General principles of cancer

chemotherapy

Silvio Monfardini,MD

Director Geriatric Oncology Program

Istituto Palazzolo,Fondazione Don

Gnocchi,Milano

DISCLOSURE

No conflict of interests

Can cancer chemotherapy be

prescribed and administered by

Geriatricians?

Cancer patients with advanced

Neoplastic disease in a Geriatric ward

No Medical Oncologists available

Centralyzed preparation of drugs

Catharanthus roseus (Madagascar

Periwinkle) :

Vinca alkaloids :viblastine,vincristine

Podophyllum peltatum

:etoposide teniposide

Camptotheca acuminata

:Topotecan

Taxus brevifolia

:Taxol

The last 50 years.

Empirical drug screening of

cytotoxic agents against

uncharacterized tumor models

Target-oriented drug screening of

agents with defined mechanisms of

action.

Mechloretamin

Methotrexate6-mercaptopurinBusulfan

ClorambucilCiclophophamide

Vinblastin, vincristinFluorouracile, actinomycinaDMelphalan

Procarbazin, 6-thioguaninCytosin arabinosideAdriamicyn

VAMP e POMP in acute leukemias

First adj chemother with actinomycin D in Wilms Tumor

MOPP for Hodgkin’s disease

1950

1945

1955

1960

1965

1970

Bleomycin, dacarbazine

CCNU, BCNU, cisplatin

EpirubicinEtoposide, mitoxantrone

Ifosfamide + mesnaCarboplatin

VinorelbinPaclitaxelDocetaxel

Camptotecin

TARGETED THERAPY

1970

1975

1980

1985

1990

1995

ABVD in Hodgkin’s disease

adjuvante CMF in breast. Ca.

adjuvante therapy forosteosarcoma

Bone marrow transplantation

PVB in testicular tumors

Initial neoadjuvant chemother in various non resectable tumors

Autologous bone marrow transplant with GM-CSF

Combination of chemotherapeutic drugs

with specific molecular targets

(Herceptin, Iressa)

Drug Development time line

2-4 yrs 3-6 yrs

The goal of chemotherapy in

patients with advanced cancer

Chemotherapy objective response

rates(CR,PR) are leading to an

increase in survival

And generally to an improvement

in the quality of life

Gestional choriocarcinoma

Testicular cancer

Hodgkin’s lymphoma

Aggressive non-Hodgkin’s lymphoma

ALL,AML

Tumors in which cure by chemoterapy is possible in

advanced-stage disease

Tumors in which useful responses by

chemoterapy are possible in advanced-stage

disease

• Breast Carcinoma

• Lung Carcinoma

• Colorectal Carcinoma

•Ovarian Carcinoma

•Prostate Carcinoma

Cancer chemotherapy

Not only for advanced disease but also:

Adjuvant

Neoadjuvant

COMBINATION CHEMOTHERAPY :

a strategy to increase response and tolerability and to

decrease resistance

1) use drugs with non overlapping

toxicities so that each drug can be administered at near-

maximal dose;

2)combine agents with different mechanisms of action

to inhibit the emergence of broad spectrum drug

resistance

Objective responses in advanced

solid tumors have usually a limited

duration.

WHY?

The problem of cell resistance to

anticancer chemotherapy

Cancer chemotherapy resistance is

the innate and/or acquired ability of

cancer cells to evade the effects of

chemotherapeutics

Chemotherapy Acronyms

Alphabetical Search

ABVD Hodgkin's Lymphoma

AC Breast Cancer

AD Sarcoma

ADE AML

ADOC Thymoma

NCI. A to Z List of Cancer

Drugs

This list includes more than 200

cancer drug information summaries

How many regimens in a

pocket ?

A modern trend for Medical

Oncology:various subspecialists

Breast,Gi,Gyn,GU,Lung,soft

tissue,brain,HN,Hematol. Etc

More experience with one drug or

combination rather than with another

one

Side effects of chemotherapy

1. Immediate

- Anaphylactic shock

- Cardiac arrhythmia

- Pain at the site of injection

Side effects of chemotherapy

2. Early

- Nausea, vomiting

- Fever

- Hypersensitivity reactions

- Flu-like syndrome

- Cystitis

3. Intermediate (within days)a) Bone-marrow depression

- after 1-3 weeks (majority of immunodepressive drugs)- after 4-6 weeks (nitrosoureas)

b) Stomatitis

c) Diarrhoea

d) Alopecia

e) Peripheral neuropathy, loss of reflexes

f) Paralytic ileus

g) Renal toxicity

h) Immunosuppression

Side effects of chemotherapy

4. Late (within months)

- Injury to vital organs or system (heart-

adriamycin; lung-bleomycin and busulfan;

liver-methotrexate)

- Effects on reproductive capacity

(amenorrea, decreased sperm concentration)

- Carcinogenic effects

From L Balducci

Mediterranean J 2010

Toxicity, the reasons why

Due to a general inability to differentiate between normal and neoplastic cells,

little selectivity exists for anticancer drugs

Damage to the bone marrow, gastro-intestinal tract, or hair follicles: anticancer drugs kill actively dividing cells.

Usually manageable and reversible

Unfortunately, several of the most important anticancer drugs also damage tissues in which the growth fraction is relatively

small.

Cancer chemotherapy administration

1. Specific knowledge and experience of the side

effects and toxicities of the various cytostatic

drugs

2. Broad medical knowledge

3. Knowledge of the natural course of all

neoplastic diseases

4. Staging and therapeutic strategy

WHY GERIATRICIANS

SHOULD BE INFORMED

ON SIDE EFFECTS OF

CHEMOTHERAPY?

Why Geriatricians should be informed on side effects of

chemotherapy

• 1)Follow up of patients receiving chemotherapy

• 2)Preexistent comorbidity and possible effect on

that organ ( example cardiac insufficiency and

cardiac toxicity)

• 3)Limits to chemotherapy administration(example

anemia,ipoalbuminemia)

Which are the physiologic

changes with aging associated

with possible increased

chemotherapy toxicity

Physiologic changes and consequences of Chemotherapy

associated with aging in Elderly Cancer Patients

PHYSIOLOGIC CHANGE

• Slower repair of DNA

damage

• Reduced stem-cell mass and

Hematopoiesis

• Reduced functional reserve

of organ

Greater anemia

Decreased nephron mass

CHEMOTHERAPY

• Prolonged toxicity

• Slow recovery of blood and

mucosal cells

• Risk of organ failure with

additional tissue loss

Increased levels of circulating

drugs

Reduced drug excretion

Should Geriatricians know also about ?

• Treatment of complications of advanced

neoplastic diseases

•Management of side effects of

chemotherapy

•Prediction of toxicity?

Management of main toxicities from

chemotherapies in patients followed by

Geriatricians

Leukopenia, infection

Anemia

Mucositis

Cardiac toxicity

Clinical trials and drug toxicity in the elderly. The experience

of the ECOG Group. Cancer , 1983.

1Review by Balducci (2000)2Baraldi-Junkins (2000)3Aapro (2002)

Anemia in the Elderly

When admitted to hospital, 50% of elderly patients present with anemia compared with 40% of younger

patients2

Older individuals are also at increased risk for myelosuppression due to cancer therapy (CT)1

Anemia often overlooked in elderly cancer patients due to expectation that fatigue is associated with ‘aging’ and

is physiologic vs pathologic3

Anemia and Hypoalbuminemia lead to increased

toxicitySeveral circulating antitumor drugs(antracyclins,

epipodofillotoxines ,taxanes,camptotecins) are

bound to red cells and to albumin.

If there is a decrease of red cells as well as of

albumine ,

the unbound drug concentration increases

A low hemoglobin concentration is therefore an

independent risk factor for toxicity.

And the same for albumin

Changes in hepatic metabolism in older patients

leading to possible increased toxicity

• Reduced Blood Flow

• Reduced liver dimensions

• Changements in the microsomial Cytocrom P450( age after 70)

-Inductors P450: sex steroids , Fenobarbital

-Inhibitors P450: omeprazol,erithromycin

• Polipharmacy

DRUGS AFFECTED BY CHANGES IN HEPATIC

METABOLISM (Cancer care in the older population,ASCO

curriculum)% dose reduction for hepatic dysfuction

Mild

(bili*1.5-3.0;SGOT**60-180)

Moderate

(bili*3.1-5.0;SGOT**>180)

Severe

(bili*>5.0)

Anthracyclines

Andriamycin

daunorubicin

50%

25%

75%

50%

Omit

Omit

Taxanes Omit Omit Omit

Vinca Alkaloids

Epipodophyllotoxins 50% Omit Omit

Methotrexate 0% 25% Omit

Cyclophosphamide 0% 5% Omit

5-fluorouracil 0% 0% Omit

Excretion of drugs•A decline in glomerular filtration rate (GFR) is

one of the most predictable changes associated

with age

•Additional effect of comorbid conditions on

renal function

•Serum creatinine alone is insufficient as a

method of renal function evaluation : creatinine

clearance should be evaluated in every elderly

cancer patient.

Drugs requiring dose modification in renal

dysfuction(Cancer care in the older population,ASCO curriculum)% dose reduction based on Crcl(ml/min)

30-60 10-30

Cardiotoxicity / Cardiomiopathy

• Risk Factors.

- previous RT to the chest wall

- preexisting cardiac disease

- age > 65 years

• Responsible drugs:

- Antracyclines - Trastuzumab

- 5-Fluorouracil

- Paclitaxel

Anthracycline cardiotoxicity in the elderly cancer

patient: a SIOG expert position paper

Doxorubicin-induced cardiotoxicity is related with

cumulative dose

Conventional doxorubicin-related CHF was

5% at a cumulative dose of 400 mg/m2,

16% at a dose of 500 mg/m2

26% at a dose of 550 mg/m2

Age was risk factor,

hazard ratio (HR) of 2.25 in patients older than 65 years

compared with those aged 65 years or younger.

Central and peripheral nervous system possible

toxicity of chemotherapeutic agents•

• Peripheral nervous system (distal peripheral

neuropathy ) : cisplatin, vincristine, taxanes, and

thalidomide

•

• CNS (encephalopathy of various severities):

methotrexate, vincristine, ifosfamide,, fludarabine,

cytarabine, 5-fluorouracil, cisplatin ,cyclosporine and

the interferons

Bone marrow Tolerance to

Chemotherapy

Lessens With Age•

• With age comes increased risk of

– neutropenia and its complications

7,2

4,5

0,9

17,1

9,2

4,0

Toxicity of adjuvant chemotherapy

for breast cancer increases with age

Crivellari D, et al. J Clin Oncol. 2000;18:1412-1422.

20

15

10

5

0

Patients (%)

Grade 3 toxicityany type

Grade 3 hematologic toxicity

Grade 3 mucositis

65 years (n = 76)

Postmenopausal women, “classic” CMF q28d × 3

In summary,chemotherapy complications are more common in the elderly

• Myelosuppression1: neutropenia, thrombocytopenia,

anemia

• Mucositis2: oropharyngo-esophagitis, enterocolitis

• Cardiomyopathy3

• Peripheral neuropathy1

• Central neurotoxicity4: cognitive decline, delirium,

cerebellar dysfunction

•1. Balducci The Oncologist 2000;

2. 2. Stein Cancer 1995

3. Von Hoff Ann Intern Med 1979; 4. Gottlieb

Cancer 1987

But:some drugs are elderly friendly

• Some drugs are better candidates for elderly:

• vinorelbine,

• gemcitabine,

• carboplatin,

• Caelix

Can cancer chemotherapy be

prescribed and administered

by Geriatricians?