Medicine II: 1.6
Gracieux Fernando
SYSTEMIC THERAPY IN CANCER
OUTLINE
I. History of Cancer
II. Treatment Modalities
III. Cytotoxic Chemotherapy
IV. Pharmacologic Aspects
V. Fractional Cell- Kill Hypothesis
VI. Skipper and Scable Principle
VII. Resistance to Anti- Cancer Agents
VIII. Causes of Resistance
IX. Combination Therapy
X. Indications of Chemotherapy
XI. Types of Responses to Chemotherapy
XII. Response Evaluation of Chemotherapy in Solid Tumors
XIII. Calculating the Sum of the Longest Lesion
XIV. Tumor Response to Chemotherapy
XV. Contraindications to Chemotherapy
XVI. Hormonal Therapy in Cancer
XVII. Immunotherapy in Cancer
XVIII. Targeted Therapy
XIX. Side Effects of Immunotherapy
HISTORY OF CANCER
Remote sympathy: Most accepted approach to treating cancer from 200
BC to middle ages
o First report of malignancy
o Galens Humoral Theory of Disease: malignancy is a systemic
disease and so there was no attempt to treat the malignancies
locally
o Cancer patients at that time were left best on their own because
they had a very poor understanding of what the disease is all
about.
Andreas Vesalius: Performed anatomical dissections and revealed that
there was no basis for Galens Humoral Theory.
th
15 century: Localized management of malignancies through surgery
was considered, but actual success was achieved when the practices of
anesthesia and antisepsis were established.
Late 1800s: Surgery as a treatment modality for malignancies had
become the standard, but recurrences were common.
William Stewart Halsted: played a prominent role in the surgical
management of malignancies, especially those of the breast
o He observed that the most common way that a tumor could recur
is when it would grow back particularly at the site where it was
first removed.
o Theorized that the reason for recurrence was due to inadequacy
of the surgical procedure.
o Proposed solution was to perform more surgeries or extend the
field of surgery, such as resection of the breast, pectoralis major
and minor, and the entire content of the axillary components in
breast cancer.
o Halsteds radical mastectomy named after him
Halsteds subsequent colleagues took the concept of radical mastectomy
to its logical limits and created procedures such as extended radical
mastectomy (clavicle was taken out and the chest opened up to reach
the internal mammary chain of nodes), and the ultra-radical
mastectomy (dissection reached the neck). During those times,
dissecting and removing as much viable and potential tissue as possible
was the solution for malignancy.
THE NEED FOR SYSTEMIC THERAPY
Years later, physicians compared results of various surgical techniques to
check for survival improvements or recurrence improvements. It was
noted that recurrence rates and survival rates among those who
underwent a radical mastectomy, a simple mastectomy and a
THE MED MEN | MEDRANO, P. | MENDOZA, C. | MENDOZA, G. | MENDOZA, J. | MERCADO, L.
Dr.
June 27, 2014
mastectomy followed by radiation, were practically the same for all
procedures. The only difference between the two was that patients
with node- positive disease tended to have a poor prognosis compared
to node negative disease.
Figure 1. Distant disease- free survival (left) and overall survival (right)
Rudolf Virchow: Proposed the cellular concept of disease and concluded
that there are only two ways in which cell increases their size which is
through hypertrophy or hyperplasia.
o He realized that malignant cells are cells with a disorganized
growth potential, and they acted as if they had a life of their own.
Since this was something that he had not seen before, he called it
neoplasia. He concluded that the main cellular characteristic of
malignancies was continuous proliferation.
Edward and Hellen Kumar: Pathologists who studied deaths caused by
mustard gas, which was invented during World War I. They discovered
one innate characteristic in many patients who have been exposed:
bone marrow aplasia. This suggested that the gas acted on tissues with
rapid proliferation.
Louis Goodman and Albert Gilman: Pharmacologists from Yale
University who were sent to study the toxic effects of mustard gas
exposure during World War II.
o They concluded that mustard gas is a vesicant in its gaseous
forms, and that it actually causes severe damage to the pulmonary
system leading to death. In order to remove the vesicant effects,
they gave it via IV to experimental animals, and they noted that
although there were no vesicant effects, bone marrow aplasia was
replicated.
o They returned to Yale University and convinced a thoracic surgeon
colleague to put a patient with lymphoma through a 10-day
infusion of nitrogen mustard via IV. Complete regression of the
lymphoma was noted after the treatment, and it became the first
successfully documented system therapy for a solid malignancy.
Today, nitrogen mustard is used under the name Mechlorethamine and
is still used as a treatment option for patients with Hodgkins
lymphoma.
TREATMENT MODALITIES
Systemic modalities:
1. Cytotoxic chemotherapy- the most common systemic therapy
2. Hormonal therapy
3. Biologic therapy
Immunologic therapy
Targeted therapy
Gene Therapy
Today, molecular targeted therapies are also being used.
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CYTOTOXIC CHEMOTHERAPY
Effectiveness is primarily on cell multiplication and tumor growth
Most agents affect macromolecular synthesis and function (DNA, RNA,
proteins)
Agents are classified roughly on their activities relative to the cell
generation cycle
Cytotoxic chemotherapy targets DNA replication. Most of them would
have their activity within the cell cycle and are capable of hitting mostly
cells that are in active proliferation
Figure 2. The cell cycle
MECHANISMS OF DRUG ACTIVITY
1. Phase non- specific drugs would be active in any phase of the cell
cycle
A. Cycle non- specific drugs - drugs that can be active whether the
cell is replicating of not
EXAMPLES:
Nitrosoureas family (BCNU, CCNU and CDNU) and
Methazolamide-- Both are used for the treatment of CNS
tumors
Corticosteriods (Prednisone, dexamethasone and
prednisolone)used for hematopoietic malignancies
B. Cycle specific drugs drugs that are only active if the cell is
anywhere within the cell cycle; increased dose=increased efficacy
EXAMPLES:
Alkylating agents (Cyclophosphamide, thiphosphamide) and
platinum analogs (Cisplatin, carboplatin)Full cycle specific
(can act on any phase of the cycle)
Tumor antibiotics (Doxorubicin and epirubicin)-- Cycle specific
but have the greatest activity in the S phase of the cell cycle
2. Phase specific drugs that are cycle specific- phase specific
IMPLICATIONS:
o Limited to a single- exposure cell kill. Phase- specific agents
given as a single dose, will only kill cells that are in that phase
of the cell cycle. This is why they are considered to have a
limited cell- kill potential.
o Increasing cell- kill by prolonged exposure and recruitment.
Prolonging the infusion rate of a cycle-specific phase-specific
agent is the best way to improve its efficacy. This will allow
the other cells to enter into the phase of the cell cycle that is
sensitive to the agent, eventually destroying them.
EXAMPLES:
o 5- FU A pyrimidine analog and S- phase specific agent
o Since it is an S- phase specific agent, it is not given as a single
bolus dose when treating colon cancer. It is most effectively
used either as a 5-day continuous bolus injection or a weekly
continuous injection. It can also be given as a 28-day
continuous intravenous infusion.
THE MED MEN | MEDRANO, P. | MENDOZA, C. | MENDOZA, G. | MENDOZA, J. | MERCADO, L.
SITES OF ACTION OF CYTOTOXIC AGENTS
The figure shows an example of the general family or classification of
chemotherapeutic agents and the sites of actions in relation to the cell
cycle.
Figure 3. Sites of action of cytotoxic agents at the cell cycle level.
Alkylating agents are effective in the entire cell cycle
Antibiotics are cycle- specific although they have a preferential activity
in the S- phase
Antimetabolites are cycle- specific for the S- phase of the cell cycle
because they act as analogs of the backbones of DNA
Vinca alkaloids and taxanes are effective in the M- phase of the cell
cycle because they attack the mitotic spindle
PHARMACOLOGIC ASPECTS
1. Absorption
Determines route of administration
Majority are deactivated by gastric acid and are fully absorbed in
the GIT so majority of the agents are given via IV, although some
agents like 5-FU already have oral analogs that are used in the
clinics.
2. Area of Distribution
Determines the compartments in the body where the agents are
going to be active
Since they are macromolecules, it will be difficult for them to
traverse certain barriers particularly the blood brain barrier.
Because of that, the CNS can become a potential site of
malignancy recurrence.
3. Biotransformation
Many of these agents are actually utilized as pro- drugs and will
require certain enzymes of the body to convert them into the
active metabolites.
These enzymes are mainly located in the liver, and in cases of
hepatic insufficiency, there can be decreased conversion to an
active agent resulting to low plasma levels of the drugs.
4. Drug Dosing
For cancer patients, the computation for the dose of these
chemotherapeutic agents is largely based on the total body
surface area, due to their toxicity and their narrow profile of
toxicity vs therapeutic range.
5. Excretion
Determines need for dosage adjustment in the presence of organ
insufficiency
Many of these drugs are demetabolized or metabolized eventually
by the liver and many of them are excreted by the renal system.
The presence of hepatic or renal insufficiency is going to require
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dosage adjustment otherwise there will be prolonged half- life
leading to higher potential for toxicity.
FRACTIONAL CELL- KILL HYPOTHESIS: 3 LOG- KILL- 1 LOG REGROWTH
PRINCIPLE
Fractional cell - kill Hypothesis: states that every cycle of
chemotherapy will kill the same fraction of cancer cells. Also known as
the 3- log kill, 1 log regrowth principle.
10 3
In a tumor with 10 cells, a cycle of chemotherapy will result in 10 (3
7
log kill) cells dying and 10 cells remaining. During recovery, tumor is
1 2
expected to grow by 10 (1 log regrowth). Net cell kill per course is 10 .
Figure 4. 3-log kill, 1 log regrowth principle.
It is estimated mathematically that in 1 chemotherapeutic cycle, 99.9%
of cancer cells are killed. So, if one cycle can already kill 99.9% of cancer
cells, why is there a need for 4-6 cycles?
10
In a hypothetical patient with 10 number of cells at baseline, one cycle
10
of chemotherapy would leave him with 0.1% tumor cells. 0.1% of 10 or
10 -3 7
10 x 10 equals 10 , which is still a very large number. This is the
reason why patients have to undergo 4-6 cycles of chemotherapy.
Chemotherapy cannot be given consecutively because it is a very toxic
procedure. On the average, a 3-week interval is given before the patient
can actually receive the next cycle of chemotherapy to allow for bone
marrow recovery.
It is also estimated that when the patient recovers from the side
effects, the tumor also recovers by a factor of 1 log. So the net
decrease in the tumor cells after one cycle is 2 logs (3 logs to kill, 1 log
to regrow).
To decrease the number of tumor cells to a point where the patients
own immune system can handle them, which is only about 1000 tumor
cells, 4 cycles of chemotherapy is needed. Usually, when a test response
th
is gotten at the 4 cycle, an additional 2 cycles of chemotherapy is given
to consolidate the response. This is why on the average, cancer patients
receive about 4-6 cycles of chemotherapy.
CLINICAL IMPLICATIONS OF THE FRACTIONAL CELL- KILL HYPOTHESIS
Chemotherapy cycles must be given on time.
o With 1 log of regrowth after every cycle, a delay in the treatment
could mean more regrowth or probable return to baseline,
wasting the effects of the initial cycle.
o To have an effective chemotherapy cycle, it should be emphasized
that patients must receive it on a strict schedule.
One cycle will be ineffective in providing any type of relief to the cancer
patient. The implication of the Fractional Cell- Kill Hypothesis is that
treatments have to be planned, and that to be effective, chemotherapy
must be completed.
THE MED MEN | MEDRANO, P. | MENDOZA, C. | MENDOZA, G. | MENDOZA, J. | MERCADO, L.
TUMOR GROWTH
The fractional cell-kill hypothesis makes the wrong assumption that in a
tumor, all the cells are proliferating. However, this is not the case. There
are phases in the cell cycle where there is practically zero growth
potential, such as in a clinically apparent tumor in the plateau phase of
the Gompertzian growth.
Figure 5. Gompertzian growth.
The problem here is that, in a clinically apparent tumor where, most of
the cells are no longer proliferating, can chemotherapy still be utilized
especially if there is already metastasis? This can be explained by the
Skipper and Scable Principle.
SKIPPER AND SCABLE PRINCIPLE
Growth fractions and doubling times may differ from cells in the primary
site versus those in micro- metastases
Magnitude of response in plateau phase of the Gompertzian growth
need not reflect the response of micro- metastases in exponential
growth
st
1 order kinetics relative to cell kill by cytotoxic agents apply to those
cells with constant growth fraction in exponential growth
Ablation of primary tumor with a resultant decrease in total tumor cell
burden may alter the growth characteristics of residual micro-
metastases
Primary site: crowded, with lots of competition for nutrients, plateau
phase in Gompertzian growth is usually in order
Micro-metastasis: cells that escaped the primary site and are already in
logarithmic growth, but still undetectable
The Skipper and Scable Principle differentiates the growth potentials of
cells that are in the primary site, and cells in micro-metastases
When a tumor is in the Gompertzian plateau phase, the number of
proliferating cells is equal to number of dying cells/cells not
proliferating resulting to a growth potential of zero. This is why
chemotherapy can still be given in very large tumors, as there are still
proliferating cells present. This is the concept of induction
chemotherapy.
In patients with locally advanced diseases, such as a 10 cm breast cancer
with metastasis of the skin involving majority of the axillary nodes,
chemotherapy is given prior to surgery to decrease the size of the
tumor, and in so doing, lessen the extent of surgery performed. Once
surgery is done, chemotherapy can be resumed to target the remaining
cells.
RESISTANCE TO ANTI- CANCER AGENTS
1. Natural Resistance
Initial non- responsiveness of a tumor to a given drug
Tumors which are naturally resistant probably express substances
that render them naturally immune to the effects of chemotherapy
or because their growth potential is very slow. An example is thyroid
carcinoma
Chemotherapy plays a very poor role in naturally resistant tumors.
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2. Acquired Resistance
Unresponsiveness to certain drugs that emerge after initial
successful treatment
In acquired resistance, the patient is exposed to the drug. The
patient initially responds to the drug but subsequent use of the drugs
renders the tumors unresponsive
Once acquired resistance occurs, it sometime extends to several
member of the same family of drugs.
CASUSES OF RESISTANCE
1. CELL KINETICS
Mechanism:
o Effects are due to different growth fractions in the tumors
Gompertzian growth curve.
o Goldie-Coldman Hypothesis: As a tumor cell population increases,
there is an ever expanding number of drug-resistant phenotypic
variants which arise due to somatic mutations that become
difficult to eradicate. Initially good response since all of the
sensitive cells are killed remission because all that is left are the
mutated cells that developed resistance.
Overcoming resistance from cell kinetics
o Reduce tumor bulk with loco-regional modalities (surgery, RT)
o BIG TUMOR MASS debulk smaller mass cells left rapidly
proliferating sensitive to chemotherapy
o Use combinations that include drugs that can affect resting
populations.
o EXAMPLE:
CHOP chemotherapy regimen frontline treatment for non-
Hodgkins lymphoma)
Cyclophosphamide (alkylating agent) cycle specific,
hits proliferating cells
H-Adriamycin cycle specific, hits cells in the S-phase
Oncovin (Vincristine) hits cells in the M phase
Prednisone cycle non-specific; hits resting cells
o Schedule drugs to prevent phase escape or to synchronize cell
populations and increase cell kill.
2. BIOCHEMICAL CAUSES
Mechanism
o Inability of tumor to convert drug to active form
o Many of these drugs are prodrugs, and patients with deficiencies
in enzymes that can convert these drugs to active agents, or
patients with hepatic insufficiency may have problems with
maintaining adequate plasma levels of these drugs giving the
tumor some form of resistance. [3]
o Presence of substances that may overcome a potential lethal
blockade.
o EXAMPLE:
Increased expression of BCL2 which is an anti-apoptotic, so
even if p53 cells express proteins like BAX, BAD and BID which
are pro-apoptotic, no apoptosis is going to occur
Total loss of P53 function: nothing triggers apoptotic process
Multi drug resistance through p-glycoprotein expression
(glycoprotein is an active transmembrane cytoplasmic pump)
ATP-mediated mechanism: Due to MDR p-glycoprotein
expression, the cell pumps the drug out of the cell
drug does not reach the nucleus no
chemotherapeutic effect tumor resistance to the
particular drug
THE MED MEN | MEDRANO, P. | MENDOZA, C. | MENDOZA, G. | MENDOZA, J. | MERCADO, L.
Figure 6. Active Pump of the MDR gene
o Overcoming biochemical causes of resistance
o Use combination chemotherapy: Hits different populations of cells
o Use biologic response modifiers:
o EXAMPLE:
Folinic Acid used in conjunction with 5-FU improves
affinity of 5-FU with its target enzyme thymidilate synthase ;
used in colon CA patients
3 ways to improve response by increasing dose w/o risk of toxicity:
nd
o Use a 2 agent to rescue normal cells :
Folinic Acid in conjunction with Methotrexate(purine analog)
Methotrexate targets Dihydrofolate reductase
amt of folate for DNA synthesis prevents the effects
of high dose Methotrexate, such as in fulminant renal
toxicity and failure
In osteosarcoma give Methotrexate at high dose
(20g) 24 hrs after give Folinic acid to replenish normal
cells toxicity avoided
o Follow marrow-lethal doses of chemotherapy with autologous
bone marrow transplantation (eg leukaemia, multiple myeloma,
relapselymphoma)
o Combine high dose chemotherapy with blood cell regrowth factors
(e.g. F-CSF, GM-CSF). Used to overcome the problem of bone
marrow depression which comes with administering high doses of
chemotherapy.
3. PHARMACOLOGICAL CAUSES
Mechanism:
o True resistance does not exist: Tumor is sensitive to drug, but drug
has below optimal plasma level
Poor or erratic absorption
Increased excretion or catabolism:
Ex. Fast acetylators metabolize drugs much faster
lower plasma levels and lower efficacy
Drug Interaction:
Ex. TCAs, anticonvulsants, some corticosteroid
increase the activity of the cytochrome 450 enzyme
systems increase the metabolisms of certain agents
their plasma levels again fall lower drug efficacy
Sometimes, the drug itself can increase its own metabolism:
Ex. Ifosfamide (alkylating agent) if given beyond a
certain duration, it starts to metabolize itself; now, it is
given in a shorter infusion time (2-4 hour)
Imatinib 6-8 months lower response; increase dose
at time of resistance.
o True pharmacological resistance:
Poor transport of tumor cell lymphomas: sites that cannot be
reached by drugs particularly CNS and testes (sanctuary sites
for high grade tumors such as leukemia and lymphoma)
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COMBINATION THERAPY Neo-adjuvant (Induction Chemotherapy): Chemotherapy given prior to
ADVANTAGES surgery prevent metastases and decrease tumor size (to facilitate a
Prevention of resistant clones less debilitating or less disfiguring type of surgery e.g. breast cancer
Cytotoxicity to resting and dividing cells o Osteosarcomas Usually affect young individuals, teenagers;
Biochemical enhancement or effect: Synergistic affects extremities (proximal tibia, distal femur) leading to
Sanctuary access: Examples are the CNS and the testis amputation (only surgery for osteosarcoma). Neo-adjuvant
Rescue: One agent is combined with another to rescue the patient from chemotherapy will decrease tumor size then do limb sparing
the toxic effects of the first agent operation, hence no need for amputation. Remove the tumor and
the affected bone then do reconstructive surgery on functional
[3]
AIM OF COMBINATION CHEMOTHERAPY extremity; increases survival
The aim of the combination is to achieve a balance. There must be Concurrent Chemotherapy Used at the same time with radiotherapy.
efficacy combined with safety, less toxicity in the patient. Chemotherapy is a good radiosensitizer increases the tumors
sensitivity to the effect of radiotherapy. Ex. Neck malignancies, late
stage lung cancer
Salvage Chemotherapy - Failed the first treatment. But there are
subsequent treatments that may create a complete response. Ex. Non-
Hodgkins lymphomas

2. PALLIATIVE CHEMOTHERAPY
Objective is not to cure or prolong survival of patients; rather, it aims to
control symptoms. When giving palliative chemotherapy, all rules of
chemotherapy are broken:
o Give single agent rather than a combination: less toxicity, maybe
Figure 7. Aim of combination therapy. equal efficacy
The concept of maintaining that balance is very important because the o 6 cycles not completed: initially symptomatic after 3 cycles
margin between the therapeutic efficacy dose and toxic dose of a asymptomatic stop (Why continue? Survival of patient will not
chemotherapeutic agent is very narrow. For some drugs and some drug improve)
combinations, the therapeutic dose is the toxic dose; therefore, if the
patient is given a dose that is higher than the computed, there will be TYPES OF RESPONSE TO CHEMOTHERAPY
better tumor control, but the patient is going to suffer from toxicity. On
the other hand, if the dose is lowered to the point that there is no
toxicity, there will also be no efficacy and the patient could eventually
develop resistance to chemotherapeutic agents.

Figure 9. Complete response. There is disappearance of all clinical,

radiologic and biologic signs of the tumor.

Figure 8. Therapeutic effect and toxic effects.

A good oncologist knows how to balance between the efficacy of

chemotherapeutic agent and the potential toxic side effects. Patients
should always be informed that there are always going to be side
effects, and that the absence of those could mean that adequate levels
of the drug for it to be effective are not achieved.

INDICATIONS OF CHEMOTHERAPY
1. CURE CONTROL
Primary Chemotherapy: Chemotherapy is the main treatment for a
particular tumor e.g. hematologic in origin(lymphoma, leukeaemia), Figure 10. Partial response. There is a decrease of the multiple of two tumor
rapidly proliferating, metastatic in early stages (SCLC) diameters by at least 50%.
Adjuvant Chemotherapy: Chemotherapy given after a surgical
procedure to kill micrometastatic disease, which is a cause of
treatment failure and recurrence eg breast cancer, colorectal
malignancy

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 MEDICINE II 1.6
o Lymphangitic cutis
o Cystic lesions
o Abdominal masses that are not confirmed and followed by
imaging techniques
Once the lesion has been classified as either measurable or non-
measurable, target lesions should be determined among the measurable
lesions. These will be the baseline lesions, measured at every response
of chemotherapy.

Figure 11. Stable disease. There is regression in tumor size less than 50% or
no change in size from the baseline.
1. TARGET LESION
All measurable lesions up to a maximum of 5 lesions per organ and no
more than 10 in total
Representative of all involved organs
Selected based on their longest diameter
Used to calculate sum of longest diameter (SLD) at baseline
For a patient with several lesions in the lung or liver, a physician will
choose the three biggest lesions in the lungs and three biggest lesions in
the liver as long it can be measured in one diameter and will use this
measurement in calculating the SLD

2. NON-TARGET LESION
All other lesions and non-measurable lesions
Not required to be measured

CALCULATING THE SUM OF THE LONGEST LESION (DIAMETER SLD)
# Scan Target Baseline Scan SLD
Figure 12. Progressive . There is an increase of the multiple of two tumor Method Lesions Measurements
diameters by at least 25%. (cm)
1 Spiral CT R lobe liver 2.5 x 1.6 8.8 (2.5 + 3.9 +
The type of response that you would want to see will depend on the Spiral CT L lobe liver 3.9 x 1.8 2.4)
endpoints: if you want to: 3 Spiral CT LLL lung 2.0 x 2.4
o Cure patient: there should be a complete response
o Prolong survival/ palliate symptoms: No response / Stable Disease RECIST CRITERIA: EVALUATION OF TARGET LESIONS
acceptable Complete Response (CR) Disappearance of ALL target lesions
o Partial response (good response) Partial Response (PR) >30% DECREASE in Sum of Longest Diameter
o Stable disease (acceptable response because tumor will not grow): (SLD) when compared to baseline SLD
contributes to survival; diminishing symptoms Progressive Disease (PD) >20% INCREASE in SLD when compared to
Problem with WHO definitions of response smallest SLD since initiation of treatment of
o Requires two dimensions and in many situation it is difficult to get appearance of any new lesions
two accurate dimensions Stable Disease (SD) Does not meet criteria for CR, PR or PD
o There are metastasis that cannot be measured
o Pleural effusion EXAMPLE:
o Multiple bone metastasis Baseline Scan Measurements
o Leptomeningeal metastasis Scan Target
# Measurements SLD after Therapy SLD
** Difficult to use and hence has effect on clinical trials Method Lesions
(cm) (cm)
Spiral R lobe
1 2.5 x 1.6 1.0 x 0.8
RESPONSE EVALUATION IN CHEMOTHERAPY IN SOLID TUMORS CT liver 8.8 4.0
(RECIST CRITERIA) Spiral L lobe (2.5 + (1.0 +
2 3.9 x 1.8 2.0 x 1.0
1. MEASURABLE LESIONS CT liver 3.9 + 2.0 +
Spiral 2.4) 1.0)
Lesions that can be accurately measured in at least one dimension with 3 LLL lung 2.0 x 2.4 1.0 x 1.0
CT
longest diameter (LD)
Overall response = 8.8 - 4.0 = 4.8/8.8 = 0.545 x 100 = 54.5%
LD 20 mm with conventional techniques
54.5% PARTIAL RESPONSE (>30% decrease in SLD)
LD 10 mm with spiral CT
RECIST CRITERIA: EVALUATION OF NON-TARGET LESIONS
2. NON-MEASURABLE LESIONS Complete Response (CR) Disappearance of ALL non-target lesions
All other lesions Progressive Disease (PD) Persistence of 1 or more non-target lesions
Small lesions that dont meet measurable criteria without progression
Truly non-measurable lesions such as: Stable Disease (SD) Unequivocal progression of existing non-
Bone lesions target lesions
Leptomeningeal diasease Appearance of one or more new lesions
o Ascites
o Pleural/ pericardial effusion
o Inflammatory breast disease
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Unable to Evaluate (UE) If a lesion cannot be assessed due to Lymphomas, certain types Islet cell neoplasms
technical reasons (e.g. radiograpg is of poor Multiple myeloma Breast cancer
quality) Gastric cancer Colorectal cancer
If a lesion was assessed using a method Cervical cancer Renal cell cancer
different from that used at baseline (e.g.
pleural effusion assessed by CT as baseline, Chemotherapy can adequately control their symptoms and in some cases,
and CXR at this time point) can prolong their survival.

RECIST CRITERIA: EVALUATION OF OVERALL RESPONSE TUMORS POORLY RESPONSIVE IN THE ADVANCED STAGE TO
New Overall CHEMOTHERAPY:
Target Lesions Non-Target Lesions Pancreatic cancer Non-small cell lung cancer
Lesions Response
CR CR No CR Biliary tract neoplasms Prostate cancer
CR Present No PR Thyroid cancer Melanoma
PR Non-PD No PR Carcinoma of the vulva Hepatocellular carcinoma
SD Non-PD No SD
PD Any Yes or No PD o Advances in chemotherapy are measured by how many of these
Any PD Yes or No PD tumors are shifted to previous classifications.
Any Any Yes PD o Renal cell carcinoma used to belong to this group but because of
newer treatment modalities, it is now considered palliative.
o Melanoma is used to be unresponsive to systemic therapy.
TUMOR RESPONSES TO CHEMOTHERAPY
CANCERS WITH A POSSIBILITY OF CURE IN THE ADVANCED STAGE:
CONTRAINDICATIONS TO CHEMOTHERAPY
Acute lymphoid and myeloid leukemias
Infection - Patients become leukopenic and cannot fight infection.
Hodgkins disease
Previous cytotoxic chemotherapy <2 weeks Patients have not
Lymphomas, certain types
recovered from the side effects. Exceptions are chemotherapeutic
Germ cell neoplasms (Embryonal cancer, teratocarcinoma, seminoma
regimen that have a 2-week schedule
or dysgerminoma , choriocarcinoma)
Neutropenia - Due to bone marrow aplastic effect
Gestational trophoblastic neoplasms
Thrombocytopenia - Also due to bone marrow aplastic effect
Pediatric neoplasms (Wilms tumor, embryonal rhabdomyosarcoma,
Severe debilitation (poor performance status/poor physical reserves) -
Ewings sarcoma, Peripheral neuroepithelioma, neuroblastoma)
They may die from the side effects of chemotherapy rather than the
Small cell lung cancer
disease.
Ovarian cancer
Pregnancy (especially in the 1st trimester) - Chemotherapy drugs are
For adults, lymphoma, ovarian carcinoma, and small cell carcinoma only.
not only cytotoxic, they are also mutagenic. Can create fetal
Children have a higher chance of cure even at the advanced stage of the
malformations or induce abortions; may be given on the third trimester
disease.
Major surgery <2 weeks
o Debilitated and have not recovered may die of side effects
ADVANCED CANCERS POSSIBLY CURABLE BY CHEMOTHERAPY WITH
o Surgical wound is rapidly proliferating affected by therapy
RADIATION THERAPY:
problems in wound dehiscence
Squamous cell carcinoma of the head and neck
Poor patient follow-up - Do not treat the patient if he/she could not
Breast cancer
understand the side effects of the chemotherapy
Cervical cancer
Psychological problem Cannot understand what youre doing to them
Non-small cell lung cancer Stage III
Terminal illness - Even if you're dealing with tumor which would
Small cell lung cancer
respond well to treatment; Illogical to treat because they will still die
and you may hasten terminal events.
CANCERS POSSIBLY CURED WITH CHEMOTHERAPY AS ADJUVANT AFTER
SURGERY:
HORMONAL THERAPY IN CANCER
Breast cancer 1. ADDITIVE HORMONAL THERAPY
Colorectal cancer The utilization of steroid hormones in a variety of cancer-related
Osteosarcoma situations
Soft tissue sarcoma Example:
o CHOP (Cyclophosphamide/Doxorubicin/Vincristine/Prednisone)
CANCERS POSSIBLY CURED WITH HIGH DOSE CHEMOTHERAPY WITH Can be used to treat increased intracranial pressure in brain
STEM CELL SUPPORT: metastasis and spinal cord compression
Relapsed myeloid and lymphoid leukemias Can be used to treat cancer pain, especially if pain is due to
Relapsed Hodgkins and non-Hodgkins lymphomas compressive effects of the tumor
Chronic myeloid leukemia Can be used as anti-emetic (especially Dexamethasone);
Multiple myeloma prevents delayed nausea and vomiting that occurs with
systemic chemotherapy
CANCERS RESPONSIVE WITH USEFUL PALLIATION BUT NOT CURABLE BY Can be used to stimulate appetite
CHEMOTHERAPY:
Bladder cancer Endometrial cancer
Chronic myeloid leukemia Soft tissue sarcomas
Hairy cell leukemia Head and neck cancers
Chronic lymphocytic leukemia Adrenocortical carcinoma

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 MEDICINE II 1.6
2. ABLATIVE HORMONAL THERAPIES
2.
1. Anti-cancer antibodies
Figure 13. Hypothalamic-Pituitary-Gonadal axis. Hypothalamus will release
LHRH which stimulates the pituitary to release FSH and LH stimulates the
ovary to produce estrogen and the testes to produce testosterone. Use of
hormonal therapy is based on knowledge of the hypothalamic-pituitary-
gonadal axis.
LEVELS WHERE ABLATIVE THERAPY CAN ACT
2. Problems with anti-cancer antibodies
A. Level of the hypothalamus using LHRH antagonist, which will then
block the LH and FSH
Also called as medical castration since there will be less activity in
the gonads after blocking this.
Luprolide and Guseraline for prostate cancer patients who do not
want to undergo organectomy and in pre-menopausal women who
have breast cancer.
B. Block at the level of the gonads (castration)
Orchiectomy (for metastatic, castration sensitive prostate cancer);
Still frontline treatment for prostate cancer
Bilateral oophorectomy (for premenopausal hormone sensitive
breast cancer)
C. Block at the periphery during the conversion of the hormone
Flutamide and Decalutamide for prostate ca
Tamoxifen for hormone-sensitive breast ca
D. Block the production of estrogen itself, by blocking the conversion of
androsteinedione
Exemestane and anastrozole
Aromatase inhibitors blocks the conversion to estrogen and
estradiol totally wipes out the estrogen production and makes
the patient estrogen deficient
Only for post-menopausal attack estrogen at the level of the
adrenals; use aromatase inhibitor, do not use LHRH agonist
If used in pre-menopausal woman, will only result in increased
estrogen production via negative feedback; can only use
Tamoxifen
Remove ovaries first or give LHRH agonist if pre-menopausal.
IMMUNOTHERAPY IN CANCER
1. ACTIVE IMMUNOTHERAPY
Immunization of patients with materials designed to elicit an immune
reaction capable of eliminating or retarding tumor growth
1. NON-SPECIFIC active immunotherapy - Generalized stimulation of the
immune system.
BCG vaccination - can stimulate T-cell activity; used in superficial
bladder carcinomas as irrigation treatment to stimulate T-cell
response
Levamisole not used anymore; used as anti-helminthic for pig;
improve effects of 5-FU but with great toxicity
THE MED MEN | MEDRANO, P. | MENDOZA, C. | MENDOZA, G. | MENDOZA, J. | MERCADO, L.
Cytokines (Interferons, Interleukin 2) - produced by WBC in
response to viral infections; at higher doses, it can have anti-tumor
effects; used in melanomas and renal cell carcinomas; side effects
include flu-like symptoms (e.g. fever)
SPECIFIC active immunotherapy - immunization with tumor antigens
Tumor cell vaccines
Autologous tumor cells modified to secrete cytokines
Tumor cells with genes that encode costimulators molecules
Gene therapy and defined antigen immunizations
Antigen-presenting cells
2. PASSIVE IMMUNOTHERAPY
Utilizes monoclonal antibodies
Mechanism: compliment-dependent cytotoxicity or antibody-
dependent cellular toxicity. Anti-tumor effect is done by inducing
an antigen-antibody reaction that activates the complement
system, which in turn kills the cancer cells
May be modified to carry materials like drugs, radioisotopes or
toxins
Selective; low toxicity profile
Only small amounts actually bind to tumor
Poor diffusion through large tumors
Inhibited by soluble antigens
Early monoclonal antibodies were non-specific because at that
time, the proper targets for the monoclonal antibodies could not
be found yet
3. ADAPTIVE IMMUNOTHERAPY
The acquisition of immunity in a nave subject as the result of the
administration of immunologically activated lymphoid cells
It was believed that if you transfused a patient with immunologically
active cells that have anti-tumor effects, this could be a potential
treatment
EXAMPLES:
a. Lymphokine activated killer cells (LAK). Represent activated null
killer cells
o Lack tumor specificity and immunologic memory
o They would take lymphocytes culture them in the
presence of IL-2 turn them into null killer cells which have
anti-tumor effects transfuse them back into the patient
b. Tumor infiltrating lymphocytes (TILs)
o Isolated from solid tumors of cancer patients
o Obstacle: TILs can only be generated from tumors that are
intrinsically immunogenic to their host
o Lymphocytes from tumor bed were cultured and increased in
number transfused back to the patient BUT the
lymphocytes were hijacked by the tumor to produce certain
substances so they actually fuel tumor cell proliferation
o 2014: Woman with cervical carcinoma positively responded
to primed T cell (using same mechanism); lymphocytes they
used were actually attacking the tumor cells
TARGETED THERAPY
Interfering with intracellular pathways crucial in maintaining malignant
phenotype
Interfering with tumor Angiogenesis (tumor cannot survive without
blood supply)
Interfering with expression of oncogenes and abnormal genes
(Example: BCR-ABL Translocation in CML)
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 MEDICINE II 1.6
IMATINIB MESYLATE (GLIVECTM)
A selective tyrosine kinase inhibitor of KIT, BCR-ABL, PDGFA/B loss of
signal that causes proliferation reaction
First used in Philadelphia chromosome-positive (Ph+) CML normal
blood picture within 1 week
First-line treatment for CML

IMATINIB CLINICAL TRIALS IN GASTROINTESTINAL STROMAL TUMORS

(GIST)

Figure 15. Pathways utilized by normal and cancer cells for proliferation

TARGETED THERAPY STRATEGIES

Functional therapy
Phenotype directed therapy

FUNCTIONAL TARGETED THERAPIES

Figure 14. Imatinib clinical trials in GIST Stop the expression of the malignant phenotype or the abnormal
function
After getting success with Imatinib in the treatment of CML, researchers Restores normal function or abrogates the abnormal function of the
then tried to translate this into solid tumors such as a gastrointestinal defective molecule in cancer cells
stromal tumor (GIST). It was found that the underlying pathophysiologic The most common target are the signaling pathways
mechanism of a GIST was that it was dependent on the expression of
KIT. Clinical trials were done to assess the effectiveness of Imatinib on Cell Signaling Targeted Therapies
GIST. Blocking the ligand receptor complex
It was a landmark clinical trial for medical oncology because it was a trial o EGFR (Most Common)
in which only one patient was enrolled. The patient was a 64 year old o EGFR 1
female who had a recurrent GIST, with metastasis to the liver, o Her 2
bone, lungs, and peritoneum. She had failed three surgeries and four Inhibition of receptor tyrosine kinases (EGFR)
cycles of chemotherapy and was practically dying of the disease Inhibition of intracellular signaling proteins and kinases (BCR-ABL,
when the drug was offered to her. Within one month, there was an raf, mTOR)
observed 50% regression of the tumor size and within six months, she Targeted therapy in angiogenesis
was back to normal. She continued to take the drug which controlled the Targeted therapy in protein degradation
tumor.
Targeted therapy by immune modulation (Specific Or Non Specific)
MOLECULAR TARGETED THERAPY EGFR SIGNALING PATHWAYS
Because of these clinical trials, strategies in cancer management had
a paradigm shift. Initially, only proliferating cells were being targeted,
now, as long as a molecular profile is present it can be used as a target
for manipulation.
Takes advantage of special molecular characteristics of cancer cells
o Ideal molecular target uniquely expressed by cancer cells
o Important in the maintenance of the malignant phenotype

ONCOGENE ADDICTION
In a normal cell, any pathway, like proliferation, can be controlled
through several ways so that if one pathway is defective, the cell
can rely on a different pathway to run the process.
But in a cancer cell, they become dependent on one particular pathway
(GIST relies on overexpression of KIT; CML relies on overexpression of
BCR-ABL). This dependence is occurring at the expense of the other Figure 16. EGFR Signaling Pathways
pathways that by blocking the single pathway, tumor growth can be
stopped. Epidermal growth factor receptor (EGFR) is one of the most common
signaling pathways being targeted
90% of tumor cells express EGFR which is associated with proliferation
in many cancer cells
EGFR can be blocked through two strategies:
o Monoclonal antibodies (MAbs) against ErbB receptors
o Small molecule tyrosine kinase inhibitors (SMTKIs)

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 MEDICINE II 1.6
MONOCLONAL ANTIBODIES (MAbs) AGAINST ERBB RECEPTORS
Specific MAbs can now be created since there are already specific
targets; they can block the receptor to prevent a ligand receptor
interaction
The first one developed; a consequence of the previous
immunotherapy concepts; the difference here is now, the targets
are more specific, and therefore the antibodies are also more specific
Designed to target membrane proteins that carry an extracellular
domain
Anti- tumor effects:
o Blocks targeted receptor preventing the transmission of
proliferative signals to the nucleus (Prevents ligand receptor
interaction)
o Activates antibody dependent cellular cytotoxicity (Antigen
antibody mediated response)
o Helps in receptor internalization which may deliver toxic
substances into the cell
Figure 17. Anti- tumor effects of monoclonal antibodies
EXAMPLE: Trastuzumab
o First monoclonal antibody used; directed against HER 2 or EGFR
type 2 receptors, which is overexpressed in breast cancer
patients
o It can block the receptor and block receptor signaling or it can kill
the tumor cell by the antibody antigen reaction
o Added to chemotherapy in patients with HER2 positive breast
cancer; patients have improved their survival by >35% compared
to chemotherapy alone
o Initially given only as an intravenous infusion; now, the drug can
be administered subcutaneously, with zero toxic side effects
Figure 18. Other monoclonal antibodies
Drugs ending in mab are monoclonal antibodies. The two letters
before the mab indicate the type of monoclonal antibody it is.
o TRASTUZUMAB (ZU) - It means that it is a partially human
or humanized monoclonal antibody (90% of it is human and the
rest come from a mouse)
o CETUXIMAB (XI) - It means that it is a chimeric monoclonal
antibody (Hybrid; 50/50; a combination of human and mouse
antibodies)
o PANITUMUMAB (MU) - It means that it is a fully human
monoclonal antibody; the advantage is that you have less
antibodies from the host which will interact with these
THE MED MEN | MEDRANO, P. | MENDOZA, C. | MENDOZA, G. | MENDOZA, J. | MERCADO, L.
therapeutic antibodies; it is a new drug being utilized in colon
cancer
o NIMONTUZUMAB - A partially humanized monoclonal antibody;
a newer drug utilized in head and neck cancers and
glioblastoma multiforme
SMALL- MOLECULE TYROSINE KINASE INHIBITORS (SMTKIs)
Gefitinib & Erlotinib
o These drugs are very effective if a lung cancer patient has an
adenocarcinoma, is a female, is Asian, and a nonsmoker.
o The response rate for patients with this profile approaches 90-95%
compared to the opposite (Male, non- Asian, smoker, non-
adenocarcinoma). This is because they have mutations in the
EGFR receptor at exons 19 and 21.
o With Gefitinib and Erlotinib, the toxicity associated with systemic
chemotherapy is not the same, because these drugs are given as
an oral tablet once a day for life. In addition, these have a side
effect of generalized body rashes, which indicate that the drug is
working. If the patient has higher amounts of rash, then this also
means higher efficacy.
Lapatinib
o A potent, oral, and reversible dual tyrosine kinase inhibitor
o A dual HER 2 inhibitor that blocks both EGFR types 1 and 2
o Because it can block EGFR type 2, it is effective in HER 2 positive
breast cancer
o Binds to the ATP site of ErbB-1 and ErbB-2 receptor kinases,
blocking kinase activity and downstream signaling
Other Receptor Tyrosine Kinase Inhibitors
o Inhibitors of BCR-ABL
Imatinib
nd
Nilotinib - 2 line
nd
Dasatinib - 2 line
o Inhibitors of BRAF
Sorafenib
Vemurafenib True BRAF inhibitor; used in BRAF expressing
melanomas; has improved the survival rate from 0 40% for
metastatic melanomas
Figure 19. Diagram of other RTK inhibitors
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 MEDICINE II 1.6
INTRACELLULAR SIGNALING TARGET: mTOR

Figure 23. Bevacizumab MOA

Figure 20. mTOR Pathway MULTI-KINASE INHIBITORS

Drugs that block mTOR (Mammalian Target Of Rapamycin)
Lies in the crucial pathway called P1-3K-AKT (P1-3 Kinase-AKT)
o Mediates cellular activities, apoptosis, energy generation,
survival, proliferation, and angiogenesis
Examples are Sunitinib, Sorafenib, Pazopanib, Axitinib
Inhibits angiogenesis almost the same way Imatinib does
Inhibits tyrosine kinase at the level of the VEGF receptor; no signal is
sent and therefore angiogenesis is limited and decreases the survival of
the endothelial cells
The blockage can hit certain receptors on the tumor that contribute to
proliferation
These multi kinase inhibitors can target both proliferation and
angiogenesis
Indicated in renal cell carcinoma, hepatocellular carcinoma, and
thyroid carcinoma

Figure 21. Activities that involve mTOR

An mTOR inhibitor can have

o Anti angiogenic effect
o Disrupts cell nutrition and cellular survival
2 Available mTOR inhibitors
o Eterolimus & Temserolimus: Both for renal cell carcinoma because
of their anti angiogenic effect
Studies have shown that mTOR inhibitors can restore hormonal
responsiveness in women who have lost hormonal sensitivity due Figure 24. Multi-Kinase Inhibitor MOA On The Endothelial Cell
to intake of aromatase inhibitors

TARGETED THERAPY ON ANGIOGENESIS

Figure 22. Stages of angiogenesis which are important in metastasis and

tumor growth
MONOCLONAL ANTIBODIES: BEVACIZUMAB
Does not block the receptor but blocks the ligand
If VEGF is sequestered, no interaction will happen because the ligand
is blocked; therefore, no angiogenesis will happen; used in the
treatment of lung cancer and ovarian cancer
THE MED MEN | MEDRANO, P. | MENDOZA, C. | MENDOZA, G. | MENDOZA, J. | MERCADO, L.
Figure 25. Multi-Kinase Inhibitor MOA at the tumor level
TARGETED THERAPY ON PROTEIN DEGRADATION
26S PROTEASOME AND THE UBIQUITIN PATHWAY
26 Proteasome Responsible for protein degradation into amino acids
Inhibitors are very important because it degrades pro-apoptotic
protein.
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 MEDICINE II 1.6
BORTEZOMIB: with CHOP treatment for Non- Hodgkins lymphoma/B
o Blocks the activity of the 26s proteasome Cell Lymphomas, success rate goes up from 60% to 85-
o There is accumulation of pro apoptotic proteins and 90%.
stimulates the tumor cells to go into apoptotic state Alemtuzumab = anti-CD52 for Relapse CML
o First line treatment for patients with Multiple Myeloma who are Ofatumumab = anti-CD20 for Relapse Follicular
candidates for bone marrow transplant Lymphoma
Epratuzumab = anti-CD22 for Relapse T Cell Lymphomas
of the Skin
2. CONJUGATED ANTIBODIES: Unconjugated antibodies combined
with other substances to target cells more specifically. Think of
2
them as guided missiles.
o Conjugated to cellular toxins:
Gemtuzumab ozogamicin: anti-CD33 + calicheamicin
Calicheamicin - poison from the bacterium
Micromonospora echinospora subspecies
calchinesis.
DNA intercalating poison that when combined with
MAB allows the monoclonal antibody to trick the
receptor into bringing it into the cell, allowing it to
kill the tumor DNA itself
For Relapse Myologenous Leukemias
o Radioimmunoconjugates: Because you connect the MAB to a
Figure 26. MOA Of Bortezomib
radioactive material, it now radiates the cell creating
radiotherapy at the cellular level.
TARGET THERAPY BY IMMUNE MODULATION
Ibritumumab tiuxetan: anti-CD20 + beta- emitting
Cancer creates an immunosuppressive environment in the patient,
yttrium-90.
which contributes to the survival of the cancer.
Only tumor cells will be radiated since it is beta-
With these drugs, we can target molecules, cytokines, and receptors
emitting, short acting, (acts only 10-12cms in
involved.
distance), patient will not become radioactive.
SPECIFIC IMMUNE MODULATORS Radiation at the cellular level (rather than the
a. CTLA-4 Inhibitors physical level).
o By blocking CTLA-4: co-stimulatory receptor which is Iodine-131-tositumumab: anti-CD20 + RAI.
responsible for inducing T-cell deactivation and apoptosis Same effects as Ibritumumab tiuxetan, but the
2
causing an immunosuppressive environment as a result. problem with iodine is its highly radioactive. When
o Commonly used for malignant melanomas giving this, patients should be isolated because they
o EXAMPLES: Ipilimumab and Tremelimumab can actually irradiate other people.
b. PD1 inhibitors: PD1: immunosuppressive receptor These 2 drugs are for patients with follicular lymphomas
o When activated, leads to decreased T-cell activation that have failed Rituximab therapy.
o Examples are CT-011 and MDX-1106
o Immunotoxins
c. TGF- antibodies: TGF-: Tumor Growth Factor cytokine
Deileukin difitox: anti-CD25 component of IL2 receptor
o Can cause apoptosis of present T-cells
+ diphtheria toxin:
o Prevents T-cells from activating natural killer cells and T- For T Cell Lymphomas of the Skin
helper cells o Antibody-drug conjugates
o Examples are GC-1008 and AP-12000 Trastuzumab emtansine:
NON-SPECIFIC IMMUNOMODULATORS Named as 2012 Drug of the Year by all
o LENALIDOMIDE Oncologists
2
Only example of nonspecific immunomodulator Anti-Her2 monoclonal antibody Trastuzumab +
Parent drug is Thalidomide Cytotoxic drug Mertansin (anti-tubulin agent): DNA
Has Anti-angiogenic properties that is why its teratogenic Intercalating combination
result is phocomelia. (notorious in the 1960s resulting to For HER-2 positive breast cancer
newborns with seal-like appendages) In one shot, you give both chemotherapy and
Used for multiple myelomas: Less sedative and neuropathic targeted therapy
side effects than Thalidomide No toxicity:
No hair loss
PHENOTYPE DIRECTED TARGETED THERAPY No nausea
Targets the unique phenotype or feature of the cancer cell No vomiting
Function has no role, but you target specific identifying features No neutropenia
2
present on the cancer cell Response rates approach 90%.
Function causing expression but kill the tumor directly. Administered as monthly subcutaneous injections
NON-RECEPTOR PROTEIN-DIRECTED MONOCLONAL ANTIBODIES: o Cancer vaccines
1. UNCONJUGATED ANTIBODIES Prophylactic
o Kill the tumor cell through antibody-antigen reactions. Gardasil and Cervarix anti-HPV Recombivac
o Very specific to their targets Engerix-B anti hepatitis B
o Examples: Therapeutics
Rituximab = anti-CD 20: Classic drug. When combined Sipuleucel-T prostate CA
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 MEDICINE II 1.6
M-vax and Onco-vax - melanoma HOW MANY TARGETS ARE THERE?
TroVax: papillary renal cell cancer

SIDE EFFECTS OF IMMUNOTHERAPHY

**Not elaborated by the lecturer**
A. TYROSINE KINASE INHIBITORS SIDE EFFECTS
Most side effects are mucocutaneous
Patients mostly manifest with rash, diarrhea, and pruritus
Not much neutropenia, alopecia, or nausea and vomiting
1. Imatinib:
o Hematologic: Moderate neutropenia and
thrombocytopenia
o GI: Nausea, vomiting, abdominal pain, diarrhea
o Mucocutaneous: Rash
o Miscellaneous: Fluid retention and edema,
musculoskeletal pain, cramps, headache, arthralgia
2. Gefitinib and Erlotinib
o GI: Anorexia, dyspepsia, nausea, vomiting, diarrhea,
constipation, and abdominal pain. Transaminase
elevations
o Mucocutaneous: Rash, stomatitis, keratoconjunctivitis Figure 28. There are a lot of available targeted treatments, and more can be
o Miscellaneous: Fatigue, weight loss, edema, fever, bone developed depending on the findings on the malignancies concerned. The
pain, myalgia, dyspnea issue is, how many targets are there? The problem with thinking about
targets is that the underlying pathophysiology is mutation, and this creates
B. MULTI-TARGETED TKI AND ANTI-ANGIOGENIC AGENTS SIDE EFFECTS the pressure to generate more mutations (Nowells hypothesis). Therefore, it
Side effects are associated with vascular events. is necessary to be able to distinguish between driver mutations and
o Hypertension, fatigue o Pain at tumor sites passenger mutations.
o Increased clotting o Proteinuria
2
events o Hypothyroidism There are Dumb Tumors and Smart Tumors.
o Bleeding o Skin rash o Chronic Lymphocytic Leukemia (CLL)
o Headache o Myelosupression dumb tumor
o Neurologic events o Nausea/vomiting Has only 10 mutations, thus, easy to treat
o Increased LFTs (Liver o Diarrhea o GIST and CML
Function Tests) dumb tumor
Has only 1 mutation
C. MONOCLONAL ANTIBODIES SIDE EFFECTS
Treat with Imatinib and tumor is controlled
Infusion-related reactions
o Breast CA
o Usually occurs during first infusion
smart tumor
o Acute immune response from antigen-antibody reactions 285 mutations
o Activation of immune effector cells: Cytokines Complement o Colon CA
o Inflammatory response: Fever, chills, rigors, asthenia, smart tumor
headache. Urticaria, pruritus, bronchospasm, dyspnea, 180 mutations
angioedema, rhinitis, vomiting, hypotension, flushing, throat o Pancreatic CA
irritation, pain at tumor site smart tumor
o Pre-medication to prevent said side effects with 200 mutations
Acetaminophen and diphenhydramine Bert Volgenstein did research on the genome of the cancer cells and
Hypersensitivity reactions introduced the concept of Landscape using negative and positive space
o Skin rash and itching, feeling of swelling of the tongue or to highlight the relationships of these mutations.
throat, irritation of nasal passages, wheezing, cough, and
shortness of breath
o Dyspnea and laryngeal edema are the most dreaded
consequences
o Pre-medications: anti-histamines and/or steroids
D. IMMUNE MODULATORS SIDE EFFECTS
Autoimmune reactions
Usually involve the skin and GIT Grade III-IV in 33-40% of
cases
Specific toxicities:
Dermatitis
Colitis
Uveitis
Thyroiditis

Figure 29. Vogelsteins Landscape Concept

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 MEDICINE II 1.6
There are negative and positive spaces to highlight the relationships of
these mutations. This is a template where chromosomes would be
lined up like a continuous string starting at the top-left corner with
chromosome 1 and ending at the bottom-right with chromosome X.
Mutations found are indicated with a dot. White dots indicate solitary
mutation. In some chromosomes, mutations are not that common are
noted in the shallow peaks. Those with tall peaks there have very high
incidences of mutation critical areas in cell proliferation and
apoptosis.
RAS-RAF-myc pathway mitigates proliferation and they found out in
breast cancer there are a lot of mutations associated in that particular
pathway in that particular chromosome.
The P13k-AKT pathway mitigates apoptosis and again they found that
in that particular chromosomal locus, a lot of mutations were present Figure 30. Summary of Drug groups, Action, and Side effects
Implication:
o Genome, that have very high incidences of mutation are areas
with critical roles for proliferation, evasion of apoptosis; all those REFERENCES
mechanisms that result to generation of the cancer cells. 1. Dr. Fernandos lecture slides
2
Malignancy Mutations are two-fold: 2. Audio Recording of lecture
o Driver mutations 3. 2015B Trans
Mutations that directly drive the phenotype
Contributes to the expression of the malignant
You are lucky, as far as I am concerned. I can see the potential of
transformation; only occur in certain critical pathways that
understanding and knowing the future in Oncology. I will envy your
occur within certain genome
generation doing what I have always wanted to do. Fight cancer with
13 in number
enough tools to really beat it. Maybe we can? Were not going to kill
Should be the main target of therapy
it. Its very hard to kill this. Its an evolutionary animal whose drive to
o Passenger mutations
survive may way surpass us. But its drive to survive, that is what we
Mutations that are accidental and occur because of unstable
have to fight. If we can create a situation, where there is an
genomic apparatus
agreement between the cancer patient and the disease, in which both
These are mutations that may be there but do not contribute
can live in peaceful coexistence with one another, then you will
to the malignant transformation
transform a disease with a terminal unrelenting course into one with
285 in number
a chronic manageable history. That is the future that awaits you. You
In perspective, malignancy is not a mutation disease, but it is a pathway
2 will see the future that I have always wanted to see. It will be up to
disease.
you to carry on. - Dr. Gracieux Fernando (2014)
o For example: in one patient there can be mutations in the RAS and
in one patient there can be mutations in the MYC, but they are the
same pathway. Therefore they can be labelled as the SAME Edited by: Dai
PATHWAY DISEASE
By recognizing that what were dealing with are pathway diseases, our
targets are now limited to only 10-20 pathways in comparison to the
previous theory of targeting countless number of mutations.
However, this concept is still just a theory and is reserved for the future
generation of doctors to discover optimal and individualized
treatments for each patient.

SUMMARY OF DRUG ACTIONS

**Not elaborated by the lecturer**
So to summarize, there are several systemic treatment avaiable for
malignancy.
o CYTOTOXIC CHEMOTHERAPY kills cancer cells but it has certain
side effects like bone marrow aplasia, nausea and vomiting that
can be very detrimental.
o HORMONAL TREATMENT uses hormonal manipulation. They are
cytostatic. They put the cancer to sleep but they do not really kill it
and they have certain side effects related to hormonal lesions such
as osteoporosis, hot flashes, hyperlipidemia.
o IMMUNOTHERAPY uses immune mediated mechanisms. They can
be cytostatic or cytotoxic depending on the strategy used. If you
use interferons they tend to be cytotoxic. If you used monoclonal
antibodies, they tend to be cytostatic. There side effects are flu-
like syndromes and hypersensitivity reactions.
o TARGETED THERAPIES, they tend to be cytostatic. They do not kill
the tumor cells but they block the expression of the malignant
phenotype and render the tumor inactive.

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