Transcript and/or Tyrosine Kinase Inhibitors

Principles of
Chemotherapy &
Radiotherapy
Zeeshan Rana
General Surgery PGY 2
POS Presentation – October 8, 2013
Faculty Advisor: Dr. T. Abbas
S
Objectives
S Identify and contrast the:
a. principles
b. general indications
c. modes of action
d. techniques
e. and potential complications of radiotherapy
and chemotherapy
Preoperative (Neoadjuvant)
Chemotherapy
S Preoperative
S Advantages
S Pre-op regression of tumor can facilitate resection
S Treats micrometastasis without delay
S Assesses tumor response to treatment
S Disadvantages
S Disease progression in relatively chemo-resistant tumors
S Can introduce challenges to tumor localization, margin
analysis, lymphatic mapping, pathological staging
Neoadjuvant Chemotherapy
S Usually given to facilitate surgical resection by shrinking the
primary tumor or convert an unresectable tumor into a
resectable tumor
S Determines if primary tumor is sensitive to particular
chemotherapeutic regimen
Adjuvant Chemotherapy
S Adjuvant chemo: high risk of distant recurrence
but no evidence of distant disease
S Goal
S Eradication of micrometastatic disease
S Decrease relapse rate
S Improve survival after surgical resection
Palliative Chemotherapy
S Primary modality of therapy with documented
distant metastatic disease
S Goal
S Decrease tumor burden
S Prolong survival
S Cure is rare for metastatic disease of most solid
tumors
Response to Chemotherapy
S Complete response
S Disappearance of all target lesions
S Partial response
S At least 30% decrease in the sum of target lesions
S Stable disease
S Neither sufficient shrinkage nor increase
S Progressive disease
S At least 20% increase in the sum of target lesions
Principles of Chemotherapy
S Destroys cells by first-order kinetics
S Constant % of cells killed with each
administration
S Classification
S Cell cycle phase-nonspecific
S Cell cycle phase-specific
Principles of Chemotherapy
Cell Cycle Non-specific
S Alkylating agents
S Platinum Analogues
S Antitumor Antibiotics
S Agents targeting Epidermal Growth Factor
Receptors / Tyrosine Kinase Inhibitors
Alkylating Agents
S Transfer alkyl group to DNA, resulting in strand breaks,
crosslinking or miscoding
S Effective in hematological malignancies & solids tumors
such as breast, melanoma, lung, endometrial
S Adverse reactions: myelosuppression, hemorrhagic cystitis
S Classic alkylators: cyclophosphamide, chlorambucil,
dacarbazine, procarbazine, mechlorethamine
S Nitrosoureas: carmustine, semustine, lomustine
Platinum Analogues
• Form intra- and interstrand crosslinks that inhibit DNA
synthesis and transcription
• Used to treat colon, rectal, breast, gastric, esophagus,
testicular, gynecological, head & neck cancers
• Adverse effects: myelosuppression, hemolytic-uremic
syndrome, electrolyte abnormalities, neuropathy
• Cisplatin, carboplatin, oxaliplatin
Antitumor Antibodies
S Most derived from soil fungus streptomyces
S Interfere with nucleic acid synthesis by intercalating DNA
S Block synthesis & induce strand breakage
S Doxorubicin (causes cardiomyopathy), dactinomycin,
plicamycin, mitomycin
S Bleomycin: used for testicular cancer, causes interstitial
pulmonary fibrosis
Agents targeting EGFR /
Tyrosine Kinase Inhibitors
S
Used in cancers that overexpress a specific epidermal growth factor receptor (EGFR)
and/or Tyrosine Kinase Inhibitors
S
Cetuximab: EGFR inhibitor, used in metastatic colorectal and head and neck
cancer, blocks signaling events that lead to proliferation
S
Trastuzumab: monoclonal antibody that binds extracellular domain of Her-2/neu
receptor. In breast cancer, trastuzumab diminishes downstream signaling, allowing
cytotoxic chemotherapies to become effective
S
Sunitinib –directly affecting the signalling by inhibiting multiple tyrosine kinase
pathways including VEGF
Cell Cycle Phase Specific
S Plateau with respect to cell killing
S Toxic to actively proliferating cells
S Antimetabolites
S Plant alkaloids/antimicrotubule agents
S Topoisomerase inhibitors
Antimetabolites
S
Structural analogues of nucleic acids or their precursors
S
Substitute purines or pyrimidines in the metabolic pathway to inhibit
critical enzymes
S
Major activity during S phase of the cell cycle, little effect in G0
S
Used primarily for hematologic malignancies and colorectal cancer
S
Adverse effects: skin rashes, myelosuppression, neuropathy, nausea, vomiting
S
Methotrexate, mercaptopurine, thioguanine, cytarabine, fluorouracil
Plant Alkaloids
/Antimicrotubule Agents
S
Vinca alkaloids
S
S
S
S
S
Bind to tubulin in S phase
Block microtubule polymerization and result in mitotic arrest in metaphase
Used for hematological malignancies & breast and lung cancer
Vinblastine, vincristine
Taxanes
S
S
S
S
Block tubulin depolymerization
Used for ovarian, breast, lung, bladder cancers
Cause myelosuppression, weakness, peripheral neuropathy, hypersensitivity
reactions
Paclitaxel, docetaxel
Topoisomerase Inhibitors
S Topoisomerase enzymes I & II maintain DNA strands and
correct any alterations during replication or transcription
S Inhibition causes structural DNA damage
S Used to treat hematologic malignancies & lung, prostate,
bladder, colorectal and testicular cancers
S Cause myelosuppression and diarrhea
S Etoposide, teniposide, topotecan
Combination Chemotherapy
S Provides greater efficacy than single agent therapy by three
mechanisms
S Provides max cell kill within range of toxicity for each drug
S Offers broader range of coverage of resistant cell lines in
heterogenous population
S Prevents or delays emergence of drug resistant cell lines
S Drugs with different mechanisms of action are combined to
allow for additive or synergistic effects, esp combining cell
cycle specific with non specific
Drug Resistance
S Goldie Coldman hypothesis:
S Tumors are heterogenous, genetically unstable and tend to
mutate to form different cell clones
S Argument for giving chemotherapy as soon as possible in
treatment – to reduce the likelihood of resistant clones
emerging
S Tumor size is another important variable. The greater the
tumor, the larger the heterogeneity. Because of the large
portion of cells dividing, smaller tumors are more
chemosensitive
Drug Toxicity
S Tumors more susceptible than normal tissue to
chemotherapeutic agents because of higher proportion of
dividing cells
S Normal tissues with high growth fraction (bone marrow,
hair follicles) also sensitive
S Toxic effects: bone marrow suppression, alopecia, GI tract
ulceration
S Toxic effects grades from 0 – 4 on WHO criteria
Question
S Of the list of chemotherapeutic agents listed
below, which is not an alkylating agent?
a.
b.
c.
d.
e.
Cyclophosphamide
Vincristine
Chlorambucil
Melphalan
Ifosfamide
Question
S Of the list of chemotherapeutic agents listed
below, which is not an alkylating agent?
a.
b.
c.
d.
e.
Cyclophosphamide
Vincristine
Chlorambucil
Melphalan
Ifosfamide
Question
S Doxorubicin (adriamycin) is an antibiotic with
anti-neoplastic properties. Which of the side
effects listed below is associated with its use?
a.
b.
c.
d.
e.
Nephrotoxicity
Peripheral neuropathy
Myelosuppression
Cardiac toxicity
Stomatitis
Question
S Doxorubicin (adriamycin) is an antibiotic with
anti-neoplastic properties. Which of the side
effects listed below is associated with its use?
a.
b.
c.
d.
e.
Nephrotoxicity
Peripheral neuropathy
Myelosuppression
Cardiac toxicity
Stomatitis
Radiotherapy
S Treatment with ionizing radiation
S Half for cure & remainder for palliation
S Goal - Uniformly irradiate a specified target eg.
S Gross tumor
S Surgical bed
S Areas high risk for microscopic disease
S Minimize dose to surrounding normal tissues
Types of Radiation
S Electromagnetic via high-energy photons
S Gamma rays = photons released from the nucleus of radioactive atom
S
Typically used in brachytherapy
S X-rays typically used in external beam radiotherapy
S
Linear accelerator: narrow beam electron accelerated, as decelerate emit xrays
S
Indirectly ionizing through short lived hydroxyl radicals
S Charged particles (protons and electrons)
S Directly ionizing & directly damage DNA
S Unit of absorbed dose is Gray (Gy) = J/kg
Biological Basis
S Radiation deposition
S Single- and double-strand breaks in the backbone of DNA
molecule
S Crosslinking between DNA strands & chromosomal proteins
S Loss of cellular reproductive integrity
Biological Basis
S Indirectly ionizing radiation
S Less efficacious in tumors with areas of hypoxia
S Presence of oxygen thought to prolong half-life of free radicals
S Extent of DNA damage dependent on phase cell cycle
S
S
Most sensitive: G2 and M
Less sensitive: G1 and S
S Directly ionizing radiation
S Independent of cellular oxygen levels
S Less dependent on cell-cycle phase
Cell Sensitizers
S Metronidazole, misonidazole
S Mimic oxygen and increase cell kill of hypoxic cells
S Thymidine analogues: iododeoxyuridine,
bromodeoxyuridine
S Incorporate into DNA and render cells more sensitive to
radiation damage
S Others: 5-fluorouracil, actinomycin D, gemcitabine,
paclitaxel, topotecan, doxorubicin, vinrelbine
Therapy Planning
S Goal: deliver homogeneous dose to well-defined area that includes
tumor and surrounding tissue at risk for subclinical disease
S
S
S
Define target to be irradiated & dose-limiting organs in the vicinity
Simulation (evaluation of alternative treatment techniques)
Immobilization devices & markings/tattoos on patient’s skin to ensure that
daily treatment is given in the same way
S Conventional fractionation is 1.8 – 2 Gy/day administered 5 days
each week for 3 – 7 weeks
S
S
Fractionation = delivery of radiation in divided doses
Reassortment = allowing the surviving G1 and S phase cells to progress to more
sensitive phases
Side Effects
Adverse Effects
Question
If a dose of 200 cGy of Cobalt-60 radiation reduces the
number of viable cells in a tumor from 100,000,000 to
60,000,000, then a subsequent dose of 200 cGy will
reduce the number of viable cells to
a.
b.
c.
d.
e.
10,000,000
16,000,000
20,000,000
24,000,000
36,000,000
Question
If a dose of 200 cGy of Cobalt-60 radiation reduces the
number of viable cells in a tumor from 100,000,000 to
60,000,000, then a subsequent dose of 200 cGy will
reduce the number of viable cells to
a.
b.
c.
d.
e.
10,000,000
16,000,000
20,000,000
24,000,000
36,000,000
Question
Dose fractionation is frequently used when treating
malignant tumors with radiotherapy. The reasons for
dose fractionation include all of the following EXCEPT
a.
b.
c.
d.
Tumor cells are able to repopulate between treatments
Normal cells are able to repair damage between
treatments
Tumor cells are redistributed through the cell cycle
Tumor cells become less hypoxic
Question
Dose fractionation is frequently used when treating
malignant tumors with radiotherapy. The reasons for
dose fractionation include all of the following EXCEPT
a.
b.
c.
d.
Tumor cells are able to repopulate between treatments
Normal cells are able to repair damage between
treatments
Tumor cells are redistributed through the cell cycle
Tumor cells become less hypoxic