Metronomic Chemotherapy

Metronomic

Chemotherapy

IAAHPC SAN DIEGO, OCTOBER

3-6,2015

ALICE VILLALOBOS, DVM, FELLOW EMERITUS NAP

PRESIDENT EMERITUS: SOCIETY FOR VM ETHICS

PAST PRESIDENT: AM.ASSOC. HUMAN-ANIMAL BOND VETERINARIANS DIRECTOR: PAWSPICE & ANIMAL ONCOLOGY CONSULTATION SERVICE

WWW.PAWSPICE.COM [email protected]

Metronomic

Chemotherapy

What is it?

How does it work?

Metronomic chemotherapy

(mCTx) 

The use of very low doses of anticancer drugs 

given at a constant daily 

or alternate day schedule 

with no rest periods. 

What is Different about mCTx?

mCTx goes against typical CTx

CTx is based upon the concept of:

◦

MTD (maximally tolerated dose)

◦

DLT (dose limiting toxicity)

◦

The largest dose deliverable

◦

With reversible adverse events over

Rationale for mCTx Use

There is enough research

rationale to justify its use in

veterinary medicine.

There are a few limited

randomized clinical trials to

prove that mCTx is effective

in dogs and cats.

The implication is that tumor

Angiogenesis

All types of cancers (sarcomas, carcinomas

and adenocarcinomas) except blood cancers

(leukemia and lymphoma) recruit capillaries

and blood vessels to grow.

This process is called angiogenesis. If we

change the cancer microenvironment and

reduce or cut off cancer’s recruitment of its

blood supply (anti-angiogenesis), we may slow

down the cancer’s fatal agenda.

Center for B iomedical Continuing Education

Proteomics

Genomics

Metabolomics

Cell Signaling:

Receptors and    

Pathways to target

Pharmacogenomics 

Microbiome 

Microbiota

Rationale for mCTx

Rediscovery of what has been called

continuation or maintenance therapy (MTx)

MTx as been part of the curative regimens

for patients, especially children with acute

lymphoblastic leukemia for over 50 years.

MLM: Masitinib

Lomustine

Meloxicam

Rationale for mCTx

mCTx takes

TIME

into account

A more critical variable than dose

Once an effective concentration of

drug is achieved and maintained

continuously

Using a LD 10,000 will not get more

mileage than the LD 100/unit over

TIME

.

Prospective trial of metronomic chlorambucil chemotherapy in dogs with naturally occurring cancer, T.N. Leach, M.O. Childress, S.N. Greene, et. al.

Accumulating evidence shows that there is an MEC (Minimally Effective Concentration) that can be applied to the patient for a prolonged period of time using mCTx.

The paradigm shift, even for conventional cytotoxic drugs, is that in the generation of AUC (area under the curve) as a measure of drug exposure (Concentration x Time)

TIME

is a critical parameter,

Success of mCTx

Tumors are a heterogenous

tissues; containing cancer cells,

inflammatory cells, immune cells,

cancer associated fibroblasts

(CAF), pericytes, endothelial cells,

etc.

The growth and spread of the

tumor may be controlled by

primarily controlling or

modulating specific cells other

than the cancer cell.

. 

Success of mCTx

Low dose provides some selectivity in

sparing normal tissues

Less toxicity to the patient

Minimally Effective Concentrations

(MEC) successful over time

mCTx in Cancer

May help patients live longer

May achieve durable stable disease

May be effective in the inhibition of

common mechanisms & pathways

◦

Angiogenesis

◦

Mitosis

mCTx

Viable palliative option for veterinary cancer patients at Dx and at any Stage

◦ Resistant ◦ Inoperable ◦ Advanced

◦ Lest costly for clients with financial problems

Cancer patients that are entered into “Pawspice” (pet hospice) management programs may derive benefit.

Decision Making for mCTx

Use the recommended framework

for ethical decision making, as

described in the CVC Central

Proceedings paper titled,

Over-treatment at a Veterinary Cancer

Referral Clinic

.

http://www.ethics.ubc.ca/people/mc

donald/conflict.htm

.

Recurrence

There comes a time when the pet’s family declines previously successful standard recommendations such as salvage surgery, rescue chemotherapy or radiation therapy. The family may feel that the first round of treatments took a lot out of their pet and that their dog or cat might not be able to handle further aggressive treatments.

Some pet owners feel that they just do not want to put their pet through the demands of another round chemotherapy again.

Good News About mCTx

Very well tolerated by most patients

Inherent low toxicity

Offers a safer, more gentle approach

Fragile & geriatric cancer patients with

compromising comorbidities, dehydration,

cachexia or malnourishment may benefit.

Antiangiogenesis Effect of mCTx

Documented to target growing tumor

vascular endothelial cells.

Since mCTx targets tumor

vasculature, it may achieve an

antiangiogenesis effect and

stabilization of disease.

Continuous Therapy

May be curative in some patients.

Some STS respond to weekly vincristine

Repetitive daily steroids helps LSA,

Leukemia

ALL cases survive on mCTx with weekly

methotrexate and daily 6 mercaptopurine

LD-Cyclophosphamide in combo protocols

LD-Methotrexate helps MGAC & rat OSA

Lazarus Davis ALL-CLL: WBC 650,000 Entered Pawspice 3X 5 Year Survival ! Sable Davis MCT, cHSA, MGAC

AntiangiogenicmCTx

antiangiogenic action:

◦ NSAIDs, COX-2-inhibitors block PGE2 (proangio) ◦ Minocycline, Doxycycline (anticollangenase) ◦ Tamoxifen, Metformin (MDR1 suppression)

◦ Small Molecule Kinase Inhibitors (Kinavet, Palladia)

Oral Antineoplastic Agents

Cytoxan™

Leukeran™

Alkeran™

Xeloda™

CCNU™ (

Lomustine)

Cyclophosphamide

Low dose cyclophosphamide may

selectively remove T-regulatory

lymphocytes but not cytoxic T-cells,

and be anti-angiogenic.

Metronomic dose in vivo controlled

a tumor that was resistant in vitro.

Target is likely a component of the

tumor microenvironment rather than

the cancer cell itself.

Repositioning known Rx’s

NSAID’s Metformin Astazanthins

Kinase Inhibitors: Masitinib, Toceranib, Dasatinib Immodium

Rapamycin Mebendazole

Bisphosphonates: pamidronate, zoledronate,etc. Beta Blockers: for ovarian & types of cancer

Histone Deacetylase (HDAC)

Acetylation vs. Deacetylation of Histones A-Histones condense chromatin

Wraps chromatin to heterochromatin Enhances genome stability

Represses transcription

Regulates the expression of genes D-Histones increase carcinogenesis

HDAC Inhibitors for mCTx

Valproic Acid: anti seizure Rx

◦

Inhibits tumor cell invasion

◦

Inhibits tumor cell proliferation

◦

Inhibits angiogenesis

◦

Enhances chemosensitivity

◦

Do not use with NSAIDs, protein

Epigenesis & Epigenetics

Development from a simpler to more

complex forms through division and

progressive differentiation of the

component cells.

Epigenetics

Epigenetic Changes in Cancer

Chemical modification of DNA or

histones can lead to changes in

DNA stability and gene expression

These processes are DNA and

histone methylation and histone

de-acetylation

May also include transcription

factor interactions, cell-cell

interactions, and cell-matrix

interactions

J. Bryan, DNA Methylation in Cancer, Theilen Tribute Symposium 2008

Evidence Based Rationale mCTx

Epigenetic changes are STABLE, HERITABLE, and REVERSIBLE covalent alterations of chromatin.

DNA methylation changes can cause genomic instability (global hypomethylation) and gene

silencing (promoter hypermethylation)

DNA methylation changes may be the earliest cellular alterations that initiate malignancy.

This is a new theory for cancer development. The epigenetic disruption of progenitor cells.

Epigenetic disruption of progenitor cells Initiating mutation

Genetic and epigenetic plasticity

Feinberg, Ohlsson, Henikoff (2006) Nat Rev Gen 7: 21-33

Critical Pathways Dysregulated

Normal gene

Hypomethylated, normally imprinted gene

Hypermethylated gene Normal gene

Hypomethylated, normally imprinted gene

Rationale for mCTx

Restoring global methylation

levels

Can be a goal of preventive strategies. Can be a goal for metronomic CTx.

May be achieved with chemoprevention? May be achieved with nutrigenomics?

OSA Left humerus Tx: Pain Rx

mCTx:

Weight bearing for 10 mo.

Dr. Alice Villalobos 

mCTx for Lymphoma

Using mCTx for lymphoma patients is not intended to induce remissions.

It is best to use mCTx following induction protocols when the patient is in CR

Metronomic cytoxan, chlorambucil, melphalan, procarbazine, lomustine,

dexamethasone may be helpful in sustaining CR, PR.

Might achieve stable partial remissions [SPR]. When the patient relapses; aggressive drug doses are required for re-induction.

Canine cancer patients with any

type of carcinoma, may benefit

from the use of low dose oral

Xeloda™ (capecytabine). Toxic

in cats!!

◦

a derivative of 5-fluro-uracil)

◦Given PO at 250mg/M2/day

low dose cytoxan: 10-12/M2 PO

q 24-48 hr. (with broth or fluids)

Xeloda™ for K-9 mCTx

250mg/M2 in dogs on a daily basis

or 500mg/M2 on an alternate day basis Canine carcinoma patients may receive it indefinitely at these low doses.

Cancer patients on mCTx need CBC parameters evaluated q 14-30 d

Continue mCTx protocol if CBC values remain within or just below normal limits.

Rusty Kraft: 11 YO Mx GR Huge Pulmonary Mass Family Declined Sx

Elected Pawspice & mCTx

Xeloda®, Cytoxan®, Doxy

Combination of mCTx & CTx

Protocol with metronomic Xeloda™ and

IV injections of Gemzar™ at 200 mg/M2 on

alternate weeks for dogs with:

◦ Hepatocellular carcuinoma ◦ Intestinal carcinoma

◦ Pancreatic carcinoma ◦ Anal sac carcinoma.

Soft Tissue Sarcoma

doxycycline, in combination with IV carbo, metro-nomic CTx using low dose cytoxan, Tamoxifen, etoposide, etc.

Hemangiosarcoma cases may benefit with: T-K Inhibitors and histone deacetylase

inhibitors: SAHA, VPA, mCTx Leukeran, etc.

(Cohen 2004) (Bryan 2008) (Leach

2012) (VCS 2013, 2014)

Expanding the Philosophy of mCTx

There is a need to avoid using certain chemotherapeutic drugs that predictably cause a high rate of adverse events at their MTD.

CTx has a bad reputation due to the adverse effects at MTD.

Some commonly used CTx drugs have inherent toxicity to certain organs and species (not safe in cats vs. dogs).

Consider expanding the metronomic

philosophy into every day CTx.

When using drugs with high risk of

AE’s it is reasonable to divide the

MTD into 2-4 smaller doses which

can be administered over 2 to 7 days.

Use this example: drink a pint of

liquor all at one time in the exam

room or sip it over a few days.

mCTx: Future Combinations

◦

Soluble decoy receptors

◦

Antibodies

◦

Small molecule therapy

◦

Tyrosine Kinase Inhibitors

◦

Masivet, Palladia

Products to block Angiogenic

Factors & Receptors

mCTx: Future Combinations

Angiogenesis Inhibitors

◦MMP inhibitors ◦VEGF Vaccines

◦Gene therapy to modify endothelial cells ◦Vascular Toxins

◦Angiostatin, Endostatin,

Thrombospondin, etc.

Combine mCTx with ImNTx

For older pets at high risk for cancer For post operative cancer patients For lymphoma management

As an adjunct to standard protocols

Combine Chemoprevention and ImNTx

For all dogs over 2 years of age

For cats prone to immunosupression

Resources:

Bryan, J.N., DNA Methylation in Cancer: Techniques and Preliminary Evidence of

Hypermethylation in a Canine Gene, www.cancer-therapy.org, Theilen Tribute

Symposium Proceedings, June 15, 2008, Special Section, Clinicians Brief July 2008, p 36.

Cohen, L.A., Powers, B., Amin, S., Desai, D., Treatment of Canine

Hemangiosarcoma with Suberoylanilide Hydroxamic Acid, a histone deacetylase Inhibitor, Veterinary and Comparative Oncology, Vol. 2, No. 4, December 2004, p 243-248.

Kamen, B.A., M.D., Ph.D., METRONOMIC THERAPY: A re-discovery of basic principles & better use of old drugs, Vet. Cancer Society NL, Summer, 2008 p 6-7. Martin, C.K., et al, Combined zoledronic acid and meloxicam reduced bone loss and tumor growth in an orthotopic mouse model of bone invasive oral squamous cell carcinoma, Journal of Veterinary and Comparative Oncology, Vol. 13, No. 3, September 2015.