chemotherapy · chemo & the cell cycle •cycle nonspecific agents-–toxic in all phases of...
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Chemotherapy
Jacqueline Morgan MD
Sept 4th, 2019
Cell Cycle
• M phase- Active cell division
• G1 phase- Protein & RNA synthesis, normal cellular activites
• S phase- DNA replication• G2 phase- Short pre-
mitotic phase with double the DNA content
• Post mitosis cells can– Differentiate– Rest (G0 phase)- can
return to cell cycle– Die
Cell Kinetics
Health tissues
Cell
divisionCell
lossTerminal
differentiation
Tumor cell kinetics
Actual cell division occurs over same amount of time
Growth unregulated due to either:-
Increased growth factor signalling
or
Loss of normal checkpoint or apoptosis mechanisms
Cell Kinetics• 3 levels of cell proliferation in normal tissues
– Static
– Expanding
– Renewing
Tumor tissue has different growth characteristics that
are targeted by antineoplastic therapies
Static
• Rarely divide after embryonic period
• Well differentiated
– Neurons
– Striated muscle cells
– Oocytes
Less acute toxicity, but more late chronic effects due to
inability to repair tissues
• Expanding
– Retain potential to divide when stimulated
– Are normally quiescent
Hepatocytes
—Vascular endothelium
• Renewing
– Constantly proliferating cells
– Bone marrow
– GI tract
– Epidermis
Most sensitive to acute effects of chemotherapy
Doubling Time
• Time for tumor to double in size
• Varies by tumor type 20-150 days
• 1mm tumor- 20 doublings
• 5mm tumor- 27 doublings
• 1 cm tumor- 30 doublings
• 8cm tumor- 33 doublings
Gompertzian Growth
• As tumors grow, the time to double tumor
volume increases
• Concurrent exponential tumor growth and
exponential growth retardation
Cell Kinetics• Cell cycle- Approx. 24 hours
– (0.5 to 5 days) for most tumor cells
– Not significantly different to non tumor cells
• But tumor mass doubling times approx. 20 – 150 days
• Only portion of tumor cells entering cell cycle at one time
• Tumor growth rate determined by:– Growth Fraction
• Fraction of cells undergoing division
• Varies widely, 25-95%
– Cell death
• Decreased in tumors relative to normal cells
Chemo & the Cell Cycle
• Cycle Nonspecific Agents-
– Toxic in all phases of the cell cycle, not
dependant on proliferation.
• Cycle Specific Agents-
– More effective against tumors with high growth
fraction
– Different agents effective at different stages in
cell cycle
Cell Cycle
• M phase- Active cell division
• G1 phase- Protein & RNA synthesis, normal cellular activites
• S phase- DNA replication• G2 phase- Short pre-
mitotic phase with double the DNA content
• Post mitosis cells can– Differentiate– Rest (G0 phase)- can
return to cell cycle– Die
Cycle Non specific
Direct DNA damage
Alkylating agents eg. Carboplatins
Radiation
Alter intracellular signal transduction
Growth factors eg. Bevacizumab
Hormonal agents eg. Tamoxifen
Cell cycle Specific
Inhibit nucleotide synthesis
Antimetabolites eg. Methotrexate, 5FU
Inhibit DNA synthesis
Inhibit topoisomerase eg. Topotecan
Antimicrotubule agents
Taxanes
Log Kill Hypothesis
• First order kinetics
– Kill a constant fraction of cells, rather than a
constant number.
• Lead to the use of:
– Multiple cycles,
rather than a large single dose
– Combination chemotherapy
Chemotherapy Resistance
• Primary Resistance vs. Secondary Resistance– Increased deactivation
– Decreased activation
– Increased efflux
– Decreased drug uptake
– Altered enzyme production
• Rate of spontaneous mutation linked to resistance– 1 in 10,000 to 1 in 1,000,000 cell divisions
Strategies to Reduce Resistance
• Start chemotherapy early
– Less likely to have resistant cells present
• Use multiple agents
– Less likely to develop resistance to single agent
– Multi-drug resistance can develop after exposure to
single agent despite different structures and
mechanisms of action
• Use alternating treatments
Administration
• Route of Administration
– PO
– IV
– IM
– Regional- IP
• Schedule
– Affects results and toxicity
• Doxorubicin and cardiac toxicity
Dosing Strategies
• Dose Intensity
– Higher total doses result in better response and
decreased resistance development
– Also higher toxicity
• Dose Density
– Increased frequency of dosing
– Weekly vs. q3weekly paclitaxel
Chemotherapy
• Treatment Plan- Planned treatment course
– eg. Six cycles of Carbo/Taxol
• Cycle- Predefined schedule of chemo
administration
– eg. Carbo/Taxol administered on Day 1 of 21 day cycle
– eg. EMACO- EMA administered on Day 1&2 and CO
administered on Day 8 of 14 day cycle
• Dose- Individual dose of each chemo agent
– eg. Paclitaxel 175mg/m² over 3 hours
Treatment Response
• Complete Response
– Absence of objective evidence of tumor
– Resolution of all symptoms and signs of tumor
• Partial Response
– 30 – 50% reduction in measurable tumor
diameter, no new lesions
• Stable disease
• Progressive disease
Chemotherapy
• Ideal chemo agent would
—Target neoplastic cells
—Be non-toxic to normal cells
—No side-effects
—Easy to administer
—Cheap
Which patient gets which
drugs Need to consider
Natural history of the cancer
Patient characteristics
Care environment
Treatment goals
Natural History of the Cancer
Tissue confirmation
Tumor origin
Stage
Grade
Spread pattern
The Patient
Performance status
Nutritional status
Age??
Organ dysfunction
Renal
Hepatic
Bone marrow
Comorbidities
Prior therapies
Care Environment
Facilities to assess and treat potential toxicities
Medical team
Emotional and social support
Financial status
Clinical Trial
Treatment Goals
How to monitor therapy response
CURE??
Palliation of symptoms
Control disease
Improve quality of life
Methotrexate
Anti-metabolite
Inhibits Dihydrofolate reductase
Ultimately causes thymadine starvation in cell
Renal clearance
Given IV, IM or IT
Mucositis, elevated LFTs, myelosuppression,
Cyclophosphamide
Alkylating agent DNA adducts distort DNA structure
IV or PO
Hepatic metabolism- active metabolites
Alopecia Hemorrhagic cystitis (Mesna) N/V Headache/confusion Myelosuppression Secondary malignancies
Cisplatin
Alkalyting like drug
Adducts b/n DNA and platinum compound
Inhibits DNA synthesis
IV or IP
N.V
Neuropathy, ototoxicity
Nephrotoxicity
Low K, Low Mg
Myelosuppression
Carboplatin
Alkalyting like drug
Adducts b/n DNA and platinum compound
Inhibits DNA synthesis
Rapid renal clearance
Dosing based on AUC using Cr clearance
Myelosupression
Less N/V renal and neuro toxicity than cisplatin
Hypersensitivity reaction
Bleomycin
Antitumor antibiotic
Induces single strand DNA breaks
IV
BEP for germ cell tumors
Fever
Pulm fibrosis, can be triggered by high O2 exposure
Rash, hyperpigmentation
Mucositis
Alopecia
Doxorubirin (red devil)
Antitumor antibiotic
Inhibits topoisomerase II, DNA intercalation and free
radical formation
Hepatic metabolism
Cardiomyopathy- total lifetime dose dependant
Myelosuppression
N/V
Tissue necrosis with extravasation
Radiation recall
Liposomal Doxorubicin
Smaller vol of distribution
Longer half life
Hepatic metabolism
Less myelosuppression and cariomyopathy
Hypersensitivity reaction
PPE- hand foot syndrome
Etoposide
Plant derived antitumor agents- Mandrake
Inhibits topoisomerase II and binds microtubules
IV or PO
N/V
Myelosuppresion
Alopecia
Anaphylaxis
Paclitaxel
Plant derived antitumor agent- Western Yew tree
Binds and stabilises microtubules- abnormal spindles
IV
Poor solubility, in Cremaphor
Non linear hepatic metabolism
Alopecia
Myelosuppression
Hypersensitivity- premed -H1&2 blockers & steroids
Peripheral neuropathy
VEGF agents
Human monoclonal antibodies to VEGF
Impairs angiogenesis
Headache
HTN/PRES
DVT
GI perforation
Impaired wound healing
Proteinuria
PARP Inhibitors Inhibit Poly ADP ribose polymerase Single strand DNA nicks Works best in cells with impaired DS DNA repair (BRCA
mutation, HRD)
PO
Olaparib (Lynparza), Rucaparib (Rubraca), Niraparib(Zejula)
Diarrhea N/V fatigue Myelosuppression Myeloproliferative disorders
PD1 Agents
Binds to PD1 receptor, preventing PDL ligands on
tumor cells from inactivating T cells
Approved for tumors that express PDL ligands
MSI-high or MMR deficient tumors
Pembrolizumab (Keytruda)
“itis” of anything (colitis, hepatitis, thyroiditis,panc)
Endocrinopathies
Random CREOG Pearls
Alopecia- Taxanes (also Neuropathy)
Doxorubicin- Cumulative cardiotoxicity
PPE skin rash- Doxil, Etoposide
Hemorrhagic cystitis- Ifosphamide, acrolein
neutralised by mesna
Radiation Recall- Doxorubicin
Bleomycin- Pulmonary fibrosis
Secondary malignancies- Etoposide, melphalan
Questions