PresentationPDF Available

A tool for comparing radiotherapy treatment plans in terms of later fertility for survivors

Authors:

Abstract

Talk given at the EUOS Conference 2021
A tool for comparing radiotherapy
treatment plans in terms of later fertility for
survivors
Tom Kelsey
Professor of Health Data Science
School of Computer Science
University of St Andrews
EUOS Conference 2021
3rd April 2021
Colleagues
Edinburgh
Prof. Hamish Wallace MD FRCP FRCPCH FRCS
Consultant paediatric oncologist at the Royal Hospital for Sick Children
Florida
Danny Indelicato MD -professor of Pediatric Radiotherapy
Amber Wyatt -dosimetrist
Department of Radiation Oncology, University of Florida
Tennessee
Chia-Ho Hua PhD
Department of Radiation Oncology, St. Jude Children's Research Hospital
Motivation
Improved Mortality &
Survival
5 year relative survival by year
of diagnosis
1975-1979: 62.8%
2011: 87.1%
Motivation
Robison LL, Hudson MM. Survivors
of childhood and adolescent
cancer: life-long risks and
responsibilities. Nat Rev Cancer.
2014 Jan;14(1):61-70. doi:
10.1038/nrc3634
Background:Fertility after Radiotherapy
The radiosensitivity of the human oocyte
W H B Wallace, A B Thomson, T W Kelsey
Human Reproduction 18(1): 117-121, doi:10.1093/humrep/deg016
Estimate LD50 for the human
oocyte
Use to plan conformal RXT to
optimise dose to the least-
affected ovary
Calculate window of opportunity
for fertility
Calculate the age-related effective
sterilising dose
Use to inform fertility
preservation decision making
Minimise the long-term effects of
radiotherapy on healthy tissue
Whilst maintaining cure rates
Predicting age of ovarian failure after radiation to a field that includes the ovaries
W H B Wallace, A B Thomson, F Saran, T W Kelsey
International Journal of Radiation Oncology * Biology * Physics 62(3): 738–744 , doi:10.1016/j.ijrobp.2004.11.038
Research Goals
Improve predictions of age at ovarian insufficiency
A validated model of the decline in ovarian reserve with age
An estimate of the LD50 for the human oocyte
Incorporate modern treatment plans
Pencil-scanning protonbeams, 3D conformal therapy, …
Provide a tool for use by planners & oncologists
To guide treatment planning
To inform patient/parent discussions concerning fertility preservation
What’s changed (1)
The human ovary has a population of
non-growing follicles (NGFS) at birth
These are the ovarian reserve
Menopause occurs at ages 45-55 when
the population falls below 1,000
12% remain at age 30
3 % remain at age 40
Age-related model published in 2010
Validated – using new external data – in
2015
Human ovarian reserve from conception to the menopause
W H B Wallace, T W Kelsey
PLoS One 5(1): e8772, doi:10.1371/journal.pone.0008772
The relation between variation in size of the primordial follicle pool and menopause: a cohort comparison of observed and predicted distribution of age at menopause
M Depmann, J Faddy, T van der Schouw, P H M Peeters, S L Broer, T W Kelsey, S M Nelson, F J M Broekmans
Journal of Clinical Endocrinology and Metabolism 100(6): E845-E851, doi:10.1210/jc.2015-1298
What’s changed (2)
Proton therapy
Less radiation to healthy tissue
Volumetric modulated arc therapy (VMAT)
Less radiation to healthy tissue
Motion compensation
With fractionated doses over several days, tissue might not be in the same place
Automated planning
Use AI to mimic a human expert
Intraoperative radiation therapy (IORT)
Delivery while the tumour is exposed during surgery
What’s changed (3)
Fertility preservation was
science fiction in 2005
It is now common (routine?)
for ovarian tissue to be frozen
before treatment
Advice is a complex issue
Age, prognosis, treatment(s),
assessment of ovarian reserve,
delay, …
A clear need for a reliable
estimate of the damage done
to the ovarian reserve by the
treatment
Methods
Assuming that
(a) the NGF population is close to the average for age at diagnosis and
(b) the rate of decline after treatment is similar to that which would have occurred
without treatment
Predict the age a premature ovarian insufficiency (POI) at a known age and for a
given dose as follows:
1. Calculate the surviving fraction of NGFs for that dose, using the LD50 of 2Gy
2. Solve the Wallace Kelsey model to find the (later) reproductive age that matches
the surviving fraction
3. Predict age at POI to be 50 years plus chronological age less reproductive age
𝑙𝑜𝑔!" 𝑁𝐺𝐹 =5.56
41 + 𝐸𝑟𝑓
𝑎𝑔𝑒 +25.6 + 52.7
2
0.074/𝑠𝑞𝑟𝑡 21 − 𝐸𝑟𝑓
𝑎𝑔𝑒 25.6 − 52.7
2
24.5 2
8 y/o with pineoblastoma
Source: Danny Indelicato MD & Amber Wyatt - University of Florida Proton Therapy Institute
Photon
Plan
Proton
Plan
8 y/o with pineoblastoma
Source: Danny Indelicato MD & Amber Wyatt - University of Florida Proton Therapy Institute
Photon Plan
Proton Plan
8 y/o with pineoblastoma
Source: Tom Kelsey & Chia-Ho Hua
Compare two treatment plans by
overlaying on dose-response chart
Dots are predicted age at menopause
after mean dose
Fertility window ranges between
predicted ages for minimum &
maximum dose
LD50 is 2 Gy
Dose is to the least affected ovary
8 y/o with pineoblastoma
Incorporate uncertainty due to variation in NGF population at birth
Or, equivalently, variation in ages at menopause
The z-score 0 value are the same ranges as on the previous slide
68% of the population will fall in the left-to-right shaded area
3 year old with a >8 cm unresectable pelvic Ewing sarcoma
Source: Danny Indelicato MD & Amber Wyatt - University of Florida Proton Therapy Institute
§Double-scattered 3D
conformal proton plan
§Pencil beam intensity
modulated proton plan
§for proton therapy, the
unit of the radiation
dose is Gy (RBE) or
Cobalt Gray
Equivalent (CGE)
§6 MV photon therapy
(VMAT) using 2 arcs for both
the initial and boost phases
§CSI comparison photon
plans: 3D conformal using 3-
4 fields for the CSI phase
and 5 fields for the boost
phase
3 year old with a >8 cm unresectable pelvic Ewing sarcoma
Source: Tom Kelsey & Chia-Ho Hua
Compare two treatment plans by
overlaying on dose-response chart
Dots are predicted age at menopause
after mean dose
Fertility window ranges between
predicted ages for minimum &
maximum dose
LD50 is 2 Gy
Dose is to the least affected ovary
3 year old with a >8 cm unresectable pelvic Ewing sarcoma
The two plans inform the fertility preservation decision making
Both plans conform to contemporary disease-specific treatment protocols
Fertility after Radiotherapy
We have developed an online tool, available at
https://tom.host.cs.st-andrews.ac.uk/radiosensitivity-protected.html
We think this improves on tools with asimilar aim
https://fertilitypreservationpittsburgh.org/fertility-resources/fertility-risk-calculator/
https://ccss.stjude.org/tools-and-documents/calculators-and-other-tools/ccss-ovarian-risk-calculator.html
Strengths and limitations
Based on a validated NGF model
Incorporates the precise doses
from modern planning
Considers the full reproductive
lifespan of each patient
Easy to compare plans in terms of
later fertility
The LD50 is still an estimate
Chemotherapy is not taken into
account
There is no current biomarker for
the ovarian reserve for ages below
25 years
There is evidence to support the
2nd modelling assumption, but not
yet conclusive
Conclusions
15 years is a long time in modern oncology
Treatment and fertility preservation techniques have progressed
The Multi-Disciplinary Team meetings that examine treatment options
should be informed by estimates of the late effects of the treatments
Lehmann et al. (2017) found that over 80% of childhood cancer survivors
wanted to have their own biological children in the future, but that most
survivors of childhood or young adulthood cancer (77%) did not know their
fertility status
Our framework is aimed at improving fertility-related knowledge and the
achievement of reproductive of goals
Lehmann V, et al. Fertility-related knowledge and reproductive goals in childhood cancer
survivors: short communication. Hum Reprod 2017;32 :2250-2253.
Thank you
ResearchGate has not been able to resolve any citations for this publication.
ResearchGate has not been able to resolve any references for this publication.