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.

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

11. Cellular sites of action
Tepper & Gunderson, 2015

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

13. Route of Administration
 PA (per aeram), by air
Tepper & Gunderson, 2015

14. Absorption
Photons
Electrons
Tepper & Gunderson, 2015

15. Comparing Particles

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

22. Tepper & Gunderson, 2015
Radiation Manufacturing Plant

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

33. Uses in Non-Metastatic Malignancies
Malignancy Stage Role Target Volume
Bladder
cT3 N0-1 or T2, Gr3 Chemosensitization CTV = Whole Pelvis
pT4 or N1 Chemosensitization CTV = Whole Pelvis
Colon (not rectum)
pT3-4, N+ Chemosensitization CTV = Whole Abdomen
Gastric cT2-3 or pT3-4, N+ Chemosensitization CTV = Whole Abdomen
Glioblastoma
Postop, away from
chiasm/brainstem
Chemosensitization
w/full dose
temozolomide
CTV = GTV+ 3 cm
Ovary
Bulky Neoadjuvant
chemosensitization,
biologic response
modifier
CTV = Whole Abdomen
II-III Chemosensitization CTV = Whole Abdomen
Pancreas pT3-4 N0, N1 Chemosensitization CTV = Whole Abdomen
cT3-4, unresectable Chemosensitization GTV=SBRT, CTV=low dose
whole abdomen
No established doses, consider 25-50 cGy pre-chemotherapy

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