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Uncertainties in cervical cancer radiotherapy and management strategies

Uncertainties in cervical cancer radiotherapy and management strategies. Dr Gemma Eminowicz Consultant Clinical Oncologist, UCLH, London. Background Radical radiotherapy (RT) in cervical cancer Recent advances in cervical RT IMRT. Uncertainties. Management strategies. Guidelines

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Uncertainties in cervical cancer radiotherapy and management strategies

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  1. Uncertainties in cervical cancer radiotherapy and management strategies Dr Gemma Eminowicz Consultant Clinical Oncologist, UCLH, London

  2. Background • Radical radiotherapy (RT) in cervical cancer • Recent advances in cervical RT • IMRT Uncertainties Management strategies Guidelines Patient preparation Adaptive RT • Anatomical target delineation • Organ Motion

  3. Radical RT in cervical cancer • 1906 – case report treating cervical cancer with RT (CXH) • Established standard of care in FIGO IB2-IVA • FIGO stage IB-IIA • equivalent survival with surgery but less morbid • 1999 –platinum based chemoRT superior to RT • Meta-analysis - 6% survival advantage • 45-50.4Gy/25-28# • Treat primary and areas at risk • Primary CTV - cervix, uterus, parametria, vagina • Nodal CTV - obturator, iliacs • Brachytherapy (BT) boost to cervix and tumour • Minimum EQD2 > 80Gy CCCMAC 2008, Landoni et al 1997

  4. BUT • Toxicity: • GU 18% low grade, 1.5% G3/4 • GI 45%, 8% G3/4 • Haem 53% low grade, 28% G3/4 • Late; 5-25% • Survival 35-75% at 5 years depending upon stage Mutch 2009, Loiselle et al 2010

  5. Recent advances in cervical cancer RT • Reduction in toxicity: • Reduce dose to organs at risk • IGBT (with interstitial needles) • IMRT • Improvement in survival • IGBT • Improved dose coverage • Dose escalation • Nodal boost using IMRT • Additional treatment- chemotherapy before or after RT

  6. Intensity Modulated Radiotherapy (IMRT) • Modulated beam intensity (fluence) • Numerous beam segments • Achieves steep dose gradient/shapes • Eg concave to avoid rectum • Initial use in head and neck • Spinal cord is dose limiting • Different methods of delivery • Step and shoot • Dynamic MLC • Fixed field vs rotational

  7. IMRT dosimetric benefits • 45-50.4Gy/25-28# with concurrent chemotherapy • Small bowel V45 halved • Bladder volume V45 halved • Rectal volume V45 decreased 7 fold • Pelvic bone dose • Can dose escalate within previously accepted tolerances Roeske, Radiother Oncol 2003;69:201, Portelance IJROBP 2001;51:261

  8. IMRT clinical benefits • Stat sig reduced bowel toxicity (unmatched cohort) • Acute 95% vs 53% • Chronic 50% vs 11% • Clin sig reduced genitourinary toxicity • 16% vs 7% • Lower G2 white cell toxicity if chemoRT • 60% vs 31% • Bone complications/QoL • PA nodal RT (cohorts only, bowel tox) • Concurrent chemoRT (haem tox) Roeske, Radiother Oncol 2003;69:201, Portelance IJROBP 2001;51:261

  9. Factors affecting IMRT and IGBT • Delineation accuracy • Organ position accuracy • Tumour regression during RT • Low dose radiation increase • Second Cancer Risk • Cost effectiveness

  10. Uncertainties • Delineation accuracy • Organ position accuracy • Tumour regression during RT • Low dose radiation increase • Second Cancer Risk • Cost effectiveness

  11. Delineation • Delineation of OARs • Bladder • Rectum • Bowel (sac/bag/loops) • Target delineation • Nodal CTV • Primary CTV

  12. Largest uncertainty in RT planning • Cervical cancer (21 observers, 2 cases) • Two fold difference in CTV volume • Up to 4cm difference in superior border • JCI 0.51-0.81 vs gold standard Eminowicz, Radiother Oncol 2015;117:542-117

  13. Dose effect? • Cervical ca (21 observers 2 cases): • 0 achieved GSPTV V95%>95% • V95% ≤ 90% in 29% and 36% • V95%< 80% in 2 of both cases • Mean GSPTV V95%:85.9%/87.9% (range 70-95%) • Rectal ca (4 observers, 10 cases) • Mean V95% to target PTV with IMRT was 86.5% • 3D-CRT maintained V95% at 93.7% Eminowicz RO 2016;120(3):493-499, Lobefalo RO 2013;8:176

  14. Management strategies • Education • Collaboration/Peer review • Participation in trials and the radiotherapy quality assurance • Guidelines • Step by step pictorial atlas • Example cases Eminowicz Pract Rad Onc 2016;6(5):e203-213

  15. Management strategies: Guidelines • Rectal cancer (4 observers, 10 cases) • Mean V95% improved from 86.5% to 94.5% • Prostate cancer (RADICALS trial, 6 observers, 3 cases) • Decreased coefficient of variation by 1.3-1.8 fold • Cervical cancer (INTERLACE trial, 21 centres, 2 cases) • Improved compliance after atlas inclusion in trial Lobefalo Radiat Oncol 2013;8:176, Mitchell IJROBP 2009;75(4):990-3, Eminowicz Pract Rad Onc 2016;6(5):e203-213

  16. Organ motion • Bladder filling/emptying • Rectal filling/emptying • (Bowel mobility) • Traditionally: • Bladder ‘comfortably full’ • Reproducible • Reduce bowel in RT field • No specified bowel preparation

  17. Bladder filling • Variation throughout day • Overall hydration important • Decreased by nausea/diarrhoea • Increased by IV fluids with chemotherapy • Post chemo 49cc larger • Filling decreases through treatment • ~40% decrease through treatment • Larger volumes at planning less reproducible • >300cc • Bladder variation affects uterus coverage unless bladder much smaller (>200cc) than at planning Jadon Clin Onc2014;26(4):185-96 , Eminowicz Clin Oncol (RCR) 2016;28(9):e85-91, Ahmad RO 2008;89(2):172-9

  18. Rectal filling • Less data as less predictable • No pattern throughout treatment • Inverse relationship with bladder volume • Dehydration increases constipation • Larger AP diameter at planning associated with decreased CTV coverage during treatment • More impact on cervix position than uterine position • Clinically more concerning Eminowicz Clin Oncol (RCR) 2016;28(9):e85-91

  19. Management strategies • Control of bladder and rectum volume • Strict patient preparation • Daily imaging • Regular monitoring and feedback to patient • Adapting RT delivery according to bladder volume etc • Larger or individualized margin • Daily imaging and soft tissue matching • Adaptive IMRT

  20. Patient preparation • Bladder volume control • Not overfilled at planning <400cc • Ultrasound bladder pre planning and treatment • Daily feedback to patient/education • CBCT on set • Rectal filling • Regular laxatives pre planning and treatment • ?Microenema • Replan if AP > 5cm, or 4cm? • Increased posterior margin

  21. Margin adaptation • Current practice: • 10-20mm • BUT • CTV motion with bladder filling 5-40mm • Increases overlap with OAR • Counteract the benefit of IMRT • Should be trying to reduce margins to reduce toxicity Jadon Clin Onc2014;26(4):185-96

  22. Adaptive IMRT • ITV to cover all bladder filling • Bladder full & empty planning CT • Full and empty plan if ‘mover’ • Fiducial markers in cervix • Soft tissue matching daily • 3D-CRT back up plan (18%) • uterus out 27.5% • markers out 21.3% • both out 21.7% • poor CBCT 10.5% Heijkoop IJROBP 2014;90(3):673-679

  23. Summary • IMRT • Improves conformity to target • Dosimetricand clinical benefit BUT • Strict QA necessary • Delineation accuracy • Margins • Reproducibility • Image guidance daily is ideal • Increasing complexity/cost • Prospective monitoring and collaboration to reach consensus approach

  24. Ongoing research questions • Neoadjuvant chemotherapy • Adjuvant chemotherapy post chemoRT: OUTBACK • Dose modification at brachytherapy • Nodal dose escalation: DEPICT

  25. gemmaeminowicz@nhs.net

  26. Unknown late effects • Increased peripheral dose: • 0.12% prescribed dose • Less with 6MV vs 15MV • Clinical consequence unclear • Second cancer risk • Absolute risk 1.75% at 10 years compared with 1% for 3D-CRT • Due to increased low dose volume (0.5%) and MU (0.25%) • Higher energy worse; <1% absolute increase risk Salz et al 2012, Hall et al 2003, Zwahlen et al 2009

  27. Cost effectiveness • More expensive initial cost • Gynaecological patients: • Increasingly cost effective with time • Lower toxicity • Post operative pts • Too expensive unless treating PA nodes Chen et al Gynecol Oncol 2015;136:521. Lesnock et al Gynecol Oncol 2013;129: 574

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