Systemic Therapy Flashcards
√What are 6 beneficial mechanisms of chemoradiotherapy?
- Increase bioavailable dose of radiotherapy by ~10Gy
- Can act on different subsets of tumor cells
- Recruit cells from G0 into radiation sensitive phases (M phase), and synchronizes them into the same phase
- Chemotherapy inhibits repair of sublethal radiation injury (Decreases repopulation)
- Tumor shrinkage decreases interstitial pressure, therefore increases drug and O2 delivery
- Prevents radiation resistance
- Cell-cycle Synchronization increases the effectiveness of both therapies
√What are the benefits of combined chemotherapy in general? What are the disadvantages? What is the gold standard?
- Higher response rates/local control with some combinations
- Overall suvival not improved
- Toxicity is more severe, decreased repair, improved blood supply to tumor
- Cisplatin & 5-Fu are gold standard, act synergistically: Carbo-taxol also used recently
√What are 6 main roles for chemotherapy in head and neck oncology?
- Post-operative adjuvant therapy (e.g. + margins, + ECS)
- Recurrent or metastatic disease
- Unresectable disease, non-surgical or palliative
- Primary treatment of NPC
- Organ preservation in advanced laryngeal cancer (T3-4)
- Investigative therapy
- Neoadjuvant chemotherapy
√What is the only subsite that should be treated with chemoradiotherapy as the primary modality?
Nasopharynx
√What are three tumor factors affecting chemotherapy success?
(Not curative alone, act as radiosensitizers)
- Tumor burden (number of tumor cells)
- Number of cells with inherent or acquired resistance to chemotherapeutic agents
- Percentage of cells in a chemo-responsive phase of cell cycle (M-phase)
- Cycle dependent drugs = schedule specific
- Non-specific = dose dependent
√What are the general indications for chemotherapy in head and neck cancer? 6
PRIMARY INDICATIONS:
1. Combination with radiation therapy for certain malignancies (nasopharyngeal, oropharyngeal, hypopharyngeal, laryngeal)
2. Lymphoma
3. Not surgical candidate
ADJUVANT INDICATIONS:
1. Positive margins
2. Extracapsular extension
3. Trial drug
√What is the maximum age for consideration of chemotherapy?
70 years old (see MACH trial later for explanation)
√Name 5 general chemotherapy emergencies
- Febrile neutropenia
- Thrombocytopenia
- Allergy
- Overdose
- Tumor lysis syndrome (AKI)
FATTO
√What is the general overall mechanism of action of most chemotherapy drugs?
What are the overall side effects of most chemotherapy drugs?
- Chemotherapy drugs interfere with DNA specifically, or Microtubules specifically, to cause their mechanism of action.
- Interfering with DNA causes myelosuppression/mucositis/dermatitis
- Interfering with icrotubules cause neuropathies, alopecia
√What are the different classes of chemotherapy agents? 9
- Akylating agents (e.g. Platinums - Cisplatin, Carboplatin)
- Anthracyclines (Topoisomerase inhibitors) - Adriamycin (Doxorubicin) (II)
- Antimetabolites (e.g. Methotrexate, 5-FU)
- Vinca Alkaloids (e.g. Vincristine, Vinblastine)
- Taxanes (e.g. Paclitaxel, Docitaxel)
- Antibiotic derivatives (e.g. Bleomycin, Mitomycin, Hydroxydaunomycin)
- Topoisomerases (e.g. Etoposide, Topotecan)
- Targeted Biologics (e.g. “Mabs” - Cetuximab, Ipilumamb)
- Non-specific Biologics (e.g. “Nibs” - Gefitinib, Sunitinib)
√Regarding Akylating agents, discuss:
1. What is the mechanism of action?
2. What are common examples?
3. What are common side effects?
MOA: Cross link DNA, interfere with DNA replication (S phase)
Examples: Cyclophophamide, Chlorambucil, Nitrogen mustard, Dacarbazine
Other types (Platinums):
1. Cisplatin (most effective single-agent chemotherapy)
2. Carboplatin (less oto/neuro/nephro toxic effects, but ++ myelosuppression)
SIDE EFFECTS:
1. Ototoxicity, Neurotoxicity, Nephrotoxicity (Cisplatin more common)
2. Myelosuppression (Carboplatin more common)
3. Mucositis
4. Dermatitis
√What is the mechanism of action and examples of DNA binding chemotherapeutic agents?
MOA: Covalent DNA intercalators - interfere with normal DNA function and alter replication
Platinum containing compounds (-platins)
EXAMPLES:
Platinums:
- Cisplatin - binds to the N7 reactive center on purine residues and as such can cause deoxyribonucleic acid (DNA) damage in cancer cells
- Carboplatin - undergoes activation inside cells and forms reactive platinum complexes that cause the intra- and inter-strand cross-linkage of DNA molecules within the cell.
Antibiotic derivaties:
- Bleomycin (induces DNA strand breaks in G2 phase)
- Mitomycin (inhibits fibroblasts - decreases scar formation; and cross links DNA
√What are 7 side effects of cisplatin? What are relative contraindications of Cisplatin?
- Myelosuppression
- Nephrotoxicity
- Ototoxicity (dose limiting, affects high frequencies, cumulative toxicity)
- Peripheral neurotoxicity
- Nausea
- Electrolyte disturbances
- Anorexia
Contraindication: Renal Failure
√How does the side effect profile of carboplatin compare to cisplatin?
- Less ototoxicity, neurotoxicity, and nephrotoxicity
- Myelosuppression is the main side effect
√What is the standard concurrent chemo-RT regimen for Cisplatin in H&N?
Standard high dose = 100mg/m^2 on days 1, 22, 43 of radiation (for primary CRT, q3wk x3)
- Only for patients with high performance status, < 70 years old, and minimal comorbidities
Alternatively: Weekly dose 40mg/m^2 every 1 week
- Better tolerated by low performance status and patients with comorbidities, but compromised survival overall
———
Adjuvant - ENE+ or margin+
Usually uses the alternate regimen x6 weeks
√Discuss the findings of MAC-NC meta-analysis (2009)
- Compared 93 randomized trials for chemo in H/M cancer (Cetuximab not included)
- Found a 6.5% improvement in 5-year survival for concurrent chemo-RT
- Cisplatin was the best, but low benefit with advanced age (age > 70)
- Reason that chemo is rarely offered to age > 70
√Regarding antibiotic derivatives, discuss:
1. MOA?
2. Side effects? 2
3. Examples? 3
MOA: Interferes with DNA synthesis and replication
SIDE EFFECTS:
1. Pulmonary fibrosis
2. Myelosuppression
EXAMPLES:
1. Bleomycin
2. Mitomycin
3. Hydroxydaunomycin
√What is the mechanism of action and examples of antimetabolite chemotherapeutic agents? What are the common side effects?
MOA:
- Actively interferes with cellular metabolism, act in S-phase
- Methotrexate - interferes with folate metabolism, inhibits dihydrofolate reductase enzyme, interrupts DNA synthesis in S phase
- 5-FluoroUracil - S phase, Defective Uracil Analogue is used –> either incorporated into DNA and halts replication, or inhibits Thymidilate Synthase and blocks synthesis of the pyrimidine thymidine (nucleoside required for DNA replication)
- Hydroxyurea, Gemcitabine - incorporates into DNA, blocking replication
- Interferon A/B/G1 - antiviral effect
SIDE EFFECTS:
1. Mucositis
2. Dermatitis
3. Myelosuppression
√What are the side effects of methotrexate? (6)
What can be used to reduce the side effects?
What is the response rate of methotrexate as a single agent?
- Myelosuppression
- Mucositis
- Dermatitis
- N/V/D
- Hepatic fibrosis
- Interstitial pneumonitis
Leucovorin (Folinic acid - folic acid derivative) can be used as a rescue treatment (because MTX is a folate inhibitor) – can also help 5-FU bind better to thymidilate synthase
30% partial response rate as a single agent
√What are the side effects of 5-FU? What is the % partial response 5
- Myelosuppression
- Mucositis
- Dermatitis
- Diarrhea
- Cardiotoxicity
13% single agent partial response
√Regarding vinca alkaloid chemotherapeutic agents, dicuss:
1. What is the mechanism of action?
2. What are common examples?
3. What are the common side effects?
MOA:
- Interfere with mitotic spindle formation (microtubule disruptors) - M phase
Examples:
- Vincristine
- Vinblastine
- Vinorelbine
SIDE EFFECTS:
1. Peripheral neuropathy
2. Alopecia
√What chemotherapy agent can cause vocal fold palsy in children?
Vincristine
√Mechanism of action and examples of taxane chemotherapeutic agents?
MOA:
- Stabilize tubulin polymers & prevent progression of mitosis/cell division, cause cell cycle arrest in G2 (microtubule stabilizers)
- Opposite effect of vinka alkaloids
Examples:
1. Paclitaxel
2. Docitaxel
√What are the side effects of taxanes? 4
What is the % single agent partial response rate?
- Neuropathy
- Muscular pain
- Alopecia
- Allergic reactions
30-40% single agent partial response rate
√What is the mechanism of action and examples of topoisomerase inhibitor chemotherapeutic agents? What are the common side effects?
MOA:
- Prevent unwinding of DNA for replication by inhibiting topoisomerases I or II
Examples:
1. Inhibits I: Irinotecan, Topotecan
2. Inhibits II: Etoposide, Doxorubicin
SIDE EFFECTS:
1. Mucositis
2. Dermatitis
√Regarding targeted biologics, what are their MOA and 2 side effects?
Targeted Biologics:
- “Mabs”
- Cetuximab, Ipilimumab
MOA: Monoclonal antibodies against EGFR (epidermal growth factor receptor)
SIDE EFFECTS:
1. Cardiotoxicity
2. Dermatitis
√What is the Mechanism of action of Cetuximab?
What is the common dosage?
What are the benefits?
What are the indications?
What are the side effects (and less-so side effects compared to others?)? 3
aka. Erbitux
MOA:
- Anti-EGFR Monoclonal antibody
- Inhibits the receptor by blocking the ligand binding site of EGFR (inhibiting growth)
Dosage:
- 400mg/m^2 week 1, then 250mg/m^2 weeks 2-7
Benefits:
- Potentiates RT - improves locoregional control
Indications:
- Used if performance status, age, comorbid conditions precludes platinum based treatments
- However recent studies still show no benefit for age > 65 (Bonner trial)
Side effects:
- Cardiotoxicity (pericarditis, ischemic heart disease)
- Acneiform Rash - treated with tetracyclines or clindamycin
- Hypomagnesemia
- No neuro/oto/nephrotoxicity as much
√How does concurrent CRT + CIsplatin compare to concurrent CRT + Cetuximab?
2014 Petrelli Systematic review
- Found cisplatin was better - 12% better absolute overall survival
- Suggests that MAC-NC finding of 6.5% was an underestimate (although Cetuximab was not included in that study)
√Discuss the Bonner trial (2006)
- Compared RT vs. Concurrent RT + Cetuximab in stage III/IV oropharyngeal hypopharyngeal, and laryngeal carcinoma
- Results: 10% improvement in survival rate in 5 years
- Although this study did not compare directly Cisplatin, this is why Cetuximab is used in patients who are not candidates or cannot tolerate cisplatin
- Found the main side effects of Cetuximab are hypersensitivity and acneiform rash - future studies has not proven that the rash predicts response
Western update: apparently misled field, later apparently Cetuximab showed no benefit; Bonner trial says “no toxicity” but actually it’s quite terrible.
√List 3 examples of tyrosine kinase inhibitors and their side effects?
Tyrosine kinase is involved in the mediation of immune cascades (inhibits EGF/VEGF) - Epidermal growth factor / Vascular endothelial growth factor (VEGF)
- Gefitinib, Erlotinib, Vandetinib - anti-VEGF/EGFR (used in end stage Medullary thyroid cancer)
- Imatinib - DFSP (Dermatofibrosarcoma protuberans) and melanoma
- Diarrhea and acneiform rash (in 50%) which is predictive of better response rate and progression-free survival (not proven!)
√Differentiate the terms: Systemic therapy, chemotherapy, immunotherapy, targeted therapy
Systemic Therapy - Overarching term for all therapies given systemically that’s not radiation
Chemotherapy - Drugs that interfere with cell cycle and DNA synthesis / inhibiting progression of cell cycle
Immunotherapy - Anything that causes BOOSTING of the immune system (allow the immune system to work MORE)
Targeted therapy - Targeting a specific receptor or ligand, enzyme, etc. to elicit a function.
Example of this is Cetuximab. Even though it’s a monoclonal antibody, its function is to target anti-EGFR so it’s a targeted therapy. Anti-PD/PDL-1 inhibitors is a monoclonal antibody, but it’s function is to boost the immune system
√Describe the anti PD-1 and PDL-1 pathways. List examples of anti-PD-1/PDL-1 inhibitors
Pathways:
- PD-1 and PD-L1 are proteins.
- PD-L1 is found on many different cell types and antigen presenting cells, including tumor cells
- PD-1 are found on immune cells like T, B, and NK cells
- When PD-L1 is bound to PD-1, it prevents the immune cell (E.g. T-cell) from killing other cells (ie. tumor cells). As such, this decreases immune function and leads to cancer growth
- Anti-PD-1 / PD-L1 inhibitors are monoclonal antibodies that are immunc checkpoint inhibitors. Essentially, they block PD-1 on the immune cell, or PD-L1 on the tumor cell, effectively preventing the binding of PD-1 with PD-L1. This prevents the decrease in immune function (effectively, “increases” the immune system) thereby making it an option for tumor treatment
Anti-PD-1 inhibitors:
1. Pembrolizumab
2. Nivolumab
3. Cemiplimab
Anti-PD-L1 inhibitors:
1. Atezolizumab
2. Avelumab
3. Durvalumab
√Discuss examples of palliative chemotherapy agents 4
- Cisplatin/Carboplatin
- Taxanes
- 5-FU/Methotrexate
- Cetuximab
√List the different phases of the cell cycle and the type of chemotherapy that the drug acts on (cytotoxic effect)
- Mitosis - Vincristine
- S phase - 5-Fluorouracil
- G2 phase - Bleomycin
√How does concurrent chemoRT regimen with cisplatin differ for advanced nasopharyngeal cancer?
NP is one location in H/N where concurrent chemoRT followed by adjuvant chemo is used in some centres
The benefit of this strategy is at present uncertain (negative studies) and toxicity is substantial
√In general, is combination chemotherapy more effective than a single agent?
- No change in overall survival
- More side effects
- Higher response rates are seen with SOME combinations (e.g. Cis+5FU, Carbo-Taxil)
- Carbo-5FU used sometimes instead of cisplatin, when cisplatin is contraindicated due to renal failure
√In general, is induction chemotherapy any more effective than concurrent?
- No change in overall survival
- Some studies suggest concurrent is better, but can do either (centre-specific)
- CANNOT do BOTH induction and concurrent (too toxic for anyone to handle) - rare exception is nasopharyngeal cancer
- Best induction combination: Docitaxel-5FU-Cisplatin
