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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