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Head and Neck > Systemic Therapy > Flashcards

Systemic Therapy Flashcards

1
Q

√What are 6 beneficial mechanisms of chemoradiotherapy?

A
  1. Increase bioavailable dose of radiotherapy by ~10Gy
  2. Can act on different subsets of tumor cells
  3. Recruit cells from G0 into radiation sensitive phases (M phase), and synchronizes them into the same phase
  4. Chemotherapy inhibits repair of sublethal radiation injury (Decreases repopulation)
  5. Tumor shrinkage decreases interstitial pressure, therefore increases drug and O2 delivery
  6. Prevents radiation resistance
  7. Cell-cycle Synchronization increases the effectiveness of both therapies
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2
Q

√What are the benefits of combined chemotherapy in general? What are the disadvantages? What is the gold standard?

A
  1. Higher response rates/local control with some combinations
  2. Overall suvival not improved
  3. Toxicity is more severe, decreased repair, improved blood supply to tumor
  4. Cisplatin & 5-Fu are gold standard, act synergistically: Carbo-taxol also used recently
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3
Q

√What are 6 main roles for chemotherapy in head and neck oncology?

A
  1. Post-operative adjuvant therapy (e.g. + margins, + ECS)
  2. Recurrent or metastatic disease
  3. Unresectable disease, non-surgical or palliative
  4. Primary treatment of NPC
  5. Organ preservation in advanced laryngeal cancer (T3-4)
  6. Investigative therapy
  7. Neoadjuvant chemotherapy
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4
Q

√What is the only subsite that should be treated with chemoradiotherapy as the primary modality?

A

Nasopharynx

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5
Q

√What are three tumor factors affecting chemotherapy success?

A

(Not curative alone, act as radiosensitizers)

  1. Tumor burden (number of tumor cells)
  2. Number of cells with inherent or acquired resistance to chemotherapeutic agents
  3. Percentage of cells in a chemo-responsive phase of cell cycle (M-phase)
    - Cycle dependent drugs = schedule specific
    - Non-specific = dose dependent
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6
Q

√What are the general indications for chemotherapy in head and neck cancer? 6

A

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

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7
Q

√What is the maximum age for consideration of chemotherapy?

A

70 years old (see MACH trial later for explanation)

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8
Q

√Name 5 general chemotherapy emergencies

A
  1. Febrile neutropenia
  2. Thrombocytopenia
  3. Allergy
  4. Overdose
  5. Tumor lysis syndrome (AKI)

FATTO

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9
Q

√What is the general overall mechanism of action of most chemotherapy drugs?
What are the overall side effects of most chemotherapy drugs?

A
  • 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
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10
Q

√What are the different classes of chemotherapy agents? 9

A
  1. Akylating agents (e.g. Platinums - Cisplatin, Carboplatin)
  2. Anthracyclines (Topoisomerase inhibitors) - Adriamycin (Doxorubicin) (II)
  3. Antimetabolites (e.g. Methotrexate, 5-FU)
  4. Vinca Alkaloids (e.g. Vincristine, Vinblastine)
  5. Taxanes (e.g. Paclitaxel, Docitaxel)
  6. Antibiotic derivatives (e.g. Bleomycin, Mitomycin, Hydroxydaunomycin)
  7. Topoisomerases (e.g. Etoposide, Topotecan)
  8. Targeted Biologics (e.g. “Mabs” - Cetuximab, Ipilumamb)
  9. Non-specific Biologics (e.g. “Nibs” - Gefitinib, Sunitinib)
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11
Q

√Regarding Akylating agents, discuss:
1. What is the mechanism of action?
2. What are common examples?
3. What are common side effects?

A

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

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12
Q

√What is the mechanism of action and examples of DNA binding chemotherapeutic agents?

A

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

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13
Q

√What are 7 side effects of cisplatin? What are relative contraindications of Cisplatin?

A
  1. Myelosuppression
  2. Nephrotoxicity
  3. Ototoxicity (dose limiting, affects high frequencies, cumulative toxicity)
  4. Peripheral neurotoxicity
  5. Nausea
  6. Electrolyte disturbances
  7. Anorexia

Contraindication: Renal Failure

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14
Q

√How does the side effect profile of carboplatin compare to cisplatin?

A
  1. Less ototoxicity, neurotoxicity, and nephrotoxicity
  2. Myelosuppression is the main side effect
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15
Q

√What is the standard concurrent chemo-RT regimen for Cisplatin in H&N?

A

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

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16
Q

√Discuss the findings of MAC-NC meta-analysis (2009)

A
  • 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
17
Q

√Regarding antibiotic derivatives, discuss:
1. MOA?
2. Side effects? 2
3. Examples? 3

A

MOA: Interferes with DNA synthesis and replication

SIDE EFFECTS:
1. Pulmonary fibrosis
2. Myelosuppression

EXAMPLES:
1. Bleomycin
2. Mitomycin
3. Hydroxydaunomycin

18
Q

√What is the mechanism of action and examples of antimetabolite chemotherapeutic agents? What are the common side effects?

A

MOA:
- Actively interferes with cellular metabolism, act in S-phase

  1. Methotrexate - interferes with folate metabolism, inhibits dihydrofolate reductase enzyme, interrupts DNA synthesis in S phase
  2. 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)
  3. Hydroxyurea, Gemcitabine - incorporates into DNA, blocking replication
  4. Interferon A/B/G1 - antiviral effect

SIDE EFFECTS:
1. Mucositis
2. Dermatitis
3. Myelosuppression

19
Q

√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?

A
  1. Myelosuppression
  2. Mucositis
  3. Dermatitis
  4. N/V/D
  5. Hepatic fibrosis
  6. 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

20
Q

√What are the side effects of 5-FU? What is the % partial response 5

A
  1. Myelosuppression
  2. Mucositis
  3. Dermatitis
  4. Diarrhea
  5. Cardiotoxicity

13% single agent partial response

21
Q

√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?

A

MOA:
- Interfere with mitotic spindle formation (microtubule disruptors) - M phase

Examples:
- Vincristine
- Vinblastine
- Vinorelbine

SIDE EFFECTS:
1. Peripheral neuropathy
2. Alopecia

22
Q

√What chemotherapy agent can cause vocal fold palsy in children?

A

Vincristine

23
Q

√Mechanism of action and examples of taxane chemotherapeutic agents?

A

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

24
Q

√What are the side effects of taxanes? 4

What is the % single agent partial response rate?

A
  1. Neuropathy
  2. Muscular pain
  3. Alopecia
  4. Allergic reactions

30-40% single agent partial response rate

25
Q

√What is the mechanism of action and examples of topoisomerase inhibitor chemotherapeutic agents? What are the common side effects?

A

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

26
Q

√Regarding targeted biologics, what are their MOA and 2 side effects?

A

Targeted Biologics:
- “Mabs”
- Cetuximab, Ipilimumab

MOA: Monoclonal antibodies against EGFR (epidermal growth factor receptor)

SIDE EFFECTS:
1. Cardiotoxicity
2. Dermatitis

27
Q

√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

A

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

28
Q

√How does concurrent CRT + CIsplatin compare to concurrent CRT + Cetuximab?

A

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)

29
Q

√Discuss the Bonner trial (2006)

A
  • 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.

30
Q

√List 3 examples of tyrosine kinase inhibitors and their side effects?

A

Tyrosine kinase is involved in the mediation of immune cascades (inhibits EGF/VEGF) - Epidermal growth factor / Vascular endothelial growth factor (VEGF)

  1. Gefitinib, Erlotinib, Vandetinib - anti-VEGF/EGFR (used in end stage Medullary thyroid cancer)
  2. Imatinib - DFSP (Dermatofibrosarcoma protuberans) and melanoma
  3. Diarrhea and acneiform rash (in 50%) which is predictive of better response rate and progression-free survival (not proven!)
31
Q

√Differentiate the terms: Systemic therapy, chemotherapy, immunotherapy, targeted therapy

A

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

32
Q

√Describe the anti PD-1 and PDL-1 pathways. List examples of anti-PD-1/PDL-1 inhibitors

A

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

33
Q

√Discuss examples of palliative chemotherapy agents 4

A
  1. Cisplatin/Carboplatin
  2. Taxanes
  3. 5-FU/Methotrexate
  4. Cetuximab
34
Q

√List the different phases of the cell cycle and the type of chemotherapy that the drug acts on (cytotoxic effect)

A
  1. Mitosis - Vincristine
  2. S phase - 5-Fluorouracil
  3. G2 phase - Bleomycin
35
Q

√How does concurrent chemoRT regimen with cisplatin differ for advanced nasopharyngeal cancer?

A

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

36
Q

√In general, is combination chemotherapy more effective than a single agent?

A
  • 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
37
Q

√In general, is induction chemotherapy any more effective than concurrent?

A
  • 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

Head and Neck (15 decks)

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