriamycin/Idarab Green Tea Green Tea AHCC - Fluorouracil/Il-2 Turmenic AHCC Green Tea/Astragalo Panax ginseng- Tamoxifen Green Tea/Panax quinqu.- Mitomycin C Panax ginseng- Taxol AHCC

DRUGS increased reduction antineoplastic action toxicity

We know that some natural substances have the ability to block proliferation genes neoplastic brain, COX-2 and 5-LOH, blockade of angiogenesis, activation of apoptosis, stimulation of Immune System. Moreover, these substances have the ability to pass the BBE and then to carry out their action, even in brain cells. These substances are the Boswellia Serrata, Curcumin phospholipid, the polydatin, alpha-and beta-glucans, the Ruta and Calcarea phosphoric (low-dose).

If we consider brain tumors then we realize that our hopes to have positive results are truly reduced and all the efforts in finding new therapeutic approaches must always be taken into consideration

PolydatynFor tissue distribution study, 18 rats were assigned randomly to three groups and were given piceid orally at 50 mg/kg. Heart, liver, spleen, lung, kidney, stomach, small intestine, brain and testis were collected at 10, 30 and 120 min after administration, respectively.After 10 min, the highest level was found in stomach, then in small intestine, followed by spleen, lung, brain, testis, liver, kidney and heart. At 30 min, the highest concentration of piceid was still detected in stomach. The amount of piceid in testis reached a peak level at 30 min. In the other organs, the content of piceid decreased to some degree at 30 min. - Determination of piceid in rat plasma and tissues by high-performance liquid

chromatographic method with UV detection- Biomed. Chromatogr. 20: 1260–1266 (2006)

- Polydatin, A Natural Precursor of Resveratrol, Induces β-Defensin Production and Reduces Inflammatory Response. INFLAMMATION 2013, Feb. 1

- A lipoxygenase inhibitor in breast cancer brain metastases. Flavin DF. Foundation for Collaborative Medicine and Research, Greenwich, CT J Neurooncol. 2007 Mar;82(1):91-3

- Nutritional and botanical modulation of the inflammatory cascade eicosanoids, cyclooxygenases, and lipoxygenases as an adjunct in cancer therapy Wallace JM. Nutritional Solutions, Inc., 2935 North, 1000 East, North Logan, UT 84341, USA Integr Cancer Ther. 2002 Mar;1(1):7-37

- Acetyl-11-keto-beta-boswellic acid (AKBA) is cytotoxic for meningioma cells and inhibits phosphorylation of the extracellular-signal regulated kinase 1 and 2. Park YS, Lee JH, Harwalkar JA, Bondar J, Safayhi H, Golubic M. Department of Neurosurgery, Cleveland Clinic Foundation, 9500 Euclid Avenue/NB2-120A, Cleveland, OH 44195, USA Adv Exp Med Biol. 2002;507:387-93

- Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: a prospective, randomized, placebo-controlled, double-blind pilot trialKirste S, Treier M, Wehrle SJ, Becker G, Abdel-Tawab M, Gerbeth K, Hug MJ, Lubrich B, Grosu AL, Momm F.Department of Radiation Oncology, University Hospital Freiburg, Freiburg, GermanyCancer. 2011 Aug 15;117(16):3788-95

Brain Tumor Treatment With Homeopathy Prasanta Banerji Homeopathic Research Foundation

Treatment with the medicines Ruta 6ch two doses a day, Calcarea Phosphorica 3D two doses a day

For the 91 cases treated exclusively with the Ruta /Calc Phos protocol, mean survival time was 92 months. For the 11 cases treated with conventional plus Banerji therapy, mean survival time was 20 months.

Banerji Protocol without any other treatment7% of the cases were completely cured with our therapy. 60% were improved, 22% achieved status quo, and 11% were worse or expired. Mean follow-up time was 23 months

after 6 mo from Rt.; with Xeloda and Boswellia- Curcumin- Polydatin- Lactofer- Oncophyt 8 and diet

Pz. 54 aa. mts. breast ca: protocol FEC and RT

70 year old man with Glioblastoma.

Radiotherapy and Temodal on April 2011

Temodal weekly; July 2011

20 months after Boswellia Serrata, Ruta 6 CH, Calcarea Phosphorica D7, Polydatin and Curcumin regimen and nutrition. Very good regression on December 2012

Brain lesions treated and under treatment

- Malignant Oligodendroglioma disease-free from 6 years

- Glioblastoma disease-free from 1- ½ year - Anaplastic Astocytoma disease-free from 1 year- Glioblastoma disease-free from 1 year- Glioblastoma stable from 1- 1/2 year

Actually there are other four patients with malignant brain tumor that are beginning the integrative treatment.

- Health spending cuts (short, medium and long term) - Reduction in hospitalization- Reduced costs for home care-  Reduction of working days lost-  Reduced costs for Companies- Increase in activities related to the well-being

EFFICIENCY OF EXPENSE

AHCC- Alfa/Beta Glucan- 43 cancer patients (median age 66,3 – range 35-85 years) were

selected and divided into two groups

- A group (31) will take 3 gr/day patients after surgery/chemotherapy in absence of desease- A group (12) will take 6 gr/day patients with desease or in progression

Parameters evaluated:- Blood count, liver function, inflammatory state, Ferritin, LDH,

lipid profile, Immunoglobulins, Dhea-s, lymphocytic typing.

All patients were evaluated at time 0-1-2 and 3 months and evaluated parameters and health status

POLYDATIN- 49 cancer patients were selected and divided into two groups (after sugery/chemotherapy)

- A group (24) took 160 mg/day (2 cps x 2 time per day) patients after surgery/chemotherapy in absence or stable desease (3 pat. with

mts)- A group (25) took 240 mg/day (2 cps x 3 time per day) patients with desease or in progression (4 pat. no desease) Parameters evaluated:- Blood count, liver function, inflammatory state, Ferritin, LDH, lipid profile,

Immunoglobulins, lymphocytic typing.

All patients were evaluated at time 0-1-2 and 3 months and the same parameters will be followed for 1 year

AHCC- Alfa/Beta Glucan

Patients n. 43 %

with mts 12 27

no desease 31 73

reduction 3 7

stable 7 16

progression 2 4

12 pt with mts

POLYDATIN

Patients n. 49 %

with mts 28 57

no desease 21 43

reduction 11:9-2 22

stable 11 22

progression 6 13

28 pt with mts

POLYDATIN- The results indicate the Polydatin can modulate the

Immune System:- About all patients showed an increase of lynphocytes

and neutrophyls.- 43 patients showed an increase of Th4, reduction of

Th8 and normalization or increase of NK-11 patients (9 with 6 pills and 2 with 4 pills.) showed a

further reduction or desapeared of lesions after a three months of integrative treatment.

-All patients non reported side effects with the Polydatin

AHCC:Alfa/Beta Glucan- The results that we are noticing in a group with

desease: Almost all patients (about 80%), reported a general

improvement of their condition.-10 patients showed an increase of lymphocytes and

neutrophyls.- 10 patients showed an increase of Th4, reduction of

Th8 and normalization of NK-Three patients in particular showed a further

reduction in size of lesions after a two months of integrative treatment.-All the patients reported mild difficulty in taking the

capsules, especially those who assume 12 per day

Of the 49 patients who used the Polydatin and of the 43 patients who used the Glucan-AHCC we can estimate a calculation to reduce health care spending

- Less use of pain medication and / or antiemetics A - Less use of stimulators of hematopoiesis (granulopoiesis and / or hematopoiesis) B- Reduction of blood tests C- Reduction of working days lost D

Calculated for the 14 patients in remission / reduction of injuries- A Euro 1.500- B “ 25.200- C “ 1.000- D “ 2.800Total “ 30.000

IJACM 2013“Effect of AHCC in women receiving adjuvant chemotherapy for breast

cancer: a retrospettive study” Dep. Hemat. And Oncol. University of Tokio

….we calculated the number of G-CSF usage per taxane infusion weekly (paclitaxel)….the AHCC group had significantly lower usage of G-CSF per administration of taxane therapy that did the control group (0.14 in the AHCC group and 0.41 in the control group , p=0.008)

Conclusions: AHCC has the potential to reduce the severity of neutropenia induced by breast cancer chemotherapy and the use of G-CSF during chemotherapy

Clinical evidence with Lactoferrin

Experimental Study (MULTICENTRIC)

Lactoferrin in Patient with higth risk of cancer or colon relapse (post polipectomy/after neoplasia)

-20 patients without ill after surgery-20 patiebts with intestinal polips-10 patients ttreated with surgery, chemotherapy e/o radiotherapy

Valutation at 0, 3, 6 e 12 mounth:

- Colonscopy, blood tests of the inflammation, lymphocyte immunophenotyping; DHEA-S; Ferritin; Fibrinogen; Cortisol.

Safety study with

- Mangostano (METABOLIC SYNDROME)

- Colostro di capra (ENHANCING WHITE CELLS)

- Ossigeno in gocce (WELLNESS/PREVENTION)

Integrative therapy is needed to cure cancer

Integrative therapy increase compliance with reduction side effects

Integrative therapy is good for prevention and protection for release

Integrative therapy increase expected lifetime Integrative Oncology is our new arm

Learn……………..to care for the best

……..to continue to dream