1. Adaptive radiotherapy in Head and Neck cancer Dr Maria Najim TCRC Fellow

2. Head and neck cancer ● HN cancer is the fifth most common cancer worldwide. ● in Australia, ~4000 people are diagnosed with a HN cancer each year (70% men and 30% women) ● incidence continues to increase ● majority – squamous cell carcinomas - tobacco - alcohol ● but, changing aetiology

3. Humanpapilloma virus ● marked increase in HPV related HN cancers - oropharyngeal cancers (OPSCC) – HPV in > 60-80% - younger age (45-55 yrs) - non-smoker/non-drinkers - more responsive to treatment - better prognosis (decades of survival)

4. Overall survival by p16 status. Rischin D et al. JCO 2010;28:4142-4148

5. Organ preservation approach ● radiotherapy is often used as the principal modality. locoregional control rate with RT alone (stage 3-4 ) 50% ● multiple trials over last 20 years - intensification of treatment ● evidence for altered fractionation/concurrent chemoradiotherapy - improved LC/OS (standard of care) ● however, significant increase in both acute/ late toxicities. MA – CRT trials - severe pharyngeal dysfunction - 27% - feeding tube dependency - 13% - xerostomia – 70-80%

6. De-escalation HPV – associated OPSCC – focus now on treatment de- escalation Aim - reduce toxicity without compromising LRC multiple trials - replacing chemotherapy with biotherapy - RTOG / De-ESCALate/ TROG reducing RT dose - ECOG 1308/RTOG (54-60Gy)

7. Intensity modulated radiotherapy ● IMRT – standard of care in management of HN cancers ● IMRT allows the delivery of a very conformal dose to the tumour volume, with a rapid dose gradient, allowing sparing of critical structures which lie in close proximity ● significant reduction in late toxicity - main advantage of IMRT is parotid sparing (PARSPORT trial) xerostomia 74% 38% ● late toxicity continues to be an issue and impact on QOL

8. As patient undergoes 6-7 weeks of IMRT there are marked anatomical changes Tumour volume on initial pCT Tumour volume midway through treatment

9. Reasons for this – multifactorial - tumour and nodal regression - weight loss (treatment related ) - volumetric and positional changes in normal organs at risk (OAR) (e.g. parotid gland) ● Hansen et al – mean reduction in Parotid volume 15-21.5% ● Duprez et al – Parotid shrinkage of 24% ● Castadot et al – mean shrinkage of Parotid 0.9-1% per day - moving medially by mean distance 3.4 mm

10. Intensity Modulated Radiotherapy ● minor change in anatomy could result in significant dosimetric change ● O’Daniel et al. - mean dose to increase above the planned dose by 5-7Gy ● Ballivy et al.- dose higher in contralateral parotid and in 57% of pts

11. Intensity Modulated Radiotherapy ● using a single set of planning data does not take into account these anatomical changes ● may lead to an increase in dose delivered to normal structures and contribute to the incidence of late toxicity (e.g. xerostomia)

12. Adaptive radiotherapy ● volumetric and dosimetric changes have lead to the concept of adaptive IMRT (ART) ● ART involves the modification of the initial plan to account for patient specific anatomical changes (replan) ● Wu et al – combination of replanning and reduced margins – 30% difference in Parotid dose ● several studies have also shown that ART – prevent underdosing of TV by several Gy

13. Retrospective review ● 20 patients 2013-14 ● comprehensive IMRT ● GTV+ relevant OAR contoured manually on initial pCT/weekly CBCT ● compared initial volume – end of treatment ● compared initial dose planned with cumulative dose with the use of DIR

14. Results ● total of 20 patients - 17 male - 3 female ● median age 61 years (43-76) ● ex-smokers = 9 current = 3 non smokers = 8

15. Site SITEFREQUENCY oropharynx11 Nasopharynx6 RMT1 Soft palate1 Unknown primary1

16. TNM stage T StageFrequency Tx1 T16 T27 T32 T44 N stageFrequency N01 N13 N214 N31 N41

17. P16 status p16 statusFrequency positive6 negative5 unknown9

18. Weight loss and volume changes ● most patients lost weight throughout treatment. ● mean weight change: -4.7% (+2.8 to -15.5%) ● GTV decreased throughout treatment: -9% (+38 to -54%)

19. Volume and positional change in OAR ● cumulative dose/volume of OAR - (constrictors/SGL/GL/SMG) – not sign. different ● only difference detected – parotid gland

20. Volume and positional change in Parotids ● mean volume reduction in parotid 24.4% (0 - 53.6%) - 80 - 90% patients ● more pronounced in the contralateral parotid - (mean vol loss -27% vs -22%) ● mean parotid volume loss 0.7%/day (0 - 1.5%)

21. Volume and positional changes in Parotids Parotid shifted - medially by mean 3.4mm (2 - 6.7mm) 100% - posteriorly by mean 2.7mm (0 - 8mm)

22. Dose change in Parotid ● mean increase in parotid dose was 19.5% (-6.7 - 61%) ● more pronounced in the contralateral parotid ● mean dose 23.4% vs 15.7% ● 65% of contralateral > 10% increase in dose ● 45% ipsilateral

23. Contralateral Parotid Mean change in Parotid volume Excess dose to Parotid beyond 24Gy

24. Conclusion ● no significant change in most OAR ● mean volumetric change in parotid - 24.4% - particularly within first 3-4 weeks ● medial shift parotid mean 3.4mm ● increase in cumulative dose 19.5% (contralateral) SIGNIFICANCE?

25. Acknowledgement Louise Bendall - Research Medical Physicist Rachel Stensmry - Medical Physicist Shamira Cross - Data Manager Prof. Val Gebski - Statistician