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Head and Neck > Tumor biology, Histology, Radtx > Flashcards

Tumor biology, Histology, Radtx Flashcards

1
Q

Describe the 5 phases of the cell cycle.
a) Which is the longest and shortest phase?
b) During which stages are cells most and least susceptible to damage from chemo/XRT?

A
  1. G1 Growth Phase 1: Preparation for DNA synthesis with generation of enzymes, nucleic acids, and other factors
  2. S phase: Replication of DNA materials
  3. G2 Growth Phase 2: Preparation for division, growth and duplication of proteins
  4. M phase: mitosis / physical division of cells and their materials
  5. G0: Resting phase

Longest phase: G1 (4-24hrs)
Shortest phase: M (1 hr)

Most susceptible phase: M
Most Resistant: S

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2
Q

Where does each of the following chemo agents act in the cell cycle:
a) Antibiotics
b) Anti-metabolites
c) Alkylating agents
d) Vinca Alkaloids
e) Taxoids

A

antibiotics and antimetabolites - G1, S, G2

Alkylating agents - all

Vinca alkaloids and Toxoids - mitotitic inhibits (M)

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3
Q

Define vector and promoter

A

Vector - vehicle through which genetic material is transferred into a cell

Promoter - sequence of DNA that proteins bind to initiate RNA transcript (protein or specific function) from the DNA downstream of the promoter.

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4
Q

List 5 methods for targeting a vector to a specific cell type, and give a few examples

A
  1. Tumor specific promoter (e.g. CEA, AFP) - activate promoter gene expression specifically in tumor cells
  2. Non-specific promoter (e.g. CMV) - drives replication in all susceptible cell types (higher risk for toxicity)
  3. Direct, receptor targeting - ligand for specific receptor characteristic of tumro cells
  4. Indirect, Inverse targeting - DEtarget healthy non-tumor cells to improve vector selectivity for cancer cells
  5. Indirect, Protease targeting - selective infection of cells with specific surface protease (which activate the viral receptor and allow viral entry)
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5
Q

List 7 viral vectors used in head and neck cancer

A

ARRMMHV

Adenovirus
Reovirus
Rhabdovirus
Measles
Mumps
HSV
Vaccinia

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6
Q

List two gene types involved in the cell growth in cancer, and how do they lead to cancer?

A
  1. Tumor Suppressor Genes:
    - Code for proteins that inhibit abnormal cell proliferation through negative feedback
    - Mutations or loss of tumor suppressor genes abnormal cell cycling (induced by oncogenes), or amplification of oncogenes
  2. ProtoOncogenes –> Mutated oncogenes
    - Protooncogenes are genes that normally help cells grow and divide to make new cells
    - Proto-oncogenes can mutate and become active when they shouldn’t be, when they are then called oncogenes
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7
Q

Define Tumor suppressor Gene.
List 4 Tumor Suppressor genes that are implicated in head and neck cancer, their MOA, and % in H/N cancer

A

Tumor supressor Gene = Genes that suppress tumor by providing negative feedback to limit cell growth

p53, p16 protein (CDKN2A gene), RB

  1. p53 (most common mutated gene in HNSCC); Chromosome 17p13. MOA: Normally help with DNA repair proteins, mutation therefore upregulates DNA damage and increases risk of mutations. >50% HNSCC. Target for HPV E6 gene.
  2. p16 (Chromosome 9p21). Protein encoded from CDKN2A gene. MOA: Prevents phosphorylation of RB (retinoblastoma - another tumor suppressor), and this effect causes arrest in G1 phase (cell cycle arrest), preventing further replication of tumor; mutation therefore progresses cell cycle. Surrogate of HPV. >70% HNSCC.
  3. p21 (Chromosome 9p21). Suppresses Cyclin and Cyclin dependent kinase pathyways. > 70% HNSCC
  4. RB. MOA: Binds and inhibits transcription factor E2F in the CDKN2A pathway which causes cell cycle arrest. Mutation will progress cell cycle. >60% HNSCC. Target for HPV E7 gene.

See cummings Chapter 73

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8
Q

List the tumor suppressor genes in H/N cancer associated with poor vs. good prognosis 3

A

Poor prognosis - p53
Good prognosis - p16, p21

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9
Q

Define proto-oncogene. List 7 Proto-oncogenes and the effects that their mutations that lead to H/N cancer. Also state the % implicated in HNSCC. State any associated malignancies.

A

Proto-oncogene: normal gene in normal cell growth, who’s mutations result in mutations/inducing cell/tumor growth

  1. EGFR (Epidermal growth factor receptor - Chromosome 7q11.2). MOA: Mutation promotes epidermal overgrowth. >90% HNSCC. Targeted by Cetuximab (blocks ligand receptor)
  2. Cyclin D1 (Chromosome 11q13). MOA: Phosphorylates RB which promotes the cell cycle progression - mutations accelerate cell cycle progression and is associated with increased risk of recurrence, nodal mets, and death. Cell cyclin inhibitors include cyclin dependent kinase inhibitor
  3. RET translocation (Receptor Tyrosine Kinase). MOA: Involved in cell growth, mutations associated with MEN-2
  4. Ras. MOA: Signal transducer for surface growth factor receptors implicated in cell growth
  5. BRAF. MOA: Protein kinase activated by oncogenic Ras increases growth factor signalling, associated with papillary thyroid cancer (45%)
  6. C-Myc. MOA: Regulates transcription. Associated w/ Burkitt’s lymphoma
  7. BCL-2. MOA: Counteracts p53 (which is implicated in DNA damage repair), inhibits apoptosis
  8. Her-2/neu
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10
Q

Which protooncogenes indicate good vs. poor prognosis?

A

Good prognosis: BCL-2
Poor prognosis: EGFR, C-myc, Overexpression of Cyclin D1

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11
Q

In what situation does HPV+ status NOT improve prognosis?

A

History of smoking ≥ 10 pack years

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12
Q

Define Simultaneous vs. Synchronous vs. Metachronous tumor

A

Simultaneous Tumor: Separate primary tumor diagnosed at the same time

Synchronous tumor: Separate primary tumor diagnosed within 6 months of each other

Metachronous tumor: Separate primary tumor diagnosed >6 months of each other

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13
Q

Define second primary and what are its 3 main characteristics?
What is the overall incidence of a secondy primary?

A

Second primary tumor that is characterized by:
1. Different cell type / histology
2. Different location
3. Different metastatic nodal group

Overall incidence of 2nd primary is ~10%
- 80% metachronous (> 6 months)
- 50% present in first 2 years

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14
Q

What are the %risks of second primary tumors in patients with HNSCC?

A
  1. 10% risk in non-smoker
  2. 50% risk in smoker or EtOH use
    50% develop within 2 years of 1st primary
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15
Q

How does continued smoking and EtOH use affect risk of recurrence and 2nd primary?

A
  • Up to 30-50% risk of locoregional recurrence
  • 10-40% risk of second primary
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16
Q

What are the layers of the epidermis?

A
  1. Stratum Corneum
  2. Stratum Lucideum
  3. Stratum Granulosum
  4. Stratum Spinosum
  5. Stratum Basale

Come let’s get sun burnt

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17
Q

Define Acanthosis

A

Increased thickness of the prickle cell layer (Stratum Spinosum)

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18
Q

Define Anaplasia

A

Change in a cell or tissue to a less highly differentiated form (more disorganized)

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19
Q

Define Atrophy

A

Diminution in the size of cells, organ, or tissue after a stage of full development

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20
Q

Define Carcinoma in situ

A

Growth disturbance in which there is sufficient atypicality of the epithelial cells and their arrangement to warrant the diagnosis of cancer in the absence of invasion

Basically cells appear like cancer but they are not invading

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21
Q

Define Choristoma. What are some examples of this?

A

A mass of histologically normal tissue in an abnormal location (Tumor not at home)

Examples:
1. Dermoid
2. Lingual thyroid
3. Aberrant salivary tissue in mastoid or middle ear

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22
Q

Define Teratoma vs. mature teratoma

A

Tumor comprising of one or more of the three germinal layers (endoderm, mesoderm, ectoderm) and is composed of different kinds of tissue (none of which normally occur together or at the site of the tumor).

Mature teratoma = contains all three germinal layers

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23
Q

Define Desmoplasia

A

Connective tissue reaction to tumor

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24
Q

Define Dyskeratosis

A

Production of keratin at lower layers

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25
Q

Define Dysplasia

A

Change affecting the size, shape, and orientational relationship

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26
Q

Define Ectopic

A

Normal appearing tissue in an abnormal location
vs. choristoma is a MASS of normal tissue in an abnormal location

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27
Q

Define Hamartoma. What are some examples of this?

A

Circumscribed overgrowth of tissues in their USUAL location (ie. normally present in that part of the body, tumor “at home)

Examples:
1. Uterine fibroma
2. Hemangioma
3. Bowel polyp
4. Neurofibroma
5. Melanocytic nevi

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28
Q

Define Hyperkeratosis

A

Increased thickness of keratinized layers

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29
Q

Define Hyperplasia

A

Increase in the number of cells per unit of tissue or organ of origin

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30
Q

Define Hypertrophy

A

Increase in individual cell size

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31
Q

Define Keratoacanthosis

A

Large acanthoma (overgrowth of prickle layer/stratum spinosum) with surface keratosis

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32
Q

Define Metaplasia

A

Differentation of one cell into another

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33
Q

Define metastasis

A

Secondary discontinuous cancerous growths

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34
Q

Define neoplasm

A

Proliferation of cells and formation of a mass

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35
Q

Define parakeratosis

A

Retention of nuclei in cells attaining the level of the stratum corneum

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36
Q

Define Pleomorphism

A

More than one form of a single cell type

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37
Q

Define repair

A

Cell proliferation to restore toward normal structure and function

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38
Q

Define Tumor

A

Any swelling from whatever cause

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39
Q

What histologic morphologic features are suggestive of the following disease entities?
1. Granulomatous disease
2. Epithelial malignancies (squamous, glandular)
3. Sarcoma
4. Small round blue cell
5. Melanoma
6. Hodgkin Lymphoma

A
  1. Granulomatous disease - multinucleated giant cells
  2. Epithelial malignancies - Cohesive cells forming nests or islands of cells unless poorly differentiated. Squamous - intercellular bridges, keratinization. Glandular - columnar of cuboidal cells, forming glands, tubules of papillae
  3. Sarcoma - Spindle cells (melanoma and spindle cell malignancies also have spindle cells)
  4. Small round blue cell - high N:C ratio, minimal cytoplasm, small cells, not always round
  5. Melanoma - invasion of atypical melanocytes and stain for melanin
  6. Hodgkin Lymphoma - Reed Sternberg cells
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40
Q

List 5 special histochemical stains and what they do/are used for

A
  1. H&E - Eosin stains cytoplasm pink and hematoxylin stains nuclei blue
  2. PAS (Periodic acid-schiff stain) - detects polysaccharides, Glycogen (PAS only), mucin, zymogen granules (acinic cell), fungi, granular cell tumor, basement membrane
  3. Gomori’s methenamine silver (GMS) - Fungi
  4. Ziehl-Neilsen (ZN) - acid fast bacilli
  5. Congo Red - Amyloid (polarize)
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41
Q

List the specific tumor immunohistochemistry for the following pathologies:
1. Papillary thyroid carcinoma
2. Medullary thyroid carcinoma
3. Plasmacytoma
4. Rhabdomyosarcoma
5. Infantile Hemangioma
6. Merkel Cell Carcinoma
7. Melanoma
8. High grade MEC
9. Neuroendocrine origin
10. Nasopharyngeal carcinoma
11. Ewing Sarcoma
12. Granular cell tumor

A
  1. Papillary thyroid carcinoma - Thyroglobulin, BRAF, HBME-1, TTF-1
  2. Medullary thyroid carcinoma - Calcitonin
  3. Plasmacytoma - Kappa and lambda light chains
  4. Rhabdomyosarcoma - Myogenin, muscle specific actin, desmin
  5. Infantile Hemangioma - Glut-1
  6. Merkel Cell Carcinoma - CK20, Synaptophysin, Chromogranin, Neuron-specific Enolase (NSE), Neurofilament protein
  7. Melanoma - S100, HMB45, Melan-A, Tyrosinase, Vimentin, Micropthalmia Transcription Factor (MITF)
  8. High grade MEC - Mucin
  9. Neuroendocrine origin - Chromogrannin, Synaptophysin
  10. Nasopharyngeal carcinoma - EBV - Viral capsid antigen and early antigen (IGA), ADCC titres
  11. Ewing Sarcoma - CD99
  12. Granular cell tumor - S100, PAS
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42
Q

List the basic immunohistochemical panel for poorly differentiated tumors

A
  1. Broad spectrum keratin ± keratin subtypes (epithelial origin)
  2. Vimentin (mesenchymal origin, melanoma)
  3. HMB45 (melanoma)
  4. S100 (Melanoma, peripheral nerve sheath tumors, granular cell tumors, sarcoma, merkel cell, others)
  5. Leukocyte common antigen (LCA) - lymphocytes - CD3 (T cells), CD20 (B cells)
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43
Q

Identify the histochemical markers for squamous cell carcinoma

A
  1. Cytokeratin autoantibodies (5 and 6)
  2. p40
  3. p63
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44
Q

Identify 5 histochemical markers for melanoma

A
  1. HMB45
  2. S100 (sensitive, but not specific)
  3. Tyrosinase
  4. Vimentin
  5. Melan-A/MART-1

Mucosal Melanoma is positive for cKIT, not the traditional markers.

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45
Q

What are the histochemical markers for lymphoma

A
  1. Leukocyte Common Antigen (LCA)/Panleukocyte autoantibodies
  2. CDs (clusters of differentation)
  3. Atypical melanocyte invasion
  4. Pagetoid (upward spreading) and lentinginous (freckled/speckled) spread into superficial dermal layers
  5. Ki-67 proliferation rate B cell NHL
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46
Q

What are the origins of neuroendocrine cells?

A
  1. Neural crest cells (C-cells, paraganglia)
  2. Epithelium (Merkel cells, GI tract endocrine cells)
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47
Q

Which neural crest cells are keratin positive?

A

C Cells

Not positive: paraganglia, olfactory neuroblasts

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48
Q

What are the markers of neuroendocrine tumors?

A
  1. Chromogranin (secretory granules)
  2. Synaptophysin
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49
Q

What are 7 histologic features of squamous cell carcinoma?

A
  1. Disorganized growth (Basement membrane in the surface)
  2. Dyskeratosis (keratin at lower layers)
  3. Immature cells (Lack of maturation)
  4. Keratin Pearls
  5. Intercellular Bridges
  6. Enlarged nuclei/crowding with prominent nucleoli
  7. Increased and atypical mitotic figures (rapid division)

All features seen in Carcinoma in-situ but without invasion of the BM

Images Vancouver Notes Page 73

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50
Q

Six criteria to call Squamous Cell Carcinoma ‘poorly differentiated’

A
  1. Increased number of mitoses
  2. Multineucleated cells
  3. Nuclear and cellular polymorphism
  4. Abnormal mitoses
  5. Loss of intercellular bridges
  6. Loss of (abscent) keratinization

IMPALA

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51
Q

Describe Broder’s Classification

A

Degree of differentation and extent of keratinization
1. Well - 75-100%
2. Moderate - 50-75%
3. Poorly differentiated - 25-50%
4. Anaplastic - 0-25%

Most pathologists no longer use this and comment on pattern of invasion (unifocal vs. multifocal, etc.)

52
Q

How is depth of invasion measured?

A

Measured using a “plumb line” from the basement membrane “horizon” of the closest adjacent IN TACT mucosa to the deepest point of tumor invasion

53
Q

What defines perineural invasion?

A

Cells in the nerve sheath of a nerve deeper than the dermis of >0.1mm

54
Q

What does “field cancerization” mean?

A

Premalignant changes that occur and the propensity for a second primary tumor to develop in the mucosal surface in the region adjacent to an invasive tumor.

55
Q

Discuss 2 theories of explanations for Field Cancerization

A
  1. Areas of abnormality represent independent clones, with a unique pattern of genetic alterations
  2. Areas of abnormality are genetically related and originate from a common cellular clone, with lateral spread of progenitor clones throughout squamous mucosal surfaces (predominant theory based on genetic studies). Subsequent alterations may demonstrate discordance, so the final pattern may be different. Therefore, field cancerization is likely a reflection that at least a proportion of lesions derived from lateral migration and subsequent expansion of clonally related cells develop histologic alterations surrounding the primary lesion, and ultimately lead to an increased incidence of subsequent primary tumors.
56
Q

What are two groups of genes involved in cell growth and cancer, and how do they work?

A
  1. Protooncogene - normal cell genes that influence cell growth in a positive way; when mutated or overexpressed = oncogene
  2. Tumor suppressor gene - encode proteins that normally exert negative regulatory control in a cell.
57
Q

What are common gene modifications that lead to oncogenesis?

A
  1. Deletion - p53
  2. Translocation - RET
  3. Mutation - RAS
58
Q

What are five different types of oncogenes, based on a protein’s function?

A
  1. Growth factor - INT2
  2. Growth factor receptors - ErbB/neu
  3. Signal transducers for surface growth factor receptors - RAS
  4. Protein kinases - BRAF, CRAF
  5. Transcription regulator - Myc
59
Q

What are 4 genetic alterations that have been shown to underlie the development of precancerous lesions and their progression to invasive laryngeal carcinoma?

A
  1. Loss of heterozygosity and microsatellite instability at certain genetic loci
  2. Mutation in p16 = occurs in over half of laryngeal cancers (inactivated p16 = dysplasia)
  3. Overexpression of Cyclin D1 = increase cellular proliferation and tumorigenesis = leads to carcinoma in situ = leads to carcinoma
    - This overexpression correlates with poor prognosis, recurrence, and LN metastasis
  4. Alterations in p53 (dysplasia) = destabilization of genomic repair processes leading to tumorigenesis
60
Q

What are 4 antagonistic relationships in cancer genes?

A

Mutually antagonistic: Affect of both together is worse than affect of one alone (?)

  1. p53 (tumor suppressor) & bcl-2 (oncogene)
  2. p53 (tumor suppressor) & Cyclin (oncogene)
  3. p16/p21 (tumor suppressor gene) & Cyclin (oncogene)
  4. pRB (tumor suppressor gene) & TF E2F (oncogene)
61
Q

What is the pathogenesis of HPV-related SCC? What is the surrogate marker for HPV and how does this work?

A
  1. HPV = Encapsulated, Non-enveloped, Double stranded DNA virus of family Papillomaviridae. Contains circular viral DNA
  2. HPV only productive and infectious in basal cell layer (stratum basale) in squamous epithelium. Basal cell layer is only exposed when there are microabrasions in the skin or when there are crypts. The epithelia of the tonsils and base of tongue contain cryptic invaginations that expose the basal epithelial cells at their base, which predisposes them to HPV infection. This is very different from the oral cavity where there is a thick protective layer of stratified squamous mucosa.
  3. E6 & E7 are two proteins in HPV genome that inhibit tumor suppressors, which lead to unregulated cell growth in G1
    - E6 is an oncoprotein that inactivates p53
    - E7 is an oncoprotein that inactivates pRb
  4. During the initial phase of HPV infection, the viral DNA exists primarily in episomal form (not integrated into the host DNA)
  5. If the virus is not cleared by the host, the viral DNA eventually integrates into the host genome, which then results in increased expression of E6 and E7.
  6. Most infections are cleared rapidly by the host immune system, however in cases where the infection remains, there is a later risk of neoplasm.
  7. It is unclear why some individuals clear the virus while others do not.

p16 Overexpression as a Surrogate Marker for HPV
- The p16INK4a (p16) tumour suppressor protein is over-expressed in HPV associated tumours, and is used as a surrogate to identify HPV associated carcinoma.
- p16 is a protein that inhibits cyclin-dependent kinases 4/6 (CDK4/6)
- Cyclin dependent kinases play a significant role in cell cycle progression.
- In particular, CDK4 phosphorylates (inactivates) pRB which then triggers cell cycle progression.
- Rb itself negatively regulates the production of p16 (negative feedback cycle).
- As a result, inactivation of Rb (by viral E7) causes overexpression of p16

62
Q

What chromosome is p53 on?
What are the functions of the p53 gene? List 4
What are ways it can be mutated?

A
  1. Controls cell cycle by binding to cyclin-dependent kinins and arrests cell replication in G1/S junction
  2. Can induce apoptosis if DNA repair mechanisms fail
  3. Activates DNA repair
  4. Produces factors that prevent angiogenesis

Chromosome: 17p13.1
Mutated by Benzopyrene Dioloxide in cigarettes

63
Q

What are 4 reasons why tumor specific vaccinations do not work?

A
  1. Tumor specific antigens are hard to identify
  2. Malignant cells are heterogeneous
  3. Tumor cells can modify their antigen expression
  4. Tumors secrete suppressive factors

“HIMS”
Heterogenous malignant cells
Identification of antigen is hard
tumors can Modify their own antigen expression
tumors can Secrete suppressive factors (easily resistant)

64
Q

Regarding the Gardasil vaccine, discuss:
1. What are its components
2. What are the two Gardasil vaccines available and their strains covered? How often are they done?
3. What is the CDC recommendation for vaccination
4. What are the anticipated outcomes?

A

COMPONENTS
- Contains recombinant capsid proteins that induce immune antibody response (lack viral DNA so cannot induce cancer)

VACCINES AVAILABLE
1. Gardasil (Quadrivalent HPV - 6, 11, 16, 18)
2. Gardasil 9 (9-valent HPV - 6, 11, 16, 18, 31, 33, 45, 52, 58)

FREQUENCY OF VACCINE:
1. 2 injections over 6 months for kids
2. 3 injections over 6 months for adults

CDC RECOMMENDATIONS FOR VACCINATION
1. All boys and girls aged 11 to 12 (Grade 6)
2. Catch up vaccine:
- Girls: 13-26 yo
- Boys: 13-21 yo
3. Girls and boys as young as age 9, in whom the physician believes it would be appropriate
4. In BC, the vaccine is recommended but not funded for: Women < 45 years, Males >27 who have sex with men

OUTCOMES:
- Predicted to reduce the incidence, morbidity, and mortality of the cervicovaginal HPV disease
- Vaccination could be expected to reduce the incidence of HPV-associated oropharyngeal cancers by as much as 30%

65
Q

What are the possible mechanisms of immunocompromised in Head/Neck SCC?

A

HOST-RELATED:
1. Comorbid conditions (e.g. HPV, SLE, DM2, etc.)
2. Circulating immune complexes
3. Suppressor T-cells
4. Ig-blocking antibodies
5. TGF-beta

TUMOR-RELATED:
1. Tumor production of immunosuppressant agents (e.g. VEGF, IL-1, IL-10)
2. Tumor suppression of innate immunity
3. Tumor antigenic modulation

EXOGENOUS:
1. Chemo/XRT
2. Immunosuppressant medications (e.g. steroids, IFN, methotrexate, Cyclophosphamide, etc.)

66
Q

According to RECIST and WHO, discuss:
1. How do the two differ in how they measure a tumor’s response to therapy?
2. Define: Measurable lesion, Pathologic lymph node
3. Define: Objective response ,complete response, partial response, stable disease, progressive disease

A

RECIST (2009): Focuses on “Target” lesion when measuring response to therapy
- RECIST = Response Evaluation Criteria in Solid Tumors
- MEASURABLE LESION: Minimum 10mm in long axis on clinical or CT exam
- PATHOLOGICAL LYMPH NODE: Minimum 15mm in short axis on CT
- Response is based on assessment of chosen “target” (or index) lesions
- Select largest, most representative lesions (maximum 5 paired organ sites total, 2 per organ, up to 10 total), more does not yield more accurate assessment, and just wastes time and resources

WHO: Focuses on “Measurable disease”

DEFINITIONS:
1. OBJECTIVE RESPONSE (OR):
- RECIST: Change in sum of longest dimensions of target lesions (max 2/organ or 10 overall)
- WHO: Change in sum of [longest dimension x cross dimensions] of all lesions

  1. COMPLETE RESPONSE (CR):
    - RECIST: Disappearance of all lesions/disease, AND reduction in LNs to < 10mm, by 4+ weeks
    - WHO: Same
  2. PARTIAL RESPONSE (PR):
    - RECIST: > 30% decrease by 4 weeks
    - WHO: > 50% decrease by 4 weeks
  3. STABLE DISEASE (SD):
    - RECIST: No partial response or progressive disease (no change)
    - WHO: same
  4. PROGRESSIVE DISEASE (PD):
    - RECIST: > 20% (min 5mm) increase over smallest sum, or presence of new lesions
    - WHO: > 25% increase in any lesion, or presence of new lesions

RECIST: When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and will be recorded and measured at baseline

chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://ctep.cancer.gov/protocoldevelopment/docs/recist_guideline.pdf

67
Q

How many cells must a tumor have before it’s clinically palpable?

A
  • More than 100000 (10e5)
68
Q

List the various radiation delivery methods and describe them. 7

A

A. EXTERNAL BEAM (Photons, Electron)
1. Conventional 3D-Conformational (manual, multi-beam, uniform intensity)
2. Intensity Modulated RT (IMRT) (Computerized, multi-beam, variable intensity)
3. Volumetric Modulated Arc Therapy (VMAT) - type of IMRT

  1. Image-guided RT (Repeat imaging throughout treatment course to modify target/volumes) - Not a “type of delivery” but a way to improve precision of delivery. This can be used with #1-3 above. When patient arrive, repeat the scan compare it to the plan and overlay the two and see how well they match to make sure where you want the highest dose is where the cancer is. If it doesn’t match, then you have to change the plan. This is always done in H/N patients on the day of treatment; generally CT repeated weekly and daily x-rays in between.

B. STEREOTACTIC RADIATION

C. BRACHYTHERAPY

D. INGESTED (e.g. RAI)

E. PROTON, NEUTRON

69
Q

Discuss Conventional 3D Conformation Radiation delivery (3DCRT). How does it work?
What are 3 advantages?
What is a disadvantage?
What are the indications? 2

A

Conventional 3D-Conformational:
- 2D (historical method) was taking an x-ray of the target and use the bony landmarks to design where the field would go, and give a full dose of radiation within that section
- 3D radiation started when CT scans were used to plan the radiation; now there is a 3D image of the radiation field should be.
- You draw a “box” where the radiation would go (“field-based plan” that is in a 3D target)
- Usually the angles for conventional 3D is just front, back, side to side (at most).

Advantages:
1. Quick
2. Less resource intensive
3. Less low-dose “wash” in the normal tissues (ie. doesn’t hit around the normal tissues as much)

Disadvantages:
1. Less sculpted dose around the tumor / less accurate around the tumor

Indications:
- Nowadays, this will be done for palliative cases (less resource intensive/need less radiation planning, faster to do). Can also be used for breast cancer cuz the field is easier to target

70
Q

Discuss Intensity Modulated RT (IMRT), how it works?
Name one advantage.
Name one disadvantage

A
  • The standard of care for radiation currently

How it works:
- Contour the cancer and everywhere you want the radiation to go, as well as contouring the normal tissues
- You put this into the computer system and tell it where you want it to go and what to avoid
- Computer will design different beam angles all around the patient, to achieve the concentration you want at the specific targets
- Multi-leaf collimaters live in the head of the machine and shape the beam as it comes out through the machine to target the “shape” even better
- This differs from 3D because with 3D you have less of an ability to modulate the dose because there are not as many angles to shoot from (only 4 max), whereas IMRT has more ability to change the dose.
- More degrees of freedom to control how the dose is sculpted

3D = Put it in a machine and say “blast this field”

IMRT = Put the contoured in a machine and say “figure out how to get these sections”

Advantages:
1. Less long term toxicity (shielding the normal tissues better than 3D)

Disadvantages:
1. Higher acute toxicity (more conformed dose around the tumor)

71
Q

What is VMAT?

A

Specialized form of IMRT where the machine is rotating in an arc while delivering radiation, and the MLCs are changing and you can modulate the doses at each angle of the arc.

Benefits:
- More degrees of freedom to provide a more sculpted/conformed dose around the target.

Disadvantage:
- Low dose “wash” on the non-cancerous tissues (the surrounding normal tissues get a low dose of radiation as the beams are moving) - may not be ideal for younger patients with higher risk of second primary

VMAT is the most commonly used for Head/Neck

https://www.researchgate.net/profile/Ben-Vanneste/publication/312270763/figure/fig2/AS:1086746146152451@1636111880450/Examples-of-dose-distribution-of-a-3DCRT-IMRT-5-VMAT-PSPT-IMPT-and-a-BT-treatment.jpg

72
Q

What are the different types of radiation that are used for treatment of H/N malignancy?
Describe them and their characteristics.

A

For both photons and electrons, the dose deposited decreases gradually as you go deeper and deeper. Electrons do not penetrate as deep as photons (ie. the shine through of radiation deeper than the tumor is not as high for electrons than photons)
- If something was very deep, it would probably be hard to get full dose to it with electrons, but slightly easier with photons
- Conversely, you spare more of the deeper organs with electrons vs. photons as you said

MEGAVOLTAGE X-RAYS/GAMMA RAYS (Photons)
- Most common type of radiation used
- Uses Low (4-6 MeV Mega-electron volts) or High (15-25 MeV) energy
- Skin/surface sparing properties
- Can give a bolus tissue at skin surface (ie. put a wax-like material on the skin to make it look like extra tissue and that is the “new skin” to counteract the skin-surface sparing property and get to the skin) to treat skin cancers
- Deep tissue penetration (depth-dose property)
- Isodose distribution (beam uniformity)

ELECTRON BEAM XRT (Electrons)
- Good for superficial lesions (deep to skin surface)
- Skin/surface sparing properties
- Deep tissue sparing (Electrons don’t go as deep as photons)
- Can give a bolus tissue at skin surface (ie. put a wax-like material on the skin to make it look like extra tissue and that is the “new skin” to counteract the skin-surface sparing property and get to the skin) to treat skin cancers
- Range of penetration for electrons (cm) (farthest depth that you can penetrate; higher energy goes deeper) = MeV/3

PROTON BEAM THERAPY
- Only available in the states ($$$)
- Protons lose energy at a pre-determined depth (Bragg Peak) and have little energy loss prior to or after this
- As such, protons deliver their radiation at a predetermine depth
- Therefore, protons are useful for precise delivery of treatment (because they deliver most of their dose right at the targeted depth and don’t go much beyond or before that)
- Useful for lesions close to vital structures (e.g. orbital melanoma - want to target the eye but not deeper to the brain)

ORTHOVOLTAGE
- Not skin sparing (can be used for skin)

Terence’s brain

73
Q

What are indications for proton beam therapy? (8)

A
  1. Nasopharyngeal / sinonasal carcinoma
  2. Adenoid cystic carcinoma
  3. Mucosal melanoma
  4. Oropharynx (HPV+ de-escalation)
  5. Acoustic neuroma / CNS tumors
  6. Pediatric RT
  7. Orbital melanoma / intraocular tumors
  8. Tumors close to vital structures (3-4mm)

Alberta health services:
Pediatrics
Cordomas
Chondrosarcomas
Intraocular melanoma
CNS tumors
Head/neck (Sinonasal)
Prostate

74
Q

What are the characteristics of stereotactic radiation? What are the indications?

What are the three modes of delivery?

A

Goal of Stereotactic: Higher dose in smaller number of fractions, and requires greater precision in delivery.
- Not commonly used in H/N
- Stereotactic radiation is a different way that the radiation is prescribed. Can be given with standard machines, or specialized machines to deliver stereotactic specifically (ie. Gamma knife and Cyber knife)
- Because this is more precise, mobilization of the patient needs to be more rigid
- Indications: Good for recurrences (want to be more precise because that area has seen radiation already), non-surgical candidates

Modalities of Delivery:

  1. Conventional Linear Accelerators
  2. Gamma Knife
    - Head get screwed into a metal frame and 200 different beamlets at different angles within the gamma knife machine are aimed at the same focus target, completed in usually one session
    - Uses Cobalt 60 to generate the radiation beamlet (“Cobalt reload”)
    - Delivers a large and very precise dose of radiation
    - Can only be used in the brain and head/neck because the head is screwed
    - More accurate than Cyber knife (cuz head is literally screwed on)
    - Amount of radiation that can be given is similar to cyberknife
  3. Cyber knife
    - A linear accelerator (LINAC - regular machine) that is mounted on a robotic arm
    - Advantage: Infinite amount of degrees of freedom cuz the robot can move around the target in any way it wants, allowing it to be more precise and target more tissues (than just the head/neck).
    - Disadvantage: May potentially be less accurate than Gamma (because head is not fixed with a screw) - no fixed frame used.
    - Usually multiple sessions but can just be one as well

Gamma: https://www.mayoclinic.org/-/media/kcms/gbs/patient-consumer/images/2015/03/10/09/58/mcdc7_gamma_knife_headframe-8col.jpg

75
Q

Regarding Brachytherapy, discuss:
1. Methods of delivery 3
2. What types of isotopes are used? 2
2. Advantages 3
3. Disadvantages 4

A

METHODS OF DELIVERY:
1. Interstitial (rods)
2. Intercavitary (seeds)
3. Surface mould

ISOTOPES USED:
1. Temporary treatment: short lived isotopes
2. Permanent treatment: Long lived isotopes used (palladium gold)

ADVANTAGES:
1. Direct application of radiotherapy
2. Minimizes effects on surrounding tissues
3. Continuous dose

DISADVANTAGES:
1. Local tissue necrosis
2. May miss some areas of tumor
3. Inconsistent dose delivery to cells at different proximities
4. Patient is radioactive throughout treatment duration (must remain isolated, away from kids and pregnant women, etc.)

76
Q

What head and neck tumors are considered radioresistant?

A
  1. Mucosal melanoma/melanoma in general is not that responsive
  2. Salivary tumors don’t respond to radiation as well as others
  3. Verrucous carcinoma is super well differentiated so it doesn’t divide fast enough for the radiation to work
77
Q

Which phases of the cell cycle are most sensitive to radiation? Which are most resistant?

A

Sensitive:
- M phase
- G2 (late)

Resistant: S-phase (synthesis)

78
Q

Define the following terms:
1. Gray (Gy)
2. Rad

A

Gray (Gy): The absorption of one joule of radiation energy by one kilogram of tissue

Rad: Radiation absorbed dose, 100 rad = 1Gy

79
Q

Define the following terms:
1. Cell death
2. Log cell kill
3. Therapeutic ratio

A

Cell death: Inability to proliferate; both DNA strands must be knocked out

Log cell kill: Particular radiation dose will kill the same proportion of cells

Therapeutic Ratio (TR): Dose response curves between tumor cell and normal tissue damage
- Relative positions of the curve determines safety vs tumor control

TR = [reoxygenation + redistribution] / [repair and repopulation]

80
Q

Define the following tumor volume definitions:
1. Gross tumor volume (GTV)
2. Clinical target volume (CTV)
3. Planning target volume (PTV)
4. Treated volume
5. Irradiated volume
6. At risk organ (critical structures)

A

GROSS TUMOR VOLUME (GTV):
- Palpable or visible/demonstratable extent of tumor (not used if status post-op)

CLINICAL TARGET VOLUME (CTV):
- GTV plus the microscopic / subclinical extension

PLANNING TARGET VOLUME (PTV):
- CTV plus any uncertainty from day to day variations and errors

TREATED VOLUME:
- A volume that receives a dose that is considered important for local cure/pallation

IRRADIATED VOLUME:
- The tissue volume which receives a dose that is considered significant in relation to normal tissue tolerance

AT RISK ORGAN (CRITICAL STRUCTURE):
- Anatomical structures with important functional properties located in the vicinity of the target volume

Vancouver Page 77

81
Q

What are the two main mechanisms of cell injury by radiotherapy?

Which mechanism is more common?

A
  1. Direct injury: Electron from x-ray absorption causes DNA damage (~1/3)
  2. Indirect injury: Electron from x-ray creates an oxygen free radical which then damages the DNA (~2/3)
82
Q

What are the 4 R’s of radiotherapy injury mechanisms?

A
  1. REPAIR
    - Sublethal injury will be repaired by the cell if it takes no further hits
    - Radiation inhibits ability of tumor cells with sublethal injuries to repair between doses (therefore increased fractionation helps with this - not as much time to repair)
    - Normal cells heal faster, therefore can repair before the next dose more quickly than tumor cells
  2. RE-OXYGENATION
    - Presence of oxygen increases the effects of ionizing radiation (ie. tumor cells are more radiosensitive when oxygenated)
    - Radiosensitivity stays the same down to 20mmHg oxygen, below this - sensitivity decreases
    - Hyperfractionation allows reaccumulation of oxygen into the tissues
  3. REDISTRIBUTION
    - Maximum radioresistance occurs in late S phase of cell cycle
    - Maximum radiosensitivity occurs in early M phase
    - Increased fractionation allows increased redistribution of tumor cells into radiosensitive phases (M phases)
  4. REPOPULATION
    - Tumors accelerate repopulation after cell reduction from surgery or radiation
    - This justifies the therapeutic window for post-op radiotherapy
    - Hyperfractionation delivers higher/faster doses to tissues to ensure that maximum dose is reached prior to onset of tumor repopulation (which usually occurs ~ 5weeks)
83
Q
  1. What biologic reason explains the utility of hyperfraction?
  2. What property of radiotherapy injury is accelerated fractionations addressing?
A
  1. Redistribution and reoxygenation (and repair)
  2. Minimalize repopulation of tumor
84
Q

What are 3 characteristics of a tumor that is radioresistant?
How are they typically managed? 2
What are the best type of tumors for radiation?

A
  1. Better ability to repair
  2. More well differentiated
  3. Necrotic centre: less O2 free radicals formed
  • Managed with increased dose, decreased fractionation (more toxicity)
  • Pre-treatment PET: Improves target definition and tumor volume;
  • Best tumors are small, homogeneous, and vascular (e.g. Lymphoma, HPV, SCC)
85
Q

What is the limitation of increasing radiation intensity?
What is the limitation of increasing the total dose of radiation?

A
  1. Intensity limitation (ie. how fast the overall radiation can be given): Acute toxicity/mucositis
  2. Total dose limitation: Late toxicity / soft tissue fibrosis, risk of second malignancy
86
Q

What are the general indications for radiotherapy in head and neck cancer? 8

A
  1. Neoadjuvant (shrink)
  2. T3-4 tumors
  3. N2b+ (multiple positive nodes)
  4. Extracapsular spread
  5. Perineural and lymphovascular invasion
  6. Positive margins
  7. Non-surgical candidate
  8. Palliation
87
Q

What are the typical doses of radiation in head and neck cancer to the primary site? List them for definitive/primary rads, adjuvant rads, and palliative?

A

Definitive: 60-72 Gy (in 35 fractions over 7 weeks)
- “Standard schedule” in H/N is 70 Gy in 35f over 7 weeks

Adjuvant: 56-66 Gy (in 30-33 fractions over 6-6.5 weeks)
- Standard post-op with clear margins and no ECE: 60-66 in 30-33 fractions
- 66 Gy if positive margins
- 70 Gy if gross residual disease

Palliative: 20-30 Gy in 1-5 fractions (for pain and bleeding)

88
Q

What are the typical doses of radiation in head and neck cancer in management of the neck? List them for definitive/primary rads vs. adjuvant rads?

A

Definitive:
- N0: 40-64Gy (2 Gy per fraction) to 52-63 Gy (1.6-1.8 Gy per fraction)
- N+: 66-74 Gy (same as primary site)

Adjuvant:
- N0: 44-64 Gy
- N+: 60-66 Gy (same as primary site)
- N2A/B with negative ENE = 60 Gy
- > 3cm, ENE+ = 66 Gy
- N3 or positive margin = 66 Gy

89
Q

What are the different radiation regimens/schedules? 6

A
  1. Traditional fractionation
  2. Hyperfractionation
  3. Acclerated Fractionation
  4. Accelerated + Boost
  5. Split course
  6. Hypofractionation

Vancouver Pg 78

90
Q

Regarding traditional fractionation, discuss:
1. What is the typical dose/schedule overall?

A

2 Gy daily, 5x per week

7 weeks total (70 Gy)

91
Q

Regarding Hyperfractionation, discuss:
1. What is the typical dose/schedule overall?
2. What aspect of the 4Rs does this regimen target?
3. Are there special indications for this regimen?
4. What are the advantages?
5. What are the disadvantages?

A

HYPERFRACTIONATION:
- Doses are delivered over a same total period of time, but delivered in more fractions with smaller doses per fraction (e.g. BID instead of daily), allowing higher total dose amount overall

DOSAGE/SCHEDULE:
- 1.2Gy BID 6 hours apart, 5x per week, x 7 weeks total (81 Gy)

4Rs:
- Better tumor cell reoxygenation and redistribution (and repair)

ADVANTAGES:
- 8% benefit in overall survival at 5 years (some say no OS?)
- Decrease long-term toxicity the more fractions you split the total dose in (in theory, this allows higher overall doses)
- Improved locoregional control
- Greater total dose, increasing tumor kill

DISADVANTAGES:
- More inconvenient for patients as it’s more than once daily
- Increase in acute mucositis and acute toxicities

92
Q

Regarding Hypofractionation, discuss:
1. What is the typical dose/schedule overall?
3. Are there special indications for this regimen?

A

Hypofractionation:
- Less total dose, fewer sessions with higher dosage per session

Dosage/Schedule:
- Variable depending on total dose given
- E.g. 6 Gy doses for 5 fractions, for total dose 30 Gy over 2.5 weeks
- E.g. 50 Gy in 3-5 sessions in 2-4 weeks (usually Day 1, 7, 21)

Indications:
- Palliative
- Post-op melanoma

93
Q

Regarding Accelerated Fractionation, discuss:
1. What is the typical dose/schedule overall?
2. What aspect of the 4Rs does this regimen target?
3. Are there special indications for this regimen?
4. What are the advantages?
5. What are the disadvantages?

A

ACCELERATED FRACTIONATION:
- Same overall dose with faster application (more times per week, less weeks)
- Shortens total treatment time
- Accelerated fractionation and hyperfractionation are NOT mutually exclusive (can still do both in a shorter period of time - reduced doses per fraction, shorten overall time)

DOSAGE/SCHEDULE:
- 1.6 Gy BID, 5-7x per week, x 6 weeks instead of 7 (Total 67 Gy)

4Rs:
- Better reoxygenation and redistribution
- Prevents repopulation faster

ADVANTAGES:
- 2% benefit in overall survival at 5 years (some say no OS?)
- Improved loco-regional control
- More convenient than hyperfractionation since less overall time

DISADVANTAGES:
- Increase acute toxicities, no change or slightly better late toxicity
- More inconvenient than traditional as more than once daily

94
Q

What is Accelerated Fractionation with Boost?

A

Dosage:
- 1.8 Gy daily to large field, 5x/week, x 6 weeks total
- PLUS 1.6 Gy boost to small field in a 2nd dose on last 12days of treatment (Total 72 Gy)

95
Q

What is Accelerated Fractionation with Split dose?

A
  • Accelerated course that is interrupted with a 2 week break in the middle
  • Allows for repair of normal tissues
96
Q

How does dose per fraction and rate of radiation administration modify acute and long term side effects of radiation?

A

A. INCREASED DOSE PER FRACTION:

  1. Increases long term side effects
    - This explains why pure hyperfractionation (lowering dose per fraction) decreases long term side effects (e.g. soft tissue fibrosis), and allows for increased overall dose overall
  2. Increases acute side effects

INCREASED RATE OF ADMINSTRATION:

  1. Increases acute side effects
    - Explains why pure accelerated fractionation increases acute effects (e.g. skin erythema, mucositis)
    - Acute effects may also present earlier
97
Q

What factors of radiation increases risk of long term toxicity?

A
  1. Dose per fraction
  2. Total dosage overall
98
Q

What are the advantages and disadvantages of pre-operative neoadjuvant radiotherapy? Name 5 for each

A

ADVANTAGES:
1. Better blood supply pre-operatively, thus more radiosensitive
2. Unresectable tumors can be made resectable (shrinks tumor load)
3. Malignant cells at the periphery are destroyed, thus extent of surgical resection can be diminished
4. Tumor seeding at the time of resection may be decreased due to decreased viability
5. Fewer and less viable cells intravascularly & within lymphatics at the time of surgery may decrease distant metastases

DISADVANTAGES:
1. Resection and reconstruction more difficult due to fibrosis, inflammation, and decreased blood supply
2. Obscured tumor margins by tumor shrinkage and inflammatory response
3. Wound healing problems increase as dose > 40 Gy
4. Lower overall dose can be given
5. Harder to stage clinically/pathologically during/after surgery

99
Q

What are the advantages and disadvantages of post-operative adjuvant radiotherapy? Name 6 advantages and 2 disadvantages

A

ADVANTAGES:
1. Safer administration of higher total doses of radiation
2. Destruction of subclinical residual tumor
3. Surgical resection easier, healing is better in non-irradiated tissues
4. Distinct tumor margins which facilitates more accurate and complete surgical removal
5. Ability to direct radiation specifically at areas inaccessible by surgery
6. Better staging possible

DISADVANTAGES:
1. Surgery may interrupt blood flow to remaining tumor cells, making them less radiosensitive
2. Wound breakdown or infectious complications may delay the onset or prevent radiotherapy delivery

100
Q

When is the best post-operative time interval for adjuvant XRT?

A

Within 6 weeks (ideally 3 weeks, but realistically ends up closer to 6)

101
Q

Regarding the “Overall Treatment TIme Study” (Ang, 2001), discuss:
1. What did this study?
2. What were the treatment groups?
3. What were the results?
4. What were the conclusions?

A

OVERALL TREATMENT TIME STUDY: Compared adjuvant XRT in 3 groups for advanced H/N cancer and outcomes were analyzed
- Advanced H/N cancer with primary surgical treatment, post-op were stratified into 3 groups for XRT

TREATMENT GROUPS:
1. Low risk: Did not receive radiotherapy
2. Intermediate risk: 57.6 Gy over 6.5 weeks
3. High risk: 63 Gy in 5 or 7 weeks

RESULTS:
- Proved that certain risk factors (e.g. PNI, nodal status, positive margins, and ENE) were higher risk, and adjuvant RT could be offered based on these
- Patients who completed treatment > 13 weeks after surgery had > 2 x risk of locoregional recurrence, compared to those who completed in < 11 weeks
- No significant difference in results between standard and accelerated fractionation alone; but accelerated regimens were more likely to be completed within 11 weeks

102
Q

What are the general indications for Adjuvant XRT vs. Adjuvant ChemoXRT? 8 for adjuvant rads, 2 for chemorads

A

XRT:
1. Presence of residual microscopic disease
2. T3/T4 lesions
3. Perineural invasion (PNI)
4. Lymphovascular invasion (LVI)
5. Oral or oropharyngeal cancers with level IV or V lymph nodes
6. Multiple positive nodes
7. Aggressive histology
8. Poor differentiation

CHEMO XRT:
1. Extranodal extension
2. Positive margins

103
Q

What are the most common acute and late radiotherapy-related toxicities?

A

ACUTE = Mucositis
LATE = Tissue Fibrosis

104
Q

What are all the possible acute 2 and late 10 toxicities of radiotherapy? List as many as you can think of

A

ACUTE:
1. Mucositis (most common)
2. Xerostomia (50% reduction after 10-20 Gy, 75% reduction after 50Gy (above 20))

LATE (think structure by structure):
1. Skin necrosis
2. Tissue fibrosis
3. Myelopathy
4. Hypothyroidism
5. ORN (50Gy)
6. Dental caries
7. Trismus
8. Xerostomia
9. ETD
10. SNHL
11. Cataracts (6 Gy)
12. Retinopathy, optic nerve injury (50Gy)
13. Cranial neuropathies
14. Carotid artery stenosis
15. Transverse Myelitis (L’Hermitte’s sign) (50Gy)
16. Spinal necrosis (50Gy)
17. Brain Necrosis (70 Gy)
18. Secondary malignancy

Most bad side effects happen > 50 Gy total doses

105
Q

Regarding Radiation Mucositis, discuss:
1. What does this look like?
2. At what dosages does this occur?
3. What is the pathophysiology?
4. What is the treatment?

A

RADIATION MUCOSITIS:
- Edema and erythema, patchy fibrinous exudate ± ulcers
- Caused from damage by high cell turnover rates
- Worse with chemotherapy

DOSAGE:
- Starts around 20 Gy

PATHOPHYSIOLOGY:
- Atrophy of submucous glands –> decreased salivary production –> infections

TREATMENT: Healing takes 3-4 weeks, slowed by tobacco
1. Oral hygiene
2. Topical anesthetics
3. Hydrogen peroxide
4. Sodium bicarbonate rinses
5. Analgesia
6. Antibiotics
7. Antifungals
8. Cryotherapy (ice chips) have been shown to decrease pain
9. Trials: Amifostine, Allopurinal, Glutmate - all previously tried with mild success
10. Prophylaxis: Prostaglandin E3, Pentoxyphyline, Chlorohexidine

106
Q

Describe the WHO Mucositis Grading

A
  1. GRADE 1: Edema and erythema
  2. GRADE 2: Erythema ± patchy ulceration, solid diet tolerated
  3. GRADE 3: Diffuse ulceration, only liquid diet tolerated
  4. GRADE 4: Severe ulceration and pain, PO diet impossible, enteral support/intubation necessary
  5. GRADE 5 (NCI criteria): Death
107
Q

Describe the RTOG Mucositis grading

A
  1. Grade I: Injection, may experience mild pain, not requiring analgesics
  2. Grade II: Patchy mucositis which may produce an inflammatory discharge, may experience moderate pain requiring analgesia
  3. Grade III: Confluent fibrinous mucositis; severe pain; needs narcotics for analgesia
  4. Grade IV: Ulceration, hemorrhage, or necrosis
  5. Grade V: Death due to mucositis
108
Q

What are 6 intraorbital complications of radiotherapy? What are the dosages that could lead to these complications?

What modalities help protect the eye when treating nasal cancers?

A
  1. Cataracts (as little as 6Gy)
  2. Lacrimal gland injury (~35 Gy in 3.5 weeks)
  3. Radiation Retinopathy (50Gy)
  4. Optic nerve injury (50Gy)
  5. Dry eye/conjunctivitis/keratitis
  6. Glaucoma (30-40Gy)

PROTECTIVE MODALITIES:
1. IMRT
2. Protons
3. Eye shields

109
Q

What are toxic CNS doses of radiotherapy? What are 4 different complications it could cause, and at what dosages?

A
  1. Somnolence Syndrome (70 Gy, typically by 5-6 weeks post-treatment) - extreme lethargy, signs of increased ICP, headache/N/V/anorexia
  2. Myelopathy (50Gy in 25 fractions)
  3. Transverse Myelitis (50 Gy)
  4. Brain necrosis (70 Gy)
110
Q

What is L’Hermitte’s sign?

A

Electric shock sensation down arms from cervical spine transverse myelitis (also seen in MS)

111
Q

Regarding radiation induced salivary damage, discuss:
1. At what doses is this seen?
2. What does the histopathology look like?
3. What is the major risks? 1
4. What are the treatment?

A

DOSAGE:
- 50% at 1 week (10-20 Gy)
- 75% at 6 eweks (doses above 20-30 Gy, usually seen at 50)

HISTOPATHOLOGY:
- Parotid serous acini are the most sensitive
- Heavy metal ions are present in the granules and catalyze lipid peroxidation –> enzymatic spillage and cell lysis –> inflammation causes purulent exudate within ducts into parenchyme

MAJOR RISKS:
1. Permanent changes may increase risk of secondary neoplasia

TREATMENT:
1. Amifostine (cytoprotective adjuvant) can be given to decrease toxicity
2. Treatment for Xerostomia: Pilocarpine (muscarinic agonist) - increases the flow of undamaged cells

112
Q

Regarding iodine-induced salivary injury, discuss:
1. What proportion of RAI patients get this?
2. What causes this to happen?
3. Which gland does this happen more commonly in?

A

INCIDENCE:
- 10-60% of patients receiving RAI

MOA:
- Na-K transporter in salivary tissue concentrates I-131 levels that are 30-40 times higher than plasma levels, causing glandular damage
- More common in parotid (9:1 Parotid vs. Submandibular)

113
Q

What are the late complications of radiotherapy for nasopharyngeal carcinoma? Name 10

A
  1. Skin necrosis
  2. Osteoradionecrosis
  3. Cataracts - 6 Gy
  4. Middle ear effusion secondary to ET dysfunction
  5. Xerostomia - 35 Gy
  6. Transverse myelitis (50Gy)
  7. Somnolence syndrome
  8. Brain necrosis (65Gy)
  9. Carotid blowout
  10. L’Hermitte’s syndrome
114
Q

What are the main complications for radiotherapy in the neck? 9

A
  1. Xerostomia
  2. Mucositis
  3. Dental caries
  4. Osteoradionecrosis - in up to 5% of patients, rare < 60 Gy, increased risk if chemoXRT
  5. Pigment changes
  6. Soft tissue fibrosis - obliterative endarteritis
  7. Hypothyroidism - 1% clinically overt, 10% occult after 50 Gy in 4 weeks
  8. Immunosuppression
  9. Spinal cord necrosis - limit to 45-50 Gy in 5 weeks
115
Q

What spinal cord complications can occur post-radiotherapy? At what dosages can these occur? 4

A
  1. Radiation myelopathy
  2. L’Hermitte’s sign (electric shock sensations triggered by flexing the cervical spine
  3. Transverse myelitis
  4. Spinal cord necrosis

Doses of 50 Gy in 5-6 weeks

116
Q

What is the grading system for osteoradionecrosis?

A

MARX CLASSIFICATION:

  1. Stage I: Exposed bone, responds to HBO
  2. Stage II: Does not respond to HBO
  3. Stage III: Pathologic fractures, orocutaneous fistula, resorption of inferior border of mandible; or failure to respond to stage II
117
Q

What are the typical osseous findings of mandibular ORN on CT? (5)

A
  1. Cortical disruption or thinning
  2. Disorganization of trabeculation / loss of structure
  3. Osseous fragmentation
  4. Radiolucency, demineralization, sequestrum (island of dead bone), moth-eaten bone
  5. Pathologic fractures

CT POR

Vancouver Page 82

118
Q

What are the treatment modalities for osteoradionecrosis?

A

A. MEDICAL:
1. Local topical care
2. Biopsy
3. Culture
4. IV antibiotics
5. Nutritional support
6. Pentoxifylline 400mg q8h (phosphodiesterase inhibitor)

B. PROCEDURAL:
1. Hyperbaric oxygen
2. Debridement and partial mandibular resection (sequestrectomy) and removal of foreign bodies
3. Vascularized tissue transfer (local/regional/free)

119
Q

Regarding Hyperbaric Oxygen, discuss:
1. What are the different mechanisms of action? (6)
2. What are the different phases? 3
3. What are the indications? 7
4. What are the contraindications, both absolute and relative? 8

A

MECHANISMS OF ACTION:
1. Increases amount of O2 dissolved in solution
2. Increases diffusion distance from capillaries
3. Increases neovascularization
4. Increases fibroblast proliferation
5. IMproves leukocyte oxidative killing
6. Synergy with certain antibiotics (FQs, Aminoglycosides, Ampho B)

“OD NFL’S”

PHASES:
1. LAG PHASE (Treatments 1-8):
- Increased capillary budding and collagen synthesis
- Little detectable clinical change
- Little change in O2 tension

  1. LOG PHASE (Treatments 8-22):
    - Angiogenesis, increased fibroblasts/collagen/cellularity
    - Rapid response phase
    - Log increase in O2-tension
  2. PLATEAU PHASE (Treatments 22+):
    - O2 tension plateaus at 85% even with more treatments
    - Plateau of clinical response

INDICATIONS:
1. ORN
2. SSNHL
3. Decompression sickness (including inner ear decompression sickness)
4. Certain infections: Osteomyelitis, necrotizing fasciitis, malignant OE
5. Poor wound healing
6. Flap failure
7. Pre and post-dental work (especially extractions in radiated patients)
8. Air embolus

ABSOLUTE CONTRAINDICATIONS:
1. Untreated pneumothorax
2. Active cancer

RELATIVE CONTRAINDICATIONS:
1. Airway disease (e.g. asthma, COPD, bullous emphysema)
2. History of seizures (seizures from O2 toxicity are a potential complication of HBOT)
3. Claustrophobia
4. Pregnancy
5. Uncontrolled fever - higher risk of seizures
6. Medications: Doxorubicin

120
Q

What is the current protocol for treatment of mandibular osteoradionecrosis, according to Marx?

A

STAGE I: ALVEOLAR BONE EXPOSED
- 30 HBO dives (1 dive/day, 5x/week) - 2.4 atm x 90 minutes per dive
- Reassess for decreased bone exposure, granulation tissue covering, exposed bone, resorption of non-viable bone, and absence of inflammation
- If good response, do 10 more dives (40 total)
- If no response, proceed to stage II
- If develops orocutaneous fistula, pathologic fractures, resorption of inferior border of the mandible, proceed to stage III

STAGE II: DOES NOT RESPOND TO HBO
- Transoral sequestrectomy with primary closure
- If good response with this, do 10 more dives
- If no response, or complications as above, proceed to stage III

STAGE III: OROCUTANEOUS FISTULA, PATHOLOGIC FRACTURE, RESORPTION OF INFERIOR BORDER OF MANDIBLE, or STAGE II FAILURE
- Transcutaneous mandibular resection + wound closure + mandibular fixation with external fixator or maxillomandibular fixation
- If responds to this, do 10 more dives

121
Q

Regarding the drug Pentoxifylline, discuss:
1. What is it?
2. What is its utility or advantages?
3. What are 5 different mechanisms of action?
4. How is it delivered?

A

PENTOXIFYLLINE:
- Xanthine Derivative

UTILITY/ADVANTAGES:
- Increase circulation and blood flow (e.g. for ORN, claudication, PVD, etc.)
- Prevent bronchoconstriction (e.g. asthma, etc.)
- Reduce radiation late side effects

MECHANISM OF ACTION (“VD-FACE”):
1. Decreases blood viscosity and increases blood cell deformability (allows increased circulation)
2. Increases fibrinolytic activity
3. Adenosine receptor antagonist, non-selective
4. Increases cAMP
5. Erythrocyte phosphodiesterase inhibition
6. Decreases platelet aggregation
7. Vasodilation

DELIVERY METHOD:
1. Give with Tocoferol (Vitamin D analogue)

122
Q

What is the definition of a close margin?

A
  • ≤ 5mm
123
Q

What is the time required after XRT radiotherapy to call a repeat biopsy reliable, and why?

A
  • 3 months post treatment

Rationale:
- Lethally injured cells and normal surviving cells appear morphologically identical
- Injured cells must be allowed to die off (lyse), which requires 4-5 cycles of mitosis (lysis occurs at mitosis)

124
Q

List Cahan’s 4 criteria in the diagnosis of post-radiation sarcoma (PRS)?

A
  1. Histologic features of the original lesion and PRS are completely different
  2. PRS is located within the field of irradiation
  3. Tissue from which alleged RT induced tumor arose must have been normal tissue prior to radiation exposure
  4. Latent period (period between initation of radiotherapy and histologic diagnosis of seceond neoplasm) is > 4 years
125
Q

Discuss the EORTG 22931 (2004) study and RTOG 9501 (2004) study

A

Both studies evaluate the role of post-op RT alone vs. RT + concurrent chemo, randomized high risk patients

EORTG: Improved survival and locoregional control
RTOG: Improved locoregional control, no statistically significant increase in survival

Combined analysis:
- Patients with positive margins and extracapsular extension had survival benefit with addition of cisplatin post-op
- Implication: This forms the basis of offering CRT for patients with positive margins or ENE

126
Q

Define the ECOG score. What is its significance?

A

ECOG score:
- Eastern Cooperative Oncology Group
- Pre-treatment functional assessment helps predict ability to tolerate treatment
- Usually patients ECOG 1-2 or better are fit enough to undergo ChemoXRT

Score 0:
- Asymptomatic
- Fully active, able to carry on all pre-disease activities without restriction

Score 1:
- Symptomatic, but completely ambulatory
- Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (e.g. light housework, office work)

Score 2:
- Symptomatic, < 50% in bed during the day
- Ambulatory and capable of all self-care but unable to carry out any work activities
- Up and about more than 50% of waking hours

Score 3:
- Symptomatic, > 50% in bed, but not bedbound
- Capable of only limited self-care, confined to bed or chair 50% or more of waking hours

Score 4:
- Bedbound, completely disabled
- Not able to carry on any self-care, totally confined to bed or chair

Score 5:
- Death

127
Q

Describe the Karnovsky Index. What is its significance?

A
  • A performance scale to measure patient functional status and fitness for treatment
  • Parallels ECOG, slightly different scoring
  • Essentially, 0 = perfectly well, 100 = dead

Head and Neck (15 decks)

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