PHCP LEC WEEK 15: MANAGEMENT OF CANCER usually because of inactivation of tumor

suppressor genes that encode components

ONCOLOGY
of growth inhibitory pathways.
 (Greek oncos = tumor) is the study of tumors
or neoplasms ALTERED CELLULAR METABOLISM.
 Neoplasia means "new growth,"  Tumor cells undergo a metabolic switch to
 The collection of cells and stroma composing aerobic glycolysis (called the Warburg
new growths are referred to as neoplasms effect), which enables the synthesis of the
 Tumor originally described swelling caused macromolecules and organelles that are
by inflammation, but is now equated with needed for rapid cell growth.
neoplasm
EVASION OF APOPTOSIS
TUMORS  Tumors are resistant to programmed cell
 Benign tumors remain can localized at their death.
site or origin and are generally amenable to  Apoptosis – death of cells
surgical removal. Predictably, the patient
LIMITLESS REPLICATIVE POTENTIAL
generally survives.
(IMMORTALITY)
 Malignant tumors invade and destroy
 Tumors have unrestricted
adjacent structures and spread to distant
proliferative permits tumor cells to avoid
sites (metastasize).
cellular senescence and mitotic
 Malignant tumors are collectively referred to
catastrophe.
as cancers, derived from the Latin word for
 Cellular senescence – pagtanda ng mga cells
crab, because they tend to adhere to any
 Mitotic catastrophe – unexpected death of
part that they seize on in an obstinate
cells
manner.
SUSTAINED ANGIOGENESIS
HALLMARKS OF CANCER
 Tumor cells, like normal cells, are not able to
 Avoiding immune destruction grow without a vascular supply to bring
 Evading growth suppressors nutrients and oxygen and remove waste
 Enabling replicative immortality products. Hence, tumors must induce
 Tumor promoting inflammation angiogenesis.
 Activating invasion and metastasis  Mabilis magproduce ng blood vessel?
 Genomic instability (mutator phenotype) ABILITY TO INVADE AND METASTASIZE
 Resisting cell death  Tumor metastases are the cause of the vast
 Inducing angiogenesis majority of cancer deaths and arise from the
 Deregulating cellular energetics interplay of processes that are intrinsic to
 Sustaining proliferative signaling tumor cells and signals that are initiated by
All cancers display eight fundamental changes in the tissue environment.
cell physiology, which are considered the ABILITY TO EVADE THE HOST IMMUNE RESPONSE
hallmarks of cancer.  cells of the innate and adaptive immune
SELF-SUFFICIENCY IN GROWTH SIGNALS system can recognize and eliminate cells
 Tumors have the capacity to proliferate displaying abnormal antigens (e.g., a
without external stimuli, usually as a mutated oncoprotein). Cancer cells exhibit a
consequence of oncogene activation. number of alterations that allow them to
evade the host immune response.
INSENSITIVITY TO GROWTH-INHIBITORY SIGNALS
 Tumors may not respond to molecules that
inhibit the proliferation of normal cells, 
ONCOGENES SARCOMA
 Oncogenes are mutated genes that Cause
excessive cell growth, even in the absence of  refers to cancer that originates in supportive and
growth factors and other growth-promoting connective tissues such as bones, tendons,
external cues cartilage, muscle, and fat. Generally occurring in
 Oncogenes have multiple roles, but virtually young adults, the most common sarcoma often
all encode constitutively active oncoproteins develops as a painful mass on the bone. Sarcoma
that participate in signaling pathways that tumors usually resemble the tissue in which they
drive the proliferation of cells. grow.

CANCER NOMENCLATURE EXAMPLES OF SARCOMA

 Osteosarcoma or osteogenic sarcoma (bone)
 From a histological standpoint there are
 Chondrosarcoma (cartilage)
hundreds of different cancers, which are
 Leiomyosarcoma (smooth muscle)
grouped into six major categories:
 Rhabdomyosarcoma (skeletal muscle)
 Carcinoma
 Mesothelial sarcoma or
 Sarcoma
mesothelioma (membranous lining of body
 Myeloma
cavities)
 Leukemia
 Fibrosarcoma (fibrous tissue)
 Lymphoma
 Angiosarcoma or hemangioendothelioma
 Mixed Types
(blood vessels)
CARCINOMA  Liposarcoma (adipose tissue)
 Glioma or astrocytoma (neurogenic
 Malignant neoplasm of epithelial origin or connective fissue found in the brain)
cancer of the internal or external lining of the  Myxosarcoma (primitive embryonic
body connective tissue)
 Account for 80 to 90 percent of all cancer cases  Mesenchymous or mixed mesodermal
 Epithelial tissue is found throughout the body. It tumor (mixed connective tissue types)
is present in the skin, as well as the covering and
lining of organs and internal passageways, such
MYELOMA
as the gastrointestinal tract.
 Most carcinomas affect organs or glands capable  Myeloma is cancer that originates in the plasma
of secretion, such as the breasts, which produce cells of bone marrow (produces blood). The
milk, or the lungs, which secrete mucus, or colon plasma cells produce some of the proteins found
or prostate or bladder in blood.

□ ADENOCARCINOMA LEUKEMIA
- develops in an organ or gland
 ("liquid cancers" or "blood cancers") are
- generally occur in mucus membranes and
cancers of the bone marrow (the site of blood
are first seen as a thickened plaque like
cell production).
white mucosa. They often spread easily
through the soft tissue where they occur.  The word leukemia means "white blood" in
Greek.
□ SQUAMOUS CELL CARCINOMA
- Originates in the squamous epithelium.  The disease is often associated with
- Occur in many areas of the body the overproduction of immature white blood
cells.
 These immature white blood cells do not
perform as well as they should, therefore the
patient is often prone to infection.
 Leukemia also affects red blood cells and can
cause poor blood cloffing and fatigue due to
anemia
EXAMPLES OF LEUKEMIA
 Myelogenous or granulocytic
leukemia (malignancy of the myeloid
and granulocytic white blood cell series)
 Lymphatic, lymphocytic, or
lymphoblastic leukemia (malignancy of the
lymphoid and lymphocytic blood cell series)
 Polycythemia vera or erythremia (malignancy
of various blood cell products, but with red
TUMORS OF THE CONNECTIVE TISSUES
cells predominating)
Tissue Benign Tumors Malignant
Tumors
LYMPHOMA
Adult fibrous Fibroma Fibrosarcoma
 Lymphomas develop in the glands or nodes of tissue
the lymphatic system, a network of vessels,
Embryonic Myxoma Myxosarcoma
nodes, and organs (specifically the spleen,
(myxomatous)
tonsils, and thymus) that purify bodily fluids and
fibrous tissue
produce infection-fighting white blood cells,
or lymphocytes. Fat Lipoma Liposarcoma
 Unlike the leukemias which are sometimes Cartilage Chondroma Chondrosarcoma
called "liquid cancers," lymphomas are "solid Bone Osteoma Osteosarcoma
cancers.” Notochord -- Chordoma
 Lymphomas may also occur in specific Connective Fibrous Malignant
organs such as the stomach, breast or brain. tissue, probably histiocytoma fibrous
These lymphomas are referred to as extranodal fibrous histiocytoma
lymphomas.
 The lymphomas are subclassified into two TUMORS OF THE ENDOTHELIUM AND
categories: MESOTHELIUM
 Hodgkin lymphoma Tissue Benign Tumors Malignant
 Non-Hodgkin lymphoma – no reed- Tumors
sternberg cell Blood vessels Hemangioma, Hemangiosarcom
 The presence of Reed-Sternberg cells in Hodgkin hemangiopericy a, angiosarcoma
lymphoma diagnostically distinguishes Hodgkin toma
lymphoma from Non-Hodgkin lymphoma. Lymph vessels Lymphangioma Lymphangiosarco
ma
Mesothelium -- Mesothelioma
MIXED-TYPE
 The type components may be within one TUMORS OF THE BLOOD AND LYMPHOID CELLS
category or from different categories. Some Tissue Benign Tumors Malignant
examples are: Tumors
 adenosquamous carcinoma Hematopoieti "Preleukemias", Leukemia, of
 mixed mesodermal tumor c cells "myeloproliferat various types;
 carcinosarcoma – Teratocarcinoma ive aleukemic
disorders" leukemia
Lymphoid Plasmacytosis Plasmacytoma;
tissue multiple myelom
 a; Hodgkin TUMORS OF THE NEURAL SYSTEM
lymphoma and Tissue Benign Tumors Malignant Tumors
Non Hodgkin Glial cells -- Glioma, grades |-III,
lymphoma (of anaplastic;
several glioblastoma
TUMORS OF THE MUSCLE types) multiforme (grade
Tissue Benign Tumors Malignant IV)
Tumors Nerve -- Neuroblastoma
Smooth Leiomyoma Leiomyosarcoma cells -- Medulloblastoma
muscle Ganglioneuroma --
Striated Rhabdomyoma Rhabdomyosarco Meninges Meningioma Malignant
muscle ma meningioma
Nerve Schwannoma, Malignant
TUMORS OF THE EPITHELIAL sheath neurilemmoma meningioma
Tissue Benign Tumors Malignant
Tumors Neurofibroma Malignant
Stratified Papilloma Squamous cell schwannoma
squamous carcinoma; Neurofibrosarcoma
Seborrheic epidermoid
keratosis and carcinoma and DIAGNOSTIC TESTS FOR CANCER
some skin some malignant
adnexal tumors skin adnexal □ Physical Examination
tumors - Check for lumps, abnormalities
Glandular Adenoma Adenocarcinoma - Enlargement of the organs
epithelium - Change in skin color
1. Liver Hepatic Hepatoma: □ Laboratory Tests
adenoma hepatocellular  Urine
carcinoma  Blood
2. Kidney Renal tubular Renal cell □ Imaging tests
adenoma carcinoma;
 CT scan
hypernephroma
3. Bile duct Bile duct Cholangiocarcino
 MRI
adenoma ma  PET scan
Transitional Transitional cell Transitional cell  Ultrasound
epithelium papilloma carcinoma □ Biopsy
Placenta Hydatidiform Choriocarcinoma
mole
STAGES OF CANCER
Test Seminoma; □ STAGE 1
-- embryonal cell  A small, invasive mass has been found
carcinoma
 No spread to lymph or other tissues
 Sometimes called " Early stage" or "localized"
stage
 Size of the tumor depends upon the type of
cancer
□ STAGE 2
 Localized
 Cancer has spread to a regional lymph node or
tissue near the mass and/or the mass is large
enough to not be classified as stage 1.
 Spread to lymph nodes near the mass
□ STAGE 3
  Regional Spread o cisplatin
 Cancer affects more surrounding tissues  Antimetabolites
 Mass may have grown in size o 5-Fluorouracil
 Spread to distant lymphnodes away from the o Methotrexate
mass o Gemcitabine
□ STAGE IV o 6-mercaptopurine
 Distant Spread  Natural products
 Cancer have spread to other tissues or organs o Etoposide
beyond the region where it originated o Paclitaxel
 Sometimes called ADVANCED or METASTATIC o Vincristine
cancer  Antitumor antibiotics
o Bleomycin
Stage Definition o Doxorubicin
Stage 0 Carcinoma in situ (literally means: o Mitomycin
"cancer in place"). The cancer cells
 Miscellaneous
have not yet invaded into surrounding
o Imatinib
tissues; without invasion the tumor
can't spread and the cure rate is 100% o Cetuximab
Stage 1 The primary tumor is small but invasive  Hormonal
into surrounding tissues and has not o Prednisone
spread, o Tamoxifen
THE LOG-KILL HYPOTHESIS
Stage 2 The primary tumor is larger, but there
is still no clinical evidence of spread  Proposes that the magnitude of tumor cell kill by
Stage 3 The tumor has spread to lymph glands anticancer drugs is a logarithmic function.
(also called lymph nodes) in that region - For example, a 3-log-kill dose of
of the body an effective drug reduces a cancer cell
Stage 4 The cancer has spread beyond the population of 1012 cells to 10' (a total kill
region where it initiated to a distant of 999 A-109 cells); the same dose would
tissue or organ reduce a starting population of 106 cells to
103 cells (a kill of 999 Å~ 103 cells).

The progressive spread of an intestinal RESISTANCE TO ANTICANCER DRUGS

cancer and its invasion into surrounding  Mechanisms of resistance:
tissues - Increased DNA repair
* Three stages of colon cancer as the cancer - Formation of trapping agents
cells divide and the tumor grows. In stage I, - Changes in target enzymes
the tumor is small and has not penetrated - Decreased activation of prodrugs
the layer of cells lining the colon. In stage II, - Inactivation of anticancer drugs
the tumor has penetrated the muscle wall of - Decreased drug accumulation
the colon. In stage III, the tumor has spread
STRATEGIES IN CANCER CHEMOTHERAPY
to nearby lymph nodes. Source: Medline
Plus, a service of the U.S. National Library of □ Primary induction chemotherapy
Medicine and the National Institutes of - Drug therapy is administered as the
Health. primary treatment for many hematologic
cancers and for advanced solid tumors for
PHARMACOLOGIC TREATMENTS which no alternative treatment exists.
□ Neoadjuvant chemotherapy
□ ANTICANCER DRUGS
- The use of chemotherapy in patients who
 Alkylating agents
present with localized cancer for which
o Cyclophosphamide
 alternative local therapy, such as surgery, - Topotecan: Inhibits topoisomerase I,
exist is known as neoadjuvant resulting in DNA damage
chemotherapy. - Other camptothecins: irinotecan
- The goal is to render the local therapy  Taxanes
more effective. - Paclitaxel: Interferes with microtubule
□ Adjuvant chemotherapy disassembly, resulting in impaired mitosis -
- In the treatment of many solid tumors, Other taxanes: docetaxel
chemotherapy serves as an important  Anthracyclines
adjuvant to local treatment procedures - Doxorubicin: Oxygen free radicals bind to
such as surgery or radiation. DNA causing strand breakage; inhibits
- The goal is to reduce the risk of local and topoisomerase II; intercalates into DNA
systemic recurrence and to improve - Other anthracyclines:
disease-free and overall survival. daunorubicin, idarubicin, epirubicin,
mitoxantrone
TREATMENTS
- Other antitumor antibiotics:
 Alkylating agents bleomycin, mitomycin
- Cyclophosphamide: Forms DNA  Tyrosine kinase inhibitors
cross links, resulting in inhibition of DNA - Imatinib: Inhibits BCR-ABL tyrosine kinase
synthesis and function and other receptor tyrosine kinases
o Other major alkylating agents: - Other tyrosine kinase inhibitors:
mechlorethamine, procarbazine, dasatinib, nilotinib, sorafenib, sunitinib,
busulfan, carmustine, lomustine, and pazopanib
dacarbazine  Growth factor receptor inhibitors
o Platinum analogs: cisplatin, - Trastuzumab: Inhibits the binding of EGF
carboplatin, oxaliplatin to the HER-2/neu growth receptor - Other
 Antimetabolites growth factor receptor
- Methotrexate: Inhibits DHFR, resulting in inhibitors: cetuximab, panitumumab,
inhibition of synthesis of thymidylate, gefitinib, erlotinib
purine nucleotides, serine, and methionine  Vascular endothelial growth factor (VEGF)
- 6-Mercaptopurine: Inhibits de novo inhibitors
purine synthesis - Bevacizumab: Inhibits binding of VEGF to
- 5-Fluorouracil: Inhibits thymidylate its receptor, resulting in inhibition of
synthase, and its metabolites are tumor vascularization
incorporated into RNA and DNA, all  Proteasome Inhibitors
resulting in inhibition of DNA synthesis and - Bortezomib: Reversibly inhibits
function and in RNA processing chymotrypsin-like activity of the 26S
- Other antimetabolites: cytarabine, proteasome - Other proteasome inhibitor:
gemcitabine carfilzomib
 Vinca Alkaloids  Hormone agonists
- Vincristine: Interferes with microtubule - Prednisone
assembly, resulting in impaired mitosis  Hormone antagonists
- Other vinca alkaloids: - Tamoxifen
vinblastine, vinorelbine - Other hormonal antagonists:
 Podophyllotoxins aromatase inhibitors, GnRH agonist and
- Etoposide: Inhibits topoisomerase II, antagonists, androgen receptor
resulting in DNA damage antagonists.
- Other podophyllotoxins: teniposide
 Camptothecins