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

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

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
Gy/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

9. IMRT dosimetric benefits
Gy/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

10. 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

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

12. Uncertainties Delineation accuracy Organ position accuracy
Tumour regression during RT
Low dose radiation increase
Second Cancer Risk
Cost effectiveness
Other uncertainties include role of chemo etc, dose of RT/BT

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

18. 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 vs gold standard
Eminowicz, Radiother Oncol 2015;117:

19. 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): , Lobefalo RO 2013;8:176

20. 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):e

21. 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 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):e

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

26. 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 Onc 2014;26(4): , Eminowicz Clin Oncol (RCR) 2016;28(9):e85-91, Ahmad RO 2008;89(2):172-9

27. 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

28. 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

29. 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

30. 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 Onc 2014;26(4):185-96

31. 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):

32. Summary IMRT Improves conformity to target
Dosimetric and 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

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

35. 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

36. 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