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

INTEGRATIVE ONCOLOGY IN ITALY

Massimo Bonucci M.D.

ITALIAN –ISRAELI-US WORKSHOP CLINICAL oncology November 8-2013 Rome

President A.R.T.O.I.Chief of surgical pathology department

Oncology outpatientSan feliciano hospital - rome

In Italy In Italy we do not have public facilities where you can practice the Integrated Oncology. There are two realities hospital for Integrative Medicine in Italy: 1 - Hospital of Pitigliano in Tuscany 2 - Hospital of Merano in South TyrolIn both structures are practiced complementary therapies such as acupuncture, homeopathy, osteopathy, shiatsu massage and other practices to reduce pain, fatigueBut in none of these structures is administered antitumor therapy

In Italy In some Regions as Marche, Friuli

Venezia Giulia, Umbria, Emilia Romagna, were made proposals by law for the assessment of the use of Complementary Medicine.

In this last year through the

collaboration of some colleagues in the Public Facilities are going to

start the assessments for integrative observational studies.

In Italy

In some Private Hospital instead you can take advantage of

integrative treatments: chemotherapy, homeopathy,

herbal medicine, hyperthermia and other treatments.

Often, however, patients are treated with chemotherapy in a Public Hospital and then arriving

in the private practices of physicians who practice

integrative therapy, primarily homeopathy, acupuncture, herbal

medicine.

In Italy

But even in this case there are not many doctors who treat cancer patients with all complementary therapies, but are limited to their specific knowledge: homeopathy, herbal medicine, and so on.

The integrative treatments are mainly the reduction of side effects: effects of chemo and radiation therapy.

There are also economic reasons of the patients for this type of choice.

The information derived from the census EPAAC:

• Patients in the public arena are mainly sent from the

Departments of Oncology

• The CM most commonly used are:

• 1 – acupuncture; 2 -MTC; 3 - herbal medicine; 4- homeopathy;

5 – homotossicology; 6 - anthroposophy ;

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 reduction

6- gastrointestinal disorders, sleep disorders

7- 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

In Italy In my case, or in that of some other

collegues, as oncologists, the treatment concerns not only in research the

reduction of side effects but also the ability to associate natural substances

with the intent to increase positive feedback.

My patients are sent also to other colleagues for complementary

treatments: hyperthermia, acupuncture, psycho-oncology, nutrition.

Questions1- Patient who is interested to receive nutritional supplements before or during chemotherapy (clinical dilemma: Is there sufficient evidence to support the use of herbs and dietary supplements during chemotherapy for QOL improvement? How do you ensure safety in regard to supplement-chemotherapy interaction?

2- Improving patient's quality of life during radiation treatment (clinical dilemma: In which cases integrative medicine is indicated during radiation treatment? How  do you provide complementary medicine in clinical radiation setting if evidence-based medicine is lacking?)

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 3A4Bleomycin N/A

Busulfan CYP 3A4

Capecitabine Carbossilesterasi/Citidinesterasi

Cisplatin OCT2/ABCC2

Cyclofosfamide CYP2B6/CYP2C9/ CYP3A4

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

Epirubicine CYP 3A4Erlotinib 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

Cancer Res. 2010 October 1; 70(19): 7392–7399. Published online 2010 September 14. Clinical Pharmacology of Resveratrol and its Metabolites in Colorectal Cancer

Patients Ketan R Patel,1* Victoria A Brown,1* Donald JL Jones,1 Robert G Britton,1 David

Hemingway,1 Andrew S. Miller,1 Kevin P. West,1 Tristan D Booth,2 Marjorie Perloff,3 James A Crowell,3 Dean E Brenner,4 William P Steward,1 Andreas J Gescher,1 and Karen Brown1

Levels of resveratrol and its metabolites were consistently higher in tissues originating in the right side of the colon compared to the left. Consumption of resveratrol reduced tumor cell proliferation by 5% (P=0.05).

The results suggest that daily oral doses of resveratrol at 0.5 or 1.0 g produce levels in the human gastrointestinal tract of an order of magnitude sufficient to elicit anti-carcinogenic effects.

Resveratrol merits further clinical evaluation as a potential colorectal cancer chemopreventive agent

Antiossidanti, Vitamina ASelenio, Folati, PolifenoliCarotenoidi

Ac grassi Omega-3, Curcumina,riduzione di peso

Restrizione caloricaBassa insulinemiaFibre e Frutta

Enzimi Induttori Fase I° e II°Isotiocianati

Alimenti ricchi diantiossidanti, Vitamina E

Fibre, riduzione di pesoSulforafano, Soia

Grasso, Dieta Americana, Bassi folati, basso introduzionevegetali e frutta

Grasso, Ac grassi Omega-6, Obesità

Vitamina A, Ac. Grassi Omega-3, Carotenoidi, Polifenoli, Isotiocianati

Ac grassi Omega-6, grasso,eccesso alimentare, cibi che alzano Insulina

Saccarina, nitrosammine, amineEterocicliche, muffe

Ferro, Ac grassi Omega-6, acido Arachidonico

Grasso, obesità

DannoDNA

Infiammazione

Apoptosi

Prolifer. Cellulare

Esposizione ai carcinogeni

Stress ossidativo

Ormoni

Patient who is interested to receive nutritional supplements before or during chemotherapy (clinical dilemma: Is there sufficient evidence to support the use of        herbs and dietary supplements during chemotherapy for QOL improvement? How do you ensure safety in regard to supplement-chemotherapy interaction?

-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

Patients n. 43 %

with mts 12 16

no desease 31 84

reduction 3 7

stable 7 16

progression 2 4

12 pt with mts

- 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

- 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

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

after 6 mo from Rt.; with Xeloda and Boswellia- Curcumin- Polidatin- 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 Solforica D7, Polydatin and Curcumin regimen and nutrition. Very good regression on December 2012

Clinical evidence with Lactoferrin

Experimental Study

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

- Colostro di capra

- Ossigeno in gocce