There is excitement at the potential for radiation therapy to improve cancer outcomes in metastatic disease. However, using a 'local' therapy is hard to conceptualize. I recommend reimagining radiation as a drug in this setting and discuss how it might be used. Example given for metastatic breast cancer clinical trial.
Trichy Call Girls Book Now 9630942363 Top Class Trichy Escort Service Available
Radiation Therapy as a Drug and Use in Metastatic Disease
1. Radiation Therapy as a
Drug and Use in
Metastatic Disease
Reframing subatomic particles as medicine
Matthew Katz, MD
January 2020
2. Conflict of Interest
Partner, Radiation Oncology Associates PA
Stock in Dr. Reddy’s Laboratories, Healthcare
Services Group, Mazor Robotics, U.S. Physical
Therapy
3. Overview
Framing Radiation as a drug
Clinical applications
Framework
Patterns of Failure
Possible clinical trials by disease
Strategic Value
Research funding
Influence in cancer care
4. Radiation Therapy
Poorly understood specialty
Used in 50% of cancer patients at some point
during cancer experience
Often hard to determine value in treatment
efficacy and cost
5. Aim
Reframe radiation therapy as a drug to make
easier to compare to other cancer therapies
Efficacy
Design new combination therapies for systemic
disease
Consider whether there is a clinically
meaningful new role for it in metastatic
disease
6. Origins of Radiation Oncology
Particle Discovered Nobel
X-Ray (photon) 1895 1901
Electron 1897 1906
Proton 1911
Neutron 1932 1935
7. Radiation: The Original Molecular Medicine
Discovery along with x-rays made it seen as
mysterious but powerful
Not seen as a medicine but a physical force
Contemporary evaluation of cancer therapies
at molecular level makes it reasonable to
consider reframing
8. Definition of a Drug
“A substance intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of
disease.”
-- Merriam-Webster Dictionary
9. Mechanism of Action
Radiation damages DNA (or other molecular
targets)
Direct action = particles ionize target molecule
Indirect action = H2O+ radical ionizes target molecule
10. Pharmacokinetics of DNA Injury
Event Time Comment
Atom Ionization 10-12 sec
Free radical formation 10-12 – 10-2 sec
DNA damage 1 sec to hours
Unrepaired DNA or
misjoined DNA damage
repair
Hours to
years
Tumor Death, apoptosis
Normal tissue early, late effects
12. Different from many drugs
No drug receptors for subatomic particles
Cellular sites of action vary given that drug
reaches entire cell
Interact with small molecules and ions
May alter biochemistry or function
Is there any receptor
antagonist/agonist/inverse agonist activity
from radiation, or how it affects response to
other drugs
16. Other radiation drugs
PO = I-131 for thyroid cancer
IV = Radium-223
Brachytherapy = topical, interstitial insertion
17. Drug metabolism
Photons = ‘prodrug’
Create orbital electrons, which has biologic effect
Some just pass through patient without interacting
Not clear that there are phase II conjugation
reactions
Usually endoplasmic reticulum/cytosol >nucleus
No definite impact of cytochrome P450 on
radiation response?
18. Clinical Pharmacokinetics
Component Time Comment
Route of Administration EBRT: Per aeram
Other: PO, IV, topical,
interstitial
Absorption 3.34 x 10-9 s
Bioavailability No tissue binding per se
Clearance 3.34 x 10-9 s
Excretion No renal/biliary-fecal/skin
excretion for external beam but
apply with some unsealed
sources
19. Volume of Distribution
Controlled by physician, treatment planning
and equipment
Not related to plasma proteins or tissue
binding
Varies by patient shape, body composition
and position
May vary daily and affect dose delivery
Organ motion, varying air/tissue interfaces
20. Radiation reimbursement
Based on manipulating volume of
distribution
Not based upon dose but devices/techniques
[+/- particles] used for treatment
21. Whole Body vs. Partial Body
Syndrome Type 50% Lethal Dose Time to Death
Hematopoietic 250-500 cGy 4-8 weeks
Gastrointestinal 500-1200 cGy 9-10 days
Cerebrovascular 10000 cGy 24-48 hours
Disease Dose 5+ year Gr 5 toxicity
Breast cancer 4000-6000 cGy 0%
Lung cancer* 5000-6000 cGy <1%
Prostate cancer 6000-8000 cGy <1%
Whole Body
Partial Body (conventionally fractionated)
*Stereotactic lung RT in 3-5 doses similar to surgery for cT1-2a N0 NSCLC
23. Value of RT in Metastatic Settin g
Symptom relief/Improving quality of life
Avoidance of systemic therapy toxicity
Lengthening life
24. Risks of RT in Metastatic Setting
Progression free survival isn’t worth much if
it’s radiologic and not based upon patient
experience
Increases treatment toxicity
Increases financial toxicity
25. Framework
Need to reconceptualize metastatic spectrum
better
Define disease states better
Guckenberger et al, Lancet Oncol 2020
Oligometastatis, oligoprogression distinguished
Include molecular biology into solid
malignancy staging better, like in
hematologic malignancies
Foster et al, JCO 2019
Unique biology may determine whether metastatic
growth is focused, slow enough to benefit from RT
26. Patterns of Care
If we’re going to start using radiation in
metastatic disease, we need to conduct
sophisticated patterns of care studies like we
have in curative intent cancers in the 1980s,
1990s
We need anatomical/spatial patterns of
failure in treatment naïve and treatment
resistant settings
27. Tumor Heterogeneity
Need a better understanding of how to
individualize radiation dosing
May require biopsy, molecular data for
prognosis, individualization
Scott et al, Lancet Oncol 2017
Better identification of radiation resistance
Kamran et al, Clin Cancer Res 2019
28. Clinical Applications
Reimaging use of radiation therapy beyond
its cytotoxicity at higher doses
Priming agent (low vs. high dose)
Antigen presentation
Biologic response modifier for target tissue for
drug delivery
Chemosensitizer (low dose)
Reverse of curative intent chemoradiation
Full dose chemotherapy, low dose radiation
Cytotoxic/Ablative agent
Conventional to stereotactic RT doses
29. Example: HER2+ Breast cancer
Increasingly systemic drugs working for non-CNS
metastatic disease
Leptomeningeal disease still very challenging for any
systemic agents
Higher HER2 expression may improve response to
HER2-directed therapy (Scaltriti et al, Nishimura et al,
Montemurro et al)
Ionizing radiation can upregulate HER-2 antibody
targets in HER2+ and triple-negative breast cancer cell
lines and can enhance cell kill effects of trastuzumab
(Wattenberg et al)
30. Possible phase I/II clinical trial
Her2+ CNS progression only breast cancer
patients
Treat with low dose (20-75 cGy) radiation
prior to each intrathecal trastuzumab
MR-targeted to GTV vs. craniospinal CTV
Low-dose hypersensitivity without inducing
intrinsic radiation resistance
Permits retreatment of previously irradiated
patients
31. Possible uses in systemic disease
Disease Stage Role Target Volume Dose/Fx
AML CNS2/CN
S3
Chemosensitization/syne
rgy
CTV = craniospinal axis 20-40 cGy w/IT
chemotheratpy
Breast,
Her2+
IV Antigen presentation,
synergy
MR-targeted GTV vs.
craniospinal CTV
25-75 cGy w/ IT
trastuzumab
DLBCL IVA+B Synergy, increase
chemotherapy perfusion
GTV = PET+ 25-75 cGy with
R-CHOP
Melanoma IV Antigen presentation,
biologic response
modifier
GTV = PET+. Treat all
vs. one lesion per organ
w/metastases
25-150 cGy
Myeloma Chemosensitization/syne
rgy
GTV = MRI+ 25-75 cGy
NSCLC IV,
PD-L1
>50%
Priming immunotherapy
+/- consolidative ablation
GTV = PET+ 25-100 cGy +/-
SBRT
NSCLC IV,
EGFR+,
T790M-
Synergy, biologic
response modifier
GTV = PET+ 25-75 cGy
Prostate IV,
new dx
Consolidation +/-
chemosensitization
CTV = Prostate + pelvis
vs Prostate w/only + LNs
Definitive +/-
25-75 cGy
32. Advantages for low dose RT trials
Can start phase I/II trials for combination
therapy quickly vs. new drugs with no human
data
Low dose RT = 2D, 3D = low cost
Wide availability of linear accelerator makes
easier to do trials compared to some
targeted drugs
34. Assessing Efficacy
Could compare to cancer drugs if agree to use
the same endpoints for specific disease
states
Cancer control
Toxicity
Cost of treatment
Would opinions about radiation differ if
perceived as a drug?
35. Conclusion
Reimagine how we use radiation as
something other than purely cytotoxic
therapy
Conduct detailed studies to define patterns
of failure, test new therapeutic approaches
Patient-centered goals must include
treatment toxicity and financial toxicity in
the value proposition
Editor's Notes
Wilhelm Roentgen
JJ Thomson
Ernest Rutherford
James Chadwick