Head and Neck Flashcards
Describe the 5 phases of the cell cycle
- G0 = resting phase
- G1 = Growth phase 1 in preparation for DNA synthesis
- S = DNA synthesis
- G2 = Growth phase 2 in preparation for division
- M = Mitosis
During which stages of the cell cycle are cells most and least susceptible to damage from Chemo/XRT?
- S = DNA synthesis (most resistant phase)
- G2 = Growth phase 2 in preparation for division (2nd most sensitive phase)
- M = Mitosis (most susceptible phase)
Describe 5 methods for targeting a Vector to a specific cell type
- Tumor-specific promoter
- Activate promoter gene expression specifically in tumor cells (ex CEA, AFP)
- Non-specific promoter
- Drive replication in all susceptible cell types, higher risk for toxicity (ex CMV)
- Direct, receptor-targeting
- Create ligand for specific receptor characteristic of tumor cells
- Indirect, inverse-targeting
- DEtarget healthy, non-tumor cells to improve vector selectivity for cancer cells
- Indirect, protease-targeting
- Selective infection of cells w/ specific surface protease (which activate the viral receptor and allow viral entry)
List different viral vectors currently in use in H&N cancer
- Adenovirus
- Reovirus
- Rhabdovirus
- Measles
- Mumps
- HSV
- Vaccinia
What are two gene types involved in cell growth in cancer?
- Tumor Suppressor Genes (limit cell growth through negative feedback)
- ProtoOncogenes > Mutated Oncogenes (induce cell growth)
Which Tumor Suppressor Genes are involved in H&N Cancer?
p53 - Regulates cell cycle & apoptosis
- Involved in > 50% of HNSCC
- Bad prognosis
p16 (protein from CDKN2A gene) - Suppresses cyclin-dependent pathways
- Involved in > 70% of HNSCC
- Surrogate marker for HPV
- Good prognosis
RB - Inhibits transcription factor E2F
- Involved in > 60% HNSCC
Which Oncogenes are involved in H&N Cancer?
EGFR - Mutation promotes epidermal overgrowth
- Involved in > 90% HNSCC
- Poor prognosis
Cyclin D1 - Phosphorylates Rb, accelerates cell cycle
- Associated with increased recurrence, nodal mets, death
RET Translocation - Receptor TK involved in cell growth
- Associated with MEN2
RAS - Signal transducer for surface growth factor receptors
BRAF - Protein kinase activated by oncogenic RAS to increase growth factor signaling
- Associated with PTC
C-MYC - Transcription regulator
- Common in HNSCC
- Associated with Burkitt’s Lymphoma
- Poor prognosis
BCL-2 - Counteracts p53 & inhibits apoptosis
- Good prognosis
In what situation does HPV+ status NOT improve prognosis
History of smoking > 10 years
Discuss possible mechanisms of immunocompromise in HNSCC
HOST-related:
- Comorbid condition (ex. HPV, SLE, DM2, etc)
- Circulating immune complexes
- Suppressor T-cells
- Ig-blocking Antibodies
- TGF-B
TUMOUR-related:
- Tumor production of immunosuppressant agents (ex. VEGF, IL-1, IL-10)
- Tumor suppression of innate immunity
- Tumor antigenic modulation
EXOGENOUS:
- Chemo/XRT
- Immunosuppressant medications (ex. steroids, IFN, methotrexate, cyclophosphamide, etc)
Methods to assess adequate cerebral perfusion prior to carotid ligation
- Balloon occlusion test
- 4-vessel angiography (carotids & vertebrals)
- SPECT
- Xenon-133 flow scan
- CTA/MRA
What is the incidence of CVA/stroke following carotid occlusion at different speeds?
Acute occlusion (ex. ligation in OR w/o pre-op measures) = 50%
Gradual occlusion over <7d (ex. intraluminal tumor invasion) = 30%
Gradual occlusion over >7d (ex. vessel compression by tumor, or pre-op tx) = 5%
What intervention can be done pre-op to reduce the likelihood of CVA post surgical ICA ligation
Pre-op embolization (aka permanent balloon occlusion):
- Embolization of ICA just proximal to ophthalmic artery takeoff
- Reduces stump emboli
- 2 weeks pre-op
- Monitor for 72h post-procedure
List the segments of the ICA
C1 = Cervical
C2 = Petrous TB
C3 = Foramen Lacerum
C4 = Cavernous Sinus
C5 = Clinoid
C6 = Ophthalmic
C7 = Communicating
Define Simultaneous Tumors
Separate primary tumors diagnosed at same time
Define Synchronous Tumors
Separate primary tumors diagnosed within 6 months of each other
Define Metachronous Tumors
Separate primary tumors diagnosed > 6 months of each other
Define 2nd Primary
Separate primary tumor, based on:
- Different cell type
- Different location
- Different metastatic nodal group
**10% risk 2nd primary in non-smokers
**Risk increases to 50% in smokers
**50% develop within 2 years of 1st primary
How does continued smoking & ETOH use affect risk of recurrence and 2nd primary?
Up to 50% risk recurrence and/or 2nd primary
Describe the phases of clinical trials
PHASE 1 = Safety trial (dose determination, side effects)
PHASE 2 = Efficacy trial (does it work?)
PHASE 3 = Comparative trial (how does it compare to standard therapies?)
PHASE 4 = Post-marketing assessment of long-term complications
What is RECIST?
Response Evaluation Criteria in Solid Tumours
According to RECIST, what qualifies as a measurable lesion?
10mm in long axis on clinical or CT exam
According to RECIST, what qualifies as a pathological LN?
15mm in short axis on CT
According to RECIST, what is a target (or index) lesion?
Largest, most representative lesion (max 5 total, or 2/organ
- Used to track and assess treatment response
- More does not yield more accurate assessment and just wastes time & resources)
Define Objective Response (OR) according to WHO and RECIST
RECIST = Change in sum of longest dimensions of target lesions (max 2 lesion/organ, max 5 lesions overall)
WHO = change in sum of [longest dimension x cross dimension]s of all lesions
Define Complete Response (CR) according to WHO and RECIST
RECIST = Disappearance of all lesions/disease (AND reduction in LNs to <10mm) by 4+wks
WHO = (same)
Define Partial Response (PR) according to WHO and RECIST
RECIST = >30% decrease by 4+wks
WHO = >50% decrease by 4+wks
Define Stable Disease (SD) according to WHO and RECIST
RECIST = no Partial Response or Progressive Disease (no change)
WHO = same
Define Progressive Disease (PD) according to WHO and RECIST
RECIST = >20% (min 5mm) increase over smallest sum, or new lesion(s)
WHO = >25% increase in any lesion, or new lesion(s)
Seven roles for chemo in HNSCC
- Neo adjuvant
- Adjuvant (+margins, +ECS)
- Non-surgical candidate
- Palliation
- Investigative
- Primary treatment in NPC
- Organ-preservation in T3-4 larynx
What factors determine the success of chemo?
- Tumor burden (# cells)
- Inherent/acquired resistivity to chemo
- % cells in M-phase of cell cycle (responsive phase)
How many cells must a tumor have before it’s palpable?
> 100,000
Indications for chemo
Primary
- In combination with radiation therapy for certain malignancies (nasopharyngeal, oropharyngeal, hypopharyngeal, and laryngeal)
- Lymphoma
- Not a surgical candidate
Adjuvant
- Positive margins
- Extracapsular spread
- Investigative
What is the max age for consideration of chemo?
70y - above this too toxic??
What classes of chemotherapy are available?
AAAATTBB
Alkylating Agents (Cisplatin, Carboplatin)
Alkaloids (Vincristine, Vinblastine)
Antibiotics (Bleomycin, Mitomycin, Hydroxydaunomycin)
Antimetabolites (Methotrexate, 5-FU)
Taxanes (Paclitaxel, Docitaxel)
Topoisomerases (Etoposide, Topotecan)
Biologics - Targeted (Cetuximab, Ipilimumab)
Biologics - Nonspecific (Gefitinib, Sunitinib)
Aklylating Agents: MOE, Dosing, side effects
MOA: Interferes w/ DNA synthesis & replication
Dosing: Cisplatin 100mg/m2, up to 3 doses, q3wks
Side Effects: Oto/neuro/nephro-toxicity, myelosuppression, mucositis, dermatitis
Cisplatin = Most effective single-agent chemo
Carboplatin has less oto/neuro/nephro effects, but +++myelosuppression
Akaloids: MOE, Dosing, side effects
Vincristine, Vinblastine
MOA: Interferes w/ microtubule formation
Side Effects: peripheral neuropathy, alopecia
Antibiotics (Chemotherapy): MOE, Dosing, side effects
Bleomycin, Mitomycin, Hydroxydaunomycin
MOA: Interferes w/ DNA synthesis & replication
Side Effects: pulmonary fibrosis, myelosuppression
Antimetabolites: MOE, Dosing, side effects
Methotrexate: interferes w/ DNA synthesis via impaired Folate metabolism
5FU: interferes w/ DNA synthesis via defective Uracil analog
Side Effects: mucositis, dermatitis, myelosuppression
Taxanes: MOE, Dosing, side effects
Paclitaxel, Docitaxel
MOA: disrupt microtubule function = impaired cell division in M phase
Side Effects: neuropathy, alopecia
Topoisomerases: MOE, Dosing, side effects
Etoposide, Topotecan
MOA: prevent DNA unwinding for replication
Side Effects: mucositis, dermatitis
Biologics (Targeted): MOE, Dosing, side effects
Cetuximab, Ipilimumab
MOA: monoclonal antibodies against EGFR
Side Effects: cardiotoxicity, dermatitis
Biologics (Nonspecific): MOE, Dosing, side effects
Gefitinib, Sunitinib
MOA: tyrosine kinase inhibitors that inhibit EGF/VEGF
Side Effects: dermatitis
In general, is combination chemo any more effective than single agent?
- No change in overall survival
- More side effects
- However higher response rates seen w/ some combos (Cis-5FU; Carbo-Taxol)
- Carbo-5FU used sometimes instead of Cisplatin when Cis contraindicated due to renal failure
In general, is induction chemo any more effective than concurrent?
- No change in overall survival
- Some studies suggest concurrent better, but can do either (centre-specific)
- BUT can’t do BOTH induction and concurrent -> far too toxic for anyone to handle
(rare exception: NPC) - Best induction combo: Docitaxel-5FU-Cisplatin
Describe the broad categories of radiation therapy
External Beam (Photon, electron)
Brachytherapy
Ingested (RAI)
Proton, Neutron
Describe the types of External Beam Radiation
Conventional 3D-Conformational
- Manual, multi-beam, uniform intensity
Intensity Modulated RT (IMRT)
- Computerized, multi-beam, variable intensity
Image-guided RT
- Repeat imaging throughout treatment course to modify target/volumes
Stereotactic
- Uses external frame [ex. face mask] for minimal movement, high precision
Gamma knife (“Radiosurgery”)
- Stereotactic single large dose/small volume
Compare Mega-Volt (Photon) vs Electron Beam RT
MEGAVOLT = photons, deep tissue penetration, surface-sparing
EB = electrons, superficial penetration, spares deep tissues
Discuss IMRT
Intensity-Modulated Radiation Therapy
- Uses photons
- Multi-beam
- Intensity varies -> moderates dose across field to contour target volume to lesion
Possible methods of deliverying brachytherapy
- Interstitial (rods)
- Intercavitary (seeds)
- Surface Mould
Advantages of brachytherapy
- Direct application of radiotherapy
- Minimizes effects on surrounding tissues
- Continuous dose
Disadvantages of brachytherapy
- Local tissue necrosis
- May miss some areas of tumor
- Inconsistent dose delivery to cells at different proximities
- Pt is radioactive throughout treatment duration (must remain isolated, away from kids & pregnant women, etc)
Describe the different methods of cell injury by XRT
Direct injury
- Direct DNA damage
Indirect injury
- Creates oxygen free radicals which further damage DNA
4 Rs of Radiotherapy Damage
REPAIR
- Inhibits ability of tumor cells with sublethal injuries to repair between doses (normal cells heal faster, tf can repair before next dose)
REDISTRIBUTION
- Allows more cells to shift into into M-phase (the most radio-sensitive)
REOXYGENATION
- Allows reaccumulation of oxygen in tissues (tumor cells only radiosensitive when oxygenated)
REPOPULATION
- Delivers higher/faster doses to tissues to ensure maximum dose is reached prior to onset of tumor repopulation (which usually occurs ~5wks)
Define Gray and Rad
RAD - Radiation Absorbed Dose
GRAY - Dose of radiation required to have 1J of energy absorbed by 1 kg of matter
1Gy = 1 J/kg = 100 rad
**Rad has largely been replaced by Gy in modern measurement/lingo
Most common acute and late XRT-related toxicities
ACUTE = mucositis
LATE = tissue fibrosis
WHO Mucositis Grading
Grade 1: edema & erythema
Grade 2: erythema +/- patchy ulceration, solid diet tolerated
Grade 3: diffuse ulceration (liquid diet only)
Grade 4: severe ulceration and pain (PO diet impossible, enteral support/intubation necessary)
(NCI adds -Grade 5: death)
Typical XRT Indications
Neoadjuvant (to shrink)
T3-4
N2b+ (multiple +nodes)
ECS
Perineural/lymphovascular invasion
Positive margins
Unable to undergo surgery
Palliation
Typical Head and Neck Radiation Dose
DEFINITIVE = 70 Gy (in 35f over 7wks)
ADJUVANT = 60-66 Gy (in 30-33f over 6-6.5wks)
Traditional Head and Neck Radiation Regimen
2 Gy daily, 5/wk, x7wks (Total 70 Gy)
Hyperfractionated Head and Neck Radiation Regimen
1.2 Gy BID, 5/wk, x7wks (Total 81 Gy)
- Higher overall dose
- More inconvenient than once daily
- Worse acute toxicities, better late toxicities
- Better Reoxygenation & Redistribution
- No OS improvement
Accelerated Head and Neck Radiation Regimen
1.6 Gy BID, 5/wk, x6wks (Total 67 Gy)
- Same overall dose, faster application
- More inconvenient than once daily
- Worse acute toxicities, better late toxicities
- Better Reoxygenation & Redistribution, prevents Repopulation
- No OS improvement
Accelerated + Boost Head and Neck Radiation Regimen
1.8 Gy daily to large field, 5/wks, 6wks
PLUS 1.6 Gy to small field in 2nd dose on last 12d (Total 72 Gy)
Split Course Head and Neck Radiation Regimen
Accelerated course interrupted by 2wk break in the middle
- Allow repair of normal tissue
Hypofractionated Head and Neck Radiation Regimen
50 Gy in 3-5 sessions over 2-4wks
- Palliative
Radiation Regimen to Nodal Basins
Primary XRT:
- N0 = 44-64 Gy
- N+ = 66-74 Gy (same as primary site)
Adjuvant XRT:
- N0 = 44-64 Gy
- N+ = 60-66 Gy (same as primary site)
Early complications of XRT
Mucositis (most common)
Xerostomia (50% reduction after 20 Gy, 75% reduction after 50 Gy)
Late complications of XRT
Skin necrosis
Tissue fibrosis
Myelopathy
Hypothyroidism
ORN (50 Gy)
Dental caries
Trismus
Xerostomia
ETD
SNHL
Cataracts (6 Gy)
Retinopathy, Optic Nerve injury (50 Gy)
Cranial neuropathies
Carotid artery stenosis
Transverse myelitis -> L’Hermitte’s Sign (50 Gy)
Spinal necrosis (50 Gy)
Brain necrosis (70 Gy)
2e malignancy
What is L’Hermitte’s Sign?
Electric-shock sensation down arms from cervical spine transverse myelitis (also seen in MS)
Advantages of Neoadjuvant XRT
- Shrinks tumor load
- Pre-op tissues are more radio-sensitive than post-op (better blood supply)
- Tumor seeding (local & distant via LV showering of mets) during surgery may be reduced due to reduced viability
Disadvantages of Neoadjuvant XRT
- Obscures margins
- Resection/recon more difficult due to fibrosis, scar, poor blood supply
- Poor wound-healing >40 Gy
- Lowers overall XRT dose that can be given
- Harder to stage clinically/pathologically during/after surgery
Advantages of Adjuvant XRT
- Addresses bad histologic features (+margins, ECS, PNI, LVI, high T/N)
- Treat subclinical disease
- Treat disease inaccessible w/ surgery
Disadvantages of Adjuvant XRT
- Complications of XRT
- More susceptible to wound breakdown & complications
- Higher risks as # modalities increases
Best time to start post-op XRT for maximum effect
< 6wks (ideally 3wks, but realistically usually ends up closer to 6wks)
General anti-cancer mechanisms of concurrent chemo-XRT
- Recruits cells from G0 to M phases
- Synchronizes cells into same phase, increasing effectiveness of both chemo + XRT
- Radiosensitizes, prevents radiation resistance
- Inhibits tumor cell repair from sublethal XRT injury
- Causes tumor shrinkage -> allows increased drug & O2 delivery
- Can act on different subsets of tumor cells (ex. those that may be radioresistant)
What are Marx’s Stages of ORN, and how are they treated?
STAGE 1 = exposed bone
- Local topical care, debride, biopsy, culture & IV antibiotics, nutritional support, Pentoxifylline
- 30-40 HBO dives
STAGE 2 = does not respond to HBO
- Partial resection, local flap closure, and complete total 40 HBO dives
STAGE 3 = full-thickness ORN, pathologic #, orocutaneous fistula
- Resect & free flap or plate; 10 extra post-op HBO dives
What is the class and MOA of Pentoxifylline?
Xanthine Derivative
- Increases circulation & blood flow (ie. for ORN, claudication, PVD, etc)
- Prevent bronchoconstriction (asthma, etc)
MOA:
- Inhibit phosphodiesterases:
- Lowers blood viscosity: increases blood cell deformability -> allows increased circulation
- Vasodilation
- Decrease platelet aggregation
What findings on CT suggest ORN
- Radiolucency
- Cortical thinning
- Moth-eaten appearance
- Loss of trabecular structure
- Pathologic #
- Sequestrum (island of dead bone)
Mechanism of Action of Hyperbaric Oxygen
- Increases amount of O2 dissolved in solution
- Increases diffusion distance from capillaries
- Increases neovascularization
- Increases fibroblast proliferation
- Improves leukocyte oxidative killing
- Synergy w. certain abx (Fluoroquinolones, Aminoglycosides, Ampho B)
Phases of Hyperbaric Oxygen Treatment
LAG PHASE (tx 1-8):
- Increased capillary budding & collagen synthesis
- Little detectable clinical change
- Little change in O2-tension
LOG PHASE (tx 8-22):
- Angiogenesis, increased
- Fibroblasts/collagen/cellularity
- Rapid response phase
- Log increase in O2-tension
PLATEAU PHASE (22+):
- O2-tension plateaus @ 85% even w. more txs
- Plateau of clinical response
Indications for Hyperbaric Oxygen Treatment
- ORN
- SSNHL
- Decompression sickness (incl. inner ear decompression sickness)
- Certain infections: Osteomyelitis, Nec Fasc, malignant OE
- Poor wound healing
- Flap failure
- Pre and post dental work (especially extractions) in radiated pt
Contraindications to Hyperbaric Oxygen Treatment
ABSOLUTE:
- Untreated pneumothroax
- Active cancer
RELATIVE:
- Airway disease (asthma, COPD, bullous emphysema)
- History of seizures (seizures from O2 toxicity are a potential complication of HBOT))
- Claustrophobia
- Pregnancy
- Uncontrolled fever higher risk of seizures)
- Meds: Doxorubicin
Definition of a close margin
≤ 5mm
When can a biopsy be considered reliable post XRT?
3 months
- Lethally injured cells & normal cells are identical; injured cells must be allowed to die off (lyse), which requires 4-5 cycles of mitosis
Describe the ECOG scoring system and its significance
Eastern Cooperative Oncology Group
- Predicts ability to undergo/continue treatment
0 = Fully active (~Karnovsky 90-100)
1 = Symptomatic but ambulatory, can do light work (~K 70-80)
2 = Symptomatic, in bed <50% of day, can do self care (~K 60-50)
3 = Very symptomatic, in bed >50% of day, limited self-care (~K 30-40)
4 = Bedbound (~K 10-20)
5 = Dead
Usually only patients ECOG 1-2 or better are fit enough to undergo chemo-XRT
Describe the Karnovsky Index and its significance
Another performance scale to measure patient functional status & fitness for treatment
0 = Perfectly well
…
100 = Dead
Parallels ECOG
When must you treat the N0 Neck (Regardless of T Stage)?
Nasopharynx - Bilateral Levels II - V
Oropharynx - Unilateral Levels II - IV
- Tonsil - Unilateral up to T3N2b, above this do bilateral
- Palate - Bilateral
- BOT - Bilateral
Hypopharynx - Unilateral Levels II - IV +/- VI
Supraglottis - Bilateral Levels II - IV +/- VI
Subglottis - Bilateral Level VI +/- VII
When must you treat the N0 Neck with an Oral Cavity Primary?
T2+ OR tongue depth ≥4mm
- Unilateral levels I - III/IV
- Bilateral if crosses midline
When must you treat the N0 Neck with a Glottic Primary?
T3+
- Unilateral levels II - IV +/- VI
- Bilateral if bilateral disease
When must you treat the N0 Neck with a Salivary Gland Primary?
T3+
- Unless one of the low-grade tumors (acinic, low grade mucoepidermoid, PLGA)
- Decision to prophylactically treat neck for N0 in adenoid cystic is controversial
When should you never treat the N0 neck?
N0 nasal cavity, sinuses, non-melanoma skin, thyroid (except medullary)
- Exception = maxillary sinus (gets adjuvant XRT to the neck for ≥T3 disease but no neck dissection unless N+
Layers of the Epidermis
Stratum Corneum
Stratum Lucidum
Stratum Granulosum
Stratum Spinosum
Stratum Basale
