(Pcol) Cancer Chemotherapy

PHARMACOLOGY
5.08 CANCER CHEMOTHERAPY

DR. KATRINA PATTAGUAN, MD | AUGUST 9, 2022
OUTLINE ® They migrate to distant sites in the body to colonize

I. Introduction A. Anthracyclines various organs in the process called metastasis. More
A. Subheading -Doxorubicin often than not, the distant sites would be the adjacent
B. Subheading -Daunorubicin sites.
II. Cancer Treatment -Idarubicin
Modalities -Epirubicin • The incidence, geographic distribution, behaviour of
A. Primary chemotherapy -Mitoxantrone specific types of cancer are related to multiple factors,
B. Neoadjuvant B. Mitomycin including sex, age, race, genetic predisposition, and
chemotherapy C. Bleomycin exposure to environmental carcinogens.
C. Adjuvant IX. Miscellaneous • Of these factors, environmental exposure is probably
chemotherapy Anticancer Drugs most important.
III. Role of Cell Cycle A. Imatinib & other • Exposure to ionizing radiation has been well
Kinetics & Anti-Cancer Tyrosine Kinase documented as a significant risk factor for a number of
Effect Inhibitors (tkis) cancers
IV. Basic Pharmacology -Imatinib ® Acute leukemia
V. Alkylating Agents -Dasatinib ® Thyroid cancer
A. Nitrosoureas -Nilotinib ® Breast cancer
B. Nonclassic Alkylating -Bosutinib ® Lung cancer
agents -Polatinib
® Soft tissue sarcoma
C. Platinum analogs B. Growth Factor
® Basal cell and squamous cell carcinoma
VI. Antimetabolites Receptor Inhibitors
• Chemical carcinogens (particularly those in tobacco
A. Antifolate -Cetuximab,
smoke) as well as azo dyes, aflatoxins, asbestos benzene
B. Fluoropyrimidines Panitimumab,
C. Deoxycytidine Analogs Necitumumab and radon all have been well documented as leading to a
D. Purine Antagonists -Erlotinib wide range of human cancers.
VII. Natural Product Cancer -Bevacizumab, Ziv- • Several viruses have been implicated in the etiology of
Chemotherapy Drugs Aflibercept, various human cancers.
A. Vinca Alkaloids Ramucirumab, ® Hepatitis B (HBV) and Hepatitis C (HCV) are associated
B. Taxanes and other Sorafenib, Sunitinib, & with the development of hepatocellular cancer. It is more
Anti-microtubule Drugs Pazopanib on Hep C that can lead to hepatocellular CA
VIII. Antitumor X. Clinical Pharmacology ® HIV is associated with Hodgkin’s and non-Hodgkin’s
Antibiotics lymphomas
® Human papillomavirus (HPV) is associated with cervical
LEGENDS cancer, anal and penile cancers, and oropharyngeal head
Remember Lecturer Book Presentation and neck cancer
® Epstein-Barr virus (EBV), also known as human
herpesvirus 4 (HHV-4), is associated with
I. INTRODUCTION Nasopharyngeal cancer, Burkitt’s lymphoma, and
Hodgkin’s lymphoma (also remember the cancers
• Cancer
associated with EBV)
® The 2nd most common cause of death in the US,
® Merkel cell polyomavirus (MCV) causes Merkel cell
accounting for 1 in 4 deaths
cancer, a rare but aggressive form of skin cancer
® It is a disease characterized by a defect in the normal
• Cellular genes are known that are homologous to the
control mechanisms that govern:
transforming genes of the retroviruses, a family of RNA
§ Cell survival
viruses, and induce oncogenic transformation.
§ Proliferation
§ Differentiation
• Oncogenes
® It is characterized by the development of several
abnormal cells in the body and would divide ® Mammalian cellular genes
uncontrollably. ® Have been shown to code for specific growth factors
® They have the ability to infiltrate and destroy normal and their corresponding receptors
cells or normal body tissues. ® Genes may be amplified (increased number of gene
® It has the ability to spread. It will first localize to a copies) or mutated, both of which can lead to
specific organ and to other organs of the body. constitutive overexpression in malignant cells
• Tumor Stem Cells • The bcl-2 family of genes represents a series of pro-
survival genes that promotes survival by directly inhibiting
® Small subpopulation of cells
apoptosis, a key pathway of programmed cell death
® Reside within a tumor mass
• Tumor suppressor genes
® They retain the ability to undergo repeated cycles of
® May be related or mutated
proliferation
® Give rise to the neoplastic phenotype
TRANS ADAWE, CALLUENG, GABAON, GERVACIO, LLANTO, MAGO, NOVERO, PAGUNURAN, PATTAGUAN, RIVERA, SINGH, TALAUE, VILLAFUERTE 1 of 23
5.08 Cancer Chemotherapy
• p53 gene • Refers to the use of chemotherapy in patients who
® Best established tumor suppressor gene identified to present with localized cancer for which alternative local
date, and normal wild-type gene appears to play an therapies, such as surgery, exist but which have been
important role in suppressing malignant transformation shown to be less than completely effective
® p53 is mutated in up to 50% of all human solid tumor, • It is most often administered in the treatment of anal
including liver, breast, colon, lung, cervix, bladder, cancer, bladder cancer, breast cancer, gastroesophageal
prostate and skin cancer, laryngeal cancer, locally advanced non-small cell
lung cancer (NSCLC), osteogenic sarcoma, and locally
II. CANCER TREATMENT MODALITIES advanced rectal cancer
• With present methods of treatment, when the tumor • For the following disease, optimal clinical benefit is
remains localized at the time of diagnosis, about one-third derived when chemotherapy (q21 day or 3-4 weeks) is
of patients are cured with local treatment strategies, such administered with radiation therapy (daily or depends on
as surgery or radiotherapy. the rad oncologist) either concurrently or sequentially
• Earlier diagnosis might lead to increased cure rates with ® Anal Cancer
such local treatment. Most especially if the cancer doesn’t ® Gastroesophageal Cancer
have metastasis would lead to increase cure rates ® Laryngeal Cancer
• In the remaining cases, however, early micro metastasis ® NSCLC
is a characteristic feature, indicating that a systemic ® Rectal Cancer
approach with chemotherapy is required for effective • The goal of the neoadjuvant approach is to reduce the
cancer management size of the primary tumor so that surgical resection can be
• In patients with locally advanced disease, chemotherapy made easier and more effective. There are other types of
is often combined with radiotherapy to allow for cancer na surgery muna. Like your breast CA, we first
subsequent surgical resection to take place, and such a resect the CA with surgical approach and then we let the
combined modality approach has led to improved clinical px go back to the clinic after 3-4 months to start with the
outcomes. chemotherapy
® About 50% of patients who are initially diagnosed with • With rectal cancer and laryngeal cancer, the
cancer can be cured. administration of combined modality therapy prior to
® In contrast, chemotherapy alone is able to cure less surgery can result in sparing of vital normal organs, such
than 10% of all cancer patients when the tumor is as the rectum or larynx.
diagnosed at an advanced stage. • Additional chemotherapy is given for a defined period of
time, usually 3–4 months, after surgery has been
A. Primary Chemotherapy performed.
• Refer to chemotherapy administered as the primary
treatment in patients who present with advanced cancer C. Adjuvant Chemotherapy
for which no alternative treatment exists. • Additional CA treatment that is given after the primary
• It has been the main approach in treating patients with treatment to lower the risk of CA recurrence
advanced metastatic disease • One of the most important roles for cancer chemotherapy
• The goals of therapy: is as an adjuvant to local treatment modalities such as
® Relive tumor related symptoms surgery
® Improve overall quality of life • Chemotherapy is administered after surgery has been
® Prolong time to tumor progression performed, and the goal of chemotherapy is to reduce the
• Studies in a wide range of solid tumors have shown that incidence of both local and systemic recurrence
chemotherapy in patients with advanced disease confers • Improve the overall survival of patients
survival benefit when compared with supportive care, • In general, chemotherapy regimens with clinical activity
providing sound rationale for the early initiation of drug against advanced disease may have curative potential
treatment. following surgical resection of the primary tumor, provided
• However, cancer chemotherapy can be curative in only a the appropriate dose and schedule are administered
small subset of patients who present with advanced
disease III. ROLL OF CELL CYCLE KINETICS AND ANTI-
• Curable ADULT cancers include: CANCER EFFECT
® Hodgkin’s and non-Hodgkin’s lymphoma A. Cell Cycle Kinetics
® Acute myelogenous leukemia (AML) • Its key principles of cell cycle kinetics were initially
® Germ cell cancer developed using the murine L1210 leukemia as the
® Choriocarcinoma experimental model system
• Curable CHILDHOOD cancers include: • Information on cell and population kinetics of cancer cells
® Acute lymphoblastic leukemia (ALL children) explains, in part, the limited effectiveness of most
® Burkitt’s lymphoma available anticancer drugs
® Wilm’s tumor • This information is relevant to the mode of action,
indications, and scheduling of cell cycle– specific (CCS)
® Embryonal rhabdomyosarcoma
and cell cycle–nonspecific (CCNS) drugs.
B. Neoadjuvant Chemotherapy
• Cell cycle-specific (CCS)
PHARMACOLOGY 2 of 23
® Anticancer drugs exert their action on cells traversing ® 4. Mechanism of interaction: there should be a clear
the cell cyle understanding of the biochemical, molecular and
• Cell cycle-nonspecific (CCNS) drugs pharmacokinetic mechanism of interaction between the
® Can sterilize tumor cells whether they are cycling or individual drugs in a given combination, to allow for
resting in the G0 compartment maximal antitumor effect. Omission of a drug from a
® Drugs can kill both G0 and cycling cells combination may allow overgrowth by a tumor clone
sensitive to that drug alone and resistant to other drugs
in the combination.
® 5. Avoidance of arbitrary dose chances: an arbitrary
reduction in the dose of an effective drug in order to
add other less effective drugs may reduce the dose of
the most effective agent below the threshold of
effectiveness and destroy the ability of the combination
to cure disease in a given patient.
• Dosage factors
® Dose intensity is one of the main factors limiting the
ability of chemotherapy or radiation therapy to achieve
cure.
• With rare exceptions (eg, choriocarcinoma and Burkitt’s
® For chemotherapy, therapeutic selectivity is
lymphoma), single drugs are unable to cure cancers when
dependent on the difference between the dose-
they are in an advanced stage.
response curves of normal and tumor tissues.
• The era of effective combination chemotherapy began
® In experimental animal models, the dose-response
when a number of active drugs from different classes
curve usually steep in the linear phase, and a reduction
became available for use in combination in the treatment
in dose when the tumor is in the linear phase of the
of the acute leukemias and lymphomas. dose response curve almost always results in a loss in
• Following this initial success with hematologic the capacity to cure the tumor effectively before a
malignancies, combination chemotherapy was extended reduction in the antitumor activity is observed.
to the treatment of solid tumors.
® Although complete remissions may continue to be
• Importance on the use of combination chemotherapy: observed with dose reductions down to as low as 20%
® It provides maximal cell kill within the range of toxicity of the optimal dose, residual tumor cells may not be
tolerated by the host for each drug as long as dosing is entirely eliminated, thereby allowing for eventual
not compromised. relapse.
® It provides a broader range of interaction between ® Because toxicities are usually associated with
drugs and tumor cells with different genetic anticancer drugs, it is often appealing for clinicians to
abnormalities in a heterogeneous tumor population. avoid acute toxicity by simply reducing the dose and/or
® It may prevent and/or slow the subsequent by increasing the time interval between each cycle of
development of cellular drug resistance. treatment
• These same concepts apply to the therapy of chronic ® However, such empiric modifications in dose represent
infections, such as HIV and TB a major cause of treatment failure, especially in
• Certain principles have guided the selection of drugs in patients with drug-sensitive tumors.
the most effective drug combinations and they provide a ® A positive relationship between dose intensity and
paradigm for the development of new drug therapeutic clinical efficacy has been documented in several solid
programs. tumors, including:
® 1. Efficacy: only drugs known to have some level of § Ovarian cancer
clinical efficacy when used alone against a given tumor § Breast cancer
should be selected for use in combination. If available, § Lung cancer
drugs that produce complete remission in some fraction § Colon cancers
of patients are preferred to those that produce only § Hematologic malignancies (lymphomas)
partial responses. ® At present, there are three main approaches to dose-
® 2. Toxicity: when several drugs of a given class are intense delivery of chemotherapy.
available and are equally effective, a drug should be § The first approach, dose escalation, involves
selected on the basis of toxicity that does not overlap increasing the doses of the respective anti-cancer
with toxicity of other drugs in the combination. agents.
® 3. Optimum scheduling: drugs should be used in their § The second strategy is administration of anti-cancer
optimal dose and schedule, and drug combination agents in a dose-intense manner by reducing the
should be given at consistent intervals. Because long interval between treatment cycles.
intervals between cycles negatively affect dose § The third approach involves sequential scheduling of
intensity, the treatment-free interval between cycles either single agents or combination regimens.
should be the shortest time necessary for recovery of ® Each of these strategies is presently being applied to
the most sensitive normal target tissue, which usually the treatment of a wide range of solid cancers,
the bone marrow. including breast, colorectal, and NSCLC, and in
general, such dose-intense regimens have significantly § Abraxane
improved clinical outcomes. § Docetaxel
§ Cabazitaxel
• Drug resistance § Ixabepilone
® A fundamental problem in cancer chemotherapy is the § Eribulin
development of cellular drug resistance. ® Epipodophyllotoxin
® Primary or inherent resistance refers to drug resistance § Etoposide
in the absence of prior exposure to available standard ® Campthotecins
agents. § Topotecan
® For example, mutations in the p53 tumor suppressor § Irinotecan
gene occur in up to 50% of all human tumors. • Antitumor Antibiotics
® Preclinical and clinical studies have shown that loss of ® Anthracyclines
p53 function leads to resistance to radiation therapy as § Doxorubicin
well as resistance to a wide range of anti-cancer § Daunorubicin
agents. § Idarubicin
® In contrast to primary resistance, acquired resistance § Epirubicin
develops in response to exposure to a given anti- § Mitoxantrone
cancer agent. ® Mitomycin
® Experimentally, drug resistance can be highly specific ® Bleomycin
to a single drug and is usually based on a specific • Miscellaneous Anti-Cancer Drugs
change in the genetic machinery of a given tumor cell ® Imatinib & Other Tyrosine Kinase Inhibitors (Tkis)
with amplification or increased expression of one or § Imatinib
more genes. § Dasatinib
® This form of drug resistance leads to enhanced drug § Nilotini
efflux and reduced intracellular accumulation of a broad § Bosutinib
range of structurally unrelated anti-cancer agents, § Polatinib
including: ® Growth Factor Receptor Inhibitors
§ Anthracyclines § Cetuximab, Panitimumab, Necitumumab
§ Vinca alkaloids § Erlotinib
§ Taxanes § Bevacizumab, Ziv-Aflibercept, Ramucirumab,
§ Camptothecins Sorafenib, Sunitinib, & Pazopanib
§ Epipodophyllotoxins
§ Imatinib V. ALKYLATING AGENTS
• The major clinically useful alkylating agents have a
IV. BASIC PHARMACOLOGY OF CANCER structure containing:
CHEMOTHERAPEUTIC DRUGS ® bis(chloroethyl)amine
• Alkylating Agents ® ethyleneimine
® Nitrosoureas ® nitrosourea moiety
® Nonclassic Alkylating Agents • Among the bis(chloroethyl)amines, cyclophosphamide,
§ Procarbazine mechlorethamine, melphalan, and chlorambucil are the
§ Dacarbazine most useful.
§ Bendamustine • Ifosfamide is closely related to cyclophosphamide but has
® Platinum Analogs a somewhat different spectrum of activity and toxicity.
§ Cisplatin • Thiotepa and busulfan are used to treat breast and
§ Carboplatin ovarian cancer, and chronic myeloid leukemia,
§ Oxalilatin respectively.
• Antimetabolites • The major nitrosoureas are carmustine (BCNU) and
® Antifolates lomustine (CCNU).
§ Methotrexate
§ Pemetrexed • Mechanism of Action
§ Pralatrexate ® Alkylation
® Fluoropyrimidines § As a class, the alkylating agents exert their cytotoxic
§ 5-FU effects via transfer of their alkyl groups to various
§ Capecitabine cellular constituents.
§ TAS-102 § Alkylation of DNA within the nucleus probably
• Natural Product Cancer Chemotherapy Drugs represents the major interaction leading to cell death.
® Vinca Alkaloids § However, these drugs react chemically with
§ Vinblastine sulfhydryl, amino, hydroxyl, carboxyl, and phosphate
§ Vincristine groups of other cellular nucleophiles as well.
§ Vinorelbine § The general mechanism of action of these drugs
® Taxanes & other Anti-Microtubule Drugs involves intramolecular cyclization to form an
§ Paclitaxel ethyleneimonium ion that may directly or through
formation of a carbonium ion transfer an alkyl group • Although the majority of alkylations by the nitrosoureas
to a cellular constituent. are on the N7 position of guanine in DNA, the critical
® Carbamoylation alkylation responsible for cytotoxicity appears to be on the
§ A secondary mechanism that occurs with O6 position of guanine, which leads to G-C crosslinks in
nitrosoureas involves carbamoylation of lysine DNA.
residues of proteins through formation of
isocyanates. B. Nonclassic Alkylating Agents
• Several other compounds have mechanisms of action that
• Resistance involve DNA alkylation as their cytotoxic mechanism of
® The mechanism of acquired resistance to alkylating action
agents may involve: ® Procarbazine
§ Increased capability to repair DNA lesions through ® Dacarbazine,
increased expression and activity of DNA repair ® Bendamustine
enzymes
§ Decreased cellular transport of the alkylating drug 1. Procarbazine
§ Increased expression or activity of glutathione and • Procarbazine is an orally active methylhydrazine
glutathione-associated proteins (which are needed to derivative, and in the clinical setting, it is used in
conjugate the alkylating agent, or increased combination regimens for:
glutathione S-transferase activity, which catalyzes ® Hodgkin’s lymphoma
the conjugation) ® Non-Hodgkin’s lymphoma
® Brain tumors
• Adverse Effect • The precise mechanism of action of procarbazine is
® The adverse effects associated with alkylating agents uncertain; however, it inhibits DNA, RNA, and protein
are generally dose-related and occur primarily in: biosynthesis; prolongs interphase; and produces
§ Rapidly growing tissues such as bone marrow chromosome breaks.
(myelosuppression) • One metabolite is a weak monoamine oxidase (MAO)
§ Gastrointestinal tract (diarrhea) inhibitor, and adverse events can occur when
§ Reproductive system procarbazine is given with:
® Nausea and vomiting also can be a serious issue with ® Other MAO inhibitors as well as with sympathomimetic
a number of these agents. agents
® In addition, they are potent vesicants and can ® Tricyclic antidepressants
damage tissues at the site of administration as well as ® Antihistamines
produce systemic toxicity.
® Central nervous system depressants
® As a class, alkylating agents are carcinogenic in
® Antidiabetic agents
nature, and there is an increased risk of secondary
® Alcohol
malignancies, especially acute myelogenous leukemia.
® Tyramine-containing foods
® Cyclophosphamide is one of the most widely used
alkylating agents. • There is an increased risk of secondary cancers in the
form of acute leukemia, and its carcinogenic potential is
§ One significant advantage of this compound relates
thought to be higher than that of other alkylating agents.
to its high oral bioavailability
§ It can be administered via the oral and intravenous
routes with equal clinical efficacy. 2. Dacarbazine
§ It is inactive in its parent form and must be activated • Dacarbazine is a synthetic compound that functions as an
to cytotoxic metabolites by liver microsomal alkylating agent following metabolic activation in the liver
enzymes. by oxidative N-demethylation to the monomethyl
® These active metabolites are delivered to both tumor derivative.
and normal tissue, where nonenzymatic cleavage of • This metabolite spontaneously decomposes to
aldophosphamide to the cytotoxic forms— diazomethane, which generates a methyl carbonium ion
phosphoramide mustard and acrolein—occurs. that is believed to be the key cytotoxic species.
® The liver appears to be protected through the • Dacarbazine is administered parenterally and is used in
enzymatic formation of the inactive metabolites 4- the treatment:
ketocyclophosphamide and carboxyphosphamide. ® Malignant melanoma
® Hodgkin’s lymphoma
A. Nitrosoureas ® Soft tissue sarcomas
• These drugs appear to be non-cross-resistant with ® Neuroblastoma
other alkylating agents; all require biotransformation, • The main dose-limiting toxicity is myelosuppression, but
which occurs by nonenzymatic decomposition, to nausea and vomiting can be severe in some cases.
metabolites with both alkylating and carbamoylating • This agent is a potent vesicant, and care must be taken
activities. to avoid extravasation during drug administration.
• The nitrosoureas are highly lipid-soluble and are able to
readily cross the blood-brain barrier, making them 3. Bendamustine
effective in the treatment of brain tumors.
• Bendamustine is a bifunctional alkylating agent consisting resistance, and clinical pharmacology are identical to
of a purine benzimidazole ring and a nitrogen mustard those described for cisplatin.
moiety. • As with cisplatin, carboplatin has broad-spectrum activity
• As with other alkylating agents, it forms cross-links with against a wide range of solid tumors.
DNA resulting in single- and double-stranded breaks, • However, in contrast to cisplatin, it exhibits significantly
leading to inhibition of DNA synthesis and function. less renal and gastrointestinal toxicity.
• This molecule also inhibits mitotic checkpoints and • Its main dose-limiting toxicity is myelosuppression.
induces mitotic catastrophe, which leads to cell death. • It has, therefore, been widely used in transplant regimens
• Of note, the cross-resistance between bendamustine and to treat refractory hematologic malignancies.
other alkylating agents is only partial, thereby providing a • Vigorous intravenous hydration is not required for
rationale for its clinical activity despite the development of carboplatin therapy
resistance to other alkylating agents. ® Carboplatin is viewed as an easier agent to administer
• This agent is approved for use in chronic lymphocytic to patient
leukemia, with activity also observed in Hodgkin’s and ® It has replaced cisplatin in various combination
non-Hodgkin’s lymphoma, multiple myeloma, and breast chemotherapy regimens
cancer.
• The main dose-limiting toxicities include 3. Oxaliplatin
myelosuppression and mild nausea and vomiting. • Oxaliplatin is a third-generation diaminocyclohexane
• Hypersensitivity infusion reactions, skin rash, and other platinum analog.
skin reactions occur rarely. • Its mechanism of action and clinical pharmacology are
identical to those of cisplatin and carboplatin.
C. Platinum Analogs • Tumors that are resistant to cisplatin or carboplatin on the
• Three platinum analogs are currently used in clinical basis of mismatch repair defects are not cross-resistant to
practice: oxaliplatin, and this finding may explain the clinical activity
® Cisplatin of this platinum compound in colorectal cancer.
® Carboplatin • Oxaliplatin was initially approved for use as second-line
® Oxaliplatin therapy in combination with the fluoropyrimidine 5-
fluorouracil (5-FU) and leucovorin, termed the FOLFOX
1. Cisplatin regimen, for metastatic colorectal cancer.
• Cisplatin (cis-diamminedichloroplatinum [II]) is an • There are various iterations of the FOLFOX regimen,
inorganic metal complex that was initially discovered which have now become the most widely used
through a serendipitous observation that neutral platinum combinations in the first-line treatment of advanced
complexes inhibited division and filamentous growth of colorectal cancer.
Escherichia coli. • This regimen also plays a major role in the adjuvant
• Although the precise mechanism of action of the platinum therapy of stage III colon cancer and high-risk stage II
analogs is unclear, they exert their cytotoxic effects in the colon cancer.
same manner as alkylating agents. • Clinical activity has also been observed in other
® As such, they kill tumor cells in all stages of the cell gastrointestinal cancers, such as pancreatic,
cycle and bind DNA through the formation of gastroesophageal, and hepatocellular cancer.
intrastrand and interstrand cross-links, thereby leading • Neurotoxicity is the main dose-limiting toxicity, and it is
to inhibition of DNA synthesis and function. manifested by a peripheral sensory neuropathy.
• Cisplatin has major antitumor activity in a broad range of • There are two forms of neurotoxicity
solid tumors, including: ® An acute form that is often triggered and worsened by
® Non-small cell and small cell lung cancer exposure to cold
® Esophageal and gastric cancer ® A chronic form that is dose-dependent.
® Cholangiocarcinoma • Although the chronic form of oxaliplatin toxicity is
® Head and neck cancer dependent on the cumulative dose of drug administered, it
® Genitourinary cancers, particularly testicular, ovarian, tends to be more readily reversible than that observed
and bladder cancer with cisplatin-induced neurotoxicity.
• When used in combination regimens, cisplatin-based
therapy has led to the cure of non seminomatous VI. ANTIMETABOLITES
testicular cancer. A. Antifolates
• Cisplatin and the other platinum analogs are cleared by • Three platinum analogs are currently used in clinical
the kidneys and excreted in the urine. practice:
• As a result, dose modification is required in patients with
renal dysfunction. 1. Methotrexate
• Folic acid analog that binds with high affinity to the active
2. Carboplatin catalytic site of of dihydrofolate reductase (DHFR)
• Carboplatin is a second-generation platinum analog • This results in inhibition of synthesis of tetrahydrofolate
whose mechanisms of cytotoxic action, mechanisms of (THF), the key one carbon carrier of enzymatic processes
involved in de novo synthesis of thymidylate, purine
neuclotides, and the amino acids serine and methionine.
• Inhibition of these metabolic processes interferes with the ® Myelosuppression
formation of DNA, RNA, and key cellular proteins. ® Skin rash
• MTX polyglutamates are selectively retained within CA ® Mucositis
cells, and they display increased inhibitory effects on ® Diarrhea
enzymes involved in de novo purine nucleotide and ® Fatigue
thymidylate biosynthesis, making them important ® Hand foot syndrome
determinants of MTX’s cytotoxic action • Vitamin supplementation with folic acid and vitamin
• Several resistance mechanisms to MTX have been B12 has been shown to significantly reduce the toxicities
identified, and they include: associated with premetrexed, while not interfering with
1. Decreased drug transport via the reduced folated clinical efficacy
carrier or folate receptor protein
2. Decreased formation of cytotoxic MTX polyglutamates 3. Pralatrexate
3. Increased levels of the target enzyme DHFR through
gene amplification & other genetic mechanisms B. Fluoropyrimidines
4. Altered DHFR protein with reduced affinity for MTX 1. 5-Fluorouracil
• Recent studies have suggested that decreased • 5-FU is inactive in its parent form and requires activation
accumulation of drug through activation of the multidrug via a complex series of enzymatic reactions to ribosyl
resistance transporter P170 glycoprotein also may result and deoxyribosyl nucleotide metabolites
in drug resistance • One of the metabolites, 5-fluor-2’-deoxyuridine (FdUMP),
• MTS is administered by the intravenous, intrathecal, or forms a covalently bound ternry complex with the enzyme
oral route TS and the reduced folate 5,10-
• However, oral BA is saturable and erratic at doses greater methylenetetrahydrofolate, a reaction critical for the de
than 25mg/m2 novo synthesis of thymidylate
• Renal excretion is the main route of elimination and is • Formation of this ternary complex results in inhibition of
mediated by glomerular filtration and tubular secretion DNA synthesis through “thymineless death”
® As a result, dose modification is required in the setting • 5-FU conversions:
of renal dysfunction ® 5-fluorouridine-5’triphosphate (FUTP), w/c is then
• Care must also be taken when MTX is used in the incorporated into RNA, where it interferes with RNA
presence of drugs such as aspirin, NSAIDS, penicillin and processing and mRNA translation
cephalosporins, as these agents inhibit the renal excretion ® 5-fluorodeoxyuridine-5’-triphosphate (FdUTP), which is
of MTX subsequently incorporated into cellular DNA, resulting
• The biologic effect of MTX can be reversed by in inhibition of DNA synthesis and function
administration of the reduced folate lecovorin (5- • Thus, the cytotoxicity of 5-FU is thought to be mediated
formyltetrahydrofolate) or by L-leucovorin, which is by the combined effcts of both DNA and RNA mediated
the active enantiomer events
® Leucovorin rescue is used in conjunction with high • 5-FU is administered IV, and the clinical activity of this
dose MTX therapy to rescue normal cells from undue drug is highly schedule-dependent
toxicity • Because of its extremely short half-life, approx. 10-15
® It has also been used in cases of accidental drug minutes, infusion of administration schedules have been
overdose generally favored over bolus schedules
• Up to 80-85% of an administered dose of 5-FU is
2. Premetrexed catabolized by the enzyme dihydropyrimidne
• Premetrexed is a pyrropyrimidine antifolated analog with dehydrogenase (DPD)
activity in the S phase of the cell cycle • There is an autosomal recessive pharmacogenetic
• As in the case of MTX, it is transported into the cell via the syndrome involving partial or complete deficiency of the
reduced folate carrier and requires activation by FPGS to DPD enzyme that is seen up to 5% of CA patients
yield higher polyglutamate forms • In this particular setting, severe, excessive toxicity is
• While this agent targets DHFR and enzymes involved in observed with classic triad:
de novo purine nucleotide biosynthesis, its main ® Myelosuppression
mechanism of action is inhibition of thymidilate synthase ® GI toxicity in the form of diarrhea and/mucositis
• Premetrexed is currently approved for: ® Neurotoxicity
® Combination with cisplatin in the treatment of • 5-FU remains the most widely used agent in the treatment
mesothelioma of colorectal CA, both as adjuvant therapy and for
® As a single agent in the second line therapy of NSCLC advanced disease
® In combination with cisplatin for the first line treatment • It also has activity against a wide range of solid tumors,
of NSCLC including: cancers of the breast, stomach, pancreas,
® Maintenance therapy in patients with NSCLC whose esophagus, liver, head and neck, and anus
disease has not progressed after four cycles of
platinum based chemotherapy 2. Capecitabine
• As with MTX, premetrexed is mainly excreted in urine • Capecitabine is a fluoropyrimidine carbamte prodrug with
® Dose modification is required with renal dysfunction 70-80% oral BA
• The main adverse effects include:
• As with 5-FU, capecitabine is inactive in its parent form: • The clinical activity of cytarabine is highly schedule
® Undergoes extensive metabolism in the liver by the dependent and because of its rapid degradation, it is
enzyme carboxylesterase to an intermediate, 5’-deoxy- usually administered via continuous infusion over a 5-7
5-fluorocytidine day period
® This metabolite is then converted to 5’-deoxy-5- • Its activity is limited exclusively to hematologic
fluorouridine by the enzyme cytidine deaminase malignancies, including acute myelogenous leukemia
• These two initial steps occur mainly in the liver. and non-Hodgkin’s lymphoma
• The 5’-deoxy-5-fluorouridine metabolite is finally • The agent has absolutely no activity in solid tumors
hydrolysed by thymidine phosphorylase to 5- directly • The main adverse effects associated with cytarabibine
in the tumor therapy include myelosuppression, mucositis, nausea
• The expression of thymidine phosphorylase has been and vomiting, and neurotoxicity when high dose
shown to be significantly higher in a broad range of solid therapy is administered
tumors than in corresponding normal tissue, particularly in
breast CA and colorectal CA (CRC) 2. Gemcitabine
• Capecitabine is used in the treatment of: • Gemcitabine is a fluorine-substituted deoxycytidine
® Metastatic breast CA either as a single agent or in analog that is phosphorylated initially by:
combination with other anti-CA agents, including ® Deoxycytidine kinase to the monophosphate form
docetaxel, paclitaxel, lapatinib, ixabepilone, and ® Nucleoside kinases to the diphosphate and
trastuzumab triphosphate nucleotide forms
® It is also approved for use in the adjuvant therapy of • The antitumor effect is considered to result from several
stage III and high risk stage II colon CA mechanisms:
® Used in the tx of metastatic CRC as monotherapy or in ® Inhibition of ribonucleotide reductase by gemcitabine
combination with other active cytotoxic agents, diphosphate, w/c reduces the level of
including irinotecan and oxaliplatin deoxyribonucleoside triphosphates required for DNA
• The main toxicities of capecitabine include diarrhea and synthesis;
hand foot syndrome ® Inhibition by gemcitabine tri-PO4 of DNA polymerase-
• While myelosuppression, nausea and vomiting, a and DNA polymerase-B, thereby resulting in
mucositis, and alopecia are also observed with blockade of DNA synthesis and DNA repair;
capecitabine, their incidence is significantly less than ® Incorporation of gemcitabine tri-PO4 into DNA, leading
observed with IV FU to inhibition of DNA synthesis and function
• In contrast to cytarabine, which has no activity on solid
3. TAS-102 tumors, gemcitabine has broad spectrum activity against
• TAS-102 is an oral fluoropyrimidine analog approved in both solid tumors and hematologic malignancies
2015 by the US FDA for the tx of progressive, refractory • In fact, this nucleoside analog was initially approved for
metastatic CRC use in advanced pancreatic CA and is now widely used
• As with 5-FU, TAS102 is inactive in its parent form to treat a broad range of malignancies, including NSCLC,
• Trifluridine is metabolized to the monophosphate form w/c bladder CA, ovarian CA, soft tissue sarcoma and non-
inhibits TS, albeit a much weaker TS inhibitor than Hodgkin’s lymphoma
FdUMP, and also to the triphosphate form, w/c is directly • Myelosuppression in the form of neutropenia is the
incorporated into DNA, leading to inhibition of DNA principal dose-limiting toxicity
synthesis and function • Nausea and vomiting occur in 70% of patients, and flu-like
syndrome has also been observed
C. Deoxycytidine Analogs • In rare cases, renal microangiopathy syndrome, including
1. Cytarabine haemolytic uremic syndrome (HUS) and thrombotic
• Cytarabine (ara-C) is an S-phase specific antimetabolite thrombocytopenic purpura (TTP), have been reported
that is converted by deoxycytidine kinase to the 5’-
mononucleotide (ara-CMP) D. Purine Antagonists
• Ara-CMP is further metabolized to the diphosphate and 1. 6-Thiopurines
triphosphate metabolites, and the ara-CTP triphosphate • 6-Mercaptopurine (6-MP) was the first of the thiopurine
is thought to be the main cytotoxic metabolite analogs found to have clinical efficacy in cancer therapy
• Ara-CTP competitively inhibits DNA polymerase-a and • This agent is used primarily in the treatment of childhood
DNA polymerase-B, thereby resulting in blockade of DNA acute leukemia, and a closely related analog,
synthesis and DNA repair, respectively. azathioprine, is used as an immunosuppressive agent
• This metabolite is also incorporated into RNA and DNA • As with other thiopurine, 6MP is inactive in its parent form
• Incorporation into DNA leads to interference with chain and must be metabolized by hypoxanthine-guanine
elongation and defective ligation of fragments of newly phosphoribosyl transferase (HGPRT) to form the
synthesized DNA monophosphate nucleotide 6-thioinosinic acid, which in
• The cellular retention of ara-CTP appears to correlated turn, inhibits several enzymes of de novo purine
with its lethality to malignant cells nucleotide synthesis
• After IV administration, the drug is cleared rapidly, with • The monophosphate form is eventually metabolized to the
most of an administered dose being deaminated to triPO4 form, which can then be incorporated into both
inactive forms RNA and DNA
• 6-TG has a synergistic action when used together with A. Vinca Alkaloids
cytarabine in the tx of adult acute leukemia • The vinca alkaloids inhibit the process of tubulin
• Allopurinol, a potent xanthine oxidase (XO) inhibitor, is polymerization, which disrupts assembly of
frequently used as a supportive care measure in the tx of microtubules, esp those involved in the mitotic spindle
acute leukemias to prevent the development of apparatus
hyperuricemia that often occurs with tumor cell lysis • This inhibitory effect results in mitotic arrest in
® Because allopurinol inhibits XO, simultaneous therapy metaphase, bringing cell division to a halt, w/c then leads
with allopurinol and 6-MP would result in increased to cell death
level of 6-MP, thereby leading to excessive toxicity • Thus, the vinca alkaloids work in the M phase of the cell
® In this setting, the dose of mercaptopurine must be cycle
reduced by 50-75% • Microtubules also play an important role in maintaining
® In contrast, such an interaction does not occur with 6- cell shape and cellular motility, and they facilitate the
TG, w/c can be used in full doses w/ allopurinol intracellular transport of cellular proteins
• As such, inhibition of microtubule formation has important
2. Fludarabine consequences that can lead to cell death
• Fludarabine PO4 is rapidly dephosphorylated to 2-
fluoroarabinofuranosyladenosine and then 1. Vinblastine
phosphorylated intracellularly by deoxycytidine kinase to • Vinblastine is an alkaloid derived from the periwinkle plant
the monoPO4, w/c is eventually converted to the triPO4 Vinca rosea
• Fludarabine triPO4 interferes w/ the processes of DNA • Vinca and other vinca alkaloids are metabolized by the
synthesis and DNA repair through inhibition of DNA liver P450 system, and the majority of the drug is
polymerase-a and DNA polymerase-B excreted in feces via the hepatobiliary system
• This purine nucleotide analog is used mainly in the tx of • As such, dose modification is required in the setting of
low grade non-Hodgkin’s lymphoma and chronic liver dysfunction
lymphocytic leukemia (CLL) • The main adverse effects are nausea and vomiting, bone
• It is given parenterally, and up to 25-30% of parent drug is marrow suppression, and alopecia
excreted in the urine. • This agent is also a potent vesicant, and care must be
• The main dose limiting toxicity is myelosuppression. taken in its administration
• This agent is a potent immunosuppressant with inhibitory • It has clinical activity in the tx of Hodgkin’s and non-
effects on CD4 and CD8 T cells Hodgkin’s lymphomas, breast CA, and germ cell CA
• Patients are at increased risk for opportunistic infections,
including fungi, herpes, and Pneumocystis jiroveci 2. Vincristine
pneumonia (PCP) • Vincristine is another alkaloid derivative of V. rosea and is
• Patients should receive PCP prophylaxis with closely related in structure to vinblastine
trimethoprim-sulfamethoxazole (double strength) at least • Its mechanism of action, mechanism of resistance, and
3x a week, and this should continue for up to 1 year after clinical pharmacology are identical to those of vinblastine
stopping fludarabine therapy. • Despite these similarities to vinblastine, vincristine has a
strikingly different spectrum of clinical activity and safety
3. Cladribine profile, w/c results, in large part, from its higher affinity
• Cladribine (2-chlorodeoxyadenosine) is a purine for axonal microtubules
nucleoside analog with high specificity for lymphoid cells • Vincristine has been effectively combined with
• Inactive in its parent form, it is initially phosphorylated by prednisone for remission induction in acute
deoxycytidine kinase to the monoPO4 form and lymphoblastic leukemia in children
eventually metabolized to the triPO4 form, w/c can then • It is also active in various hematologic malignancies such
be incorporated into DNA as Hodgkin’s and non-Hodgkin’s lymphomas and multiple
• The triPO4 metabolite can also interfere with DNA myeloma, and in several pediatric tumors including
synthesis and DNA repair by inhibiting DNA polymerase-a rhabdomyosarcoma, neuroblastoma, Ewing sarcoma, and
and DNA polymerase-B respectively. Wilms’ tumor.
• It is indicated for the tx of hairy cell leukemia, with • The main dose-limiting toxicity is neurotoxicity, usually
activity in other low-grade lymphoid malignancies such as expressed as a peripheral sensory neuropathy, although
CLL and low grade non-Hodgkin’s lymphoma ANS dysfunction w/ orthostatic hypotension, urinary
• It is normally administered as a single continuous 7-day retention, and paralytic ileus or constipation, CN palsies,
infusion; under these conditions, it has a very ataxia, seizures, and coma have been observed
manageable safety profile with the main toxicity consisting • While myelosuppression occurs, it is generally milder and
of transient myelosuppression much less significant than with vinblastine
• As with other purine nucleoside analogs, it has • The other adverse effect that may develop is the
immunosuppressive effects, and a decrease in CD4 and syndrome of inappropriate secretion of ADH (SIADH)
CD8 T cells, lasting for over 1 year, is observed in
patients 3. Vinorelbine
• Vinorelbine is a semisynthetic derivative of vinblastine
VII. NATURAL PRODUCT CANCER CHEMOTHERAPY whose MOA is identical to that of vinblastine and
DRUGS
vincristine, ie, inhibition of mitosis of cells in the M phase • It is approved for use in combination with prednisone in
through inhibition of tubulin polymerization the second line therapy of hormone-refractory metastatic
• This agent has activity in NSCLC, breat CA, ovarian CA prostate CA previously treated with docetaxel-containing
• Myelosuppression w/ neutropenia is the dose limiting regimen.
toxicity, but other adverse effects include nausea & • Its major toxicities include myelosuppression,
vomiting, transient elevations in liver function tests, neurotoxicity and allergic reactions.
neurotoxicity, and SIADH
• EPIPODOPHYLLOTOXINS
B. Taxanes and other Anti-microtubule Drugs
1. Etoposide
1. Paclitaxel • Is a semisynthetic derivative of podophyllotoxin, which is
• Paclitaxel is an alkaloid ester derived from the pacific yew extracted from mayapple root (Podophyllum peltatum)
(Taxus brevifolia) and the European yew (Taxus baccata) • IV and oral formulation of etoposide are approved for
• The drug functions as a mitotic spindle poison through clinical use in the USA.
high affinity binding to microtubules with enhancement of • Oral bioavailability is about 50%, requiring oral dosage to
tubulin polymerization be twice that of IV dosage.
® This promotion of microtubule assembly by paclitaxel • Up to 30-50% of an administered dose of the drug is
results in inhibition of mitosis and cell division excreted in the urine, and dose reduction is required in
® As such, paclitaxel and other taxanes work in the M- patients with renal dysfunction.
phase of the cell cycle • Etoposide has a clinical activity in germ cell cancer, small
• Paclitaxel has significant activity in a broad range of solid cell and NSCLC, Hodgkin’s and Non-Hodgkins
tumors, including ovarian, advanced breast, NSCLS, and lymphomas, and gastric cancer.
SCLC, head & neck, esophageal, prostate, and bladder
CA as well as AIDS-related Kaposi’s sarcoma • CAMPTOTHECINS
• It is metabolized extensively by the liver P450 system, ® They are natural products derived from the
and nearly 80% of the drug is excreted in feces via the Camptotheca acuminata tree originally found in China
hepatobiliary route ® They inhibit the activity of topoisomerase I, the key
• Dose reduction is required in patients with liver enzyme responsible for the cutting and religating single
dysfunction DNA strands.
• Hypersensitivity reactions may be observed in up to 5% of ® Inhibition of this enzyme results in DNA damage
patients, dexamethasone, diphenhydramine, and an ® Topotecan and Irinotecan are the 2 camptothecin
H2 blocker analogs used in clinical practice in the USA.
® Although they BOTH inhibit the same molecular target,
2. Abraxane their spectrum of clinical activity is quite different.
• This is an albumin-bound paclitaxel nanoparticle
formulation that is approved for several solid tumors, 1. Topotecan
including breast CA, pancreatic CA, and NSCLC • Indicated in the tx of advanced ovarian cancer as
• In contrast to paclitaxel, this nanoparticle formulation is second-line therapy following initial TX PLATINUM-
not associated with hypersensitivity reactions, and BASED CHEMOTHERAPY.
premedication to prevent such reactions is not required • Also approved as second-line therapy for small lung
• Moreover, this agent has significantly reduced cancer
myelosuppressive effects compared with paclitaxel, and • Main route of elimination is renal excretion, and dosage
the neurotoxiciyty that results appears to be more readily must be adjusted in patients with renal impairment.
reversible than is typically observed with paclitaxel.
2. Irinotecan
3. Docetaxel • Is a prodrug that is converted mainly in the liver by the
• It is a semisynthetic taxane derived from the European carboxylesterase enzyme to the SN-38 metabolite, which
yew tree. is 1000-fold more potent as inhibitor of topoisomerase I
• Its MOA, metabolism, elimination are identical to those of than the parent compound.
paclitaxel • In contrast to topotecan, irinotecan and SN-38 are mainly
• It is approved for use as a second line therapy in eliminated in bile and feces, and dose reduction is
advanced breast CA and NSCLC, and it also has major required in the setting of liver dysfunction.
activity in head and neck CA, SCLC, gastric CA, • Irinotecan used as first-line tx when used in combination
advanced platinum-refractory ovarian CA, and bladder CA with 5-FU and leucovorin
• Main adverse effect is myelosuppression and diarrhea
4. Cabazitaxel • Used as second-line for metastatic colorectal cancer who
• It is a semisynthetic taxane and its MOA, metabolism, and fail to respond using 5-FU initially
elimination are identical to those of other taxanes.
• However, unlike other taxanes, cabazitaxel is a poor VIII. ANTITUMOR ANTIBIOTICS
substrate for the multi-drug resistance P-glycoprotein
efflux pump and may, therefore, be useful for treating
multi-drug resistant tumors
• Screening of microbial products led to the discovery of • In contrast to DOXORUBICIN, its efficacy in solid tumors
number of growth-inhibiting compounds that have proved is limited
to be clinically useful in cancer chemotherapy. • Until now it most commonly used in AML, the most
• Many of these antibiotics bind to DNA through common leukemia in adults.
intercalation between specific bases and block synthesis 3. Idarubicin
of RNA, DNA, or BOTH; cause DNA stand incision; and • It is a semisynthetic anthracycline glycoside analog of
interfere with cell replication. daunorubicin, and it is approved for use in combination
• All of the anti-cancer antibiotics now being used in clinical with cytarabine for induction therapy of acute myeloid
practice are products of various strains of the soil microbe leukemia.
Streptomyces. • When combined with Cytarabine, Idarubicin appears to be
• These include the anthracyclines, bleomycin, and more active than Daunorubicin in producing complete
mitomycin. remission and improving survival in patients with acute
myelogenous leukemia.
A. Anthracyclines
• “Rubicins” and the peculiar one, the Mitoxantrone 4. Epirubicin
• Isolated from Streptomyces peucetius var caesius, are • It is an anthracycline analog whose moa and clinical
among the most widely used cytotoxic anti-cancer drugs. pharmacology are identical to those all other
• They exert their cytotoxic action through major anthracyclines.
mechanisms: • It was initially approved for use as a component of
® 1. Inhibition of topoisomerase II; adjuvant therapy in early-stage, node-positive breast
® Generation of semiquinone free radicals and oxygen cancer but is also used in the tx of metastatic breast
free radicals trough an iron-dependent, enzyme- cancer and gastroesophageal cancer.
mediated reductive process;
® High-affinity binding to DNA through intercalation, 5. Mitxantrone
with consequent blockade of the synthesis of DNA and • The peculiar one in your anthracyclines
RNA, and DNA strand incision; • Dihydroxyanthracenedione; is an anthracene compound
® 4. Binding to cellular membranes to alter fluidity and whose structure resembles the anthracycline ring.
ion transport • It binds to DNA to produce strand breakage and inhibits
• Administered via the IV route both DNA and RNA synthesis.
• Metabolized extensively in the liver, with reduction and • It is currently used in the tx of advanced, hormone-
hydrolysis o the ring substituents refractory prostate cancer and low-grade non-
• Up to 50% of rug is eliminated in the feces via biliary Hodgkin’s lymphoma.
excretion, and dose reduction is required I patients with • It is also indicated in breast cancer and in pediatric and
liver dysfunction. adult acute myeloid leukemias.
• Although anthracyclines are usually administered on an • Myelosuppression with leukopenia is the dose-limiting
every-3-week schedule, alternative schedules such as toxicity, and mild nausea and vomiting, mucositis, and
low-dose weekly or 72- to 96- hours continuous alopecia also occur.
infusion have been shown to yield equivalent clinical • Although the drug is thought to be less cardiotoxic than
efficacy with reduced toxicity. Doxorubicin, both acute and chronic cardiac toxicities are
observed.
1. Doxorubicin • A blue discoloration of the fingernails, sclera, and urine
• It is one of the most important anti-cancer drugs in clinical is observed 1-2 days after drug administration.
practice, with major clinical activity in: • The main dose-limiting toxicity of all anthracyclines is
® Cancers of the breast, endometrium, ovary, testicle, myelosuppression, with neutropenia more commonly
thyroid, stomach, bladder, liver, and lung; observed than thrombocytopenia.
® Soft tissue sarcomas; • In some cases, mucositis is dose-limiting.
® Several childhood cancer, including neuroblastoma, • 2 forms of cardiotoxicity observed:
Ewing’s sarcoma, osteosarcoma, and ® Acute form occurs within the first 2-3 days and
rhabdomyosarcoma presents as arrythmias and conduction abnormalities
• It is also has clinical activity in hematologic other electrocardiographic changes, pericarditis, and
malignancies, including acute lymphoblastic leukemia, myocarditis.
multiple myeloma, and Hodgkin’s and non-Hodgkin’s § This form is usually transient and in most cases is
lymphomas. asymptomatic.
• It is generally used in combination with other anti-cancer ® Chronic form is a dose-dependent, dilated
agents (eg cyclophosphamide, cisplatin and 5-FU) cardiomyopathy associated with heart failure.
• Clinical activity is improved with combination regimens § The chronic cardiac toxicity appears to result from
as opposed to single-agent therapy. increased production of oxygen free radicals within
the myocardium.
2. Daunorubicin § This effect is rarely seen at total DOXORUBICIN
• First agent in this class to be isolated dosages below 400-450 mg/m2.
• Use of lower does or continues infusions of Doxorubicin
appear to reduce the incidence of cardiac toxicity.
• Tx with the iron chelating agent Dexrazoxane (ICRF-187) ® This translocation results in the Bcr-Abl fusion
dis currently approved to prevent or reduce anthracycline- protein, the causative agent in CML, and is present in
induced cardiotoxicity in women with metastatic breast up to 95% of patients with this disease.
cancer who have received a total cumulative dose of • This agent also inhibits other receptor tyrosine kinases for
300mg/m2. platelet-derived growth factor receptor (PDGFR), and
• The anthracyclines can also produce a “radiation recall c-kit.
reaction” with erythema and desquamation of the skin
observed a sites prior radiation therapy. 1. Imatinib
• It is well absorbed orally, and it is metabolized in the
B. Mitomycin liver, with elimination of metabolites occurring in feces via
• Mitomycin C is an antibiotic isolated from Streptomyces biliary excretion.
caespitosus. • This agent is approved for use as first-line therapy in
• This agent is active in all phases of the cell cycle and is chronic phase CML, in blast crisis, and as second-line
the best available drug for use in combination with therapy for chronic phase CML that has progressed on
radiation therapy to attack hypoxic tumor cells. prior IFN-a therapy.
• Its clinical use is mainly limited to the tx of squamous cell • It is also effective in the tx of gastrointestinal stromal
cancer of the anus in combination with 5-FU and tumors (GIST) expressing the c-kit tyrosine kinase.
radiation therapy.
• One special application of mitomycin has been in the 2. Dasatinib
intravesical tx of superficial bladder cancer. • It is an oral inhibitor of several tyrosine kinases, including
® Because virtually none of the agent is absorbed, there Bcr-Abl, Src, c-kit, and PDGFR-a.
is little to no systemic toxicity when used in this way. • It differs from IMATINIB that it binds to the active and
• Hemolytic uremic syndrome, manifested as inactive conformations of the Abl kinase domain and
microangiopathic hemolytic anemia, thrombocytopenia, overcomes IMATINIB resistance resulting from mutations
and renal failure, as well as occasional instances of in the Bcr-Abl kinase.
interstitial pneumonitis have been reported. • It is approved for use in CML and Philadelphia
chromosome-positive (Ph+) acute lymphoblastic leukemia
C. Bleomycin (ALL) with resistance or intolerance to Imatinib therapy.
• It is a small peptide that contains a DNA-binding region
and iron-binding domain at opposite ends of the molecule. 3. Nilotinib
• It acts by binding to DNA, which results in single and • It is second-generation phenylamino-pyrimidine
double strand breaks following free radical formation, and molecule that inhibits Bcr-Abl, c-kit and PDGFR-B
inhibition of DNA biosynthesis. kinases.
• Bleomycin is a cell cycle- specific drug that causes • It has higher binding affinity (up to 20- to 50-fold) for
accumulation of cells in the G2 phase of the cell cycle. the Abl kinase when compared with imatinib, and it
• It is indicated for the tx of Hodgkin’s and non-Hodgkin’s overcomes imatinib resistance resulting from Bcr-Abl
lymphomas, germ cell tumor, head and neck cancer, and mutations.
squamous cell cancer of the skin, cervix, and vulva. • It was originally approved for chronic phase and
• One advantage of this agent is that it can be administered accelerated phase CML with resistance or intolerance
subcutaneously, IM, or IV. to prior therapy that included imatinib and was recently
• Elimination of bleomycin is mainly via renal excretion, and approved as first-line therapy that included Imatinib and
dose modification is recommended in patients with renal was recently approved as the first-line therapy of chronic
dysfunction. phase CML.
• Pulmonary toxicity is dose-limiting for Bleomycin (came
out in the board exam) and usually presents as 4. Bosutinib
pneumonitis with cough, dyspnea, dry inspiratory crackles • It is a potent inhibitor of the Bcr-Abl tyrosine kinase,
on physical examination, and infiltrates on chest x-ray. and it retains activity in 16 of 18 imatinib-resistant Bcr-Abl
® The incidence of pulmonary toxicity is increased in mutations.
patients older than 7- years of age, in those who • However, it is NOTE effective against T315I and V299L
receive cumulative doses greater than 400 units, in mutations, which reside within the ATP-binding domain of
prior mediastinal or chest irradiation. the Abl tyrosine kinase.
® In rare cases, pulmonary toxicity can be fatal. • It is currently approved for the tc of adult patients with
chronic, accelerated, or blast phase Ph chromosome-
VIII. MISCELLANEOUS ANTICANCER DRUG positive CML with resistance or intolerance.
A. Imatinib and Other Tyrosine Kinase Inhibitors (TKIS)
• Imatinib is an inhibitor of the tyrosine kinase domain of 5. Ponatinib
the Bcr-Abl oncoprotein and prevents phosphorylation of • It is a potent inhibitor of the Bcr-Abl tyrosine kinase, it
the kinase substrate by ATP. inhibits all known mutant form of Bcr-Abl, including the
• It is indicated for the tx of chronic myelogenous gatekeeper mutation T315.
leukemia (CML), a pluripotent hematopoietic stem cell • It inhibits other kinases, including members of VEGF-R,
disorder characterized by the t(9:22) Philadelphia PDGF, FGF, FIt3, TIE-2, Src family kinase, Kit, TET, EPH
chromosomal translocation.
• This agent is currently FDA approved for adult patients • Acneiform skin rash and hypomagnesemia are the 2
with chronic, accelerated, or blast phase CML that is main adverse effects associated with its use.
resistance or intolerant to prior TKI therapy.
3. Necitumumab
B. Growth Factor Receptor Inhibitors • It is fully human IgG1b monoclonal antibody directed
• Cetuximab, Panitumumab, Necitumumab against EGFR.
® The epidermal growth factor receptor (EGFR) is a • Like Cetuximab and Panitumumab, it works through
member of the erb-B family of growth factor receptors, inhibition of the EGFR signaling pathway.
and it is overexpressed in a number of solid tumors, • It is approved for use in combination with GEMCITABINE
including colorectal cancer, head and neck cancer, and CISPLATIN chemotherapy for the tx of squamous
NSCLC, and pancreatic cancer. NSCLC.
• Activation of the EGF signaling pathway: • The main adverse effects are what have been previously
® Results in downstream activation of several key cellular described for other anti-EGFR antibodies, and both
events involved in cellular growth proliferation, venothrombolic and arteriothrombolic have also been
invasion, and metastasis, and angiogenesis described.
® Also inhibits the cytotoxic activity of various anti-cancer
agents and radiation therapy, presumably through 4. Erlotinib
suppression of key apoptotic mechanisms, thereby • It is small molecule inhibitor of the tyrosine kinase domain
leading to the development of cellular rug resistance. associated with the EGFR.
• It is now approved as first line tx of metastatic NSCLC
1. Cetuximab in patients whose tumors have EGFR exon 19 deletions
• It is a chimeric monoclonal antibody directed against the or exon 21 (L858R) mutations and are refractory to at
extracellular domain of the EGFR, and it is presently least one prior chemotherapy regimen.
approved for use in combination with IRINOTECAN for • It is also approved for maintenance tehrapy of patients
metastatic colon cancer in the refractory setting or as with metastatic NSCLC whose disease has NOT
monotherapy in patients who are deemed be irinotecan- progressed afte four cycles of platinum-based
refractory. chemotherapy.
• Its efficacy is restricted to only those patients whose • Patients who are non-smokers and who have
tumors express the wild-type RAS gene, which included bronchoalveolar histologic subtype appear to be more
both KRAS and NRAS. responsive to these agents.
• Combination regimens of CETUXIMAB with cytotoxic • In addition, erlotinib has been approved for use in
chemotherapy may be of particular benefit in the combination with GEMCITABINE for the tx of advanced
neoadjuvant therapy of patients with liver-limited pancreatic cancer.
disease. • It is metabolized in the liver by the CYP3A4 enzyme
• Although this antibody was initially approved to be system, and elimination is mainly hepatic with excretion
administered on weekly schedule, pharmacokinetic in feces.
studies have shown that an every-2-week schedule • Caution must be taken when using these agents with
provides same level of clinical activity as the weekly drugs that also are metabolized by the liver CYP3A4
schedule. system, such as Phenytoin and warfarin, and use of
• This agent is also approved for use in combination with grapefruit products should be avoided.
radiation therapy in patients with locally advanced head • An acneiform skin rash, diarrhea, and anorexia and
and neck cancer. fatigue are the most common adverse effects observed
• It is well tolerated, with the main adverse effects being an adverse effects with these small molecules.
acneiform skin rash hypersensitivity infusion
reaction, and hypomagnesemia. 5. Afatinib
• However, when cetuximab is combined with radiation • It is small molecule inhibitor of the tyrosine kinase
therapy for head and neck cancer, there is very low but domains associated with EGFR, HER2, and HER4, and
real increased risk (1%) of sudden death, which has causes inhibition of downstream ErbB signaling.
resulted in black-box warning for the drug • It is approved for the first-line tx of metastatic NSCLC
with EGFR exon 19 deletions or exon 21 substitution
2. Panitimumab mutations.
• It is fully human monoclonal antibody directed against the • The toxicities associated with this agent are similar to
EGFR works through inhibition of the EGFR signaling those with Erlotinib.
pathway.
• It is now approved for use in combination with FOLFOX 6. Osimertinib
chemotherapy in the frontline tx of metastatic CRC. • It is a small molecule inhibitor approved in 2015 for the tx
• As with CETUXIMAB, this antibody is only effective in of metastatic EGFR T790M mutant NSCLC following
patients whose tumors express wild-type RAS. progression on or after EGFR tyrosine kinase inhibitor
• Recent clinical studies have shown that his antibody can therapy.
also be effectively and safely combined with • The adverse effect profile is similar to erlotinib and
IRINOTECAN based chemotherapy in the second-line tx afatinib, but unique cardiac toxicities are associated with
of metastatic CRC.
this agent, including QTc prolongation and • The main adverse effects are similar to those observed
cardiomyopathy. with bevacizumab and other anti VEGFR inhibitors.
• Bevacizumab, Sorafenib, Sunitinib, and Pazopanib 10. Sorafenib

® The vascular endothelial growth factor (VEGF) is • Small molecule that inhibits multiple receptor tyrosine
one of the most important angiogenic growth factors. kinases (RTKs), especially VEGF-R2 and VEGF-R3,
The growth of both primary and metastatic tumors platelet-derived growth factor-β (PDGFR-β), and raf
requires an intact vasculature. kinase.
® As a result, the VEGF-signaling pathway represents an • It was initially approved for advanced renal cell cancer
attractive target for chemotherapy. and is also approved for advanced hepatocellular cancer.
® Several approaches have been taken to inhibit VEGF
signaling; they include: 11. Sunitinib
§ Inhibition of VEGF interactions with its receptor by • Similar to sorafenib in that it inhibits multiple RTKs,
targeting either the VEGF ligand with antibodies or although the specific types are somewhat different.
soluble chimeric decoy receptors, or • They include PDGFR-α and PDGFR-β, VEGF-R1, VEGF-
§ By direct inhibition of the VEGF receptor-associated R2, VEGF-R3, and c-kit.
tyrosine kinase activity by small molecule inhibitors • It is approved for the treatment of advanced renal cell
cancer and for the treatment of gastrointestinal stromal
7. Bevacizumab tumors (GIST) after disease progression on or with
• Recombinant humanized monoclonal antibody that intolerance to imatinib
targets all forms of VEGF-A.
• This antibody binds to and prevents VEGF-A from 12. Pazopanib
interacting with the target VEGF receptors. • Small molecule that inhibits multiple RTKs, especially
• Bevacizumab can be safely and effectively combined with VEGF-R2 and VEGF-R3, PDGFR-β, and raf kinase.
5-FU-, irinotecan-, and oxaliplatin-based chemotherapy in • This oral agent is approved for the treatment of advanced
the treatment of metastatic colorectal cancer. renal cell cancer.
• Bevacizumab is FDA approved as a first-line treatment for • Sorafenib, sunitinib, and pazopanib are metabolized in the
metastatic colorectal cancer in combination with any liver by the CYP3A4 system, and elimination is primarily
intravenous fluoropyrimidine-containing regimen and hepatic with excretion in feces. Each of these agents has
is now also approved in combination with chemotherapy potential interactions with drugs that are also metabolized
for metastatic non-small lung cancer and breast cancer. by the CYP3A4 system, especially warfarin.
• One potential advantage of this antibody is that it does not • In addition, patients should avoid grapefruit products and
appear to exacerbate the toxicities typically observed with the use of St. John’s wort, as they may alter the clinical
cytotoxic chemotherapy. activity of these agents.
• The main safety concerns associated with bevacizumab • Hypertension, bleeding complications, and fatigue are
include: the most common adverse effects seen with both agents.
® Hypertension, an increased incidence of arterial • With respect to sorafenib, skin rash and the hand- foot
thromboembolic events (transient ischemic attack, syndrome are observed in up to 30–50% of patients.
stroke, angina, and myocardial infarction), • For sunitinib, there is also an increased risk of cardiac
® Wound healing complications, dysfunction, which in some cases can lead to congestive
® Gastrointestinal perforations, and heart failure.
® Proteinuria
X. CLINICAL PHARMACOLOGY OF CANCER
8. Ziv-Aflibercept CHEMOTHERAPEUTIC DRUGS
• Recombinant fusion protein made up of portions of the A. Acute Leukemia
extracellular domain of human VEGF receptor 1 & 2 fused • Acute lymphoblastic leukemia (ALL) is the main form of
to Fc portion of the human IgG1 molecule. leukemia in childhood, and it is the most common form of
• This agent is FDA approved in combination with FOLIRI cancer in children.
regimen for patients with metastatic colorectal cancer that • Children with this disease have a relatively good
has progressed on oxaliplatin- based chemotherapy. prognosis.
• The main adverse effects are similar to what has been • A subset of patients with neoplastic lymphocytes
observed with bevacizumab. expressing surface antigenic features of T lymphocytes
has a poor prognosis
9. Ramucirymab • This led to interest in the use of the ADA inhibitor
• An IgG1 antibody that targets the VEGFR2 receptor pentostatin (deoxycoformycin) for treatment of such T-cell
• This agent inhibits binding of the VEGF ligands, VEGF-A, cases.
VEGF-C and VEGF-D to the target VEGFR2 receptor • Until 1948, the median length of survival in ALL was 3
which then results in inhibition of downstream VEGFR months
signaling. • With the advent of methotrexate, the length of survival
• This agent is now FDA- approved for adverse gastric or was greatly increased.
gastroesophageal junction adenocarcinoma, matastatic • Subsequently, corticosteroids, 6-mercaptopurine,
NSCLC and metastatic CRC. cyclophosphamide, vincristine, daunorubicin, and
asparaginase have all been found to be active against this • Nearly all patients treated with imatinib exhibit a complete
disease. hematologic response, and up to 40–50% of patients
• A combination of vincristine and prednisone plus other show a complete cytogenetic response.
agents is currently used to induce remission. • As described previously, this drug is generally
• Over 90% of children enter complete remission with this
therapy with only minimal toxicity. D. Chronic Lymphocytic Leukemia
• Patients with early-stage chronic lymphocytic
B. Adult Leukemia leukemia (CLL) have a relatively good prognosis, and
• Acute myelogenous leukemia (AML) is the most therapy has not changed the course of the disease.
common leukemia in adults. However, in the setting of high-risk disease or in the
• The single most active agent for AML is cytarabine; presence of disease-related symptoms, treatment is
however, it is best used in combination with an indicated.
anthracycline, which leads to complete remissions in • Chlorambucil and cyclophosphamide are the two most
about 70% of patients. widely used alkylating agents for this disease.
• While there are several anthracyclines that can be • In most cases, cyclophosphamide is combined with
effectively combined with cytarabine, idarubicin is vincristine and prednisone (COP), or it can also be given
preferred. with these same drugs along with doxorubicin (CHOP).
• Patients often require intensive supportive care during the • Bendamustine is the newest alkylating agent to be
period of induction chemotherapy. approved for use in this disease, either as monotherapy
® Such care includes platelet transfusions to prevent or in combination with prednisone.
bleeding, the granulocyte colony-stimulating factor
filgrastim to shorten periods of neutropenia, and E. Hodgkin’s Lymphoma
antibiotics to combat infections. • The treatment of Hodgkin’s lymphoma has undergone
® Filgrastim should always be prepared to prevent cases dramatic evolution over the last 30 years.
of neutropenia • This lymphoma is now widely recognized as a B-cell
• Younger patients (eg, age < 55) who are in complete neoplasm in which the malignant Reed-Sternberg cells
remission and have an HLA-matched donor are have rearranged VH genes.
candidates for allogeneic bone marrow transplantation. • In addition, the Epstein-Barr virus genome has been
® The transplant procedure is preceded by high-dose identified in up to 80% of tumor specimens.
chemotherapy and total body irradiation followed by • Complete staging evaluation is required before a definitive
immunosuppression. treatment plan can be made.
® This approach may cure up to 35–40% of eligible • For patients with stage I and stage IIA disease, there has
patients. been a significant change in the treatment approach.
• Patients over age 60 respond less well to chemotherapy, • Initially, these patients were treated with extended-field
primarily because their tolerance for aggressive therapy radiation therapy.
and resistance to infection are lower • However, given the well-documented late effects of
• Once remission of AML is achieved, consolidation radiation therapy, which include hypothyroidism, an
chemotherapy is required to maintain a durable remission increased risk of secondary cancers, and coronary artery
and to induce cure. disease, combined-modality therapy with a brief course of
combination chemotherapy and involved field radiation
C. Chronic Myelogenous Leukemia therapy is now the recommended approach.
• Chronic myelogenous leukemia (CML) arises from a • More recently, the anthracycline-containing regimen
chromosomally abnormal hematopoietic stem cell in termed ABVD (doxorubicin, bleomycin, vinblastine, and
which a balanced translocation between the long arms of dacarbazine) has been shown to be more effective and
chromosomes 9 and 22, t(9:22), is observed in 90–95% of less toxic than MOPP, especially with regard to the
cases. incidence of infertility and secondary malignancies.
• This translocation results in constitutive expression of the ® Four cycles of ABVD are given to patients.
Bcr-Abl fusion oncoprotein with a molecular weight of
210 kDa. F. Non-Hodgkin’s Lymphoma
• The clinical symptoms and course are related to the white • Non-Hodgkin’s lymphoma is a heterogeneous disease,
blood cell count and its rate of increase. and the clinical characteristics of non-Hodgkin’s
• Most patients with the white cell counts over 50,000/μL lymphoma subsets are related to the underlying
should be treated. histopathologic features and the extent of disease
• The goals of treatment are: involvement
® To reduce the granulocytes to normal levels, • In general, the nodular (or follicular) lymphomas have
® To raise the hemoglobin concentration to normal, and a far better prognosis, with a median survival up to 7
® To relieve disease-related symptoms years, compared with the diffuse lymphomas, which have
• The tyrosine kinase inhibitor imatinib is considered as a median survival of about 1–2 years.
standard first-line therapy in previously untreated patients ® Combination chemotherapy is the treatment standard
with chronic phase CML. for patients with diffuse non-Hodgkin’s lymphoma.
• The anthracycline-containing regimen CHOP
(cyclophosphamide, doxorubicin, vincristine, and
prednisone) has been considered the best treatment in commonly with thalidomide, somehat less often with
terms of initial therapy. pomalidomide and rarely in lenalidomide
• Randomized phase III clinical studies have now shown
that the combination of CHOP with the anti-CD20 • Bortezomib
monoclonal antibody rituximab results in improved ® Was first approved for use in relapsing or refractory
response rates, disease-free survival, and overall survival multiple myeloma and is now widely used in the first-
compared with CHOP chemotherapy alone. line treatment of multiple myeloma.
• The nodular follicular lymphomas are low-grade, relatively ® This agent is thought to exert its main cytotoxic effects
slow-growing tumors that tend to present in an advanced through inhibition of the 26 S proteosome, which
stage and are usually confined to lymph nodes, bone results in down-regulation of the nuclear factor kappa B
marrow, and spleen. (NF-κB) signaling pathway.
• This form of non-Hodgkin’s lymphomas, when presenting ® Of note, inhibition of NF-κB has been shown to restore
at an advanced stage, is considered incurable, and chemosensitivity.
treatment is generally palliative. ® One potential advantage is that it can be administered
• To date, there is no evidence that immediate treatment by the intravenous or subcutaneous route
with combination chemotherapy offers clinical benefit over
close observation and “watchful waiting” with initiation of H. Breast Cancer Stage 1 and 2
chemotherapy at the onset of disease symptoms. • The management of primary breast cancer has
• Take home: RCHOP REGIMEN undergone a remarkable evolution as a result of major
efforts at early diagnosis (through encouragement of
G. Multiple Myeloma self-examination as well as through the use of cancer
• This plasma cell malignancy is one of the models of detection centers) and the implementation of combined
neoplastic disease in humans as it arises from a single modality approaches incorporating systemic chemo-
tumor stem cell. therapy as an adjuvant to surgery and radiation therapy.
• Moreover, the tumor cells produce a marker protein • Women with stage I disease (small primary tumors and
(myeloma immunoglobulin) that allows the total body negative axillary lymph node dissections) are currently
burden of tumor cells to be quantified. treated with surgery alone, and they have an 80% chance
• Multiple myeloma principally involves the bone marrow of cure.
and bone, causing bone pain, lytic lesions, bone • Women with node-positive disease have a high risk of
fractures, and anemia as well as an increased both local and systemic recurrence.
susceptibility to infection. • Thus, lymph node status directly indicates the risk of
• Most patients with multiple myeloma are symptomatic at occult distant micrometastasis.
the time of initial diagnosis and require treatment with • In this situation, postoperative use of systemic adjuvant
cytotoxic chemotherapy. chemotherapy with six cycles of cyclophosphamide,
• Treatment with the combination of the alkylating agent methotrexate, and fluorouracil (CMF protocol) or of
melphalan and prednisone (MP protocol) has been a fluorouracil, doxorubicin, and cyclophosphamide (FAC)
standard regimen for nearly 30 years. has been shown to significantly reduce the relapse rate
• About 40% of patients respond to the MP combination, and prolong survival.
and the median remission is on the order of 2–2.5 years • Women with four or more involved nodes have had limited
• In patients who are considered candidates for high-dose benefit thus far from adjuvant chemotherapy
therapy with stem cell transplantation, melphalan and • Breast cancer was the first neoplasm shown to be
other alkylating agents are to be avoided, as they can responsive to hormonal manipulation.
affect the success of stem cell harvesting. • Tamoxifen is beneficial in postmenopausal women when
used alone or in combination with cytotoxic
• Thalidomide chemotherapy. The present recommendation is to
® Thalidomide is a well-established agent for treating administer tamoxifen for 5 years of continuous therapy
refractory or relapsed disease, and about 30% of after surgical resection.
patients will achieve a response to this therapy. • Postmenopausal women who complete 5 years of
tamoxifen therapy should be placed on an aromatase
• Leflunomide and Pomalidomide are two inhibitor such as anastrozole for at least 2.5 years,
immunomodulatory analogs (IMIDs) of thalidomide. although the optimal duration is unknown.
® Leflunomide, combination regimens incorporated with • Clinical surveillance: monitor every 3 months for
dexamethasone for multiple myeloma patients who recurrence
have received at least one prior therapy and clinical • In practice, tamoxifen is already suffice
data show that this combination is effective as the first • Results from several randomized trials for breast cancer
line therapy. have established that adjuvant chemotherapy for
® Pomalidomide is the most recent IMID to receive premenopausal women and adjuvant tamoxifen for
approval and this drug may be able to overcome postmenopausal women are of benefit to women with
resistance to thalidomide and lenalidomide stage I (node-negative) breast cancer.
§ The side effect profiles of the IMIDs appear to be • While this group of patients has the lowest overall risk of
similar, although neurotoxicity was ibserverd more recurrence after surgery alone (about 35–50% over 15
years), this risk can be further reduced with adjuvant and antiandrogen agent compared with single- agent
therapy. therapy.
• Hormonal treatment reduces symptoms—especially bone
I. Breast Cancer Stage 3 and 4 pain—in 70–80% of patients and may cause a significant
• The approach to women with advanced breast cancer reduction in the prostate-specific antigen (PSA) level,
remains a major challenge, as current treatment options which is now widely accepted as a surrogate marker for
are only palliative. response to treatment in prostate cancer.
• Combination chemotherapy, endocrine therapy, or a • Although initial hormonal manipulation is able to control
combination of both results in overall response rates of symptoms for up to 2 years, patients usually develop
40–50%, but only a 10–20% complete response rate. progressive disease.
• Breast cancers expressing estrogen receptors (ER) or
progesterone receptors (PR), retain the intrinsic hormonal K. GI Cancer
sensitivities of the normal breast—including the growth- • Colorectal cancer (CRC) is the most common type of
stimulatory response to ovarian, adrenal, and pituitary gastrointestinal malignancy.
hormones. • At the time of initial presentation, only about 40–45% of
• Patients who show improvement with hormonal ablative patients are potentially curable with surgery.
procedures also respond to the addition of tamoxifen. • Patients presenting with high-risk stage II disease and
• The aromatase inhibitors anastrozole and letrozole are stage III disease are candidates for adjuvant
now approved as first-line therapy in women with chemotherapy with an oxaliplatin-based regimen in
advanced breast cancer whose tumors are hormone- combination with 5-FU plus leucovorin (FOLFOX or
receptor positive. In addition, these agents and FLOX) or with oral capecitabine (XELOX) and are
exemestane are approved as second-line therapy generally treated for 6 months following surgical
following treatment with tamoxifen. resection.
• Patients with significant involvement of the lung, liver, or • Treatment with this combination regimen reduces the
brain and those with rapidly progressive disease rarely recurrence rate after surgery by 35% and clearly improves
benefit from hormonal maneuvers, and initial systemic overall patient survival compared with surgery alone.
chemotherapy is indicated in such cases. • The incidence of gastric cancer, esophageal cancer, and
• For the 25–30% of breast cancer patients whose tumors pancreatic cancer is much lower than for CRC, but these
express the HER-2/neu cell surface receptor, the malignancies tend to be more aggressive and result in
humanized monoclonal anti-HER-2/neu antibody, greater tumor-related symptoms
trastuzumab, is available for therapeutic use alone or in • In most cases, they cannot be completely resected
combination with cytotoxic chemotherapy. surgically, as most patients present with either locally
• Other agents that target HER 2/ neu signaling include, advanced or metastatic disease at the time of their initial
pertuzumab, adotrastuzumab entansibe, and small diagnosis.
molecule lapatinib • 5-FU-based chemotherapy, using either intravenous 5-FU
• Pertuzumab humanized IgG1 antibody that targets a or oral capecitabine, is generally considered the main
different epitope on the HER 2/neu receptor than backbone for regimens targeting gastroesophageal
trastuzumab, and this antibody inhibits heterodimerization cancers.
of HER2 with other HER family members, including
EGFR, HER 3 AND HER4 L. Lung Cancer
• This drug is used in combination with trastuzumab and • Lung cancer is divided into two main histopathologic
dicetaxel for HER2 POSITIVE metastatic breast cancer in subtypes, non-small cell and small cell.
patients who have not previously received anti-HER • Non-small cell lung cancer (NSCLC) makes up about 75–
chemotherapy for metastatic disease 80% of all cases of lung cancer, and this group includes
adenocarcinoma, squamous cell cancer, and large cell
J. Prostate Cancer cancer, while small cell lung cancer (SCLC) makes up the
• Prostate cancer was the second cancer shown to be remaining 20–25%.
responsive to hormonal manipulation. • When NSCLC is diagnosed in an advanced stage with
• The treatment of choice for patients with advanced metastatic disease, the prognosis is extremely poor, with
prostate cancer is elimination of testosterone production a median survival of about 8 months.
by the testes through either surgical or chemical • It is clear that prevention (primarily through avoidance of
castration. cigarette smoking) and early detection remain the most
• Bilateral orchiectomy or estrogen therapy in the form of important means of control.
diethylstilbestrol was previously used as first-line therapy. • When diagnosed at an early stage, surgical resection
• Presently, the use of luteinizing hormone-releasing results in patient cure.
hormone (LHRH) agonists— including leuprolide and • In patients with advanced disease, systemic
goserelin agonists, alone or in combination with an chemotherapy is generally recommended.
antiandrogen (eg, flutamide, bicalutamide, or • Combination regimens that include a platinum agent
nilutamide)—is the preferred approach. (“platinum doublets”) appear superior to non-platinum
• There appears to be no survival advantage of total doublets, and either cisplatin or carboplatin are
androgen blockade using a combination of LHRH agonist appropriate platinum agents for such regimens.
• Squamous cell NSCLC makes up approximately 30% of • The development of secondary malignancies is a late
NSCLC complication of the alkylating agents and the
• This form of NSCLC is responsive to platinum based epipodophyllotoxin etoposide.
chemotherapy with either cisplatin or carboplatin in • The most frequent secondary malignancy is acute
combination with gemcitabine myelogenous leukemia (AML).
• Small cell lung cancer is the most aggressive form of lung • In general, AML develops in up to 15% of patients with
cancer Hodgkin’s lymphoma who have received radiotherapy
• It is exquisitely sensitive, at least initially, to platinum- plus MOPP chemotherapy and in patients with multiple
based combination regimens, including cisplatin and myeloma, ovarian carcinoma, or breast carcinoma treated
etoposide or cisplatin and irinotecan. with melphalan.
• Drawback: resistance in all patients with extensive • The increased risk of AML is observed as early as 2–4
disease years after the initiation of chemotherapy and typically
• When diagnosed at an early stage, this disease is peaks at 5 and 9 years.
potentially curable using combined therapy and
radiotherapy REFERENCES
• The topoisomerase I inhibitor topotecan is used as • Dr. Pattaguan’s PPT
second-line monotherapy in patients who have failed a
platinum-based regimen.
M. Secondary Malignancies and Cancer Chemotherapy
APPENDIX

(Pcol) Cancer Chemotherapy

Uploaded by

Copyright:

Available Formats

(Pcol) Cancer Chemotherapy

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

(Pcol) Cancer Chemotherapy

Uploaded by

Copyright:

Available Formats

PHARMACOLOGY

5.08 CANCER CHEMOTHERAPY

OUTLINE ® They migrate to distant sites in the body to colonize

• Bevacizumab, Sorafenib, Sunitinib, and Pazopanib 10. Sorafenib

M. Secondary Malignancies and Cancer Chemotherapy

You might also like