Describe log cell kill kinetics
- A given treatment kills a constant fraction of cells
- Subsequent doses reduce cancer burden proportionally over time
- More cells killed, higher chance for cure
Describe Gompertzian model of tumor cell growth
Growth fraction of a tumor is NOT constant
-As tumor gets larger, growth fraction decreases
-This results in lower number of cells susceptible to chemo
(so treat earlier!)
What are the principles of combining chemo drugs?
- Efficacy: each drug must have some anticancer activity on its own
- Toxicity: minimize overlapping toxicities
- Optimum scheduling: give each drug in intervals to maximize its activity
- MOA: multiple to help overwhelm cells’ ability to develop resistance
Describe first line local primary therapy
Used in advanced cancer cases in which systemic treatments would NOT be effective
Describe neoadjuvant chemo
Used PRIOR to local therapies to improve their effect by reducing size of the tumor
Describe adjuvant chemo
Used AFTER local therapies to improve their long term effect by eliminating any remaining undetected cancer cells
Describe dose density of chemo
- Give repeated doses of multiple agents over a period of time
- Regular exposure provides a wave-like approach to killing cancer cells over time
Define cure in relation to cancer
- Sustained cancer-free period
- Usually 5 years
Define control of cancer
- Reduce cancer burden
- Prevent extension of cancer
- Extend survival
- Cure unlikely
Define palliation
- Reduce symptoms of disease
- Improve QOL
- Prolong survival
- Cure not likely
Define remission/complete response (CR)
Unable to detect presence of cancer
Define partial response
Reduction in tumor burden but cancer still present
Define treatment failure/progressive disease
Cancer continues to grow despite treatment
How can chemo resistance develop?
- Mutations within cancer cells could block chemo actions/uptake, transport drug back out
- Drug interactions could decrease exposure to chemo within the body
- Calculated doses could not match pts individual body characteristics
What are the options if primary cancer treatment is unsuccessful?
- Salvage treatment (use other combos)
- SCT
- Investigational therapies
Define autologous SCT
High dose chemo followed by re-infusion of pt’s own stem cells
Define allogeneic SCT
Chemo and immune modulation plus infusion of DONOR stem cells
What are the cell cycle non-specific chemo agents?
CAP’N
- Cytotoxic abx
- Alkylating agents
- Platinum compounds
- Natural products
MOA alkylating agents
- Disrupts normal DNA structure
- Prevents use of DNA as blueprint for cell division
- Cell cycle NON-specific
Examples of alkylating agents
- Melphalan
- Procarbazine
- Cyclophosphamide
- Carmustine
Indications for cyclophosphamide
Breast cancer, leukemia, lymphoma, myeloma, etc. etc.
Indications for melphalan
Myeloma
Indications for procarbazine
Lymphoma
Alkylating agents ADEs
- BM toxicity (myelosuppression)
- Mucositis
- Sterility (usually temporary)
- NV
- Tissue damage (following extravasation)
- Risk of secondary malignancies
MOA platinum analogs
Unclear
- Likely act similar to alkylating agents by binding DNA and forming crosslinks
- Also bind to cytoplasmic and nuclear proteins required for cell function
Examples of platinum analogs
- Cisplatin
- Carboplatin
- Oxaliplatin
Indications for cisplatin and carboplatin
BELHOT Bladder Esophagus Lung Head and neck Ovary Testicular
Indications for oxaliplatin
PEC
Pancreatic
Esophageal
Colorectal
Cisplatin ADEs
- Renal (increase ser Cr, K/Mg wasting)
- Anemia
- NV
- Ototoxicity
Carboplatin ADEs
Avoids the major toxicities a/w cisplatin BUT causes myelosuppresison
Oxaliplatin ADEs
- Neurotoxicity (peripheral neuropathy)
- Myelosuppression
- Diarrhea
What are antimetabolites?
- Molecules (natural or artificial) that sub for actual components of metabolic processes
- Inhibits normal cell processes that produce components of DNA
- S phase specific
Examples of antimetabolites
- MTX
- Capecitabine
- Cytarabine
- Gemcitabine
- Fludarabine
- 5-FU
- 6-MP
MTX MOA
- Antimetabolite
- Inhibits DHFR which converts one form of folic acid to another
- Inhibits TS
Capecitabine MOA
- Antimetabolite
- Inhibits TS
- Blocks incorporation of FUTP into RNA and dFUTP into DNA (blocking formation of RNA/DNA)
5-FU MOA
- Antimetabolite
- Same MOA of capecitabine
- Inhibits TS
- Blocks incorporation of FUTP into RNA and dFUTP into DNA (blocking formation of RNA/DNA)
Cytarabine MOA
- Antimetabolite
- Mimics cytidine
- Inhibits DNA pol and DNA repair that prevents DNA chain elongation
Gemcitabine MOA
- Antimetabolite
- Inhibits ribonucleotide reductase
- Prevents production of deoxytriphosphates for DNA synthesis
- Inhibits DNA pol which blocks DNA synthesis and repair
Fludarabine MOA
- Antimetabolite
- Same as gemcitabine
6-MP MOA
- Antimetabolite
- Inhibits multiple enzymes that synthesize purine nucleotides
Indications for MTX
- Leukemia
- Lymphoma
- Breast cancer
- RA
Indications for pemetrexed
Lung cancer
antimetabolite
Indications for capecitabine
Breast cancer
Indications for 5-FU
-Breast cancer
-Esophageal
-Colorectal
etc etc
Indications for cytarabine
Leukemia and lymphoma
Indications for gemcitabine
Pancreas Bladder Breast Lung Ovarian cancers
What is leucovorin? What does it do?
- Special antimetabolite: NO anticancer action
- Reduced form of folic acid
- Mimics action of tetrahydrofolate
Key uses of leucovorin
- Reduces MTX toxicity by rescuing normal cells
2. Increases 5-FU activity against colon cancer
MTX ADEs
- Mucositis
- Diarrhea
- Myelosuppression
Capecitabine ADEs
- Palmar plantar erythrodysesthesia (hand-foot syndrome)
- Diarrhea
- NV
- Myelosuppression
Which antimetabolites may cause hand-foot syndrome?
Capecitabine
Pemetrexed
How is hand-foot syndrome prevented/treated?
Dexamethasone
5-FU ADEs
- Mucositis
- Diarrhea
- Myelosuppression
Cytarabine ADEs
- Acral erythema
- Cerebellar toxicity
- Pulm toxicity
- NV
- Myelosuppression
Gemcitabine ADEs
- Diarrhea
- NV
- Myelosuppression
Pemetrexed ADEs
- Hand foot syndrome
- Mucositis
- Diarrhea
- Rash
- Myelosuppression
How are ADEs of pemetrexed reduced?
B12 and folic acid supplements
Chemo classes derived from natural products
- Vinca alkaloids (periwinkle plant)
- Taxanes (yew trees)
- Epipodophyllotoxins (mayapple root)
- Camptothecins (Camptothecin acuminata tree)
Vinca alkaloids MOA
- Inhibit tubulin polymerization required for microtubule assembly
- Results in blocked cell division and causes cell death
Indications for vincristine
- Leukemia
- Lymphoma
- Neuroblastoma
- Wilm’s tumor
- Rhabdomyosarcoma
Indications for vinblastine
- Leukemia
- Lymphoma
- Kaposi’s sarcoma
- Germ cell cancer
Indications for vinorelbine
- Lung
- Breast
- Ovarian cancer
Vinca alkaloids ADEs
- Alopecia
- Neuro (peripheral neuropathy)
- Constipation
- Myelosuppression
- Potent vesicant action upon extravasation
Taxanes MOA
- Promote microtubule formation
- Prevent disassembly of microtubules, blocking completion of cell division and leads to cell death
Examples of taxane agents
- Paclitaxel
- Docetaxel
- Cabazitaxel
- Ixabepilone
Indications for paclitaxel
- Ovary
- Lung
- Prostate
- Breast
- Head and neck
- Esophageal
- Bladder
Indications for docetaxel
- Breast
- Lung
- Head and neck
- Gastric
- Ovary
- Bladder
Indications for cabazitaxel
Prostate cancer
Indications for ixabepilone
Breast cancer
Taxanes ADEs
- Myelosuppression
- Hypersensitivity reactions
- Peripheral neuropathy
- Fluid retention (docetaxel)
Which taxane causes fluid retention?
Docetaxel
Epipodophyllotoxins MOA
- Inhibit DNA topoisomerase II
- Prevents proper unwinding of DNA resulting in blockade of DNA synth and cell division
Examples of epipodophyllotoxins
Etoposide
Teniposide
Indications for etoposide
- Lung
- Germ cell
- Lymphoma
- Gastric cancer
Indications for teniposide
Pediatric leukemia
Epipodophyllotoxins ADEs
HAM
- Hypotension (if infused too quickly)
- Alopecia
- Myelosuppression
What are antitumor antibiotics?
- Derived from bacteria to compete for resources
- Anthracyclines (doxorubicin, daunorubicin, bleomycin, etc.)
Anthracyclines MOA
- Inhibit topoisomerase 2
- Bind to DNA and intercalate strands
- Generate free radicals
- Bind to cell membranes and alter fluid/ion transport
Indications for doxorubicin
- Breast cancer
- Myeloma
- Leukemia
- Lymphoma
Indications for daunorubicin and idarubicin
Leukemia
Indications for epirubicin
- Breast
- Gastroesopageal
Indications for mitoxantrone
- Leukemia
- Lymphoma
- Prostate
- MS
Which anthracycline can be used in MS?
Mitoxantrone
Anthracyclines ADEs
- Mucositis
- Alopecia
- Myelosuppression
- NV
- Vesicant if extravasated
- Cardiotoxicity
ADE of mitoxantrone
Turns urine blue/blue-green
ADE of doxo/dauno/ida/epirubicin
Turns urine reddish-orange
Which anthracyclines turn urine blue or blue-green?
Mitoxantrone
Which anthracyclines turn urine reddish-orange?
Doxorubicin
Idarubicin
Epirubicin
Daunorubicin
Describe cardiotoxicity of anthracyclines
- Acute: within 24-72 hrs, usually subclincial, arrhythmias/pericarditis/myocarditis
- Chronic: dose dependent, delayed by years, results in cardiomyopathy and associated heart failure
What dose can cardiotoxicity of anthracyclines occur?
Any dose, but risk increases with cumulative dosing
What is dexrazoxane used for?
- To mitigate cardiotoxicity of anthracyclines
- Reduces free radical formation in cardiac tissue
- May reduce therapeutic effect of doxorubicin though
What is a major concern of bleomycin use?
Pulmonary toxicity
Risk factors for pulm toxicity with bleomycin use?
- Age over 70
- Cumulative doses over 400 units
- Underlying pulm disease
- Prior mediastinal radiation
- Supplemental oxygen
What is bleomycin used for?
- Lymphoma
- Germ cell
- Head and neck
- Squamous cell cancers
- Sclerosing agent for pleural effusions
What are tyrosine kinases?
- Families of proteins that use ATP to phosphorylate other proteins
- Often over active in cancer cells leading to enhanced tumor growth
TKI MOA
- Block tyrosine kinases
- Results in inhibiting specific regulatory pathways
- Promotes cancer cell death
How can resistance to TKIs develop?
Mutations in AA sequence of the specific tyrosine kinase could prevent a TKI from binding the targeted site
Which TKIs are indicated for Ph+ CML and ALL?
- Bosutinib
- Imatinib
- Nilotinib
- Dasatinib
- Ponatinib (off market)
Indications for erlotinib
Lung and pancreatic cancer
Which TKIs are indicated for renal cell cancer?
Sorafenib and sunitinib
Indications for lapatinib
Breast cancer
Indications for crizotinib
Lung cancer
Indications for gefinitib
Lung cancer
off market now
TKI ADEs
- Rash
- Myelosuppression
- Fatigue
- Fluid retention
- Diarrhea
- Myalgia
- CHF
Drug interactions with TKIs
CYP450
- Inhibitors (like azoles) can decrease metabolism
- Inducers (like phenytoin) can increase metabolism
- Reduced availability with PPIs and H2 blockers
Immunomodulators MOA
Unclear
- May alter TNF levels
- May increase NK cells, IL2, interferon activity
- May promote apoptosis
What are immunomodulators MC used to treat?
Myeloma
usually combined with dexamethasone
Examples of immunomodulators
Thalidomide
Lenalidomide
Pomalidomide
Immunomodulators ADEs
- Peripheral neuropathy
- Thromboembolism
- Fatigue
- Rash
- Myelosuppression
- Dizzy/drowsy
Proteasome inhibitor MOA
- Inhibit complexes of proteins that would otherwise break down unneeded or damaged proteins
- Promote activation of apoptosis pathways
Indications for proteasome inhibitors
Myeloma
Examples of proteasome inhibitors
Bortezomib
Carfilzomib
Proteasome inhibitor ADEs
- Activation of herpes zoster/simplex
- Pulm toxicity
- Diarrhea, NV
- Myelosuppression
- Neuralgia
- Peripheral neuropathy
- Heart failure
How to identify monoclonal antibodies
- Prefix: company specific
- Target: tu is tumor, ci is circulatory system
- Source: zu is humanized, xi is humanized/chimeric, mu is mouse
- Suffix: mab
How mAb kill tumor cells?
Not always clear, could be multiple mechanisms
- Block receptors
- Bind free protein ligands looking to bind receptors
- Bind to receptors and trigger apoptosis or ADCC
Indications for rituximab
CD20 positive lymphoma
Indications for trastuzumab
HER2/neu overexpressing breast cancer
Indications for cetuximab
- Lung
- Head and neck
- Colorectal cancer
Indications for panitumumab
Colorectal cancer
Indications for bevacizumab
- Colorectal
- Breast
- Lung
- Renal cell cancers
mAb ADEs
Infusion related reactions (give premeds - acetaminophen, diphenhydramine plus or minus dexamethasone)
How to avoid infusion reactions with mAbs?
Give premeds (acetaminophen, diphenhydramine plus or minus dexamethasone)
Bevacizumab ADEs
- GI perforation
- Arterial thromboembolic events
- Delayed wound healing
Trastuzumab ADEs
Heart failure
Panitumumab and cetuximab ADEs
- Hypomagnesemia
- Interstitial lung disease
What is asparaginase and how does it work?
- Enzyme antineoplastic agent
- Breaks down aspargine to aspartate (deprives tumor cells of necessary AA and leads to apoptosis)
MC used form of asparaginase?
E coli asparaginase
Forms of asparaginase
- E coli asparaginase
- PEG-aspargase (long acting)
- Erwinia asparaginase (for pts who have hypersensitivity reaction to E coli form)
Indications for asparaginase
Part of combo chemo to treat ALL
Asparaginase ADEs
- Hypersensitivity
- Clotting and bleeding d/os
- Pancreatitis
- Neuro toxicity
Goal of phase I clinical trials
Assess safety (10-20 pts)
Goal of phase II clinical trials
Assess efficacy (20-40 pts)
Goal of phase III clinical trials
Assess efficacy compared to standard treatment (lots of patients, randomized)
Describe ALL
- Children
- Induction, consolidation, maintenance therapy
- Combo treatment over 2-3 yrs
- Requires intrathecal chemo d/t chance for spread to CNS
- Good chance for cure
Quick hits: AML
- Adults
- Induction and consolidation treatment
- 7 plus 3 regimen (cytarabine, daunorubicin)
- Some pts considered for ASCT
Quick hits: CML
- Philly chromosome
- Chronic, accelerated, blast stages
- Use TKIs to control disease
- ASCT only known cure
Quick hits: CLL
- Elderly
- Treat when symptomatic
- Many options and aimed at controlling symptoms, prolonging survival
- Little chance for cure
Quick hits: Hodgkin’s lymphoma
- Reed-Sternberg cells
- EBV related
- Classic B symptoms (fever, night sweats, wt loss)
- Lymphadenopathy
- Several months of chemo plus or minus XRT
- ABVD regimen
Quick hits: NHL
- B symptoms and lymphadenopathy
- NO RS cells like HL
- CHOP or R-CHOP (if CD20 positive)
Quick hits: myeloma
- Malignant plasma cells produce abnormal IGs
- Only stages 2 and 3 receive treatment
- Requires pain and anemia management
- Bisphosphonates to control bone lesions
Quick hits: breast cancer
- Both men and women
- Screening is key
- Treatment based on stage and pre/postmeno status
- Cure possible in all but stage IV disease
Quick hits: prostate cancer
- Elderly men
- Treatment not always provided
- Treatment types: hormonal, chemo, brachytherapy, surgical
- Monitor PSA and androgen levels for response to treatment
MC GI cancer?
Colorectal
Quick hits: colorectal cancer
- MC GI cancer
- Common chemo regimens: FOLXFOX, FOLFIRI
FOLFOX and FOLFIRI are common chemo regimens for which cancer?
Colorectal
Quick hits: ovarian cancer
- Typically slow growing and difficult to detect until later stages
- Chemo options: paclitaxel with cisplatin/carboplatin, topotecan, altretamine, liposomal doxorubicin
Quick hits: testicular cancer
- Younger population 20s-40s
- Combo chemo: BEP (bleomycin, etoposide, cisplatin), ICE (ifosfamide, cisplatin, etoposide)
Quick hits: malignant melanoma
- Curable in early stages w/surgery
- Mets is relatively drug-resistant
- Chemo aims to prolong survival (dacarbazine, temozolomide, cisplatin, aldesleukin)
Quick hits: brain cancer
- Multiple types
- Require chemo to be able to cross BBB (carmustine, lomustine, temozolomide)
Which chemos can cross BBB?
Carmustine
Lomustine
Temozolomide
Quick hits: secondary malignancies
- Caused by previous XRT/chemo
- MC acute leukemia or lymphoma
- More difficult to treat
- MC a/w alkylating agents and etoposide
What is the MC type of secondary cancer?
Usually acute leukemia or lymphoma
What agents are MC a/w development of secondary cancers?
Alkylating agents and etoposide
Define vesicant
Blistering agent - severe skin, eye, mucosal pain and irritation
Define extravasation
- Administration of IV infusions into the extravascular space/tissue around infusion sites
- Can cause severe damage
Which chemotherapies are potent vesicants upon extravasation?
- Anthracyclines
- Vinca alkaloids
Which chemo may cause pulmonary toxicity?
Bleomycin
Which chemo may cause thromboembolism?
Thalidomide (immunomodulator)
Which chemo may cause cardiotoxicity?
Doxorubicin (anthracycline)
Which chemo may cause myelosuppression?
Carboplatin
Which chemo may cause nephrotoxicity?
Cisplatin
Which chemo may cause hypersensitivity reaction?
Asparaginase
Which chemo may cause delayed wound healing?
Bevacizumab
Which chemo may cause cerebellar toxicity?
Cytarabine (antimetabolite)
Which chemo may cause neurotoxicity?
Vincristine (vinca alkaloid)
Ways to avoid cardiotoxicity with anthracyclines?
- Limit lifetime doses
2. Use dexrazoxane
What does the Philadelphia chromosome create?
BCR-ABL (over active tyrosine kinase)
What are hormone sensitive cancers?
- Breast
2. Prostate
What is imatinib MC used to treat?
CML
What is thalidomide MC used to treat?
Myeloma
What is asparaginase MC used to treat?
ALL
What would 5-FU with leucovorin be used to treat?
Colon
What would trastuzumab be used to treat?
Breast
What would goserelin be used to treat?
Hormonal for prostate (androgen dependent) cancer
