Cancer Chemotherapy

Dr.Ammar Rasoul
Clinical Oncologist
MBChB. DMRT. MSc
ISCO,ESMO,ASCO MEMBER
 History of chemotherapy

 Chemotherapy is the treatment of cancer with drug therapy –

traditionally this applies to cytotoxic drugs
 Over the years more classes of drugs have been introduced to
treat cancer..
– Hormones
– Steroids
– Now… targeted drug therapy eg
 Monoclonal antibodies
 Drugs inhibiting angiogenesis
 Drugs targeting gene expression
 Signal Transduction inhibitors
 Cytokines
History :
The first use of drugs to treat cancer was in
the early 20th century, although it was not
originally intended for that purpose.
Mustard gas was used as a chemical warfare
agent during World War I and was discovered
to be a potent suppressor of hematopoiesis . A
similar family of compounds known as
nitrogen mustards were studied further
during World War II . Therefore, in 1942,
several patients with advanced lymphomas
were given the drug by vein, rather than by
breathing the irritating gas. Concurrently,
during a military operation in World War II,
several hundred people were accidentally
exposed to mustard gas .
 History of Chemotherapy

 In 1940s investigators used nitrogen mustard to treat lymphoma

 Folic acid antagonists then used to treat children with ALL

 1940-70 several cytotoxic drugs from natural sources had been

discovered

 Since the 1970's the discovery of cytotoxic drugs had significantly

improved the prognosis for some types of cancer.

 From early 1990’s design of ‘novel’ or targeted cancer treatments

Ideally, these anticancer drugs should interfere only with
cellular processes that are unique to malignant cells.
Unfortunately, most currently available anticancer drugs do
not specifically recognize neoplastic cells but, rather, affect all
kinds of proliferating cells both normal and abnormal .
Treatment strategies
Goal of treatment: The ultimate goal of chemotherapy is
a cure. A true cure requires the eradication of every
neoplastic cell. If a cure is not attainable, then the goal
becomes control of the disease (stop the cancer from
enlarging and spreading) to extend survival and
maintain the best quality of life.
Tumor susceptibility and the growth
cycle: Rapidly dividing cells are
generally more sensitive to anticancer
drugs, whereas slowly proliferating
cells are less sensitive to chemotherapy.
In general, nonproliferating cells (those
in the G0 phase usually survive the toxic
effects of many of these agents.
 Cell biology: Cell Proliferation
variation in cycle 9-43hrs between
cancer cells

M G0

G2 G1

S
M – mitosis (<1hr)• G1 Gap number 1 (0-•
30hrs)
S – DNA synthesis (6-8hrs)•
G2 Gap number 2 (2-4hrs)
Chemotherapy - Cancer
biology
 The Growth Fraction of a cancer
represents the percentage of cells actively
progressing through the cell cycle
 Some drugs cause cytotoxicity when
exposed to cancer cells at any stage of the
cell cycle
 Some drugs are phase-specific
 cytaribine - S-specific – will only kill cells if
M
present when synthesizing DNA
 Vincristine – M-specific
G2 G1

S
Cell-cycle specificity of drugs:
Chemotherapeutic agents that are effective
only against replicating cells that is, those
cells that are cycling are said to be cell-cycle
specific whereas other agents are said to be
cell-cycle nonspecific. The nonspecific drugs,
although having generally more toxicity in
cycling cells, are also useful against tumors
that have a low percentage of replicating cells.
Chemotherapy - Cancer biology
– Chemotherapy drugs interfere with some essential
step required for cell growth or division, often with the
synthesis and replication of DNA

– The damaged cancer cell will either repair the

damage or initiate programmed cell death –
apoptosis

– Apoptosis is initiated at G1S or G2M checkpoints,

provided the mechanisms for apoptosis are in place - not
the case in some cancers – consider those with p53 mutations
or deletions
 Chemotherapy – mechanisms of action
– Anthracyclines - doxorubicin - Topoisomerase inhibition –
prevents the enzyme from religating cleaved DNA

– Alkylating agents - cyclophosphamide – formation of DNA

cross links – interferes with cellular replication

– Antimetabolites – disrupt the synthesis of essential

compounds required for cell synthesis
• - methotrexate inhibits the enzyme required to convert
folate to its active form
• - cytarabine inhibits DNA synthesis

– Vinca Alkaloids – vincristine - bind to tubulin – prevent

formation of the mitotic spindle
Treatment regimens and scheduling
Log kill: Destruction of cancer cells by
chemotherapeutic agents follows first-order kinetics;
that is, a given dose of drug destroys a constant
fraction of cells. The term log kill is used to describe
this phenomenon. For example, a diagnosis of
leukemia is generally made when there are about 109
(total) leukemic cells. Consequently, if treatment
leads to a 99.999-percent kill, then 0.001 percent of
109 cells (or 104 cells) would remain. This is defined
as a five-log kill (reduction of 105 cells). At this point,
the patient will become asymptomatic; For most
bacterial infections, a five-log (100,000-fold)
reduction in the number of microorganisms results
in a cure, because the immune system can destroy
the remaining bacterial cells. However, tumor cells
are not as readily eliminated, and additional
treatment is required to totally eradicate the
leukemic cell population.
 Chemotherapy - Cancer biology
• By the time a patient presents with symptomatic cancer already large
nos. of tumour cells

• A tumour 1cm diameter ~ 109 cells

• Imagine lethal tumour burden ~ 1012 cells

• Cell kill of a drug (90% , 99% or 99.9%) depends on both sensitivity of

the cells to the drug and dose
• 99.9% cell kill (999 of 1000) reduces tumour population 1011 to 108 cells

• The aim of several courses of chemotherapy is to kill several logs of

tumour cells

• Technical inability to detect fewer than 103 to 104 cells (minimal

residual disease) explains recurrence after apparent complete
remission
Tumor growth rate: The growth rate of most
solid tumors is initially rapid, but growth rate
usually decreases as the tumor size
increases .This is due to the unavailability of
nutrients and oxygen caused by inadequate
vascularization and lack of blood circulation.
Reducing the tumor burden through surgery or
radiation often promotes the recruitment of the
remaining cells into active proliferation and
increases their susceptibility to
chemotherapeutic agents.
.
Pharmacologic sanctuary: Leukemic or other
tumor cells find sanctuary in tissues such as
CNS, where transport constraints prevent
certain chemotherapeutic agents from
entering. Therefore, a patient may require
irradiation of the craniospinal axis or
intrathecal administration of drugs to
eliminate the leukemic cells at that site.
Similarly, drugs may be unable to penetrate
certain areas of solid tumors.
Treatment protocols: Combination-drug
chemotherapy is more successful than single-
drug treatment in most of the cancers for which
chemotherapy is effective.
.
Combinations of drugs: Cytotoxic agents
with different toxicities, and with different
mechanisms of action, are usually combined
at full doses. This results in higher response
rates, due to additive and/or potentiated
cytotoxic effects, and nonoverlapping host
toxicities. In contrast, agents with similar
dose-limiting toxicities, such as
myelosuppression, nephrotoxicity, or
cardiotoxicity can be combined safely only
by reducing the doses of each.
Advantages of drug combinations:
1) provide maximal cell killing within the
range of tolerated toxicity.
2) are effective against a broader range
of cell lines in the tumor population
3) may delay or prevent the development
of resistant cell lines.
Problems associated with chemotherapy:
Resistance: Some neoplastic cells (for
example, melanoma) are inherently resistant
to most anticancer drugs. Other tumor types
may acquire resistance to the cytotoxic effects
by mutation particularly after prolonged
administration of suboptimal drug doses. The
development of drug resistance is minimized
by
1-short-term
2-intensive
3-intermittent therapy
4- combinations of drugs.
Chemotherapy – why doesn’t it always
work? - mechanisms of cancer cell
resistance
The cancer cells may evade kill by the
chemotherapy in many ways, such as:
• Decreased drug uptake – alteration of folate
receptor – methotrexate
• Increased drug efflux –→ p-glycoprotein –
many drugs
• Increased DNA repair mechanisms
• Mutations leading to alteration of drug
target – Topoisomerase II mutations –
anthracyclines
 Chemotherapy: cytotoxic drugs
• Considered ‘dangerous’ drugs, need specialists to prescribe
because:

• Narrow therapeutic indices

• Significant side effect profile

• Dose needs to be altered for the individual patient based on

– their surface area and/or body mass index
– drug handling ability (eg liver function, renal function…
dependent on the metabolism and excretion routes)
– general wellbeing (performance status and comorbidity)
 Chemotherapy .. clinical
indications

•predicted response is also different within

the same cancer based on:
– performance score
– clinical stage
– prognostic factors or score (often
involving biological factors)
– Molecular or cytogenetic markers
Indications for treatment: Chemotherapy is
indicated when neoplasms are disseminated
and are not amenable to surgery.
Chemotherapy is also used as a supplemental
treatment, to attack micrometastases
following surgery and radiation treatment in
which case it is called adjuvant
chemotherapy. Chemotherapy given prior to
the surgical procedure in an attempt to
shrink the cancer is referred as neoadjuvant
chemotherapy, and chemotherapy given in
lower doses to assist in prolonging a
remission is known as maintenance
chemotherapy.
 Chemotherapy: the aim of
treatment
The aim is variable…

• Neoadjuvant – given before surgery or radiotherapy

for the primary cancer
• Adjuvant – given after surgery to excise the primary
cancer, aiming to reduce relapse risk eg breast cancer
• Palliative - to treat current or anticipated symptoms
without curative intent
• Primary – 1st line treatment of cancer.. In many
haematological cancers this will be with curative
intent, initially aiming for remissiom
• Salvage – chemotherapy for relapsed disease
 Chemotherapy – route of
administration
• Routes of administration:

– IV is the most common – bolus, infusional

bag, continuous pump infusion
– PO convenient, dependent on oral
bioavailability
– SC convenient in community setting
– Into a body cavity – bladder, pleural effusion
– Intralesional - directly into a cancerous area
– Intrathecal - into the CSF – by lumbar
puncture or directly into ventricles.
– Topical -medication will be applied onto the
skin
– IM rarely
Toxicity: Therapy aimed at killing rapidly
dividing cancer cells also affects normal cells
undergoing rapid proliferation (for example,
cells of the buccal mucosa, bone marrow,
gastrointestinal (GI) mucosa, and hair),
contributing to the toxic manifestations of
chemotherapy.
Chemotherapy adverse effects – those due to
toxicity to cells of normal tissues
Need a balance between cancer cell kill and toxicity to normal cells
undergoing cell division , eg:


Myelosuppression (temporary ↓ bone marrow function)
↓ neutrophils leads to risk of overwhelming infection
symptoms of anaemia
thrombocytopenia leading to bleeding (rare)

GI effects – mucositis, diarrhoea

Temporary alopecia

Skin and nail changes

Cardiomyopathy or arrhythmia

Gonadal failure – temporary or permanent

Teratogenicity – must be advised to use contraception

Neurotoxicity – peripheral (common) and central

Hepatocellular damage
Common adverse effects: Most
chemotherapeutic agents have a narrow
therapeutic index. Severe vomiting,
stomatitis, bone marrow suppression, and
alopecia are common to many
chemotherapeutic agents whereas other
adverse reactions are confined to specific
agents, such as, cardiotoxicity with
doxorubicin and pulmonary fibrosis with
bleomycin.
 Chemotherapy adverse effects – those
due to effect of treatment on the tumour
• Acute renal failure -– hyperuricaemia
caused by rapid tumour lysis leads to
precipitation of urate crystals in renal
tubules

• GI perforation at site of tumour – reported

in lymphoma

• Disseminated intravascular coagulopathy eg

onset within a few hours of starting
treatment for acute myeloid leukaemia
 Chemotherapy adverse effects – those
due to other properties of the drug

• Some iv chemotherapy drugs are vesicants –

extravasation may lead to extensive skin and
subcut tissue necrosis

• Nausea – multifactorial but includes direct

action of chemotherapy drugs on the central
chemoreceptor trigger zone
A 62-year-old woman received six cycles of docetaxel chemotherapy during a six-month period
for recurrent metastatic breast cancer

Mortimer N and Mills J. N Engl J Med 2004;351:1778

Oral Mucositis after Chemoradiotherapy in a Patient with Leukemia, Who Was Later Treated with
Bone Marrow Transplantation

Garfunkel A. N Engl J Med 2004;351:2649-2651

Minimizing adverse effects: Some toxic reactions
may be ameliorated by interventions, such as

promoting intensive diuresis to prevent bladder

toxicities.
The megaloblastic anemia that occurs with
methotrexate can be effectively counteracted by
administering folinic acid (leucovorin, 5-
formyltetrahydrofolic acid.
With the availability of human granulocyte colony-
stimulating factor (filgrastim), the neutropenia
associated with treatment of cancer by many drugs
can be partially reversed.
Treatment-induced tumors: Because most
antineoplastic agents are mutagens,
neoplasms (for example, acute
nonlymphocytic leukemia) may arise 10 or
more years after the original cancer was
cured. Its especially a problem after
therapy with alkylating agents.
 Chemotherapy - important drug
interactions

Other drugs may increase plasma levels of the

chemotherapy drug (and therefore side effects)


Vincristine and itraconazole (a commonly used antifungal) leads
to more neuropathy

6-Mercaptopurine and allopurinol (commonly used to prevent
gout and renal failure) the latter inhibits the breakdown of 6-MP

Metotrexate – caution with prescribing penicillin, NSAIDs
 Chemotherapy – monitoring during
treatment
Response of the cancer

Reassessment of solid tumours by radiological imaging;
leukaemias by bone marrow examination after a predetermined
no of cycles to ensure response

Drug levels

Eg Methotrexate drug assays taken on serial days to ensure
clearance from the blood after folinic acid rescue

Checks for organ damage


Some regimens stipulate measurement of creatinine clearance,
echocardiograms or lung function tests b/w cycles
 Chemotherapy – randomised controlled trial
evidence

Diffuse large B cell lymphoma (DLBCL)

A common aggressive non-Hodgkin’s lymphoma
For many yrs ‘CHOP’ has been standard treatment

CD20 ag is a protein found on B lymphocytes and is

highly expressed in B cell lymphomas
Rituximab is a chimeric unconjugated monoclonal
antibody directed at the CD20 antigen – specifically
designed to treat lymphoma
R-CHOP is now standard (and NICE approved) 1st line
treatment for DLBCL
Pivotal trial of 399 Patients aged 60-80 yrs
assigned to CHOP or CHOP plus Rituximab
(RCHOP)

5 years survival is statistically increased in the R-CHOP

arm

The 5-year DFS was 66% in R-CHOP patients compared

with 45% in CHOP patients.

The 5-year OS was 58% in R-CHOP patients compared

with 45% in CHOP patients.
DFS ~ disease free survival~ patients alive with no evidence of
lymphoma
OS ~ overall survival ~ patients who are alive