Radiotherapy and radiosensitizers in head and neck cancers.pptx

radiotherapy in head and neck cancer

1. Radiotherapy & Radiosensitizers in Head & Neck Cancers Presented by: Dr. sudin kayastha Resident, Orl hns Bir hospital, nams

2. Principles of Radiotherapy

3. Radiation Propagation of energy through space or a medium Types Particulate/ Corpusular Radiation Carried by particle that has rest mass E.g. electrons, beta particles, protons, neutrons, heavy charged particles Electromagnetic Radiation Packet of energy (photon) that propagates through space Has no rest mass Propagates at speed of light

4. Electromagnetic Radiation Energy of electromagnetic radiation given by E = hv , where E = Energy h = Planck’s constant = 6.626 x 10 34 Joule-second v = frequency Energy of photon expressed as eV 1eV = amount of energy required to accelerate an electron through a potential of 1 V

5. Electromagnetic Spectrum Electromagnetic radiation divided into ionizing and non-ionizing Non Ionizing have wavelength >10 -7 m and energies <12eV

6. Radiation Therapy Radiotherapy Therapeutic use of ionizing radiation Unit of Radiation = Gray ( Gy ) 1 Joule per Kg of material 1 Gy = 100 rad Centigray = cGy = 0.01 Gy . Rad = cGy . Aim To deliver a precisely measured dose of radiation to a defined tumor volume with as minimal damage as possible to surrounding healthy tissue, resulting in eradication of tumor, a high quality of life, and prolongation of survival

7. Radiation Therapy Four Intents of Radiotherapy Radical / Curative: curing cancer often with CT Adjuvant: in addition to curative surgery to reduce risk of recurrence Palliative: to help symptoms control Neo-Adjuvant: prior to surgery

8. Source of Ionizing Radiation Natural Produced by radioactive decay Uranium, Plutonium, Radium, Cobalt, Iodine, Gold, Iridium Man-made Produced by sudden deceleration of high speed electrons when it hits a tungsten target LINAC (Linear Accelerators)

9. Effects of Radiation Radiation  interacts with matter to eject electrons from their orbits  ionization Ionized particle  interact with further atoms  cascade of ionizations

10. Biological Effects of Radiation Ionization of water molecules  free radicals formation  cell death Mechanisms Direct damage to DNA Single strand break  repairable (sub-lethal damage) Double strand break  not repairable  cell death Plasma membrane damage  activation of multiple signal transduction pathways  radiation induced apoptosis

11. Biological Effects of Radiation Cell death  occurs at attempt of cell division Rapidly dividing tissues manifest effect of radiation sooner than those where cell division is slow Effects of radiation seen early Bone marrow, skin, mucosa of upper aerodigestive tract Effects of radiation seen late Connective tissue, bones, neural tissue

12. Mechanism of Treatment 4 “R”s of Radiotherapy Repair of sub-lethal damage Redistribution Repopulation Reoxygenation Radiotherapy works not because tumors more radiosensitive than normal tissues but because normal tissues are better at repair and repopulation

13. Mechanism of Treatment Repair Dividing total radiation dose into smaller fractions allows for normal tissue sparing because of repair of sub-lethal damage between fractions May also influence tumor cells Tumor cells poor at repair of sub-lethal damage Redistribution Cells most radiosensitive early in M-phase of cell cycle Each fraction allows tumor cells to be in M-phase and allow considerable damage

14. Mechanism of Treatment Repopulation Tumor cells can repopulate when incompletely damaged Each fraction must cause more damage than a tumor cell’s ability to repopulate Reoxygenation Most radiation damage produced by indirect DNA damage through free radicals Oxygen is key in producing toxic superoxide radicals Fractionation causes oxygen-rich tumor to die first and previously hypoxic cells to be re-oxygenated Re-oxygenated cells more susceptible in next fraction of radiotherapy

15. Fractionation Delivering the total radiation dose in divided doses in different sessions Makes radiotherapy more effective and minimizes adverse effects Conventional Fractionation Fractions of each use of 1.8–2 Gy each given daily for 5 days per week. Curative doses 66–70 Gy delivered in 33–35 fractions over 6.5–7 weeks. Hypofractionation fewer fractions and larger dose per fraction courses of treatment using larger fraction sizes than 2 Gy

16. Fractionation Hyperfractionation use of smaller fractions (i.e. less than 1.8 Gy ) Reduce the risk of late damage for a given total dose but reduce the effectiveness of treatment Accelerated Fractionation overall treatment time has been shortened combining acceleration with hyperfractionation  reduced risk of normal tissue damage with the benefits of completing treatment in a shorter overall time.

17. Factors affecting effectiveness of Radiotherapy

18. Treatment Aspects of Radiotherapy Pre-treatment Imaging + diagnosis  patient consultation  consent  Immobilization  planning CT scan T/t planning Delineation of tumor  addition of margin  delineation of normal tissue  Radiotherapy t/t planning  Plan review and prescription Treatment delivery and follow up Attendance for daily t/t  t/t delivery and veerification  Clinical Review during t/t  long term follow ups

19. Treatment Aspects of Radiotherapy Consent Immobilization CT Simulation Tattoo Volume Definition Radiotherapy T/t Close Follow ups

20. Treatment Aspects of Radiotherapy Simulation Patient setup assessed for ease of positioning and daily reproducibility Use of immobilization devices, treatment aids, supports to make patient comfortable CT images obtained for image-based treatment planning

21. Treatment Aspects of Radiotherapy Treatment Planning Plan to deliver prescribed dose uniformly to tumor while maintaining very low dose to critical normal structures Technical parameters looked into Verification Process of ascertaining that individualized plan is correct and deliverable

22. Treatment Aspects of Radiotherapy Dose Delivery External beam radiotherapy Radiation beam is directed from a machine placed outside the patient to a treatment volume located within Devices Cobalt 60 machine – Gamma rays Linear accelerator Brachytherapy Radioactive material introduced directly to within a tumour or tumour -bearing area Materials: Radium 226 Iridium 192

23. Linear Accelerator (LINAC) Can produce high voltage energy of both photons and electrons Stream of electrons produced by heating filament  accelerated through a series of wave guides in conjunction with a radiofrequency pulse to within a fraction of the speed of light

24. Linear Accelerator (LINAC) Electron beam can itself be used for treatment or can impact on a target to produce a photon beam of maximum energy between 4 and 20MV according to the design and calibration of the machine Beams of 4–6MV are most appropriate for the treatment of head and neck cancer

25. Response to Treatment Intrinsic radiosensitivity Hypoxia Greater degrees of hypoxia  worse outcome following radiotherapy Human Papilloma Virus (HPV) infection Oropharyngeal cancers treated with radiotherapy  significantly better outcomes in those with evidence of HPV infection compared to those without

26. Response to Treatment Change of oxygenation Cell death following radiotherapy  oxygen penetrates progressively further  stimulation of hypoxic cells to proliferate Normal tissues in resting phage enter cell cycle  cell cycle time shortens  rate of proliferation increases  rapid healing of acutely responding normal tissues e.g mucosa and skin Assessment of Response 4-6 weeks after end of course of radiotherapy for maximum tumor response to become evident CT or further biopsies: 8 weeks after treatment MRI: 12 weeks after treatment to allow general increase in signal in irradiated area to subside

27. 3D C onformal Radiotherapy Done by computerized treatment planning system CT scan with patient in immobilization device 3D radiation conforming with the dose to tumor using multiple fields Shape beams to confirm dimensions of tumor mass Shield normal structures and reduce toxicity

28. Intensity Modulated Radiotherapy Use of radiation fields whose intensity varies across the field a/c to tumor thickness and critical organs in path Multiple beams of varying intensity  relatively uniform dose in a irregularly shaped target ; avoiding high dose to surrounding structures Possible due to Computer Controlled Multileaf Collimators and Computerized optimization (Inverse planning)

29. Intensity Modulated Radiotherapy Tight Dose gradients around targets  improved tumor control Limit the dose to non involved tissue  reduce constraints on tumor sode because of critical organs Uses in HNC Nasopharyngeal and PNS Ca  spares inner ear and middle ear, TMJ, Temporal lobe of Brain, optic pathways, brain stem Oraopharyngeal Ca  spares salivary glands, spinal cord

30. Intensity Modulated Radiotherapy Defining the Target: Imaging Physical examination and endoscopy Simulation contrast enhanced CT MRI FDG PET Selection and outlining of target Gross Tumor Volume (GTV) Clinical Tumor Volume (CTV) Planning Tumor Volume (PTV) Optimization process: Number and Direction of beams

31. Intensity Modulated Radiotherapy Reducing PTV can reduce toxicity  each 1 mm of margis adds 1.3 Gy of dose to parotid gland Magnitude of margin 3 to 5 mm  extra 5 mm ring of normal tissue around target receives full dose Standard IMRT plan  70 Gy over 35 fractions to GTV, lower fraction dose to PTVs: 63Gy to high risk, 56 to 59 Gy to lower risk over 35 fractions

32. Intensity Modulated Radiotherapy Prescripton dose should encompass at least 95% of PTV No more than 20% PTV can receive more than 110% of prescribed dose No more than 1% PTV can receive less than 93%

33. Intensity Guided Radiotherapy P erformance of patient and tumor imaging with electronic portal imaging devices (EPIDs) or CT before each fraction or every few fractions of therapy Ensures tracking of tumor by t/t beams Enables reduction of PTV margins A ssess anatomic changes PTV safety margins become smaller during therapy Weight loss and muscle wasting  shifts normal tissue and tumor positions Median shrinkage rate 1.8% per t/t day (max 70%)

34. Brachytherapy Uses Ra 226, Cs 137, Au 198, I 125, Ir 192 Advantage Delivering a high dose to a small area less toxicity to normal tissues Disadvantage Invasive In appropriate where wider field irradiation is required, e.g. to cover adjacent nodal area High Dose Rate (HDR) remote afterloading devices  pushes single high activity Ir 192 via interstitial catheters 3 to 3.5 Gy given to distance of 1 cm ; 2 times a day 6 hrs apart

35. Gamma Knife (Stereotactic Radiosurgery ) Highly focused and precisely targeted radiation minimizing the exposure to normal tissue. Highly focused: gamma knife containing fixed array of 201 cobalt source Precise target: stereotactic frame Can treat benign and malignant conditiion of brain 1 to 5 sessions of radiation as in acoustic neuroma of CP angle Patients head kept still in a frame ; also map for radiation MRI guided 3 D imaging  radiation targeted No Incision, No Infection Outpatient treatment

36. Steps Fitting of sterotactic frame(LA) Radiological imaging Gamma plan Treatment delivery.

37. Limitation Not possible to target disease extending down the neck. Ideal targets are less than 3 cm.

38. Proton Therapy Better able to concentrate dose inside targets and minimize dose to surrounding normal tissues Less energy delivered before and after the target  reduce lower rate secondary malignancy Used in Paediatirc cancer patients, PNS, Nasopharyngeal Cancer (close to optic nerves, optic chiasma and brain

39. Neutron and Carbon Ion Therapy Neutron therapy used in sallivary gland tumors Carbon ion therapy has conformality advantage of protons greater relative biologic efficacy (RBE), more effective in hypoxic cells Used in adenoid cystic carcinoma and locally advanced SCC of Head and Neck

40. Radiation Side Effects Types Acute Toxicity Damage to tissues with rapid rate of cellular turnover Interfere with and delay treatment  interefere with local tumor control 5 day delay  3.5-8 % reduction in local control of laryngeal cancer Late Toxicity Damage to tissues with slow rate of cellular turnover

41. Radiation Side Effects Depends on T/t related factors Dose received Schedule of RT used Accompanying CT Tumor Related factors Location Invasion of vital structures Patient related factors Oral hygiene Nutritional status Continued tobacco use Diabetes mellitus Collagen vascular dis HIV

42. Acute Toxicity Tiredness Most common May start upon initiation of t/t and build up as t/t progresses Biological basis poorly understood Chemotherapy adds to tiredness

43. Acute Toxicity Dryness of mouth ( Xerostomia ) 1 st week of treatment S elective damage to plasma membrane of secretory granules, fibrosis End of 2 nd week  salivatory flow rates < 20 % Beyond 4 th week  increasing thick sticky saliva B read becomes more difficult to swallow, difficult sleeping due to dry mouth Effects of dryness more in submandibular gland excision as part of neck dissection

44. Acute Toxicity Dryness of Mouth ( Xerostomia ) 10 Gy  temporary loss of saliva >26 Gy  permanent loss of function Recovery  upto 12 months after completion of t/t Prevention: R educe salivary gland dose in formal planning Amifostine Amifostine reduced incidence of significant acute xerostomia from 78% to 51% and chronic xerostomia at 12 months from 57% to 34%. No impact on rates of mucositis and tumor control

45. Acute Toxicity Dryness of Mouth ( Xerostomia ) Treatment Saliva substitutes ( mucin based products preferred than cellulose based) Submandibular gland transfer: swinging contralateral submandibular gland on its pedicle and relocating it to more anterior position

46. Acute Toxicity Mucositis Radiation induced damage of stem cells in basal layer  defective replacement of cells in superficial mucosal layer Develops from 3 rd week of treatment E rythema  patchy mucositis  confluent mucositis with contact bleeding Painful swallowing increases progressively and aggravated by difficulty clearing thick saliva Higher incidence in RT + CT

47. Acute Toxicity Mucositis Treatment Mouth care, antiseptic mouthwash, narcotic analgesics Alcohol-based mouthwashes avoided Water-based mouthwash preferred Analgesics in increasing strength is essential Candidal infection common  low threshold for antifungals ; fluconazole preferred Dietary Support, Percutaneous endoscopic gastrostomy

48. Acute Toxicity Dermatitis Damage to stem cells in basal layers of skin As early as 2 nd week of RT Aggravated by CT ( eg : 5-FU) F aint erythema  bright erythema  moist desquamation Treatment Skin care with aqueous cream Prevention and treatment of secondary infection, avoid direct sun exposure, chemical irritants (cosmetic creams)

49. Acute Toxicity H ypogeusia / Dysgeusia Permanent taste loss may occur at > 60Gy Particularly if the tongue is within the volume of tissue radiated recovery -several months Both mucositis and decreased saliva flow may contribute to taste alteration Chemoreceptors on the dorsal tongue that allow discriminative taste acuity can be markedly affected by mucosal ulceration that can last months to years.

50. Recovery of Acute Toxicity

51. Late Toxicity

52. Late Toxicity

53. Dental Care and Radiation Radiotherapy increases risk of dental caries and its sequelae Dental evaluation should be done before radiotherapy Teeth extraction for dental caries should be done before radiotherapy Teeth in good condition need not to be sacrificed Regular dental evaluation should be done Post radiotherapy dental extraction possible with antibiotic coverage, but better avoided

54. Radiosensitizers A  radiosensitizer or a radiosensitizing agent, is a drug that makes cancer cells more vulnerable to radiation therapy

55. Radiosensitizers There is no point in using a drug that increases sensitivity of both tumor and normal cells to same extent Existing strategies area: Reducing hypoxia Concomitant chemotherapy Targeted therapy

56. Radiosensitizers Reducing Hypoxia: Hypoxic cells are 2.5 to 3 times less radiosensitive than well oxygenated cells Hypoxic cell fraction in solid tumors ranges from <1% to more than 50% increased interstitial pressure  vascular collapse  hypoperfusion  local hypoxia Anemia  hypoxia

57. Radiosensitizers Reducing Hypoxia: Hyperbaric oxygen (HBO) therapy  response rate 84% vs 54% without it Inhalation of Carbogen (95% O2, 5% CO2) with accelerated radiation and oral nicotinamide (ARCON) treatment Hypoxic cell sensitizers  nimorazole and tirapazamine Correcting anemia with recombinant human erythropoietin

58. Radiosensitizers Concominant Chemotherapy Synergistic effect of RT and CT CT  effective in eradicating micrometastases and reduce distant metastases Spatial cooperation  independent activity of each t/t Toxicity independence  allows use of each t/t at near full dose without increase in normal tissue damage (higher rates of mucositis in Chemoradiation )

59. Radiosensitizers Concominant Chemotherapy CT drug acts as a sensitizer, enhancer or potentiatorof radiation Cisplatin , mitomycin C, 5 FU, hydroxyurea , bleomycin , paclitaxel , docetaxel , cetuximab

60. Radiosensitizers Concominant Chemotherapy Mechanisms of synergistic effects of CRT D rug interefere with cellular DNA repair after sublethal damage ( eg . Cisplatin ) Drug may reduce cell repopulation by enhancing the cytotoxic effect following RT Drug  cytoreduction  reduction interstitial pressure  reduce hypoxia Hypoxic cell toxin  Mitomycin is activated in hypoxic cells Hydroxyurea is toxic to radioresistant S phase Paclitaxel  causes accumulation of cells in G2/ mitosis phase of cell cycle  radiation most effective

61. Radiosensitizers Targeted Therapy Cetuximab  monoclonal antibody directed against epidermal growth factor receptor (often expressed in Head and Neck Cancers) A study shows  better median survival rate, better locoregional control rates and higher organ preservation rate Approved in USA in combination with RT for locally and regionally advanced Head and neck SCC Considered in older patients intolerable to Cisplatin based CRT

62. Radioprotectors SH compounds Cysteine Amifostine Soybean-derived serine protease inhibitor known as the Bowman- Birk inhibitor (BBI ) Antioxidants: L- selenomethionine , ascorbic acid, N-acetyl cysteine, alpha-lipoic acid, vitamin E succinate, and coenzyme Q10. AES-14 ( Saforis TM ) is an oral suspension delivering concentrated L-glutamine to the oral mucosa

63. Reirradiation

64. Care of Patient during Radiotherapy Care of Skin: avoid sun exposure, chemical irritants, applicaion of lotions. Avoid rubbing and scrubbing skin Care of Oral Cavity and Dentition: Rinsing mouth and gargle several times a day Use only nonalcohol based gargles  salt and NaHCO3 gargles Mucositis managed by dietary modification and topical anaesthetics Use of soft brush and apply fluoride gel  prevent tooth decay Pre radiation extraction of loose and carious teeth  prevent osteoradionecrosis

65. Care of Patient during Radiotherapy Care of Haemopoetic System: weekly haemograms  WBCs, Hb , Platelets count Care of Infections: Treatment of Concurrent infections Care of Nutrition: advised to take high protein diet with vitamins and minerals Good hydration with plenty of fluids and electrolytes Ryles Tube or percutaneous endoscopic gastrostomy may need Diet should include iron, calcium, vitamin

66. Care of Patient during Radiotherapy Psychological and Emotional Counselling : to counter depression Hospital admission: in severe infection, nutritional deprivation, supportive t/t for respiratory, vascular or neurological complications

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