Great Promise, Great Need

• Metastatic testicular cancer

– prior to 1970s, 5-10% cure rate in metastatic disease
• 11% of cancer deaths in 25-34 yr old men
– Cisplatin-based chemotherapy discovered
• Cure rate now >95%
Cancer Therapeutics – now less than 400 deaths per year in U.S.
• Pancreatic Cancer
– 43,000 people per year in U.S. are diagnosed
Peter H. O’Donnell, M.D. – fourth leading cause of cancer death
– Only 15% will be treatable by surgery (the only
Mon., November 14th 2016 AM
Department of Medicine chance for cure)
Section of Hematology/Oncology – Only 1-4% will be alive 5 yrs from diagnosis
Committee on Clinical Pharmacology and Pharmacogenomics
The University of Chicago – Even with the best current chemotherapies, survival is
approx. 6 mos
Einhorn JCO 1990; Ries et al SEER Cancer Stats Rev (2004);
Jemal A et al., CA Cancer J Clin. 2009; Mariacristina et al., Oncol Rep (2010)

Chemotherapy Purposes of Chemotherapy?

• Term coined by Paul Ehrlich (born • Treatment of surgically-amenable disease where risk of
1854) metastasis is high even with surgery
• Early 1900s, developed rodent lines – targets micrometastatic disease (given before or after surgery)
with transplanted tumors to screen
potential compounds for activity • Treatment of cancers where surgery is not possible (e.g.
• “Discovery” of first chemotherapy leukemias)
drugs resulted directly from mustard
gas program in World Wars I and II • To increase the chances of cell kill along with another
– Observation that those exposed had modality (e.g. radiation therapy)
bone marrow and lymphoid
hypoplasia • As direct instillation of a region affected by cancer (e.g.
• Nitrogen mustard tried in patients intravesicle therapy; liver perfusion therapy)
with hematologic malignancies
(Hodgkin lymphoma) at Yale in 1943 • Treatment of widespread disease
• Resulted in “dramatic regressions” in – Complete, durable response (cure)?
advanced patients – tumor control (prolong the time to progression and thereby
• Chemical warfare agents became patient survival)?
“declassified” after WW II – Induce a state of chronic stability (treatment like a chronic
• Dawn of the era of clinical disease)?
chemotherapy development
– palliation (in response to symptoms)?
Chabner et al. Pharmacologic Basis of Therapeutics (1996)
Chu and DeVita Principles of Medical Oncology (2000)

Special Considerations for Attacking Cancer Cells

Chemotherapy
• Systemic delivery of drug
• Cancer tissue effects + normal tissue
effects
• Therapeutic index narrow
• All drug therapy has some cost
• The cancer itself may have the ability to
adapt to the therapy (resistance)

www.lancastria.net
www.uvm.edu/~inquiryb/webquest/fa06/mvogenbe/
www.urgomedical.com

1
 DNA Targeted Chemotherapy DNA Targeted Chemotherapy
nitrogen
mustard
(mechlorethamine)

“alkylate”
(alkylating agents)

Chabner et al. Pharmacologic Basis of Therapeutics (1996)

Alkylating Agents Repair of DNA Damage

• DNA synthesis and cell division are disrupted

• Bi-functional alkylators more effective (inter-strand cross-
links)
– Degree of cytotoxicity correlates with degree of cross-links
• Actively proliferating tissues tend to be most affected
(those with high mitotic index)
– GI mucosa (ulceration, diarrhea, gut-related sepsis)
– Bone marrow suppression
– Germ cells (testes; decreased sperm; ovarian amenorrhea)
– Hair follicles
• Alkylation itself is lethal only if cell cannot correct the
DNA damage prior to next cellular division
• Secondary mutagenesis is a problem
– 5% incidence of secondary leukemias, 4-7 years later

Chabner et al. Pharmacologic Basis of Therapeutics (1996) Gazdar, NEJM (2007)

Oxaliplatin Oxaliplatin Toxicity

• Stomatitis (14%)
• Myelosuppression
• Neuropathy
– Acute (56%)
• distal or perioral paresthesias and
pharyngolaryngeal impairment, cold-induced, jaw
stiffness, voice changes
• appears soon after administration
• usually transient and completely reversible in
hours/days
– Chronic (~50%)
• Distal sensory loss, suppression of deep tendon
reflexes and proprioception
• High cumulative OX doses strongly associated
• Partially reversible in ~80% of patients after 6–8
months after discontinuation
www.atsdr.cdc.gov
Graham et al., Clin Cancer Res (2000)
Boulikas et al., Cancer Therapy (2007) Argyriou et al., Cancer Treat Rev (2008)

2
 Why are DNA Targeted
Resistance to DNA Targeted Drugs
Chemotherapies More Effective in
Tumors vs Normal Tissue? • Impaired entry into the cell/increased
• Any tissue undergoing cell division should theoretically efflux from the cell (drug pumps)
be affected by DNA-damaging agents
• Originally thought that tumor cells might divide and grow
• Increased production of competing
more rapidly than normal cells substrates (e.g. glutathione, alkylated
• Program of “genetic surveillance” and DNA repair (at instead)
cell-cycle progression Æ apoptosis or not) is intact in
normal cells, but dysregulated in tumor cells
• Intracellular metabolism of active
– Normal cells arrest cell cycle progression and repair DNA (or chemotherapy forms into inactive
destroy cells where damage is irreparable) metabolites
– Tumor cells less able to halt cell cycle progression, less able to
repair DNA or apoptose, ‘carry forward’ DNA damage through • Increased activity of DNA repair enzymes
each division until degree of damage triggers death

Chu and DeVita, Principles of Medical Oncology (2000) Chabner et al., Pharmacologic Basis of Therapeutics (1996)

DNA-Associated Targets Topoisomerase Inhibitors

• DNA knots block essential nucleic
acid processes because they
make it impossible to separate the
strands of the double helix
• Tangled DNA molecules cannot
be segregated during mitosis
• DNA knots and tangles can be
lethal to cells if they are not
resolved

“while essential to cell viability, the
enzyme also has the capacity to
fragment the genome”
Deweese and Osheroff, Nucleic Acids Res (2009)
• Topoisomerase II–DNA cleavage complexes are required to perform critical cellular functions
• If level of topoisomerase II–DNA cleavage complexes falls too low cells are not able to untangle
daughter chromosomes and ultimately die of mitotic failure
• If level of cleavage complexes becomes too high, the actions of DNA tracking systems can
convert these transient complexes to permanent double-stranded breaks
• Resulting DNA breaks initiate recombination/repair pathways and generate chromosome
translocations and other DNA aberrations
• If strand breaks overwhelm the cell, they trigger apoptosis
Deweese and Osheroff, Nucleic Acids Res (2009)

Topoisomerase Inhibitors (II) Toxicities of Topo II Inhibitors

• Etoposide • Etoposide – myelosuppression, mucositis, hair loss
• Doxorubicin • Doxorubicin – myelosuppression, mucositis,
• Etoposide is derived from podophyllotoxin, found in extravasation injury
Podophyllum peltatum (the mayapple or mandrake plant) • Secondary mutagenesis is a problem
• Used as folk remedy for over a 1000 years
– 6% incidence of secondary leukemias (AML), 4-7
• Etoposide was approved for clinical use in mid-1980s years later
– for several years was the most widely prescribed anticancer drug
in the world • Cardiotoxicity (doxorubicin)
• Etoposide and other drugs such as doxorubicin are front- – CHF (reduced LVEF)
line therapy for a variety of systemic cancers and solid – Dose related
tumors
• Every form of cancer that is considered to be curable by
chemotherapy utilizes treatment regimens that include
topoisomerase II-targeted drugs

topnews.in; wsahs.nsw.gov.au
Deweese and Osheroff, Nucleic Acids Res (2009) Takimoto, Principles of Medical Oncology (2000)

3
 DNA Targeted Chemotherapy Chemotherapy History – Part II
• Also around WW II, found that folic acid caused
leukemic cell growth
• Led to development of inhibitors of folic acid
pathway, known to be essential for purine and
pyrimidine synthesis

Robien et al., Pharmacogenomics (2005)

Folic Acid Analogs MTX Resistance Mechanisms

• Increase in DHFR (by gene amplification, increased
enzyme activity) or altered binding to MTX
• Defective transport into cells
• Decreased polyglutamation

• Methotrexate (MTX) – most widely-used anti-folate

• Activity against multiple types of malignancies (hematologic and
solid tumors)
• Single-agent MTX resulted in first cure of a solid tumor
(choriocarcinoma, Hertz et al., 1963)
• Enters the cell via same mechanisms as folic acid
• Metabolized intracellularly to more active polyglutamated forms
– May account for enhanced activity in malignant vs normal cells

Kummar et al. Principles of Medical Oncology (2000) Kummar et al. Principles of Medical Oncology (2000)
Robien et al. Pharmacogenomics (2005)

Toxicities of Methotrexate Why Not Mimic DNA Bases

Themselves?
• Myelosuppression, GI toxicity (mucositis) • Compete with
• Renal toxicity native
pyrimidines for
– 90% of elimination through kidneys
incorporation
– Crystallization of MTX in renal tubules into DNA
– Can alkalinize urine, aggressively hydrate • Inhibit DNA
• Accumulation in fluid spaces (pleural effusions) polymerases
• Interfere with
• Opportunity to “rescue” patients with high (or DNA chain
prolonged) blood levels of MTX with a reduced elongation
folate (leucovorin) to prevent severe toxicity (chain
terminator)

Kummar et al. Principles of Medical Oncology (2000) Parker, Chem Rev (2009)

4
 5-fluorouracil (5-FU) 5-FU (continued)
• Thymidylate synthase (TS) essential for synthesizing
• “Antimetabolite” – works by nucleotides necessary for DNA replication to continue
inhibiting essential • 5-FU active metabolite fluorodeoxyuridine monophosphate
biosynthetic processes (FdUMP) binds to TS and forms a stable complex, blocking
– can be incorporated into DNA access of other molecules and inhibiting TS function
or RNA, inhibiting their normal • Optimal binding and stabilization of FdUMP to TS enhanced by
function leucovorin

• 5-FU interferes with both

• 5-FU metabolites can be
misincorporated into DNA
• 5-FU metabolite FUTP is
extensively incorporated
into RNA, disrupting normal
RNA function
Longley et al Nat Rev Cancer (2003) Longley et al Nat Rev Cancer (2003)

Common 5-FU Toxicities Is there a way to spare normal

• Mucositis/stomatitis (50-60%) tissues from DNA targeted
• Diarrhea therapies?
• Hand-foot syndrome

• Intra-tumor Drug Activation

• Use the pyrimidine analog 5-fluorouracil as
an example

Preferential Activation of Chemotherapy in

Tumor Tissue Capecitabine
• Capecitabine: oral 5-FU prodrug • Levels of thymidine phosphorylase have
been shown to be significantly higher in
tumor tissue compared to normal tissue

www.tirgan.com/xeloda.htm

• Studies have suggested it is interchangeable with 5-FU

in most colon cancer regimens
• Adherence
Adjei A, Br J Clin Pharm (1999)

5
 Capecitabine Toxicities Oral Chemotherapies
• Toxicity Profile Slightly Different than 5-FU • Attractive to patients
• Primary toxicities: • Cancer therapy moves to the home
– diarrhea (any grade) = 40-55% overall • But are drug levels predictable?
• grades 3/4 in 10-15% of patients – requires absorption
– hand-foot syndrome (any grade) = 55-70% – food interactions
• grade 3 in 15%
– patient adherence
• False idea that “pill chemotherapies” are
• Used less frequently than IV 5-FU
not “chemotherapies” (and not as toxic)
• Patient-specific factors may make it more
or less attractive as an option

Case 1 Q1. Which of the following is the most likely

reason this patient had such severe, early
• 60 year-old black female with a recent toxicity?
diagnosis of C. diff colitis is admitted to the
hospital with severe mucositis 7 days after • A) she was given the wrong 5-FU dose
initiating first cycle of 5-FU-based • B) her malnourished state probably
chemotherapy for colon cancer caused this
– Had anorexia even before starting • C) her treatment team missed an
chemotherapy important drug-drug interaction which
– Now cannot tolerate any PO intake caused this
– Severe oropharyngeal erythema and mucosal
• D) she has a genetic or metabolic
breakdown seen on exam
deficiency which caused this

DPD Deficiency DPD Deficiency Prevalence

• Dihydropyrimidine
dehydrogenase (DPD) • Frequency of low DPD enzymatic activity,
catabolizes >80% of 5-FU into
indicating DPD deficiency, in the general
inactive compounds
• DPD is rate-limiting step
population estimated at 3% - 5%
• Causative link between DPD – partial deficiency vs complete deficiency
deficiency and severe toxicity
in response to 5-FU treatment
has been repeatedly shown
– can include 5-FU-related death
• Up to 30% of patients
experience severe 5-FU-
related toxicity Yen and McLeod, Eur J Can (2007)
Longley et al, Nat Rev Cancer (2003) Yen and McLeod, Eur J Can (2007)

6
 Ethnicity and DPD Deficiency FDA Label Includes DPD
Deficiency Consideration
• Topical 5-FU and oral 5-FU “should not be
used in patients with known DPD
deficiency”
• Precaution for intravenous 5-FU
• Dose-adjustments may be possible in
patients with partial deficiency
• Testing is not straightforward, nor easily
obtained

Mattison et al., Clin Can Res (2006) product Information: Adrucil(R) fluorouracil inj.; www.xeloda.com

Agents Targeting the Microtubule “Alternative Medicine?”

(Mitosis) Apparatus

Vinca rosea Periwinkle plant - Taxus brevifolia - Pacific Yew bark

described in medicinal folklore original source of paclitaxel
(modern observation of bone (isolated 1971)
marrow suppression 1958) from M. Maitland
Stout et al., BMC Cell Biology 2006

Vinca Alkaloids and Taxanes Common Toxicities

• Taxanes – bone marrow suppression,
• Vincristine, vinblastine, vinorelbine hypersensitivity reactions (likely vehicle effect),
• Paclitaxel, docetaxel “stocking-glove” neuropathy
• Interact with tubulin, disrupt microtubule • Vincas – constipation,
function Æ unable to form proper mitotic neuropathy
spindle/dissolve mitotic spindle Æ cell • Likely due to axonal
cannot progress through cell cycle Æ transport disruption/
apoptosis degeneration via
microtubule effects in
neurons
• Extravasation injury
www.atsdr.cdc.gov

7
 Targeting Endogenous Growth Hormonal Blockade
Stimuli • In 75% of breast
cancers, estrogen
• Factors stimulating cancer development, receptor (ER) signaling is
a key promoter of tumor
and progression, can be targeted to try to proliferation
reverse that process • Means of inhibiting ER
signaling:
• Breast cancer and prostate cancer are – partial receptor agonists,
such as tamoxifen
paradigm examples (hormone-driven – measures to reduce the
circulating level of
cancers) estrogen, including ovarian
ablation, gonadotropin-
releasing hormone
analogues, and aromatase
inhibition
– antagonism and
downregulation of ER by
antiestrogens
Cleator et al. Clin Breast Can (2009)

Hormonal Manipulation: Benefit

Targeting the Cell Surface
and Toxicity
• Tamoxifen or aromitase inhibitors used for 5
years in adjuvant (post-operative) setting for
women with ER+ breast cancers show:
– chance of recurrence at least halved
– death rate lowered by more than 1/3
• In the metastatic setting, 25% of patients will
respond to ER manipulation
• Toxicities include hot flashes, risk of deep
venous thrombosis, endometrial cancer
(tamoxifen), severe joint pains, bone loss (AIs)
Cleator et al. Clin Breast Can (2009)

B-cell Malignancies as an Example Rituximab

• Human-mouse chimeric anti-CD20 monoclonal antibody
• CD20 is a cell-surface glycoprotein highly
expressed on most B-cells shown to induce lysis of B-cells expressing CD20
• Approximately 80–85% of NHL are B-cell in origin
and are CD20+ in over 90% of cases Large B-cell lymphoma
– attractive target for antibody therapy N=399 patients
• CD20 is tightly restricted to the B-cell lineage and
is not expressed on either precursor lymphoid
cells or the vast majority of plasma cells
– Allows B-cell regeneration post-anti-CD20 therapy
• CD20 does not circulate freely in the plasma,
thereby limiting competition for anti-CD20
antibody binding to lymphoma cells
• CD20 is not internalized, down-modulated, or
shed from the surface of CD20+ cells following
antibody binding • Complete response significantly higher in CHOP + rituximab
group compared to CHOP alone (76% vs 63%, P=0.005)
• Risk of death 0.64 in rituximab arm compared to CHOP alone

Czuzman and Gregory, Leukemia and Lymphoma (2010) Coffier et al., NEJM (2002)

8
 Rituximab Toxicity Targeting a Tumor-Driving Defect
• Fever, chills, rigors, and rarely
bronchospasm
• Fatal reactivation of hepatitis B virus

Jaglowski and Byrd, Sem Hematol (2010) www.medscape.com

Targeting a Tumor-Driving Defect Imatinib

• Viewed that targeting of a single molecular defect
would not suffice to treat highly heterogeneous
cancers
• Prevailing thought that inhibitors of ATP binding
would lack sufficient target specificity to be
Druker, Blood (2008)
An et al., Leuk Res (2010) clinically useful
• Tyrosine kinase–null animals had an embryonic
lethal phenotype
• The constitutively active BCR-ABL tyrosine kinase functions by – led to the belief that tyrosine kinase inhibitors would be
transferring phosphate from ATP to tyrosine residues on various extremely toxic
substrates to cause excess proliferation of myeloid cells
characteristic of CML
• Block BCR-ABL, block tyrosine kinase downstream events?
Druker, Blood (2008)

Tyrosine Kinase Inhibitor Toxicity Targeting the Tumor Environment

• Myelosuppression (some may be due to

‘response effect’)
– severe in up to 10%
• Nausea, diarrhea (40% each)
• Edema (50-60%, rarely severe)
• Skin rashes (up to 40%, usually mild)
• Liver injury (3%)

Mauro and Deininger Best Pract Res Clin Hematol (2009)

9
 Angiogenesis Angiogenesis (II)
• Abnormal angiogenesis is a hallmark of cancer
• “Most Solid Tumors May Exist Early as – characterized by increase in the number of
Tiny Cell Populations Living by Simple proliferating endothelial cells and altered vascular
morphology
Diffusion in the Extracellular Space”
• Tumor microenvironment switches to a
• “Further Growth Requires Vascularization, “proangiogenic” state
and the Tumor Then Maintains Itself by – important in tumor development
Perfusion” – characterized by upregulation of several
proangiogenic factors, including vascular endothelial
– Judah Folkman, “The Father of Angiogenesis” growth factor (VEGF)
• Essential steps for tumor migration, metastasis,
and growth
Folkman, NEJM (1971) Grothy and Galanis Nat Rev Clin Onc (2009)

VEGF Ligands and Receptors Bevacizumab

• 813 metastatic
colon cancer
patients

• Tumor response
rates increased
from 35% to 45%

• Progression-free
survival 10.6
months with bev vs
6.2 months without

• VEGF likely has a direct effect on tumor cells, promoting survival, migration and
• VEGF monoclonal antibody, bevacizumab, results in
invasion tumor response, delays tumor progression , and
• VEGF is secreted by cancer or stromal cells increases overall survival
• Stimulates endothelial proliferation, migration and assembly into vascular networks
• VEGF receptors mediate signaling in the tumor microenvironment including
• FDA approved for colon, breast, non-small cell lung,
microvascular permeability and endothelial cell proliferation glioblastoma, renal cancer
Grothey, A. and Galanis, E., Nat. Rev. Clin. Oncol (2009) Hurwitz et al., NEJM (2004)

Tumor Stabilization Anti-angiogenic toxicities

• Hypertension
– VEGF inhibition results in decrease in nitric oxide
levels, leading to vasoconstriction
• Proteinuria
– VEGF affects glomerular vascular permeability in the
kidney (nephrotic syndrome can result)
• Hemorrhagic events
• Arterial thromboembolism
– 1-3%; CVA, MI
• Wound-healing complications
Ratain et al., JCO (2006) Koutras et al., Cancer Treatment Rev (2010)

10
 Supportive Care Agents
• Anti-emetics
• Hematopoietic Growth Factors
• Increased experience
Supportive Care – infusion times
– pre-medication against hypersensitivity
reactions
– hydration with chemotherapy (esp. for kidney-
toxic agents)
• Have increased the safety and tolerability
of many chemotherapies

Nausea and Vomiting Nausea and Vomiting (II)

• In 1983, a survey of cancer patients ranked
nausea and vomiting #1 and #2 as “most severe
side effects” of chemotherapy
• Improvements in anti-emetic medications (and in
chemotherapy regimens) have dramatically
decreased the frequency and severity of N/V
– but 2004 study showed that ~35% of patients overall
experienced acute nausea, 13% acute emesis
– delayed nausea (>50%) and emesis (>28%) were
also observed
• Over 75% of physicians and nurses
underestimated the delayed incidences
Grunberg et al., Cancer (2004) cdn.pharmacologycorner.com

Nausea and Vomiting Hematopoietic Growth Factors

• 5-HT3 receptor antagonists: • Endogenous Granulocyte Colony Stimulating
– ondansetron, granisetron Factor regulates the production, maturation, and
– used to prevent acute and delayed emesis functionality of neutrophils
– rHu G-CSF (filgrastim and peg-filgrastim)
– headache, constipation
• Reduce the time needed for stem cell Æ mature
• Neurokinin-1 antagonist neutrophil
– aprepitant • Since incidence of infection directly correlates
• Dopamine antagonists with duration and depth of neutropenia
– prochlorperazine • Prophylaxis: 50% reduction in the incidence of
febrile neutropenia
• Metoclopramide (dopamine antagonist, weak 5- • Can be used in some patients during acute
HT3 antagonist) febrile neutropenia, with antibiotics
• Dexamethasone (reduce arginine vasopressin?)
Berger and Clark-Snow, Principles and Practice of Oncology (2000) Holter and Ozer, Principles and Practice of Oncology (2000)

11
 Tumor Lysis Syndrome
• Oncologic emergency caused by massive tumor cell
lysis with release of large amounts of potassium,
phosphate, and nucleic acids into the blood
• Catabolism of the nucleic acids to uric acid leads to
hyperuricemia
– marked increase in uric acid excretion can result in precipitation
of uric acid in renal tubules and acute renal failure
• Most often occurs after initiation of cytotoxic therapy in
patients with high-grade lymphomas and acute
lymphoblastic leukemia
– can occur spontaneously and with other tumor types that have a
high proliferative rate, large tumor burden, or high sensitivity to
cytotoxic therapy
• Best management is prevention
– aggressive intravenous hydration
– administration of uric acid-lowering agents

Larson and Pui (2011)

Individualized Prescribing Using the Tumor Profile

Attacking Cancer Cells
DNA Targeted Drugs Microtubule Targeted Drugs

DNA-Associated Drugs
(Topoisomerase Inhibition)
Drugs Blocking Endogenous
Growth Signals (Hormones)
• EGFR inhibitors had 10% response rates in all
metastatic colon cancer patients
“Activation” of Drugs • Early studies suggested clinical benefit was confined to
Selectively in the Tumor Drugs Targeting Known subset of patients
Molecular Defects (BCR-ABL)
• Analyses demonstrated that benefit was limited to
Drugs Targeting Tumor patients with tumors harboring wild-type KRAS gene
Drugs Targeting the Microenvironment
Surface Antigens
and Angiogenesis www.lancastria.net
www.urgomedical.com Siddiqui and Piperdi, Ann Surg Oncol (2010)

Anti-EGFR Therapy Personalized Therapy

• Anti-EGFR therapy in
colon cancer • Response
– FDA approved 2004
rate = 0%

• Response
– FDA label change 2009 rate = 17%

9.5 vs 4.8 mo.

survival difference Amado et al., JCO (2008)
Karapetis et al., NEJM (2008)

12
 Cancer Pharmacogenetics
• “Study of genetic factors
influencing drug response”
• Can explain why the same
chemotherapy, given to two
individuals with the same disease:
– can cause one individual to
experience severe toxicity, while the
other does not
– or one individual to have anti-tumor
effect, while the other does not
• Individualized drug therapy based
on a person’s unique genetic
make-up is especially desirable in
oncology
– the therapeutic index is often narrow
– the consequences of chemotherapy
toxicity can be life-threatening
Clin Pharm Ther (Sept 2008 cover)

Inherent Risks of Chemotherapy Attainment of Complete Pathologic Response

Bladder Cancer Regimen: Methotrexate, vinblastine, doxorubicin, cisplatin
• Study of over 7,000 breast cancer patients
•Neoadjuvant chemotherapy
– some of whom received chemotherapy as part of pT0 rate = 38%
standard care •No neoadjuvant chemotherapy
pT0 rate = 15%
• The rate of emergency room visits and
hospitalizations for patients receiving
chemotherapy was 61%, compared to 42% for
those treated with only surgery and/or radiation
• Reality of all drug therapy
– adverse drug reactions are believed to be the 5th
leading cause of death in the United States

Hassett et al., J Natl Cancer Inst. (2006)

Davies et al., Curr Drug Saf. (2007) Grossman et al., NEJM (2003)

All cancer patients requiring chemotherapy for a given disease

All cancer patients requiring chemotherapy

Non-responders
and Toxic responders
Treat with alternative
dose or alternative regimen?

Responders and patients

not predisposed to toxicity
Treat with conventional
regimen and dose
White: Normal responder. Orange: Toxic responder.
Blue: Non-responder.
Adapted from Evans, Johnson. Annu Rev Genomics Hum Genet (2001)

13
 Combining Chemotherapy Agents
• Combination chemotherapy offers advantages
– Combines activity of each individual drug
– Allows action against the tumor cell via multiple
different mechanisms
Combination Chemotherapy – May prevent or delay resistance adaptation by the
tumor
– Combining drugs with different toxicity profiles offers
unique strategy for tolerability
• Treatment time interval may be important; often
limited by recovery time needed by normal
tissue

Metastatic Colorectal Cancer Metastatic Colorectal Cancer

• Five different classes of drugs • Most common “backbone” regimens:
with significant clinical activity – FOLFOX
– Fluoropyrimidines • FOL – folinic acid (leucovorin)
– Oxaliplatin • F – 5-FU
– Irinotecan • OX - oxaliplatin
– Anti-angiogenic monoclonal – FOLFIRI
antibody (bevacizumab)
• FOL – folinic acid (leucovorin)
– Anti-EGFR monoclonal antibodies
• F – 5-FU
• cetuximab
• panitumumab • IRI - irinotecan

www.hopkinsmedicine.org

Case 2 Q2. Which chemotherapy regimen should

• 50 year-old male professional pianist with
you choose to treat his colon cancer?
a history of severe HTN presents with a
• A) FOLFOX
new diagnosis of metastatic colon cancer.
• B) FOLFOX + bevacizumab
Tumor testing shows mutation of KRAS.
• C) FOLFOX + cetuximab
• D) FOLFOX + bevacizumab + cetuximab
• E) FOLFIRI
• F) FOLFIRI + bevacizumab
• G) FOLFIRI + cetuximab
• H) FOLFIRI + bevacizumab + cetuximab

14
 “Personalizing” Therapy for Your Tumor Effects and Patient Effects
Patient
• Knowledge of the goals of treatment
– Cure? Increased Survival? Palliation?
– Do toxicity risks outweigh potential benefits?
• Knowledge of patient-specific comorbidities
– uncontrolled hypertension/bevacizumab
– pre-existing neuropathy/oxaliplatin
• Knowledge of patient-specific genetics
– 5-FU/DPD deficiency
• Knowledge of patient-specific tumor
characteristics
– KRAS mutation status/addition of anti-EGFR therapy
Paugh et al., CPT (2011)
Pui et al., Lancet Oncology (2001)

Summary “Personalizing” Therapy for Your

• Cancer chemotherapy – must first determine goal of
Patient
treatment
• All therapy comes at a cost of toxicity • This is the standard, not the exception, for
• Multiple different drug targets have been successful today’s oncology care
• Increasing an understanding of tumor dysregulation
mechanisms offers potential for making • Means not just treating a “disease”, but
chemotherapies more “tumor selective” in their effects treating an individual
(potentially sparing many normal tissues)
• Oral, more well tolerated chemotherapies, and periods • Has the potential to significantly improve
of tumor stabilization, offer the potential for treating the way that cancer patients experience
cancer as a chronic disease
• Increased use of patient-specific genetic factors their care, and their outcomes
predicting drug response and toxicity represent the
future of individualized cancer therapeutics

15