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