Medical Oncology Flashcards
4 Main Histological Subtypes of Epithelial Ovarian Cancer
- Mucinous invasive.
- Endometroid.
- Clear cell.
- High-grade serous (most common).
FLUROPYRIMIDINES: 5FU + Capecitabine SEs
Diarrhoea.
Hand-foot syndrome.
Mucositis.
Coronary vasospasm/MI - rare, but described.
DPD deficiency (polymorphism) -> leads to toxicity.
Aberrations in gene observed in ccRCC
Aberrations in the von-Hippel Lindau (VHL) gene are observed in 50-90% of ccRCC.
Actionable Mutations in NSCLC and Treatment Options
- ALK
- Crizotinib.
- Ceritinib.
- Alectanib. - EGFR
- EGFR TKIs: Erlotinib, Gefitinib.
- EGFR T790M TKIs: Osimertinib. - ROS-1
- Crizotinib.
Alkylating Agents - MOA + Examples + AEs
MOA - Attach akyl groups to DNA, allow cross-linking of base pairs, damaging DNA. Atypical agents c
Typical - Cyclophosphamide.
Atypical - Platinum compounds (Cisplatin, Carboplatin, Oxaliplatin).
AEs - all can cause peripheral neuropathy and paraesthesias.
Anthracyclines - MOA + Examples + Adverse Effects
MOA: various, intercalate DNA, inhibits topoisomerase II, generate ROS.
Examples: Doxorubicin
Adverse Effects: heavy cytopenias, nausea +, Irreversible heart failure (predictable cumulative side effect for any person given high enough lifetime dose. Total cumulative dose is capped)
Anthracyclines SEs
Irreversible heart failure.
Dose capped per lifetime.
Alopecia.
Anti-CTLA-4 Examples and Mechanism
Examples: Ipilimumab.
Mechanism: CTLA-4 binding CD80 would usually attenuate/terminate T-cell proliferation. CTLA-4 inhibition thereby leads to unrestrained T-cell proliferation.
Anti-HER2 Example + Adverse Effects
Example: Trastuzumab.
Adverse Effects: idiosyncratic cardiotoxicity/heart failure.
Anti-PD-1 Examples + Mechanism of Action
Examples: Nivolumab, Pembrolizumab.
MOA: Binding of PD-1 to PD-L1 inhibits T-cell proliferation and effector functions, leading to immune evasion.
Anti-PD-L1 Examples + Mechanism of Action
Examples: Atezolizumab, Durvalumab, Avelumab.
MOA: Binding of PD-1 to PD-L1 inhibits T-cell proliferation and effector functions, leading to immune evasion.
Anti-VEGF Example + Adverse Effects
Example: Bevacizumab.
Adverse Effects: hypertension, proteinuria, impaired wound healing, GI perforation, arterial thrombosis.
Antimetabolites - MOA + Examples + Adverse Effects
Mechanism - inhibit DNA replication or repair by mimicking normal compounds; S-phase specific.
Pemetrexed - a novel multitargeted antifolate that inhibits > or = 3 enzymes involved in folate metabolism and purine and pyrimidine synthesis.
Gemcitabine - Gemcitabine is a deoxycytidine analogue that is cell phase specific, primarily killing cells undergoing DNA synthesis (S-phase) and also blocking the progression of cells through the G1/S-phase boundary.
Fluoropyrimidines (specific type of antimetabolite)
5-FU + Capecitabine (oral prodrug of 5FU).
- Inhibit pyrimidine synthesis (target thymidylate synthase).
- 5FU: diarrhoea, hand-foot syndrome, rash on sun-damaged areas, mucositis, coronary vasospasm
- Capecitabine: Diarrhoea (generally more than 5FU), hand-foot syndrome, rash on sun-damaged areas, mucositis, coronary vasospasm
BRCA and Hereditary Breast Cancer
BRCA1 and BRCA2 - DNA repair genes (tumour suppressor genes).
Risk Reducing Strategies
Bilateral prophylactic mastectomy.
Bilateral salpingo-oophorectomy at ~40 or on completion of child-bearing.
Improves survival.
NEW Therapeutic Implications
BRCA tumours are sensitive to PARP inhibitors (e.g. Olaparib).
BRCA Screening Recommendation Ovarian Cancer
All women diagnosed at = 70 yrs with high-grade non-mucinous epithelial ovarian, fallopian tube or primary peritoneal cancer should be referred for BRCA1/2 testing.
Clinical Factors Associated With Germline BRCA1/BRCA2 Mutations
- Invasive breast cancer <30 yrs.
- Triple-negative breast cancer <60 yrs.
- Male invasive breast cancer of any age.
- Ovarian or primary peritoneal cancer.
- Ashkenazi Jewish heritage.
Colorectal Carcinoma Genetic Syndromes
Polyposis Syndromes (<1% of CRC)
1. Familial adenomatous polyposis (FAP)
Characterised by >100 polyps with 90%+ risk of developing CRC by age 45 (in FAP).
Due to loss of adenomatous polyposis coli (APC) gene on chromosome 5.
2. MUTYH-associated polyposis (MAP)
Due to loss of MUTYH-gene, leading to failure of base excision pathway.
Lynch Syndrome (Hereditary non-polyposis coli - HNPCC)
Approximately 3% of CRC.
Due to loss of MLH1 (can be sporadic or due to promotor methylation (more common)); MSH2, PMS2 or MSH6. Loss of these leads to presence of large repeat sequences of DNA; referred to as microsatellite instability.
Lifetime risk if 50% in MLH1 deficient (highest).
Early Stage Breast Cancer Management Approach
Surgery
Breast conservation surgery preferred in most - WLE + Sentinel node biopsy.
If sentinel node biopsy +ve or if the nodes are clinically involved at diagnosis -> axillary clearance.
Mastectomy +/- reconstruction for >4cm, multifocal disease, previous chest RT, central tumour.
Radiation Therapy
ALL breast conserving surgery requires post-op radiation therapy (decreased local recurrence).
Post-mastectomy - larger tumour >5cm, nodes +ve.
Chemotherapy
Indications: node +ve cancer, node-negative with high-risk features (grade 3, extensive LVI, size >4cm, weak ER/PR expression).
Agents: Anthracyclines (Doxorubicin, Epirubicin) and/or Taxanes (Paclitaxel, Docetaxel).
Endocrine Therapy
Pre-menopausal - Tamoxifen.
Post-menopausal - Aromatase inhibitors (Anastrozole, Letrozole).
Treatment for 5-10 years (emerging data 10 years).
Consider HER2 targeted therapy based on expression profile.
Endometrial Cancer Risk Factors
- Unopposed oestrogen
a. Nulliparity, early menarche, late menopause.
b. Obesity.
c. Chronic anovulation state e.g. PCOS.
d. Tamoxifen use. - Age.
- Lynch syndrome and other familial cancer syndromes.
- Protective factors - OCP.
Factors Guiding Response (Predictors) in Metastatic Colorectal Cancer
Side
R vs. L
R-side poor prognosis/more aggressive disease.
Molecular KRAS/NRASm - resistance to anti-EGFR Tx. BRAFm - more aggressive disease. HER2m - response to anti-HER2. MMR-d/MSI-h - response to immune checkpoint inhibitors..
HER2 Positive Disease Treatment
Agent: Trastuzumab (Herceptin) (monoclonal antibody against HER2).
Adjuvant Treatment
Given with chemotherapy for a total of 12 months.
Note: No CSF penetration so CSF mets are frequently sanctuary sites on recurrence.
Metastatic Treatment
1st line: Given with chemotherapy + Pertuzumab + Trastuzumab (Dual HER2 action).
2nd line: Kadcyla (Trastuzumab emtansine) - antibody:drug conjugate.
Irinotecan SEs
Diarrhoea (cholinergic-mediated).
Why protocols include Atropine.
Lung Cancer Subtypes
15% Small-cell lung cancer. 85% Non-small-cell lung cancer. - 30% squamous cell lung cancer. - 70% non-squamous cell lung cancer. -- 10% large-cell carcinoma (large cell neuroendocrine carcinoma). -- 90% adenocarcinoma.
Malignant Hypercalcaemia - determining the mechanism
- Once hypercalcaemia is confirmed, measure serum PTH.
- In the presence of low-normal or low serum PTH concentrations, PTH-related protein (PTHrP) and vitamin D should be measured to assess for hypercalcaemia of malignancy and vitamin D intoxication.
- If not elevated, serum and urine EPP, serum FLC, TSH and vitamin A.
Management of Stage I to III Colorectal Cancer
Stage I
Surgical resection
Stage II (lower risk) Surgical resection
Stage IIc (higher risk) - defined as T4 disease (extending into peritoneum), obstruction/perforation, inadequate node sampling, lymphovascular or perineural invasion. Surgery Adjuvant chemotherapy (usually single agent 5FU or Capecitabine).
Stage III
Surgery with adjuvant chemotherapy (Fluoropyrimidine + Oxaliplatin).
T1-3 N1 - 3 months.
T4 and/or N2 - 6 months.
Management Stage III/IV Ovarian Cancer
- Optimally debulked (no macroscopic residual disease).
a. If suitable, consider intraperitoneal chemotherapy.
b. If not, IV Carboplatin/Taxol q3w. - Suboptimally debulked/Stage IV.
a. Carboplatin/Taxol q3w + Bevacizumab (total 18 doses).
b. If Bevacizumab contraindicated, consider Carboplatin q3w + weekly Taxol. - Stage III/IV Germline or Somatic BRCA1/2 Mutant.
a. Carboplatin/Taxol q3w -> maintenance Olaparib (maximal duration of treatment 2 years).
Metabolic Manifestations of Tumour Lysis Syndrome
Hyperkalaemia. Hyperphosphataemia. Hypocalcaemia. AKI. Elevated uric acid.
Metastatic Colorectal Cancer - Oligometastatic, resectable
Neoadjuvant chemotherapy (usually 3 months) prior to surgical resection.
Metastatic Hormone Receptor-Positive, HER2 Negative Disease
Tend to be elderly women with bone-only metastatic disease.
Respond well to endocrine therapy (Anastrozole; Letrozole; Tamoxifen; Exemestane + Everolimus).
NEW Data
1st line: CDK4/6 Inhibitor (Ademaciclib, Palbociclib, Ribociclib) + Aromatase Inhibitor.
SEs: QT prolongation, hepatotoxicity, diarrhoea, neutropenia.
Metastatic Melanoma Systemic Therapies
Known BRAF mutation:
a. Combined BRAF + MEK Inhibition
- Vemurafenib + Cobimetinib.
- Dabrafenib + Trametinib.
- Encorafenib + Binimetinib.
No known BRAF mutation:
a. Dual blockage of CTLA-4 and PD-1 for 3 months, followed by up to 2 years of anti-PD-1 maintenance therapy.
- Ipilimumab + Nivolumab.
- Then Nivolumab or Pembrolizumab maintenance.
Metastatic Prostate Cancer Treatments
- Metastatic castration-sensitive disease.
a) Androgen deprivation therapy (ADT) is mainstay.
- GnRH agonists: Goserelin, Leuprolide.
- GnRH antagonists: egarelix.
MAJOR change in last 5 years is improved overall survival by addition of 1 of following to ADT: - Docetaxel chemotherapy (6 cycles).
- Abiraterone acetate.
- Enzalutamide.
- Apalutamide.
- Local radiation to prostate.
- Metastatic castration-resistant disease.
a) Chemotherapy - Docetaxel, Cabazitaxel.
b) Novel androgen receptor targeted therapies: Abiraterone, Enzalutamide.
c) Lutetium PSMA.
