Clinical Oncology SC016: Advances In Systemic Therapy In Oncology Flashcards
Treatment classification
- Curative vs Palliative
- Neoadjuvant (before surgery) vs Adjuvant (after surgery / definitive treatment)
***Classification of Chemotherapy
- 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
- 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
- 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
- Others
- L-asparaginase
- Hydroxyurea
Cell cycle
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
***Phase specificity of Chemotherapy
- 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 - 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 - Cell cycle-non-specific agents
Cell cycle phase-specific agents
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
Cell cycle phase-non-specific agents
- Alkylating agents (crosslink guanine base in DNA)
- Procarbazine - Nitrosoureas
- Antitumour antibiotics (induce DNA lesions, inhibit topoisomerase, among other effects) (except Bleomycin: G2 phase specific)
- Platinums
- Steroid hormones
G0 + All other phases:
- Nitrogen mustard
Alkylating agents
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
- Oxazaphosphorines
- ***cyclophosphamides
- ifosfamides - Nitrosourea
- carmustine (BCNU)
- lomustine (CCNU) - Alkyl sulfonates
- busulfan - Aziridines and Epoxides
- thiotepa
- ***mitomycin C - Hydrazine + Triazine derivatives
- procarbazine
- darcabazine (DTIC)
- ***temozolomide
***Group toxicity of Alkylating agents
- ***Haematological
- kill WBC, platelet
- dose-limiting (∵ have to wait for cell count to recover) + can be delayed - ***GI (∵ rapidly dividing —> sensitive to chemotherapy)
- N+V
- mucositis
- diarrhoea - ***Pulmonary
- interstitial pneumonitis + fibrosis - ***Alopecia
- only apply to lipophilic metabolite (∵ go into SC fat) - Gonadal
- infertility - ***Carcinogenesis
- secondary leukaemia - ***Teratogenicity
Platinum compounds
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)
Anti-metabolites
- Folate analogues
- Methotrexate
- Raltitrexate
- ***Pemetrexate (lung cancer) - Pyrimidine analogues
- Fluoropyrimidines
—> **5-FU (IV form) / **Capecitabine (Oral form)
- Cytidine analogues
—> Ara-C (Cytarabine) (haematological malignancy)
—> ***Gemcitabine (solid tumour) - Purine analogues (haematological malignancy)
- Thiopurine
—> Azathioprine, ***6-MP
—> 6-TG
- Cladribine, Fludarabine
Cytotoxicity of Anti-metabolites
- Cell cycle phase-specific
- Toxicity on proliferating cells
- **BM suppression
- **GI mucosa
- ***Hand-foot syndrome (aka palmar-plantar erythrodysesthesia) (Capecitabine) (rash, swelling, desquamation of skin) - Do NOT interact directly with DNA
- ***NO long term carcinogenesis - Schedule-dependent administration (∵ cycle-specific)
- Bolus vs Continuous infusion
Natural products
- Mitotic inhibitors (Antimicrotubule agents) (solid tumour)
- Vinca alkaloids (e.g. **Vincristine, Vinorelbine, Vinblastine)
- Taxanes (e.g. **Paclitaxel, ***Docetaxel) - Topoisomerase 1 inhibitors
- ***Irinotecan
- Topotecan - Toposiomerase 2 inhibitors
- Anthracyclines (e.g. **Doxorubicin, **Epirubicin, Daunorubicin) (breast cancer)
- Epipodophyllotoxins: Etoposide - Antitumour antibiotics
- Anthracyclines (e.g. **Doxorubicin, **Epirubicin, Daunorubicin) (breast cancer)
- Bleomycin, Dactinomycin
Mitotic inhibitors (Antimicrotubule agents)
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)
Topoisomerase inhibitor
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)
Anthracycline
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
“New” Chemotherapy
- Eribulin
- microtubule dynamic inhibitor (comparable efficacy to taxane)
- ***less neurotoxicity - Pegylated liposomal Doxorubicin
- encapsulated in liposome
- ***less cardiotoxicity (∵ enhanced delivery to tumour cells) - 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
Hormonal therapy
Can be considered as Targeted therapy
Indications:
1. Hormone-sensitive cancers
- Breast cancer
- Prostate cancer
- Endometrial cancer
- Also used in palliation e.g. Megace (Progesterone) for improving anorexia
SE:
- **Fluid retention
- **Thromboembolism (∵ ↓ IV volume —> platelets closer together)
Hormonal therapy in Breast cancer
- SERM (Selective estrogen receptor modulator) (e.g. Tamoxifen)
- Aromatase inhibitor (e.g. Letrozole)
- Estrogen receptor antagonist (e.g. Fulvestrant)
SERM (Selective estrogen receptor modulator)
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
Aromatase inhibitors
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
Estrogen receptor antagonist
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
Hormonal therapy in Prostate cancer
***Androgen-deprivation therapy
1. Flutamide / Bicalutamide
- non-steroidal anti-androgen + competitive inhibit binding of androgen to androgen receptor
- 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
- 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) - 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
Targeted therapy
2 main classes:
1. Monoclonal Ab (mAb)
- act extracellularly
- target is extracellular / circulating
- Small molecule tyrosine kinase inhibitor (TKI)
- act intracellularly
- blocks downstream signaling of cell surface receptor
Lung cancer and EGFR
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
EGFR Tyrosine kinase inhibitor (EGFR TKI)
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
Breast cancer and HER2
- 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
Anti-HER2 therapy
Anti-HER2 therapy
- used to treat HER2 overexpressed **Breast cancer (~20% of patients)
- other cancers: **Gastric cancer (10-15% of patients)
-
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
- Lapatinib
- an oral small molecule (TKI) dual inhibitor of EGFR and HER2
- useful in neoadjuvant and palliative setting - 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) - TDM-1
- Ab-drug conjugate
—> deliver drug to cancer cells locally
—> maximise cancer cell kill, minimise systemic toxicity
Colorectal cancer and VEGF
- 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
Anti-VEGF
- Bevacizumab
- recombinant humanised mAb that selectively binds to + neutralise biologic activity of human VEGF - 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) - 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
Colorectal cancer and EGFR
~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
GIST and Imatinib
- > 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)
Immunotherapy
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
- 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)
Other targets for Immunotherapy
***Microsatellite instability (DNA mismatch repair (MMR))
—> useful target for Immune checkpoint inhibitors (Anti-PD1 therapy)
Other approaches of Immunotherapy
- Vaccines
- Immunomodulatory agents
- Adoptive cell transfer (e.g. CAR-T cells)
- Therapeutic Ab
***Chemotherapy vs Targeted therapy vs Immunotherapy
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
Evolution of Systemic therapy
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)
Summary
- 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
***SE of Chemotherapy
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
