Radiation Therapy

Radiation Therapy
Tabitha Galloway, MD
Jeffrey Jorgensen, MD
4.15.15
• Interesting brief history
• Radiation physics for dummies
• Basics of radiation biology
• Acute and late treatment toxicities
Outline
History
http://historyoftheatomictheoryuc.weebly.com/william-crookes.html
• Wilhelm Roentegen
• 1895
• Left piece of paper painted with barium platinocyanide
nearby while working with Crookes tube
• Paper started to fluoresce
• Caused by new, invisible ray the tube was emitting
• Discovery of the x-ray
History
http://web.calstatela.edu/faculty/kaniol/f2000_lect_nuclphys/lect1/roentgen.htm
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Henri Becquerel
• Discovered Radioactivity
• Different substances had capability to produce x-rays and
these could be emitted spontaneously
• i.e. Uranium Salts
• First radiation burn – carrying vial in his shirt pocket
• Demonstrated ability to produce biologic changes
History
http://en.wikipedia.org/wiki/Henri_Becquerel
• Pierre and Marie Curie
• Coined term “radioactivity”
• 1898 isolated radium
• 60 x higher radioactivity than uranium
History
http://en.wikipedia.org/wiki/Marie_Curie
• The almost “magical” cure for any known illness
• Direct application of radium to superficial sites
• 1899 – Thor Stenbeck
• Treated 49 yo nasal basal cell carcinoma in Stockholm
• 100 treatments over 9 months
• Alive and well 30 years after the treatment
• 1901- Dr. Frand Williams
• Successful treatment of lip cancer
• Began inserting it into deeper tumors
• Advent of brachytherapy
History
http://sv.wikipedia.org/wiki/Thor_Stenbeck
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• 1922 – Use of external beam treatments
• Henri Coutard
• Forefront of development for treating laryngeal cancer with
fractionation
• Described “radioepithelitis” which we now call mucositis
• Dependent on dose, not time of treatment
History
http://healthsciences.ucsd.edu/som/radiation-medicine/about/Pages/history-radiation-therapy.aspx
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
http://healthsciences.ucsd.edu/som/radiation-medicine/about/Pages/history-radiation-therapy.aspx
• Radiation
• Propagation of energy through space or a medium
• Particulate Radiation
• Energy is carried off by particle that has rest mass
• i.e. electrons, beta particles, protons, neutrons, heavy particles
• Electromagnetic radiation
• Packet of energy that propagates through space (no rest mass)
• i.e. x-rays and gamma rays
Basic Physics and Terminology
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
Basic Physics and Terminology
http://www.radiologyandphysicalmedicine.com/non-ionizing-radiation-applications-in-medicine/
Basic Physics and Terminology
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Treat the tumor, taking into account tumor histology,
extent of gross disease, regions of microscopic spread but
no gross disease
• Primary vs. adjuvant therapy (has the tumor bed been
disturbed)
• Tolerance of adjacent structures
Treatment Planning
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• GTV – gross tumor volume
• CTV – clinical target volume
• GTV + areas at risk for spread (ie nodal beds)
• PTV – planning target volume
• CTV + margins to correct for daily positioning changes and
patient movement.
Treatment Planning
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
http://www.woodstocksentinelreview.com/2012/09/05/london-program-helps-mask-their-fears
http://www.sciencephoto.com/channel/image/healthcare
• Radiation cell kill is exponential function of dosage
• Dosage of radiation is roughly proportional to number of
cell in the tumor (tumor volume)
• Typical dosage of HNC
• 50 Gy for control of microscopic disease
• 60 Gy with positive margins
• 70 Gy control of large tumors (T3 and T4)
Treatment planning
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Radiation kills when critical targets within a cell are
damaged
• Most critical target for biologic effects of radiation is DNA
• DNA directly ionized and damaged
• Double strand breaks
Radiation
Biology
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation
physics, radiobiology and clinical principles. in Flint PW et al. Cummins
Otolaryngology-Head and Neck Surgery. Ch 77. Elsevier Health.
• Radiation triggers signaling cascades leading to arrest
Radiation
Biology
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Relative susceptibility of cells, tissues, tumors or organisms
to radiation.
Radiosenstivity
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Repair (of sublethal damage)
• Redistribution (across cell cycle)
• Repopulation
• Reoxygenation
• Goal: to irradiate tumoral tissue while minimizing damage to
surrounding structures
The four R’s of Radiotherapy
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Dividing the total dose into a number of smaller fractions
allows for normal tissue sparing because of repair of
sublethal damage between fractions
Repair
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Fractionating allows for assortment or redistribution of
tumor cells into radiosensitive phases of cell cycle
Redistribution
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Reoxygenation causes them to be more radiosensitive as
response of cells to ionizing radiation is strongly oxygen
dependent
• Well oxygenated tissues have 3x greater sensitivity to
killing effect than hypoxic tissues
• Tumors are generally more hypoxic at baseline than normal
tissue
• Important to let tumor cells reoxygenate… but not too
much time to allow them to repopulate
Reoxygenation
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Proliferation of the tumor cells
• Create a balance between reoxygenation of tumor and its
repopulation and repair while minimizing damage to
surrounding tissue
Repopulation
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Rapidly dividing tissues are responsible for acute toxicity
• i.e. Skin, mucous membranes, bone marrow, tumor cells
• This is impacted by overall treatment time
• Late responding tissues responsible for late toxicity
• i.e. Spinal cord, brain cells, connective tissue
• Composed of terminally differentiated cells
• Overall treatment time has little importance in determining
toxicity, this depends on total dose and dose per fraction
Radiation Biology
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Predictable
• Dependent on dose
• Dependent on schedule
• Dependent on use of chemotherapy
• May interfere with and delay treatment
• Even short delays can have bad effects on tumor control
• Laryngeal Cancer – a 5 day delay associated with 3.5-8%
reduction in local control
• Dermatitis, xerostomia, mucositis, odynophagia, dysphagia,
hoarseness, weight loss
Acute Toxicities
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Commonest side effect
(80-90%)
• Sunburn like
desquamation
• Occur as early as 2 weeks
after start
• Damage to stem cells in
basal layer of skin
http://www.strataxrt.com/about-radiation-dermatitis-and-strata-xrt.html
Dermatitis
Khanna NR, Kumar DP, Laskar SG, Laskar S. Radiation dermatitis: An overview. Indian J Burns [serial online] 2013 [cited 2015 Apr 14];21:24-31. Available
from:Popovtzer
http://www.ijburns.com/text.asp?2013/21/1/24/121877
A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
Dermatitis
Khanna NR, Kumar DP, Laskar SG, Laskar S. Radiation dermatitis: An overview. Indian J Burns [serial online] 2013 [cited 2015 Apr 14];21:24-31. Available
from: http://www.ijburns.com/text.asp?2013/21/1/24/121877
Dermatitis
Khanna NR, Kumar DP, Laskar SG, Laskar S. Radiation dermatitis: An overview. Indian J Burns [serial online] 2013 [cited 2015 Apr 14];21:24-31. Available
from: http://www.ijburns.com/text.asp?2013/21/1/24/121877
Khanna NR, Kumar DP, Laskar SG, Laskar S. Radiation dermatitis: An overview. Indian J Burns [serial online] 2013 [cited 2015 Apr 14];21:24-31. Available
from: http://www.ijburns.com/text.asp?2013/21/1/24/121877
• Do not restrict gentle skin and hair washing with mild soap
• Steroid skin creams can signficant improvement
• Limited use for skin thinning and bacterial infection introduction
• Aloe Vera
• No real side effects
• Can delay appearance of and lessen effects
• Not verified in double blind trials
• Number of commercial creams available
• Gentian Violet may be used moist desquamation may be used
• Oral agents
• Amifostine, oral enyzmes, pentoxifylline, and zinc supplement all
demonstrate to decrease effects
• Moisture barrier dressings may be an option
Dermatitis
Chan RJ, Larson E, Chan P. Re-examining the evidence in radiation dermatitis management literature: An overview and critical appraisal of systematic reviews. Int J Radiation Oncol Biol Phys. 2012. 84:3; e357-e362.
Khanna NR, Kumar DP, Laskar SG, Laskar S. Radiation dermatitis: An overview. Indian J Burns [serial online] 2013 [cited 2015 Apr 14];21:24-31. Available
from: http://www.ijburns.com/text.asp?2013/21/1/24/121877
Dermatitis
Chan RJ, Larson E, Chan P. Re-examining the evidence in radiation dermatitis management literature: An overview and critical appraisal of systematic reviews. Int J Radiation Oncol Biol Phys. 2012. 84:3; e357-e362.
• Loss of stem cells in basal layer
• When cells are normally physiologically sloughed cannot be
replaced
• Epithelium denudes
• 2-3 weeks after onset of RT
• Clinically significant mucositis occurs ~ 60%
• Higher incidence with chemo-RT
• Supportive treatment
Mucositis
http://www.prothelial.com/oral_mucositis/index.html
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Antimicrobials
• Acyclovir
• Can help prevent recurrent
herpetic outbreaks
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Clarithryomycin
Nystatin
Triclosan
Kefir
Isegenan
• Recommendation against
• Povidone-Iodine
• Antimicrobial lozenge or
paste
• Recommendation against
• Fluconazole
Mucositis
• Mucosal Coating Agents
• Sucralfate
• Recommend against
• GelClair
• Anesthetics
• Tetracaine, Amethocaine,
Dylconine, MGI-209,
Cocaine
• Analgesics
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Capsacin
Ketamine
Methadone
PCA ** (morphine)
Cutaneous Fentanyl **
2% Morphine rinse **
Nortryptiline
Gabapentin
Doxepin ** 0.5% rinse
Saunders D, et al. Systematic review of antimicrobials, mucosal coating agents, anesthetics and analgesics for management of oral mucositis in cancer patients. Support Care Cancer 2013:21:3191-3207.
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Glutamine
Vitamins A, E
Honey
Zinc *
Aloe Vera Gel
Chamomile mouthwash
Chinese herbal drug mouthwash
Indigowood root
Manuka and Kanuka oils
MF 5232
R. algida
Traumeel s.
Wobe-Mugos E
Mucositis
Yarom N, et al. Systematic review of natural agents for the management of oral mucositis in cancer patients. Support Care Cancer 2013:21:3209-3221.
• Very dependent on amount of radiation to the salivary
glands
• Temporary loss after 10 Gy
• Permanent loss with >26 Gy
• Can lead to sore throat, altered taste, dental decay, voice
changes, impaired mastication, impaired swallowing
Xerostomia
Pinna R, Campus G, Cumbo E, Mura I, Milia E. Xerostomia induced by radiotherapy: an overview of the pathophysiology, clinical evidence, and management of the oral damage. Therapeutics and Clinical Risk
Management. 2015: 11. 171-188.
• Most severe and irreversible change is damage to salivary
acinar cells gives rapid composition changes of saliva and
decreased production and quality of flow
• More viscous, more acidic, electrolyte imbalance
• Changes in oral flora which cause more caries
• Mucosa becomes dry, sticky, cracks easier
• Increased susceptibility to gingivitis and bleeding
• Angular chelitis, halitosis
• Difficulty with dentures
Xerostomia
Pinna R, Campus G, Cumbo E, Mura I, Milia E. Xerostomia induced by radiotherapy: an overview of the
pathophysiology, clinical evidence, and management of the oral damage. Therapeutics and Clinical Risk Management.
2015: 11. 171-188.
Xerostomia
Pinna R, Campus G, Cumbo E, Mura I, Milia E. Xerostomia induced by radiotherapy: an overview of the pathophysiology, clinical evidence, and management of the oral damage. Therapeutics and Clinical Risk
Management. 2015: 11. 171-188.
• Treatment goals
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Increase existing saliva or replace lost secretions
Control oral health
Control dental caries
Treat possible infections
Xerostomia
Pinna R, Campus G, Cumbo E, Mura I, Milia E. Xerostomia induced by radiotherapy: an overview of the pathophysiology, clinical evidence, and management of the oral damage. Therapeutics and Clinical Risk
Management. 2015: 11. 171-188.
• Mechanical or gustatory stimulation
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Sugarfree gum/candies
Nightime anti-xerostomia dentrifices
• Amifostine (Ethynol)
• Cholinergics
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Pilocarpine - 5 mg TID
Cevimeline – 30 mg TID
•
(not FDA approved for post radiation xerostomia)
• Mouthwashes and salivary substitutes
• Accupuncture?
• Olive oil, aloe vera, rapeseed oil?
http://www.sussex.ac.uk/broadcast/read/16235
Xerostomia
Pinna R, Campus G, Cumbo E, Mura I, Milia E. Xerostomia induced by radiotherapy: an overview of the pathophysiology, clinical evidence, and management of the oral damage. Therapeutics and Clinical Risk
Management. 2015: 11. 171-188.
• Some of the acute toxicities persist into late toxicities
• Frustrating, often improves with time
• Can be longstanding or permanent
• Salivary gland sparing surgery or RT
• May use many of the same interventions used for acute
toxicities
• Frequent sips of water
Late toxicities- Xerostomia
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Radiation induced fibrosis similar to inflammation, wound healing
and fibrosis of any origin
• Inflammatory infiltrates, differentiation of fibroblasts, changes in
vascular connective tissue, excessive production and deposition of
extracellular matrix proteins and collagen
• Can cause
• Cutaneous induration, lymphedema, restrictions in joint motion,
strictures and stenosis in hollow organs, ulcerations,
• progressive trismus
• Strictures, ulcerations esophagus and hypopharynx – fistula formation
• Fibrosis to constrictors- chronic dysphagia
• Best way to prevent this- conformal planning to spare radiation
Late toxicities- Fibrosis
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
http://www.ijps.org/viewimage.asp?img=ijps_2012_45_2_325_101311_f1.jpg
• Osteoradionecrosis
• Mandible most commonly affected bone (5-29%)
• Blood supply
• Symptoms
• Pain, halitosis, dysguesia, dysesthesia, anesthesia, trismus,
masticatory problems, degluttition, speech difficulties, fistula,
pathologic fracture, spreading infection
• Post-irradiation extraction of diseased or non-restorable
teeth produces higher rate of mandibular ORN
Late toxicities-ORN
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
Late toxicities- ORN
http://www.intelligentdental.com/2011/12/29/osteoradionecrosis/
• Rates of ORN can be lowered by
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Reducing mandibular volumes receiving high doses
Improved salivary flow rates
Improved oral health
Uniform prophylactic dental care
Late toxicities- ORN
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Stage 1 is superficial osteoradionecrosis that can resolve with
irrigation and hyperbaric oxygen (HBO)
• In stage 1 osteoradionecrosis no bone surgical removal is
required.
• Stage 2 is stage 1 that progressive and can't healing with
treatment method in stage 1
• Stage 3 is ORN that have orocutaneous fistula, Pathologic
fracture or resorption of inferior border of mandible.
Late toxicities- ORN
http://oral-maxillofacial.blogspot.com/2009/02/stage-of-osteoradionecrosis-orn.html
• Treatments
• Chlorhexadine rinses, antibiotics
• HBO – hyperbaric oxygen
• In theory stimulates function of monocytes and fibroblasts to
increase collagen synthesis and vascular density
• There is contradictory data re: efficacy of HBO
• Debridement
• Resection and reconstruction
• If ORN persists despite aggressive treatment, always consider
the suspicion of recurrent cancer
Late toxicities-ORN
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Hypothyroidism
• Incidence varies widely
• Dose dependent and time dependent
• Median time 1.4-1.8 years after treatment
Late toxicities- thyroid
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Most common angiographic abnormality
• Pesudoaneurysms
• Feared complication of carotid artery rupture
• Increase in carotid intima-media thickness
• Carotid stenosis
• Longer segments of stenosis
• Accelerated atherosclerosis
• Higher risk of TIA and strokes
• Risk is 8 x higher at 5 years out from RT than those who are
<5 yrs out from RT
Late toxicities- vascular
Xu J, Cao Y. Radiation Induced carotid artery stenosis: a comprehensive review of the literature. Interven Neurol. 2013;: 183-192.
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Transient myelopathies
• 2-6 mo following spinal irradiation
• Lhermitte’s sign
• Non-painful unpleasant electric shock-like sensation that shoots
down spine during neck flexion
• Paresis, numbness and sphincter dysfunction develops 612 mo after radiation
Late toxicitiesmyelopathy
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Treatment is a balance
• Maximal tumor kill
• Minimizing dosage to critical structures
• Long term quality of life
Reducing Toxicity
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
• Avoidance of radiation
• Techniques of radiation oncologists (separate lecture material)
• Fractionationation
• Allows the 4Rs to occur
• 3D conformal radiotherapy (evolved in 1980’s)
• Better precision of delivery with sparing of critical tissues
• IMRT –Intensity modulated radiotherapy
• Tight dose gradients around targets that limit doses of non-involved tissues
• Good for paranasal sinuses, nasopharynx
• Proton therapy
• Heavier particle to concentrate dose inside targets and minize dose to
surrounding normal tissues
• Neutron therapy
• Proving useful in salviar gland tumors
Reducing toxicity
Popovtzer A, Eisbruch A. (2010) Radiotherapy for head and neck cancer: Radiation physics, radiobiology and clinical principles. in Flint PW et al. Cummins Otolaryngology-Head and Neck
Surgery. Ch 77. Elsevier Health.
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