Therapeutics 2 : synopsis 1. Basic principles of cancer chemotherapeutic agents 2. General introduction of cancer chemotherapeutic agents ( classification, basic moa , indications and common adrs ) 3. Chemo induced nausea and vomiting 4. Management of breast cancer and leukaemia
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I now have extensive material from the Lippincott Pharmacology textbook. Let me read the sections on specific drug classes (alkylating agents, topoisomerase inhibitors, hormonal agents, targeted therapy) and the breast cancer/leukemia management sections.
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I now have comprehensive data. Let me also quickly get the CINV classification (emetogenic risk) and leukemia management sections.
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Therapeutics 2 — Cancer Chemotherapy Synopsis
SECTION 1: Basic Principles of Cancer Chemotherapy
What is Cancer Chemotherapy?
Cancer chemotherapy aims to cause apoptosis or a lethal cytotoxic event in cancer cells to arrest tumor progression. Most agents target DNA or metabolic pathways essential to cell replication (e.g., purine/pyrimidine synthesis required for DNA/RNA synthesis).
Most traditional anticancer drugs do not discriminate between neoplastic and normal proliferating cells — hence the toxicity profile. — Lippincott Illustrated Reviews: Pharmacology
Goals of Treatment
| Goal | Description |
|---|---|
| Cure | Long-term, disease-free survival; requires eradication of every neoplastic cell |
| Control | Prevent cancer from enlarging/spreading; treat as chronic disease |
| Palliation | Relieve symptoms, improve quality of life in advanced/metastatic disease |
Goals are dynamic — they may shift from curative to palliative as disease progresses.
Types of Chemotherapy by Timing
| Type | Definition |
|---|---|
| Adjuvant | After surgery/radiation to eliminate micrometastases |
| Neoadjuvant | Before surgery to shrink the tumour |
| Maintenance | Low-dose after remission to prolong disease-free period |
| Palliative | To relieve symptoms when cure is not possible |
Cell Cycle and Drug Specificity
Cell Cycle–Specific (CCS) Drugs — only effective against actively dividing cells:
- Antimetabolites → S phase (DNA synthesis)
- Vinca alkaloids → M phase (mitosis)
- Taxanes → M phase
Cell Cycle–Non-Specific (CCNS) Drugs — effective against both dividing and resting cells:
- Alkylating agents
- Platinum compounds
- Anthracyclines
Nondividing cells (G₀ phase) usually survive the toxic effects of many chemotherapeutic agents, which explains tumour regrowth between cycles.
Combination Chemotherapy Principles
Combination chemotherapy is more effective than single-agent therapy. Rationale:
- Maximal cell killing within tolerated toxicity range
- Broader range of activity against heterogeneous tumour populations
- Prevents/delays the development of resistant cell lines
Agents are combined with:
- Different mechanisms of action
- Non-overlapping toxicities (to allow full dosing)
Example: R-CHOP (Rituximab + Cyclophosphamide + Hydroxydaunorubicin + Oncovin + Prednisone) — non-Hodgkin lymphoma
Drug Resistance
Primary resistance — tumour never responds (e.g., KRAS mutant tumours to upstream EGFR inhibitors)
Acquired resistance — loss of response after initial efficacy (e.g., ATP-binding site mutation preventing kinase inhibitor binding)
Multidrug resistance (MDR): Mediated by P-glycoprotein (encoded by amplified MDR1 gene) — an ATP-dependent efflux pump that expels drugs from the cell. Affects vinca alkaloids, anthracyclines, dactinomycin, taxanes (all structurally share hydrophobic aromatic ring + positive charge at neutral pH).
CNS sanctuary sites: some drugs cannot cross the blood-brain barrier; intrathecal administration or cranial irradiation may be required (e.g., meningeal leukaemia).
General Adverse Effects of Chemotherapy
Most anticancer agents have a narrow therapeutic index. Common toxicities reflect damage to rapidly dividing normal tissues:
| Tissue | Manifestation |
|---|---|
| Bone marrow | Myelosuppression → anaemia, neutropenia, thrombocytopenia |
| GI mucosa | Nausea, vomiting, diarrhoea, stomatitis, mucositis |
| Hair follicles | Alopecia |
| Gonads | Infertility, teratogenicity |
| Secondary malignancies | Treatment-induced AML (especially alkylating agents, topoisomerase inhibitors) |
Cytoprotectants:
- Leucovorin (folinic acid): rescues normal cells from methotrexate toxicity
- Mesna: binds toxic acrolein metabolite of cyclophosphamide/ifosfamide → prevents haemorrhagic cystitis
- G-CSF (filgrastim): stimulates neutrophil production → reduces risk of febrile neutropenia
SECTION 2: Classification of Chemotherapeutic Agents
Overview Diagram
CLASS 1: Antimetabolites
MOA: Structurally resemble normal purines/pyrimidines → inhibit their synthesis or compete in DNA/RNA synthesis → S-phase specific (CCS)
| Drug | Type | Key Indications | Notable ADRs |
|---|---|---|---|
| Methotrexate | Folate antagonist (inhibits DHFR) | ALL, osteosarcoma, breast cancer, RA, psoriasis | Myelosuppression, mucositis, nephrotoxicity (high dose), hepatotoxicity. Rescue with leucovorin |
| 5-Fluorouracil (5-FU) | Pyrimidine antagonist (inhibits thymidylate synthase) | Colorectal, breast, gastric cancer | Myelosuppression, diarrhoea, hand-foot syndrome |
| Capecitabine | Oral prodrug of 5-FU (activated in tumour by thymidine phosphorylase) | Metastatic breast cancer, colorectal cancer | Hand-foot syndrome (more than 5-FU), less myelosuppression |
| Cytarabine (Ara-C) | Pyrimidine antagonist (inhibits DNA polymerase) | AML, meningeal leukaemia (intrathecal) | Myelosuppression, cerebellar toxicity (high dose) |
| 6-Mercaptopurine (6-MP) | Purine antagonist | ALL | Myelosuppression, hepatotoxicity. Reduce dose 50–75% with allopurinol (XO inhibition) |
| Fludarabine | Purine analogue | CLL, low-grade lymphoma | Myelosuppression, severe immunosuppression |
| Pemetrexed | Multi-targeted antifolate | NSCLC, mesothelioma | Myelosuppression — supplement folate + B12 to reduce toxicity |
CLASS 2: Alkylating Agents
MOA: Form covalent crosslinks with DNA (primarily at N-7 of guanine) → strand breaks → cell death. CCNS (but more toxic to dividing cells).
| Drug | Key Indications | Notable ADRs |
|---|---|---|
| Cyclophosphamide | Breast cancer, NHL, CLL, SLE | Haemorrhagic cystitis (acrolein metabolite — prevent with mesna + hydration), myelosuppression, alopecia |
| Ifosfamide | Sarcomas, testicular cancer | Haemorrhagic cystitis, neurotoxicity, nephrotoxicity |
| Chlorambucil | CLL, lymphomas | Myelosuppression |
| Melphalan | Multiple myeloma, ovarian cancer | Myelosuppression |
| Busulfan | CML (conditioning for BMT) | Pulmonary fibrosis ("busulfan lung"), myelosuppression |
| Mechlorethamine | Cutaneous T-cell lymphoma (topical) | Vesicant |
| Cisplatin | Testicular, ovarian, lung, bladder cancers | Nephrotoxicity (hydrate aggressively), ototoxicity, peripheral neuropathy, severe N/V |
| Carboplatin | Similar to cisplatin | Myelosuppression (dose-limiting), less nephrotoxicity/neuropathy than cisplatin |
| Oxaliplatin | Colorectal cancer | Cold-induced peripheral neuropathy, hepatotoxicity |
| Dacarbazine | Melanoma, Hodgkin lymphoma | N/V, myelosuppression |
| Temozolomide | Glioblastoma, melanoma | Myelosuppression |
CLASS 3: Topoisomerase Inhibitors
MOA: Inhibit enzymes that relieve torsional strain during DNA replication
| Drug | Mechanism | Key Indications | Notable ADRs |
|---|---|---|---|
| Doxorubicin (Adriamycin) | Topo II inhibitor + intercalation | Breast cancer, sarcomas, lymphomas, leukaemia | Cardiotoxicity (dose-dependent, irreversible cardiomyopathy — cumulative dose limit 550 mg/m²), alopecia, myelosuppression. Vesicant |
| Daunorubicin | Topo II inhibitor | AML, ALL | Cardiotoxicity, myelosuppression |
| Epirubicin | Topo II inhibitor | Breast cancer | Less cardiotoxic than doxorubicin |
| Etoposide (VP-16) | Topo II inhibitor | Testicular, small-cell lung, lymphoma | Myelosuppression, secondary leukaemia |
| Irinotecan | Topo I inhibitor | Colorectal cancer | Severe diarrhoea (acute cholinergic + delayed), myelosuppression |
| Topotecan | Topo I inhibitor | Ovarian cancer, small-cell lung | Myelosuppression |
CLASS 4: Microtubule Inhibitors (Mitotic Inhibitors)
MOA: Disrupt microtubule dynamics → arrest cells in M phase (CCS)
Vinca Alkaloids (inhibit tubulin polymerisation)
| Drug | Key Indications | Notable ADRs |
|---|---|---|
| Vincristine | ALL, lymphomas, Wilms tumour | Neurotoxicity (peripheral neuropathy, autonomic neuropathy, constipation) — dose-limiting. NEVER give intrathecally (fatal) |
| Vinblastine | Hodgkin lymphoma, testicular cancer | Myelosuppression, neurotoxicity |
| Vinorelbine | Breast cancer, NSCLC | Granulocytopenia |
Taxanes (stabilise microtubules → prevent depolymerisation)
| Drug | Key Indications | Notable ADRs |
|---|---|---|
| Paclitaxel | Breast, ovarian, NSCLC | Neutropenia, peripheral neuropathy, alopecia, hypersensitivity reactions (premedicate with dexamethasone + diphenhydramine) |
| Docetaxel | Breast, prostate, NSCLC | Neutropenia, fluid retention, neuropathy, alopecia |
CLASS 5: Antibiotics (Antitumour)
| Drug | MOA | Key Indications | Notable ADRs |
|---|---|---|---|
| Bleomycin | DNA strand breaks (free radical generation) | Testicular cancer, Hodgkin lymphoma | Pulmonary fibrosis (dose-limiting), minimal myelosuppression, hypersensitivity |
| Dactinomycin | DNA intercalation + Topo II inhibition | Wilms tumour, Ewing sarcoma, rhabdomyosarcoma | Myelosuppression, GI toxicity, vesicant |
| Mitomycin C | Alkylation | Gastric, cervical cancers | Myelosuppression, haemolytic uraemic syndrome |
CLASS 6: Hormonal/Endocrine Agents
Selective Oestrogen Receptor Modulators (SERMs)
| Drug | MOA | Indications | ADRs |
|---|---|---|---|
| Tamoxifen | ER antagonist in breast, ER agonist in bone/endometrium | ER+ breast cancer (pre + postmenopausal) | Hot flashes, endometrial cancer risk, thromboembolism |
| Raloxifene | ER antagonist in breast/uterus, agonist in bone | Breast cancer risk reduction, osteoporosis | Hot flashes, thromboembolism (no endometrial cancer risk) |
Aromatase Inhibitors (AIs) — postmenopausal women
| Drug | Type | Indications | ADRs |
|---|---|---|---|
| Anastrozole, Letrozole | Non-steroidal (reversible) | First-line ER+ breast cancer (postmenopausal) | Hot flashes, osteoporosis, joint pain. No endometrial cancer risk |
| Exemestane | Steroidal (irreversible) | Breast cancer after tamoxifen failure | Hot flashes, fatigue, nausea |
Oestrogen Receptor Downregulator
- Fulvestrant: IM injection → ER downregulation. For hormone receptor-positive metastatic breast cancer. ADRs: hot flashes, injection site reactions, elevated LFTs.
GnRH Agonists (chemical castration)
- Leuprolide, Goserelin, Triptorelin: Desensitise GnRH receptor → ↓FSH/LH → ↓oestrogen/testosterone. Used in premenopausal breast cancer and prostate cancer.
- Important: Initial tumour flare in first weeks of therapy (receptor activation before desensitisation).
Androgen Receptor Antagonists
- Flutamide, Bicalutamide: Block androgen receptor → used in prostate cancer
CLASS 7: Targeted/Biological Agents
Monoclonal Antibodies
| Drug | Target | Indications | Notable ADRs |
|---|---|---|---|
| Trastuzumab (Herceptin) | HER2/ErbB2 | HER2+ breast cancer, gastric cancer | Cardiotoxicity (reversible), infusion reactions |
| Rituximab | CD20 | B-cell NHL, CLL | Infusion reactions, immunosuppression (PML risk) |
| Bevacizumab | VEGF | Colorectal, NSCLC, ovarian cancer | Hypertension, thrombosis, wound healing impairment, GI perforation |
| Cetuximab | EGFR | Colorectal, head & neck cancer | Acneiform rash (correlates with response), hypomagnesaemia |
Tyrosine Kinase Inhibitors (TKIs) — oral agents
| Drug | Target | Key Indications | Notes |
|---|---|---|---|
| Imatinib | BCR-ABL | CML (Philadelphia chromosome+), GIST | First TKI; monitor for cardiac failure |
| Dasatinib | BCR-ABL, SRC | CML (imatinib-resistant) | Avoid with PPIs |
| Erlotinib/Afatinib | EGFR | NSCLC (EGFR mutant) | Rash correlates with response; KRAS mutant = primary resistance |
| Lapatinib | EGFR/HER2 | HER2+ breast cancer | Severe hepatotoxicity, diarrhoea |
| Ibrutinib | BTK | CLL, mantle cell lymphoma | Monitor for cardiac failure; secondary malignancies |
| Idelalisib | PI3K | CLL, follicular lymphoma | Monitor for infections |
| Vemurafenib/Trametinib | BRAF/MEK | Melanoma (BRAF V600E mutant) | Monitor cardiac function |
| Ruxolitinib | JAK1/2 | Myelofibrosis, polycythaemia vera | Increased VTE risk |
| Midostaurin | FLT3 | AML with FLT3 mutation | Administer with antiemetics |
Immune Checkpoint Inhibitors
- Mechanism: Block PD-1/PD-L1 or CTLA-4 checkpoints → activate patient's own immune system to attack cancer cells
- Agents: Nivolumab/Pembrolizumab (anti-PD-1), Atezolizumab (anti-PD-L1), Ipilimumab (anti-CTLA-4)
- ADRs: Autoimmune toxicity (pneumonitis, colitis, hepatitis, endocrinopathies) — distinct from myelosuppression of traditional chemo
SECTION 3: Chemotherapy-Induced Nausea and Vomiting (CINV)
Classification of CINV
| Type | Timing | Mechanism |
|---|---|---|
| Acute | Within 24 h of chemo | 5-HT3 receptor activation (serotonin release from enterochromaffin cells) |
| Delayed | 24 h – 5 days post-chemo | Substance P/NK1 receptor activation |
| Anticipatory | Before next cycle | Conditioned reflex (psychological); triggered by sight/smell/anxiety |
| Refractory | Inadequately controlled despite prophylaxis | Requires additional agents |
Emetogenic Risk Classification
| Risk Level | Incidence of Vomiting | Examples |
|---|---|---|
| High (HEC) | >90% | Cisplatin, cyclophosphamide (>1.5g/m²), doxorubicin + cyclophosphamide combo, dacarbazine |
| Moderate (MEC) | 30–90% | Carboplatin, irinotecan, oxaliplatin, doxorubicin, epirubicin |
| Low | 10–30% | Docetaxel, paclitaxel, etoposide, fluorouracil, gemcitabine |
| Minimal | <10% | Bleomycin, vincristine, bevacizumab |
Antiemetic Agents for CINV
1. 5-HT₃ Receptor Antagonists ("Setrons")
- Agents: Ondansetron, Granisetron, Dolasetron, Palonosetron (2nd gen)
- MOA: Block serotonin at 5-HT₃ receptors in gut and CTZ
- Indications: Primary agents for acute CINV; palonosetron also effective for delayed CINV
- Doses (IV, 30 min before chemo): Ondansetron 8 mg; Granisetron 1 mg; Palonosetron 0.25 mg
- ADRs: Headache, dizziness, constipation; QT prolongation (esp. dolasetron — FDA warning); Serotonin syndrome risk with SSRIs/SNRIs
- Note: Palonosetron does NOT prolong QT
2. NK1 Receptor Antagonists
- Agents: Aprepitant (PO), Fosaprepitant (IV), Netupitant, Rolapitant
- MOA: Central blockade of substance P at NK1 receptors in area postrema
- Indications: Prevention of delayed CINV with highly emetogenic regimens; used in addition to (not instead of) 5-HT₃ antagonists
- Doses: Aprepitant 125 mg day 1, then 80 mg days 2 & 3; Fosaprepitant 150 mg IV single dose
- ADRs: Fatigue, neutropenia, abdominal pain, bradycardia, hypotension, insomnia
3. Corticosteroids
- Agent: Dexamethasone 8–20 mg IV/PO before chemo, then 8 mg/day for 2–4 days
- MOA: Unknown antiemetic mechanism; enhances efficacy of 5-HT₃ antagonists
- Role: Used for both acute and delayed CINV in moderate-to-high emetogenic regimens
4. Olanzapine (atypical antipsychotic)
- MOA: Blocks multiple neurotransmitter receptors (D1–4, 5-HT2, muscarinic, histamine)
- Role: Added to the three-drug cocktail for breakthrough/refractory CINV and highly emetogenic regimens; growing evidence as most effective single antiemetic agent
- Dose: 10 mg PO/IM
- ADRs: Sedation, metabolic effects (hyperglycaemia, weight gain)
5. Dopamine Receptor Antagonists
- Metoclopramide 10 mg IV/IM — dose-related extrapyramidal side effects (tardive dyskinesia)
- Prochlorperazine 5–10 mg IV/IM — extrapyramidal effects
6. Benzodiazepines
- Lorazepam 1–2 mg IV; Midazolam 1 mg IV
- Role: Anticipatory CINV, adjunct for refractory CINV; sedating
CINV Management Algorithm
Highly Emetogenic Chemo (HEC):
4-drug regimen: NK1 antagonist + 5-HT₃ antagonist (palonosetron preferred) + Dexamethasone + Olanzapine
Moderately Emetogenic Chemo (MEC):
3-drug regimen: 5-HT₃ antagonist + Dexamethasone ± NK1 antagonist
Low Emetogenic:
Dexamethasone alone (day of treatment)
Refractory/Breakthrough:
Add benzodiazepine, dopamine antagonist, or olanzapine
SECTION 4: Management of Breast Cancer and Leukaemia
BREAST CANCER MANAGEMENT
Key Biological Subtypes & Implications for Treatment
| Subtype | Receptor Status | Treatment Implication |
|---|---|---|
| Luminal A | ER+/PR+, HER2–, low Ki67 | Endocrine therapy ± chemo |
| Luminal B | ER+/PR+, HER2– or HER2+, high Ki67 | Endocrine + chemo ± trastuzumab |
| HER2-enriched | ER–/PR–, HER2+ | Anti-HER2 therapy + chemo |
| Triple Negative (TNBC) | ER–/PR–, HER2– | Chemotherapy (± immunotherapy) |
A. Hormone Receptor–Positive (ER+/PR+) Breast Cancer
Premenopausal women:
- Tamoxifen × 5–10 years (SERM; blocks ER in breast tissue)
-
- Ovarian suppression (GnRH agonists: leuprolide, goserelin) if high risk
- If switched to OFS + AI: consider exemestane or letrozole
Postmenopausal women:
- Aromatase inhibitors (AIs) are first-line: anastrozole or letrozole × 5 years
- Exemestane if AI failure
- Tamoxifen if AI not tolerated
- Fulvestrant (ER downregulator) — for HR+ metastatic disease
CDK4/6 Inhibitors (for HR+ HER2– advanced/metastatic):
- Palbociclib, Ribociclib, Abemaciclib — combined with letrozole or fulvestrant
- MOA: inhibit cyclin-dependent kinases 4 and 6 → G1 phase arrest
- ADRs: neutropenia, diarrhoea, fatigue
B. HER2-Positive Breast Cancer
Anti-HER2 targeted therapy:
- Trastuzumab (Herceptin): Monoclonal antibody against HER2; cornerstone of HER2+ BC treatment
- Pertuzumab: Binds different HER2 epitope; combined with trastuzumab + docetaxel (Pertuzumab + Trastuzumab + Docetaxel = Perjeta regimen)
- Lapatinib: Oral TKI (EGFR + HER2); used in CNS metastases (better CNS penetration)
- T-DM1 (Ado-trastuzumab emtansine): Antibody-drug conjugate; trastuzumab + cytotoxic emtansine; used in HER2+ after prior therapy
Chemotherapy backbone: Taxane-based (paclitaxel or docetaxel) combined with trastuzumab ± pertuzumab
ADR: Trastuzumab causes reversible cardiotoxicity — monitor LVEF. Avoid combining with anthracyclines (additive cardiotoxicity).
C. Triple-Negative Breast Cancer (TNBC)
No hormonal targets — chemotherapy is mainstay:
- Neoadjuvant: Anthracycline + taxane ± carboplatin (e.g., AC → Paclitaxel)
- Immunotherapy: Pembrolizumab (anti-PD-1) + chemotherapy for PD-L1+ advanced TNBC
- Olaparib/Talazoparib (PARP inhibitors): For BRCA1/2-mutated HER2– metastatic BC
- Capecitabine: Residual disease post-neoadjuvant
D. Common Breast Cancer Chemotherapy Regimens
| Regimen | Components | Use |
|---|---|---|
| AC | Doxorubicin + Cyclophosphamide | Adjuvant/neoadjuvant |
| TAC | Docetaxel + Doxorubicin + Cyclophosphamide | Adjuvant |
| TCH | Docetaxel + Carboplatin + Trastuzumab | HER2+ adjuvant |
| CMF | Cyclophosphamide + Methotrexate + 5-FU | Older regimen |
| Paclitaxel → AC | Sequential taxane then anthracycline | Neoadjuvant/adjuvant |
LEUKAEMIA MANAGEMENT
Overview of Leukaemia Types
| Type | Origin | Key Features |
|---|---|---|
| ALL | Lymphoid progenitor | Most common childhood cancer; Ph chromosome in ~25% adult ALL |
| AML | Myeloid progenitor | Most common acute leukaemia in adults |
| CLL | Mature B-lymphocytes | Most common adult leukaemia in Western countries; indolent |
| CML | Myeloid progenitor | Philadelphia chromosome (BCR-ABL) in >95% cases |
A. Acute Lymphoblastic Leukaemia (ALL)
Key drugs:
- Induction: Vincristine + Prednisone + Daunorubicin + L-Asparaginase (± cyclophosphamide)
- CNS prophylaxis: Intrathecal methotrexate (± cytarabine) or cranial irradiation (CNS sanctuary)
- Maintenance: Daily oral 6-MP + weekly methotrexate × 2–3 years
- Ph+ ALL (BCR-ABL+): Add imatinib or dasatinib (TKI) to chemo regimen
- Consolidation: High-dose cytarabine; allogeneic stem cell transplant (SCT) in high-risk/relapsed
Special drug — L-Asparaginase:
- MOA: Depletes asparagine (which leukaemia cells cannot synthesise) → protein synthesis arrest
- ADRs: Pancreatitis, coagulopathy (↓clotting factors), hypersensitivity, hepatotoxicity
B. Acute Myeloid Leukaemia (AML)
Standard induction ("7+3" regimen):
- Cytarabine × 7 days (continuous infusion) + Daunorubicin × 3 days (or idarubicin)
- Goal: achieve complete remission (CR)
Consolidation: High-dose cytarabine (HiDAC) × 3–4 cycles, or allogeneic SCT
Targeted therapy based on mutations:
- FLT3 mutant AML: Add Midostaurin (FLT3 inhibitor) to induction/consolidation
- IDH1/IDH2 mutant: Enasidenib (IDH2), Ivosidenib (IDH1)
- APL (Acute Promyelocytic Leukaemia — AML-M3, t(15;17)):
- All-Trans Retinoic Acid (ATRA) + Arsenic Trioxide (ATO) — causes differentiation of leukaemic promyelocytes
- Highly effective, potentially curative even without traditional chemo
- Risk of differentiation syndrome (fever, respiratory distress, pulmonary infiltrates — treat with dexamethasone)
C. Chronic Lymphocytic Leukaemia (CLL)
Indications for treatment: Symptomatic disease, cytopaenias, bulky lymphadenopathy, rapid lymphocyte doubling time
Targeted oral agents (now preferred over chemo):
- Ibrutinib (BTK inhibitor): First-line; especially for 17p deletion
- Venetoclax (BCL-2 inhibitor): + Obinutuzumab (anti-CD20); effective in relapsed/refractory CLL
- Idelalisib (PI3K inhibitor): Monitor for infections; pneumonitis
Chemoimmunotherapy (older standard):
- FCR: Fludarabine + Cyclophosphamide + Rituximab (anti-CD20) — for fit patients with mutated IGHV
Special consideration: Chlorambucil + anti-CD20 (obinutuzumab or rituximab) for elderly/unfit patients
D. Chronic Myeloid Leukaemia (CML)
Hallmark: Philadelphia chromosome — t(9;22) → BCR-ABL fusion oncogene (constitutively active tyrosine kinase)
Treatment — TKI therapy (oral):
| Drug | Generation | Notes |
|---|---|---|
| Imatinib | 1st | First TKI; monitor for cardiac failure, oedema, GI symptoms |
| Dasatinib | 2nd | Also inhibits SRC; avoid PPIs (pH-dependent absorption) |
| Nilotinib | 2nd | Avoid food (reduces absorption); QT prolongation |
| Ponatinib | 3rd | For T315I "gatekeeper" mutation (resistant to all others) |
- Response monitoring: PCR for BCR-ABL transcript levels (molecular response)
- Allogeneic SCT: Reserved for blast crisis or TKI-resistant/intolerant disease
- Busulfan: Historically used (now replaced by TKIs); still used in conditioning for SCT
Summary Table: Drug–Toxicity Pairs to Remember
| Drug | Unique/Memorable Toxicity |
|---|---|
| Cisplatin | Nephrotoxicity, ototoxicity, severe N/V |
| Oxaliplatin | Cold-induced peripheral neuropathy |
| Cyclophosphamide | Haemorrhagic cystitis (prevent: mesna + hydration) |
| Busulfan | Pulmonary fibrosis |
| Bleomycin | Pulmonary fibrosis |
| Doxorubicin | Irreversible dose-dependent cardiomyopathy |
| Vincristine | Peripheral neuropathy, NEVER intrathecal |
| Methotrexate | Mucositis, nephrotoxicity → rescue with leucovorin |
| Tamoxifen | Endometrial cancer, thromboembolism |
| Imatinib | Cardiac oedema/failure (monitor LVEF) |
| ATRA (APL) | Differentiation syndrome |
| L-Asparaginase | Pancreatitis, coagulopathy |
Sources: Lippincott Illustrated Reviews: Pharmacology; Katzung's Basic and Clinical Pharmacology 16e; Harrison's Principles of Internal Medicine 22e; Tintinalli's Emergency Medicine; Goldman-Cecil MedicineHere's your complete Therapeutics 2 Synopsis covering all four requested topics. Here's a quick orientation guide:
What's Covered
Section 1 — Basic Principles
- Goals of treatment (cure → control → palliation)
- Types of chemo by timing (adjuvant, neoadjuvant, maintenance, palliative)
- Cell cycle specificity (CCS vs CCNS) with diagram
- Combination chemotherapy rationale
- Drug resistance mechanisms (P-glycoprotein, MDR)
- General ADRs and cytoprotectants (leucovorin, mesna, G-CSF)
Section 2 — Drug Classification (7 Classes)
Each class includes: MOA, key drugs, indications, and notable ADRs
- Antimetabolites (methotrexate, 5-FU, cytarabine, 6-MP…) — S-phase specific
- Alkylating agents (cyclophosphamide, cisplatin, busulfan…) — CCNS
- Topoisomerase inhibitors (doxorubicin, etoposide, irinotecan…)
- Microtubule inhibitors — vincas (vincristine) + taxanes (paclitaxel)
- Antitumour antibiotics (bleomycin, dactinomycin)
- Hormonal agents (tamoxifen, AIs, GnRH agonists, fulvestrant)
- Targeted/biological (TKIs, monoclonal antibodies, checkpoint inhibitors)
Section 3 — CINV
- 4 types (acute, delayed, anticipatory, refractory)
- Emetogenic risk levels with drug examples
- 6 antiemetic drug classes with doses, MOA, ADRs
- Management algorithm for HEC, MEC, and refractory CINV
Section 4 — Breast Cancer & Leukaemia
- Breast cancer by subtype: ER+, HER2+, TNBC — with specific regimens
- ALL: Induction (VPDL), CNS prophylaxis, maintenance, Ph+ considerations
- AML: 7+3 regimen, FLT3/IDH targeted therapy, APL (ATRA + ATO)
- CLL: Ibrutinib, venetoclax, FCR
- CML: TKI generations (imatinib → ponatinib), BCR-ABL monitoring
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