radiotherapy in head and neck cancers.pptx

Covers basics regarding radiotherapy in head and neck cancers

1. Radiotherapy in head and Neck Cancers Dr. Sheril Joseph Junior resident Dept of otorhinolaryngology B. J Govt Medical college, Pune

2. WHAT IS RADIOTHERAPY? Application of radiation for the purpose of therapeutic gain. Principle: Rates of proliferation of most tumors exceed that of most normal tissues, net increase in size of tumor is a balance between Proliferation of cells GAIN Cell loss from necrosis, desquamation, hypoxia and apoptosis LOSS

3. TYPES OF RADIOTHERAPY Broadly two types: EXTERNAL BEAM RADIOTHERAPY BRACHYTHERAPY AKA TELETHERAPY Radiation beam is directed from a machine placed outside the pt to a treatment volume located within. Radioactive material introduced directly to the tumor or tumor bearing area.

4. EBRT BRACHYTHERAPY

5. RADIOBIOLOGY TERMINOLOGY REOXYGENATION: Surviving tumour cells become better oxygenated following period of oxygenation,. REPAIR: Tumour cells damaged by radiation restore cell integrity REDISTRIBUTION: return of tumour cells to a more even cell age following selective cell killing in certain phases of the cell cycle REPOPULATION: Tumour cells replenish cell numbers rapidly following a period of irradiation

6. RADIOTHERAPY EQUIPMENTS & PHYSICS Initially- low energy xrays ( 50KV- 300KV)- AKA ORTHOVOLTAGE Followed by VAN DE GRAFF generator ( >1MV)- AKA MEGAVOLTAGE Followed by COBALT UNITS – cobalt undergoes radioactive decay and emits GAMMA RAYS of 1.1 Mev Disadvantage: viable for 5 years- has to be replaced after this period : higher radiation side effects to working staff handling the radioactive material

7. LINEAR ACCELERATOR: in use at present Principle: stream of electrons produced from a filament in an electrically charged field is accelerated through a series of wave guides in conjunction with a radiofrequency pulse to within a fraction of the speed of light. Mechanism: 1) the stream of photons as such is lethal to the cells 2) the electrons can produce photon beam of max energy 4- 20 m V Head and Neck cancers- 4-6 millivolt Abdominal or pelvic cancers- >10 m V

8. MECHANISM OF CELL DESTRUCTION: PHOTON BEAM FALLS ON CELLS SECONDARY ELECTRONS + OXYGEN Free radicle formation and consequent tissue damage

9. The secondary electrons travel for a small distance beyond the irradiation Site before the concentration builds and action occurs- MAXIMUM PATH LENGTH (relative skin sparing of these accelerators) For example: 6 m V – maximum path length is 1.5 cm beneath the skin surface. IMMOBILISATION OF PATIENT: individually molded thermoplastic shells covering head and neck of patient As precise as 3mm – standard mould 1-2 mm- more rigid moulds - used in 1) stereotactic radiotherapy 2) Intensity modulated radiotherapy (IMRT)

10. BRACHYTHERAPY Two methods: AFTERLOADING REMOTE AFTERLOADING Radio-opaque hollow needles inserted into treatment site under GA- Iridium 192 later on loaded onto the applicator in the loading room Risk of exposure to radioactive material is high Applicators are inserted- the radioactive substance is stored in a lead chamber- technician regulates the length of radioactive material to be inserted in the tube from a separate room. No direct contact with the radioactive material

11. ADVANTAGES OF BRACHYTHERAPY: Delivering high dose to a small area and radiation dose falls off rapidly outside the treatment volume- radiation exposure to normal tissue minimalized DISADVANTAGES: Requires adequate radiation protection for staff Not appropriate for where wider field of irradiation is required- in locally advanced disease and patients with nodal disease.

12. TARGET DEFINITION

13. Most of the times, radiation sessions are planned as a single phase But if the tumors are locally advanced with nodal metastatic potential or possibility- sessions are planned as two step treatment plan CTV1- primary tumor + involved nodes or potentially involved nodes + potential areas of microscopic nodal spread CTV2- primary tumor+ involved lymph nodes alone are treated. While defining target areas- key organs at risk are excluded from the fields- eg : spinal cord, parotid, submandibular gland, optic nerve etc. Current convention of treatment: stated dose is the dose to the core of the treatment volume and all of the PTV receives atleast 95% of this dose and no point in the target defined gets a dose of more than 107%.

14. TUMOR CELL KINETICS AND RESPONSE TO RADIOTHERAPY INCREASE IN TUMOUR SIZE T pot: potential doubling times Average in head and neck cancers- (lab conditions- tested with H thymidine) : 2 to 67 days Actual doubling times (in vivo conditons ) : 15 to >234 days (mean 99 days) The more the proportion of cells in the clonogenic potential ( 1 to 10% avg)- more is the response og the tumour to the treatment. Proliferation of cells GAIN Cell loss from necrosis, desquamation, hypoxia and apoptosis LOSS

15. Types of DNA damage: Secondary electrons+ 02= free radicle formation = most common Hydroxyl ion (OH-) => Single strand DNA damage: repairable provided the cell gets the required conditions and time this potential is maximum for normal cells than tumor cells: Half time for SUBLETHAL damage repair: 95% complete within 6hrs Cell destruction by the direct interaction of cells and photon beam: LETHAL damage=> double stranded DNA damage- not repairable. Growth factors produced by the tumour cells= stromal cell proliferation Eg : VEGF: leads to angiogenesis- blood supply to the tumour cells More the vascularity- more the response to the radiotherapy

16. INTRINSIC RADIOSENSITIVITY OF TUMOR CELLS HYPOXIA : Cells that are >100- 150 µm away from the nearest capillary- greater risk of hypoxia- greater risk of necrosis Anoxic cells 2.5 to 3 times less sensitive to radiotherapy To identify hypoxic areas : Imaging with F Labelled Nitroimidazole/ PET Radiotherapy (combining pet scan and radiotherapy together) HUMAN PAPILLOMA VIRUS INFECTION: in patients without history of addiction – the isolation of HPV -16 DNA was found to have better treatment outcome with radiotherapy than those without. TUMOR DYNAMICS POST RADIOTHERAPY : actively dividing cells affected first => oxygen penetrates further into hypoxic areas => these areas are now more susceptible in the next session of radiotherapy Accelerated proliferation and destruction within tumour cells occur by the third week of radiotherapy

17. ASSESSING RESPONSE TO RADIOTHERAPY Generally takes 4-6 weeks after a radiotherapy course for maximum tumour response to be evident MIN of 8 WEEKS before repeat CT MIN of 12 weeks before repeat MRI ( for the generalised increased signal in the treated area to subsise post radiotherapy) >10 weeks if scans performed- greater the sensitivity

18. ACUTE TOXICITY TIREDNESS- may start as soon as the treatment commences , may build up as treatment progresses, chemotherapy worsens it, can take up to 6 months to reach pre treatment energy levels. XEROSTOMIA: starts as early as in the first week of treatment, selective damage to the plasma membrane of the secretory granules in the glands- watery and mucous components not affected equally- initial dryness gives way to thick sticky saliva beyond 4 weeks of treatment- increased if pt has had a submandibular gland excision as a part of neck dissection. Parotid gland : 50% loss of function- 22.5 GY, 75% loss of function- 40Gy : may recover completely 12 months after treatment ends. Submandibular gland: more susceptible- >39Gy- no recovery of function, <39Gy: 3% recovery of function per month upto 24 months LOSS OF TASTE

19. MUCOSITIS: starts from third week of treatment Erythematous patches- patchy mucositis ( white exudates on erythematous base)- confluent mucositis (exudative patches coalesce) Severe mucositis is seen in pts who receive more than 60Gy ( especially in concurrent chemoradiotherapy/ accelerated radiotherapy) THICK SALIVA+ MUCOSITIS- PAINFUL SWALLOWING- Impaired nutrition Skin erythema- third week onwards- faint erythema to bright erythema to moist desquamation

20. ACUTE TOXICITY MANAGEMENT: Mucositis: Antibacterial pastilles to reduce incidence of severe mucositis Good mouth care, antiseptic mouth wash, narcotic analgesics Avoid alcohol based mouth washes- increases dryness ( water based mouthwashes eg : BIOTENE) Oral fluconazole- to prevent oral candidiasis Strong analgesics- 20 to 30 min before meal 4 hourly- takes care of nutrition needs (soluble pcm to Fentanyl transdermal patches- acc to pts needs)

21. Patients with extensive disease- at risk of developing severe mucositis – to be considered candidates for Percutaneous gastrostomy prior to surgery/ radiotherapy/ chemoradiation- will ensure proper nutrition during radiotherapy, allow pt and relatives to get accustomed to Gastrostomy feeding, reduces inconvenience to pt due to nasogastric tube, maintain patients nutrition during the period of severe mucositis, dryness etc such that treatment need not be compromised. Zinc substitutes Saliva substitutes: relieve dryness, break up thick saliva, oral saliva replacement gel( prolonged continued relief at night) Radioprotective drug AMIFOSTINE - needed to be given intravenously- causes nausea, hypertension- studies proved that the incidence of dryness, mucositis decreased with the drug Skin care- aqueous cream relieves dryness and itch, moist desquamation- may require hydrocolloid dressing, secondary infection of skin may require antibiotics.

22. Acute toxicity: RECOVERY SIDE EFFECT TIME TO RECOVER DEGREE OF RECOVERY Erythema of skin 7 to 10 days Complete Mucositis (severe) 4 to 8 weeks Mostly complete (<5% may end up gastrostomy dependent) Taste 6 to 8 weeks Total Dry mouth 3 to 24 months Unilateral irradiation- 80 to 90% recovery Bilateral/ >30Gy irradiation- limited recovery Lethargy 6 months complete

23. Late toxicity Occur when damage occurs to tissues with low turnover rate: manifested late- may require months to years post radiotherapy to appear May occur due to damage to small blood vessels supplying the tissue- endarteritis obliterans Dental decay, enamel loss- may lead to dental extractions=> OSTEORADIONECROSIS of mandible More in patients that have undergone mandibulectomy, and those receiving higher doses of treatment. May appear from 1 – 3yr post radiotherapy 2) TRISMUS: due to masseter and pterygoid muscle fibrosis and damage 3) OPTIC NERVE DAMAGE 4) SPINAL CORD DAMAGE: patient may experience tingling, or electric shock sensations down the spine and sometimes onto the back of leg, and aggravated by neck flexion- may develop 6 weeks to 6 months after radiotherapy, recovers spontaneously over a period of months- needs reassurance, no active management.

24. 5) CAROTID ARTERY STENOSIS: as high as 12% at 15yrs, risk increases in pts with history of hypertension, smoking 6)HYPOTHYROIDISM: Incidence increases with increase in area of thyroid gland irradiated, eg : in laryngeal, hypopharyngeal or cervical esophageal cancers, more common in women. TFT should be checked 6months following treatment and at regular intervals thereafter.

25. MUCOSITIS- ACUTE TOXICITY OSTEORADIONECROSIS OF MANDIBLE

26. RADIOTHERAPY FRACTIONATION: Optimum total dose is a balance between tumour cell kill and the impact of early and late side effects. 1- CONVENTIONAL FRACTIONATION: Individual fractions of 1.8 – 2Gy each given daily for 5 days per week. 66 – 70 Gy in 33 to 35 fractions 60 – 64 Gy in 30 to 32 fractions ( postoperative RT- 10% LESS than primary RT) 2- HYPOFRACTIONATION: Fewer fractions with larger doses per fraction limits the time for tumour repopulation, but also reduces cells to repair damage- thus leading to more late toxicity events as compared to conventional. fractions are >2Gy by definition.

27. 3- HYPERFRACTIONATION: usage of smaller fractions for longer duration: <1.8 Gy , reduces risk of late damage to cells but leads to overall increase in treatment time and thus reduces effectiveness. eg : 50- 60 fractions over 7 weeks. ACCELERATED FRACTIONATION: overall treatment time has been reduced, number of fractions given per day is increased to a max of thrice with min of 6hr gap daily for abt 12 days without weekend gap. size of fraction is still less- 1.5 Gy eg : CHART regimen- Continuous Hyperfractionated Accelerated RadioTherapy - 1.5 Gy x 3 x 12 days- 54 Gy The min 6 hr gap between two fractions allows the sublethal damage in the normal cells to be repaired. Late damage is more with Hypofractionated cycles But, in early cases- with small treatment volume- hypofractionated cycles are more effective.

28. EFFECTIVENESS OF RADIOTHERAPY Increase in total dose: 1 Gy increase in dose increased locoregional control by 1% Concurrent chemotherapy with platinum agents or drugs like cetuximab: increased locoregional control by 10% Delay in starting treatment: for every month delayed: there is 15% decrease in loco regional control of disease new guidelines- RT should be started within 4 weeks of the decision to treat, palliative radiotherapy within 2 weeks. Treatment interruptions: for every day delayed there is 1.4% decrease in local control REFRACTIONATION: adding the missed dose onto the remaining original plan and increasing the dose per fraction- increased toxicity Anaemia: 2g/dl fall in hb leads to decrease of 10- 15% decrease in local control, fall in hb more relevant than the actual values, good prognosis with maintained hb post surgery-pre radiotherapy phase. To maintain Hb: blood transfusions, epoetin alpha; erythropoietin contraindicated- growth factor in some cancers. Smoking: smokers have 10 to 15% decreased local disease control when compared to non smokers.

29. INTENSITY MODULATED RADIOTHERAPY (IMRT) In conventional radiotherapy, only two or three fields were used to define the target volume which in turn leads to significant dose received by the tissues in between the skin and target volume and the target volume and the skin from which the beam exits PRINCIPLE: multiple fields are used such that contribution of each field is less, overlapping area corresponding to the target region receives maximum radiation and the radiation significantly drops outside the fields ( normal tissue spared) Also the relative intensity of individual parts of the beam can also be modulated assuring acute dose to target volume and sparing critical tissues nearby- This effectively constitutes IMRT. Avg - 7 to 9 fields used, sparing critical nearby structures like parotid, submandibular gland, spinal cord, brain stem etc. Disadvantage: the tight margins around the target tissue means that the dose can drop from 95% to 10% in a few mm outside the margin, leading to miss of cancer tissues and recurrences Tumour shrinkage while the treatment is ongoing can alter the fit of the shell , leading to more movement within the shell and more error of treatment- leading to normal tissues receiving increased doses.

30. NEWER MODALITIES IMAGE GUIDED RADIOTHERAPY : Involves both fitting the linear accelerator with CT capability so that the patient position may be confirmed prior to treatment and programming the linear accelerator to carry out any necessary shifts in treatment position. In recent advances in head and neck cancers- IMRT can be combined with IGRT PET BASED RADIOTHERAPY : In cases where there are sites of active disease in areas which appear anatomically normal, also would act as a hypoxia marker, help in delineating hypoxic areas and delivering more dose to these areas. Radiotherapy based on heavy particles- like neutrons, protons Proton beam used in chordomas within the clivus: due to tight edge of the beam, reducing damage to the nearby brainstem.

31. In early stages of Head and neck squamous cell carcinomas, like of larynx, oropharynx, hypopharynx- radiotherapy can be given as first line mx- good cosmesis, better speech, and swallowing. T1 , T2 and diseases where the growth is <5mm thickness of oral cavity- Brachytherapy can also be used with good outcomes. More locally advanced diseases: Surgery-> postoperative radiotherapy/chemoradiation If patient comorbidity very high- Radical Radiotherapy ( only 30- 40% cure rate)

32. RISK OF NODAL METASTASIS BASED ON TUMOUR SITE AND LOCATION % OF RISK SITE INVOLVED HIGH RISK (>60%) NASOPHARYNX, OROPHARYNX, HYPOPHARYNX, SUPRAGLOTTIS MODERATE RISK (20-60%) ORAL CAVITY, ADVANCED LARYNX, SALIVARY GLAND LOW RISK (<20%) EARLY GLOTTIC, NASAL CAVITY, PARANASAL SINUSES, SKIN PREDOMINANTLY UNILATERAL RISK Early tonsil, well lateralised oral cavity , parotid BILATERAL RISK TONGUE BASE, NASOPHARYNX, ADVANCED LARYNX, HYPOPHARYNX (PYRIFORM FOSSA)

33. POSTOPERATIVE RADIOTHERAPY IN HEAD AND NECK CANCERS INDICATIONS: Postoperative pts are classified into high, intermediate and low risk group based on the following factors: (described by CHARTWEL group) Extracapsular spread- always a high risk group Involved surgical margin Excision margins less than 5mm Stage T3 , T4 Perineural and perivascular invasion Poor differentiation Oral cavity primary More than four nodes positive Carcinoma insitu of resected margin Four out of five of these classifies the tumour as high risk two out of five as intermediate , rest low risk

34. EFFECT OF DELAY BETWEEN SURGERY AND POSTOPERATIVE RT More the delay in starting treatment, higher the total dose required for local control Post operative tumours have accelerated repopulation time- increase in growth factors and inflammatory mediators- thus minimum the delay better the outcome. Post surgery hypoxic bed of the tissues- makes residual tumor cells resistant to radiation. Minimum dose required for better local control- should not be less than 60 Gy Minimum delay between surgery and radiotherapy- should not be less than 6 weeks Prior to radiotherapy, prepare the patient in terms of dental evaluation and if necessary dental extractions, supplementary feeding ( percutaneous gastrostomy if needed) , and assuring adequate post operative Hb.

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