General principlesof cancer chemotherapy...The goal of chemotherapyin patients with advanced cancer...

General principles of cancer

chemotherapy

Silvio Monfardini,MD

Geriatric Oncology Program

Istituto Palazzolo, Fondazione Don Gnocchi,

Milano

Disclosure

No conflict of interests

Giotto. Evil exorcism in Arezzo

WHY GERIATRICIANS SHOULD BE

INFORMED ON (SIDE EFFECTS OF)

CANCER CHEMOTHERAPY?

Why Geriatricians should receive some

information on cancer 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)

4) Balance on advantages/disadvantges

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

• Breast Carcinoma

• Lung Carcinoma

• Colorectal Carcinoma

• Ovarian Carcinoma

• Prostate Carcinoma

Tumors in which useful responses by

chemoterapy are possible in advanced-

stage disease

Development of Cancer chemotherapy

resistance : ability of cancer cells to evade the

effects of chemotherapeutics

Objective responses in advanced solid

tumors have usually a limited duration

From L Balducci Mediterranean J 2010

In 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.

Catharanthus roseus (Madagascar

Periwinkle)

Vinca alkaloids: viblastine,vincristine

Podophyllum peltatum

: etoposide, teniposide

Camptotheca acuminata

Topotecan

Taxus brevifolia

: Taxol

Mechloretamin

Methotrexate6-mercaptopurinBusulfan

ClorambucilCiclophophamide

Vinblastin, vincristinFluorouracile, actinomycinaDMelphalan

Procarbazin, 6-thioguaninCytosin arabinosideAdriamicyn

VAMP e POMP in acute leukemias

First adj chemother with actinomycinD in Wilms Tumor

MOPP for Hodgkin’s disease

1950

1945

1955

1960

1965

1970

Bleomycin, dacarbazin

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 marrowtransplant with GM-CSF

Combination of chemotherapeutic drugs

with specific molecular targets

(Herceptin, Iressa)

Drug development Timeline

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

How many regimens in a pocket?

Example on the memento on dose and schedule

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. Stein Cancer 1995

3. Von Hoff Ann Intern Med 1979;

4. Gottlieb Cancer 1987

Clinical trials and drug toxicity in the elderly. The experience of the ECOG Group.

Cancer, 1983.

Main toxicities after chemotherapy possibly

requiring therapy

in patients followed by Geriatricians

Leukopenia, infection

Anemia

Mucositis

Cardiac toxicity

Geriatricians following also cancer patients should know

The type of 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

Side effects of chemotherapy

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

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

b) Stomatitisc) Diarrhoead) Alopeciae) Peripheral neuropathy, loss of reflexesf) Paralytic ileusg) Renal toxicityh) 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

Side effects of chemotherapy

Medical Oncologists: Specific knowledge and experience of

the side effects and toxicities of the various cytostatic drugs

Geriatricians know more: changes with aging associated

with possible increased chemotherapy toxicity: reduced

functional reserve (liver, kidney, heart),greater anemia,

ipoalbuminemia

Cancer chemotherapy administration

in older patients

Geriatricians should know which drugs may

cause problems in case of:

• Renal excretion: Cisplatin, Carbo, MTX, CTX,

Capecitabine

• Liver metabolism: antracyclines, taxanes, CTX, MTX,5-FU

• Anemia/ipoalbuminemia: antracyclines,taxanes

• Cardiomyopathty / cardiac function: antracyclines, Trastuzumab 5-FU, Taxol

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

• 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 <10

cisplatin 50% Omit Omit

carboplatin 20% 30% 30%

cyclophosphamide 0% 0% 50%

bleomycin 25% 25% 50%

methotrexate 50% Omit Omit

Nitrosoureas

Capecitabine

Omit

75%

Omit

Omit

Omit

Omit

• Reduced Blood Flow • Reduced liver dimensions• Changements in the microsomial Cytocrom P450

(age after 70)- Inductors P450: sex steroids , Fenobarbital- Inhibitors P450: omeprazol,erithromycin

• Polypharmacy

Changes in hepatic metabolism in older patients

leading to possible increased toxicity

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

Several 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

Why Anemia and Hypoalbuminemia may lead to

increased toxicity

Cardiotoxicity / Cardiomiopathy

Risk Factors

• previous RT to the chest wall• preexisting cardiac disease• age > 65 years

Other dugs potentially cardiotoxic:5-fuorouracil, Taxanes, Trastuzumab, Pertuzumab

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 a risk factor,

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

compared with those aged 65 years or younger.

Bone marrow Tolerance to Chemotherapy

Lessens With Age

• With age comes increased risk of

- neutropenia and its complications

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

Toxicity of adjuvant chemotherapy for breast cancer

increases with age

7,2

4,5

0,9

17,1

9,2

4,0

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

20

15

10

5

0 Grade 3 toxicity

any type

Grade 3

hematologic toxicity

Grade 3

mucositis

<65 years (n = 223)

>65 years (n = 76)

Postmenopausal women, “classic” CMF q28d ×××× 3

Pa

tie

nts

(%

)

Some drugs are better candidates for elderly:

• Vinorelbine,

• Gemcitabine,

• Carboplatin,

• Caelix

Chemotherapy complications are more

common in the elderly

But: some drugs are elderly friendly