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SC WCS > Clinical Oncology SC016: Advances In Systemic Therapy In Oncology > Flashcards

Clinical Oncology SC016: Advances In Systemic Therapy In Oncology Flashcards

1
Q

Treatment classification

A
  • Curative vs Palliative
  • Neoadjuvant (before surgery) vs Adjuvant (after surgery / definitive treatment)
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2
Q

***Classification of Chemotherapy

A
  1. Alkylating agents (cross-link DNA)
    - Nitrogen mustards (e.g. Melphalan, Chlorambucil)
  • Oxazaphosphorines (e.g. ***Cyclophosphamides, Ifosfamides)
  • Nitrosoureas (e.g. Carmustine, Lomustine)
  • **Platinums (Cisplatin, Carboplatin, Oxaliplatin) —> **Emetogenicity, Neurotoxicity, Ototoxicity, Nephrotoxicity
  1. Anti-metabolites
    - Antifolates (e.g. Methotrexate, ***Pemetrexate / Pemetrexed)
  • Pyrimidine analogues (e.g. **5-FU (Capecitabine (Xeloda)), Ara-C (Cytarabine), **Gemcitabine)
  • Purine analogues (e.g. **6-MP, Fludarabine)
    —> **    BM suppression, GI mucosa, Hand-foot syndrome
  1. Natural products
    - Antimicrotubule agents (Mitotic inhibitors)
    —> Vinca alkaloids (e.g. **Vincristine, Vinorelbine, Vinblastine)
    —> Taxanes (e.g. **    Paclitaxel, **Docetaxel) —> **Neurotoxicity
  • Topoisomerase 1 inhibitors (e.g. **Irinotecan, Topotecan) —> **Acute cholinergic syndrome (Irinotecan)
  • Topoisomerase 2 inhibitors (e.g. Etoposide)
  • Anti-tumour antibiotics
    —> Anthracyclines (e.g. **Doxorubicin, **Epirubicin, Daunorubicin) —> ***Cardiotoxicity, N+V, Extravasation
    —> Bleomycin, Dactinomycin
  1. Others
    - L-asparaginase
    - Hydroxyurea
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3
Q

Cell cycle

A

G0 phase:
- Resting phase, not committed for division but can be stimulated into cell cycle by local growth factor

G1 phase (~2-30 hours):
- Proteins, enzymes & RNA needed for DNA synthesis are being produced

S phase (~6-8 hours):
- Synthesis phase, cellular DNA ***doubles in amount

G2 phase (~2-4 hours):
- Special proteins / RNA are being synthesised

M phase (<1 hour):
- Mitosis stage where cell division occurs

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4
Q

***Phase specificity of Chemotherapy

A
  1. Cell cycle phase-specific agents
    - active in a **particular phase of cell cycle
    - depend on the production of some type of **    unique biochemical blockade of a particular reaction occurring in a single phase of the cell cycle
    - kill cells exponentially at lower doses but reach a plateau when given at a higher dose because they are only able to kill cells in a specific part of the cycle (    saturation kinetics)
    - greater cell kill is achieved if they are given in **multiple repeated fractions
    —> **     Saturation kinetics
  2. Cell cycle phase-non-specific agents
    - cytotoxic effect exerted **irrespective of cell cycle state
    - equally effective in large tumours in which cell growth is **    low (very long phase in a cell cycle —> if give cycle-specific agents —> only kill small proportion of cells over a long period of time)
    - **dose-dependent
    - single dose has **    same effect as repeated fractions totalling the same amount
    —> ***Linear cell kill
  3. Cell cycle-non-specific agents
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5
Q

Cell cycle phase-specific agents

A

G1 phase specific:
1. L-asparaginase

S phase specific:
1. Anti-metabolites (inhibit DNA synthesis)
- Antifolates (Methotrexate)
- Pyrimidine analogues (5-FU)
- Purine analogues (6-MP)
- Hydroxyurea
- Cytosine arabinoside

G2 phase specific:
1. Bleomycin

M phase specific:
1. Antimicrotubule agents
- Vinca alkaloids
- Taxanes

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6
Q

Cell cycle phase-non-specific agents

A
  1. Alkylating agents (crosslink guanine base in DNA)
    - Procarbazine
  2. Nitrosoureas
  3. Antitumour antibiotics (induce DNA lesions, inhibit topoisomerase, among other effects) (except Bleomycin: G2 phase specific)
  4. Platinums
  5. Steroid hormones

G0 + All other phases:
- Nitrogen mustard

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7
Q

Alkylating agents

A

MOA:
Alkylating agents react with (alkylate) electron-rich atoms in cells to form **covalent bonds
—> Reactions with **DNA bases
—> Antitumour activity

Binds directly to DNA:
- Limited cell cycle specificity
- Sensitivity dependent on AUC (exposure of drug over time) + relatively independent of schedule of administration
- Longer term effect: Infertility + Carcinogenesis

Classes:
1. Nitrogen mustards
- melphalan
- chlorambucil

  1. Oxazaphosphorines
    - ***cyclophosphamides
    - ifosfamides
  2. Nitrosourea
    - carmustine (BCNU)
    - lomustine (CCNU)
  3. Alkyl sulfonates
    - busulfan
  4. Aziridines and Epoxides
    - thiotepa
    - ***mitomycin C
  5. Hydrazine + Triazine derivatives
    - procarbazine
    - darcabazine (DTIC)
    - ***temozolomide
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8
Q

***Group toxicity of Alkylating agents

A
  1. ***Haematological
    - kill WBC, platelet
    - dose-limiting (∵ have to wait for cell count to recover) + can be delayed
  2. ***GI (∵ rapidly dividing —> sensitive to chemotherapy)
    - N+V
    - mucositis
    - diarrhoea
  3. ***Pulmonary
    - interstitial pneumonitis + fibrosis
  4. ***Alopecia
    - only apply to lipophilic metabolite (∵ go into SC fat)
  5. Gonadal
    - infertility
  6. ***Carcinogenesis
    - secondary leukaemia
  7. ***Teratogenicity
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9
Q

Platinum compounds

A

Similar to bifunctional alkylating agents
- bind covalently to DNA —> disrupt DNA function
1. Cisplatin (prototype)
2. Carboplatin
3. Oxaliplatin

Specific SE:
- N+V (Emetogenicity)
(三寶)
- **Neurotoxicity (for Oxaliplatin, dose-limiting)
- **Ototoxicity
- ***Nephrotoxicity (esp. for Cisplatin —> need to titrate dose according to RFT)

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10
Q

Anti-metabolites

A
  1. Folate analogues
    - Methotrexate
    - Raltitrexate
    - ***Pemetrexate (lung cancer)
  2. Pyrimidine analogues
    - Fluoropyrimidines
    —> **5-FU (IV form) / **Capecitabine (Oral form)
    - Cytidine analogues
    —> Ara-C (Cytarabine) (haematological malignancy)
    —> ***Gemcitabine (solid tumour)
  3. Purine analogues (haematological malignancy)
    - Thiopurine
    —> Azathioprine, ***6-MP
    —> 6-TG
    - Cladribine, Fludarabine
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11
Q

Cytotoxicity of Anti-metabolites

A
  1. Cell cycle phase-specific
  2. Toxicity on proliferating cells
    - **BM suppression
    - **    GI mucosa
    - ***Hand-foot syndrome (aka palmar-plantar erythrodysesthesia) (Capecitabine) (rash, swelling, desquamation of skin)
  3. Do NOT interact directly with DNA
    - ***NO long term carcinogenesis
  4. Schedule-dependent administration (∵ cycle-specific)
    - Bolus vs Continuous infusion
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12
Q

Natural products

A
  1. Mitotic inhibitors (Antimicrotubule agents) (solid tumour)
    - Vinca alkaloids (e.g. **Vincristine, Vinorelbine, Vinblastine)
    - Taxanes (e.g. **    Paclitaxel, ***Docetaxel)
  2. Topoisomerase 1 inhibitors
    - ***Irinotecan
    - Topotecan
  3. Toposiomerase 2 inhibitors
    - Anthracyclines (e.g. **Doxorubicin, **Epirubicin, Daunorubicin) (breast cancer)
    - Epipodophyllotoxins: Etoposide
  4. Antitumour antibiotics
    - Anthracyclines (e.g. **Doxorubicin, **Epirubicin, Daunorubicin) (breast cancer)
    - Bleomycin, Dactinomycin
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13
Q

Mitotic inhibitors (Antimicrotubule agents)

A

Vinca alkaloids: Prevent **polymerisation of tubulin to form microtubules as well as inducing depolymerisation of formed tubules
1. **Vincristine
2. Vinorelbine
3. Vinblastine
* **NOT used in Intrathecal injection

Taxane: Binds to tubulin + simultaneously promoting their assembly + prevent **disassembly to form stable, non-functional microtubules
1. **Paclitaxel
2. **Docetaxel
Specific SE:
- Hypersensitivity (need high dose steroid for lower risk)
- **Neurotoxicity (cumulative in nerve)

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14
Q

Topoisomerase inhibitor

A

Topoisomerase 1: Enzyme that produces reversible **single-strand DNA breaks during DNA replication
1. **Irinotecan (prototype)
- Diarrhoea
- ***Acute cholinergic syndrome (tearing, saliva production, abdominal colic, diarrhoea) —> effectively managed by Atropine
2. Topotecan

Topoisomerase 2: Enzymes that produces reversible ***double-strand DNA breaks during DNA replication
1. Etoposide (VP-16) (for SCLC)

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15
Q

Anthracycline

A

Daunorubicin (original anthracycline): product of a Streptomyces species isolated from Italian soil in 1958

**Mechanisms of cytotoxicity:
1. Topo 2 inhibition
2. Free radical formation —> **Cardiac toxicity
3. DNA intercalation
4. Cell membrane effect

Specific SE:
- **Cardiotoxicity
- **N+V (most nauseating drugs: Doxorubicin, Cisplatin)
- ***Extravasation —> implant central line for long-term anthracycline

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16
Q

“New” Chemotherapy

A
  1. Eribulin
    - microtubule dynamic inhibitor (comparable efficacy to taxane)
    - ***less neurotoxicity
  2. Pegylated liposomal Doxorubicin
    - encapsulated in liposome
    - ***less cardiotoxicity (∵ enhanced delivery to tumour cells)
  3. TAS102
    - **orally administered combination of a thymidine-based nucleic acid analogue and a thymidine phosphorylase inhibitor
    - **    directly incorporated into DNA (vs 5-FU: enzyme inhibitor to not produce DNA)
    - efficacy in refractory case
17
Q

Hormonal therapy

A

Can be considered as Targeted therapy

Indications:
1. Hormone-sensitive cancers
- Breast cancer
- Prostate cancer
- Endometrial cancer

  1. Also used in palliation e.g. Megace (Progesterone) for improving anorexia
    SE:
    - **Fluid retention
    - **    Thromboembolism (∵ ↓ IV volume —> platelets closer together)
18
Q

Hormonal therapy in Breast cancer

A
  1. SERM (Selective estrogen receptor modulator) (e.g. Tamoxifen)
  2. Aromatase inhibitor (e.g. Letrozole)
  3. Estrogen receptor antagonist (e.g. Fulvestrant)
19
Q

SERM (Selective estrogen receptor modulator)

A

MOA:
- Binds to estrogen receptor
—> inhibits translocation + nuclear binding of estrogen receptor
—> prevent transcriptional activation of estrogen-responsive genes

Limitation:
- Also have **agonist effect (apart from antagonist effect)
1. Endometrial thickening —> **Endometrial cancer —> **Regular gynaecological checkup
2. **Thromboembolic risk (e.g. DVT ∵ estrogen effect)

***Tamoxifen:
- Effective in both neoadjuvant / adjuvant / palliative setting
- for ER / PR +ve breast cancer

SE:
- Hot flushes (common)
- **Endometrial cancer
- Vaginal dryness / discharge
- **Thromboembolic event

Other benefits:
- **Lower cholesterol
- Reduce CVS disease risk
- **Preservation of bone density in post-menopausal women

20
Q

Aromatase inhibitors

A

More potent for breast cancer than SERM
- ***Better efficacy than Tamoxifen

MOA:
- Prevent peripheral conversion of androgens to estrogen
- Selective impairment of gonadal steroidogenesis

Types (equally effective):
- Type I: Enzyme inactivator (steroidal)
—> Exemestane

  • Type II: Competitive antagonist (non-steroidal)
    —> Anastrozole
    —> ***Letrozole

Peripheral aromatisation of androgen to estrogen take place in fat / liver / muscle / skin / breast tissue / tumour
—> Aromatase is the enzyme critical in the final step of conversion

CI:
- **Pre-menopausal women
—> Functioning ovary synthesise more estrogen as a result of intact hypothalamic-pituitary feedback loop
—> surge of estrogen
—> **flare of cancer symptoms

ONLY used in **post-menopausal women / pre-menopausal women with ovarian function **suppressed

SE:
- **Osteoporosis —> monitor BMD, consider use of Ca / Vit D + physical exercise, bisphosphonate)
- GI upset
- **Arthralgia
- Myalgia
- ***Increase cholesterol level

21
Q

Estrogen receptor antagonist

A

Fulvestrant
- Competitively bind to estrogen receptors + form a nuclear complex that ↓ DNA synthesis
- Downregulate ER + PR expression
- NO estrogen receptor agonist activity
- Activity against ***Tamoxifen-resistant breast cancer

Administration:
- Injection (vs SERM / Aromatase inhibitor: Oral)

SE:
- **Osteoporosis —> monitor BMD, consider use of Ca / Vit D + physical exercise, bisphosphonate)
- **Increase cholesterol level

22
Q

Hormonal therapy in Prostate cancer

A

***Androgen-deprivation therapy
1. Flutamide / Bicalutamide
- non-steroidal anti-androgen + competitive inhibit binding of androgen to androgen receptor

  1. LHRH analogue (aka GnRH analogue)
    - suppress pituitary release of LH
    - beware of ***flare reaction in initial treatment period (∵ overstimulation of GnRH receptors (web)) —> cover with Anti-androgen in initial period

SE (for 1 + 2):
- Hot flashes
- Diarrhoea
- Gynecomastia
- Impotence
- Liver function derangement
- Decreased bone mineral density

  1. Abiraterone
    - selectively inhibit CYP17A1 enzyme in testicular, adrenal, prostate tumour tissues
    - specific SE: ***Mineralocorticoid effect (HT, HypoK, Fluid overload) due to ACTH excess (Cortisol production by CYP17A1 suppressed —> ACTH excess)
  2. Enzalutamide
    - **Androgen receptor inhibitor
    - competitively inhibit binding of androgen to androgen receptors with more affinity than other anti-androgen
    - inhibits nuclear translocation of androgen receptor, DNA binding + coactivator recruitment
    - **    specific SE: HT, seizure
23
Q

Targeted therapy

A

2 main classes:
1. Monoclonal Ab (mAb)
- act extracellularly
- target is extracellular / circulating

  1. Small molecule tyrosine kinase inhibitor (TKI)
    - act intracellularly
    - blocks downstream signaling of cell surface receptor
24
Q

Lung cancer and EGFR

A

Activating **EGFR tyrosine kinase mutation:
- plays a critical role in lung cancer
- most predict increased sensitivity to **Gefitinib / Erlotinib
- **T790M mutation (2.4% in Chinese) predict **resistance

Incidence:
- 10-15% in all lung cancer patients
- ~50% in ***female, Asian, non-smoker, adenocarcinoma

25
Q

EGFR Tyrosine kinase inhibitor (EGFR TKI)

A

1st gen (reversible inhibitor): Gefitinib, Erlotinib
2nd gen (irreversible inhibitor): Afatinib
3rd gen: AZD9291 (Osimertinib)

Specific SE:
- **Acneiform skin rash
- Diarrhoea
- Electrolyte disturbance
- Infusion reaction
- **Paronychia
- Conjunctivitis
—> common to EGFR signaling pathway

26
Q

Breast cancer and HER2

A
  • Receptor-specific ligands bind to the ectodomains of EGFR, HER3 and HER4, resulting in the formation of homodimeric / heterodimeric kinase-active complexes to which HER2 (no external binding site) is recruited as a preferred partner
    —> Dimerization of receptors
    —> activation of the cytosolic TK domain with autophosphorylation of the receptor
    —> activation of downstream signaling molecules
  • RTK activity is tightly controlled in normal cells
    —> in malignant cells:
    —> through amplification, mutation, or structural rearrangement
    —> the genes encoding these receptors escape from their usual inhibitory intracellular mechanisms
27
Q

Anti-HER2 therapy

A

Anti-HER2 therapy
- used to treat HER2 overexpressed **Breast cancer (~20% of patients)
- other cancers: **Gastric cancer (10-15% of patients)

  1. Trastuzumab (Herceptin, prototype):
    - Humanised monoclonal Ab that binds to extracellular domain (subdomain IV) of HER2 and inhibit growth of HER2 over expressed cells
    - Widely used in neoadjuvant / adjuvant / palliative setting

Specific SE:
- ***Cardiac dysfunction: require regular monitoring of LVEF, cannot use with anthracycline (∵ also cardiotoxic)
- Infusion reaction

  1. Lapatinib
    - an oral small molecule (TKI) dual inhibitor of EGFR and HER2
    - useful in neoadjuvant and palliative setting
  2. Pertuzumab
    - inhibits ligand-dependent HER2 dimerisation and signaling
    - superior efficacy when combined with trastuzumab + chemotherapy in 1st line treatment (∵ bind to HER2 receptor at different sites)
  3. TDM-1
    - Ab-drug conjugate
    —> deliver drug to cancer cells locally
    —> maximise cancer cell kill, minimise systemic toxicity
28
Q

Colorectal cancer and VEGF

A
  • Tumours >2 mm in diameter require an independent blood supply to survive + grow
  • Tumours continually require VEGF to recruit new vasculature to support growth
  • VEGF continues to be expressed throughout tumour progression, even as secondary pathways emerge

VEGF:
- NOT a target / receptor on cancer cells
- ***Circulating in bloodstream
- Empirical process of angiogenesis

29
Q

Anti-VEGF

A
  1. Bevacizumab
    - recombinant humanised mAb that selectively binds to + neutralise biologic activity of human VEGF
  2. Aflibercept
    - fusion protein of key domain from human VEGF receptors 1 + 2 with human IgG Fc
    - blocks all human VEGF-A isoforms, VEGF-B, placental growth factor (PIGF)
  3. Regorafenib
    - oral multi-target TKI against angiogenesis (VEGFR1 [also known as FLT1], VEGFR2, VEGFR3, TIE2), oncogenesis (KIT, RET, RAF1, BRAF, and BRAFV600E) and the tumour microenvironment (PDGFR and FGFR))

Other use of Anti-VEGF:
- Lung cancer
- Brain tumour
- Gastric cancer

Bevacizumab, Aflibercept:
- minimal single agent activity
- have to combine with chemotherapy
- Specific SE:
—> Common: **HT, **Proteinuria
—> Severe: Bleeding, Thromboembolic events, Wound healing problem, GI perforation

Regorafenib:
- ***hand-foot skin reaction
- fatigue

30
Q

Colorectal cancer and EGFR

A

~50% of metastatic CRC are RAS-**mutant
—> predict **NO clinical benefit with use of Anti-EGFR mAb

Panitumumab, Cetuximab
- inhibit EGFR dimerisation + subsequent downstream signaling
- suitable for RAS-wild type
- specific SE:
—> **Acneiform rash
—> Diarrhoea
—> Electrolyte disturbance
—> Infusion reaction
—> **Paronychia
—> Conjunctivitis

31
Q

GIST and Imatinib

A
  • > 95% of GISTs positive for CD117 antigen (c-Kit receptor tyrosine kinase)

KIT mutation:
- Mutation in the **c-Kit proto-oncogene result in a **gain-of-function constitutive activation of ***KIT kinase and hence uncontrolled cell proliferation and resistance to apoptosis

Imatinib:
- potent inhibitor of different tyrosine kinase: ABL, PDGFR, KIT
- blocks the constitutive activity of KIT receptor tyrosine kinase in cells of GIST
- in a subset of patients with GIST lacking mutation in c-Kit have intragenic mutations in the PDGFRA gene, resulting in constitutive active PDGFR —> potentially explains the clinical responses to imatinib in GISTs with wild-type c-Kit

Indication:
- **CML
- **GIST

Specific SE (manageable):
- BM suppression (esp. neutropenia, thrombocytopenia)
- Edema
- Liver function derangement
- ***Skin reactions (quite common)

32
Q

Immunotherapy

A

Evading immune destruction: One of hallmarks for cancer

Can be considered as Targeted therapy
1. Anti-PD1 immune checkpoint inhibitor
- Nivolumab (fully human IgG4 mAb against PD-1)
- **Pembrolizumab (selective humanised IgG4 mAb against PD-1)
- **Atezolizumab: Bind to PD-L1

MOA:
- NOT kill tumour cell directly but make sure immune cell recognise cancer cell again
- Block PD-1 receptor (on immune cell) by binding to immune dampening PD-1 / PD-2 ligands (on Ag presenting tumour cells)
—> block binding of PD-L1 to PD-1
—> Anti-PD1 mAb reactivates tumour-specific cytotoxic T cells in the tumour microenvironment
—> restimulates anti-tumour immunity

  1. Anti-CTLA4 mAb
    - ***Ipilimumab (fully human mAb against CTLA4 on cancer cells)

Specific SE:
- ***Immune-mediated adverse events: GI (GE), Hepatic, Skin, Endocrine, Neurologic, Lung (pneumonitis)

33
Q

Other targets for Immunotherapy

A

***Microsatellite instability (DNA mismatch repair (MMR))
—> useful target for Immune checkpoint inhibitors (Anti-PD1 therapy)

34
Q

Other approaches of Immunotherapy

A
  1. Vaccines
  2. Immunomodulatory agents
  3. Adoptive cell transfer (e.g. CAR-T cells)
  4. Therapeutic Ab
35
Q

***Chemotherapy vs Targeted therapy vs Immunotherapy

A

Targeted therapy / Chemotherapy:
- Prolong survival initially but ↓ effectiveness afterward (∵ gain of resistance by cancer cells)
—> Early control

Immunotherapy:
- Initially survival not improved but potential to achieve cure (∵ take time to act)
—> Late control

Combination:
- Enjoy all benefits

36
Q

Evolution of Systemic therapy

A

Target cancer cells (Chemotherapy)
—> Target specific targets on cancer cells (Targeted therapy e.g. HER2)
—> Target tumour / vascular microenvironment (Targeted therapy e.g. Anti-VEGF)
—> Target immune environment (Immunotherapy)

37
Q

Summary

A
  • Chemotherapy is still the major modality of treatment for most cancer types
  • Targeted therapy represents a major advance in systemic therapy but proper patient selection is the key
  • Immunotherapy opens a new chapter in cancer treatment and is becoming a standard of care
38
Q

***SE of Chemotherapy

A

Acute:
1. N+V
2. Diarrhoea
3. Mucositis
4. Immunosuppression
5. Malaise
6. Alopecia
7. Extravasation
8. Hypersensitivity

Chronic:
1. Neurotoxicity
2. Ototoxicity
3. Nephrotoxicity
4. HT
5. Chemo-induced haematological malignancies

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