The COVID-19 pandemic has galvanized research on how to treat people ill enough to be hospitalized with SARS-CoV-2 pneumonia. Radiation therapy is being evaluated in clinical trials as an investigational treatment. This presentation from July was for colleagues at Massachusetts General Hospital to discuss the pros/cons of using radiotherapy for an infectious disease.

1. Low Dose Radiation
Therapy (LDRT)
for COVID-19 Pneumonia
Matthew Katz, MD
July 2021

2. Disclosures
 Partner, Radiation Oncology Associates PA
 Lowell, MA and Manchester, NH
 Participate in the phase II Ohio State PreVent
trial

3. Overview
 SARS-CoV-2 Pneumonia as a
 Historical Data
 Clinical use of LDRT
 Evolution of anti-radiation sentiment
 Emergence of LDRT Clinical Trials
 Implementation of PreVent trial in Lowell

4. COVID-19 Morbidity & Mortality
 Pulmonary infection progressing to ARDS, multi-
system injury
 Highly antigenic host response induces injury, not
just virus
 Age-dependent risks for mechanical ventilation
and death
 In 5700 NYC patients, the 60+ years old patient risks:
 19.0% rate of mechanical ventilation
 30.7% crude mortality rate
Richardson et al, JAMA 2020

5. Scrambling for Answers

6. ARCI Formation in April 2020
 40+ radiation oncologists, radiation biologists,
physicists, others collaborated globally to
discuss clinical trials
 DropBox of resources shared, phase I trial
developed

7. Historical Role of Radiation
 Reports on over 700 patients for pneumonia, treated 1905-
1946
 May decrease inflammatory response at doses 30-100 cGy
Calabrese et al, Yale J Biol Med 2013
Powell, JAMA 1938

8. Historical Use of Radiation
Years
1895-1910 Scientific Breakthroughs,
Excitement
1900-1920s Popular Crazes, Interest
1910-1930s Commercialization
1925-1940s Backlash to Radiation Risks
1945 Nagasaki and Hiroshima

9. Post World War II
 Most focus after WWII only on anti-cancer use
 Increasing radiation safety research
 Strong cultural biases against radiation exposure
after atomic bombs used 1945
 ”Benign” diseases not treated
 Germany continued to use for non-neoplastic
disease

10. Leading Formation of Differing Camps
Pro Con
Wally Curran Ralph Weichselbaum
Arnab Chakravarti David Kirsch
Minesh Mehta Max Diehn
Concerns: Weak clinical evidence, ?acute/late RT effects (cardiac, 2nd malignancy),
staff exposure, cancer patient exposure, no contemporary preclinical
evidence
Rationale: Thoracic RT likely tolerated well at 50-100 cGy; high morbidity/mortality
in short time frame; reasonable to do clinical trials

11. Clinical Trials in Low Dose
Radiotherapy
Trial Phase Location No.
Patients
Median Age
(Range)
% Male RT Dose
RESCUE 1-19 I/II Emory 10 78 (43-104) 40% 150 cGy
LOWRAD-CoV I/II Madrid 9 66 (53-90) 78% 100 cGy
AIIMS I/II New Delhi 10 51 (38-63) 100% 70 cGy
Iran I/II Tehran 5 69 (60-84) 80% 50 cGy
TIMING
• LOWRAD treated hospitalized patients failing other treatments
• 100% had steroids and hydroxychloroquine, 60+ antiviral
• Others all tried to treat near time of admission

12. Clinical Trials in Low Dose
Radiotherapy
Trial RT Toxicity Clinical
Improvement at 7d
%
Alive
Median Time to
Discharge (d)
RESCUE 1-19 None 100% 90% 16
LOWRAD-CoV Gr 2 lymphopenia NR 78% 13
AIIMS None 90% 90% 15
Iran None 75% 75% NR

13. RESCUE 1-19
 Matched 10 treated patients to controls
hospitalized at same time to compare
outcomes
 Endpoints
 Time to clinical recovery (similar to remdesivir trials)
and clinical course
 Monitored improvement in imaging
 Lab data

14. RESCUE 1-19
Median 3 days with radiation vs 12 days in controls (p=0.05)

15. RESCUE 1-19

16. RESCUE 1-19
Time to discharge p=0.13 Intubation p=0.12
Statistically significant improvement in CRP, ALT, trends for AST, creatine kinase

17. PreVent: Protocol Schema

18. Step 1: Randomized
 Assigned to
 Best supportive care
 35 cGy whole thorax x 1
 100 cGy whole thorax x 1
 Stratification
 Charlson Comorbidity Index (≤ 4 vs >4)
 Wuhan Prognostic Nomogram (≤ 188 vs >188)
 Use of remdesivir during current admission before
randomization (Yes/No)
 Accrue 60 patients then evaluate differences between
35 cGy and 100 cGy to select dose for Step 2

19. Step 1: Assessment after 60 patients
 Composite clinically meaningful event rate
(CMER)
 Rate of Mechanical Ventilation estimated 19%
 Rate of prolonged hospitalization >10 d estimated 5-15%
 Crude rate of all cause mortality estimated 30-35%
 Used along with other factors to determine if 35 cGy or
100 cGy should be dose for Step 2
 Grade 4-5 toxicity rate
 CMER rate
 Facility resource utilization rate (hospital stay, ICU days)
 IL-6 levels
 If no differences, 35 cGy will be dose for Step 2

20. Step 2 Primary Objective
 To determine whether low-dose thoracic
radiotherapy at 35 or 100 cGy provides clinical
benefit (CB), defined as a composite endpoint
consisting of 3 elements:
 Rate of mechanical ventilation (MV)
 Rate of prolonged hospital stay >10 days (PHS)
 Rate of all-cause mortality at 30 days

21. Inclusion Criteria
 Age ≥ 50 years
 Hospitalized for COVID pneumonia
 Lab confirmed COVID-19+ pneumonia
 At least one risk factor for pulmonary dysfunction:
 Fever >102 degrees Fahrenheit during index admission
 SaO2 ≤95% on room air
 Respiratory rate >26/min on room air
 Requiring 4L/min oxygen to maintain SpO2>93%
 Ratio of partial pressure of arterial oxygen to fraction of inspired air <
320
 Symptomatic fever, cough, SOB < 9 days
 Able to be positioned on linear accelerator for treatment

22. Exclusion Criteria
 On mechanical ventilation
 Prior thoracic radiotherapy, except for:
 a. Breast/chest wall radiation (no regional nodal irradiation) included at the
discretion of the site primary investigator, and
 b. thoracic skin radiation therapy (without regional nodal irradiation) is
allowed.
 Known hereditary syndrome with increased sensitivity to
radiotherapy
 Known prior systemic use of: Bleomycin, Carmustine,
Methotrexate, Busulfan, Cyclophosphamide, or Amiodarone
 Pulmonary fibrosis or condition responsible for significant
lung compromise at discretion of site primary investigator

23. Exclusion Criteria
 Currently requiring mechanical ventilation
 History of lung lobectomy or pneumonectomy
 Known history of pulmonary sarcoidosis, Wegener’s
granulomatosis, systemic lupus erythematosus, rheumatoid
arthritis, or other autoimmune disease
 Symptomatic congestive heart failure within the past 6 months
including during current hospitalization
 History of
 recent or current malignancy receiving any cytotoxic chemotherapy or
immunotherapy within the past 6 months
 bone marrow transplantation
 any solid organ transplant (renal, cardiac, liver, lung) requiring
immunosuppressive therapy
 Females who are pregnant or breast feeding

24. Statistical Estimates
 Anticipate 50-80% of patients on the control arm will
have an event
 Consider a 33% reduction in events to be a clinical
meaningful endpoint
 Calculations consider a 5% dropout rate
 Considering 40 control samples and 60 treated
samples, a one-sided log rank test achieves 85%
power to detect a 33% reduction in events from 0.7 in
controls to 0.47 in treated patients considering an
alpha = 0.1

25. PREVENT for LGH
 Stricter Inclusion Criteria
 Everyone getting remdesivir/dexamethasone
 May need to select higher risk patients to see a difference
 Can’t treat with radiation if re-hospitalized or symptoms
ongoing too long
 Clinical Groups based upon Rem/Dex response
 65-74 years, no improvement or limited improvement
 75+ years, significant improvement to no improvement
 Symptoms <4 days
 Screening to treatment on trial requires 2 days

26. Process for Protocol
 Day 1
 Screening for eligible patients
 5AM inpatient screening and chart review
 Contact hospitalist to approve consultation
 Same evening Zoom telehealth consult, no direct contact to assess
interest, eligibility
 Day 2
 Consent, and then examine
 Randomization and enrollment
 Study labs
 Treatment after 5PM when cancer center patients done
 Floor staff support needed for transportation/monitoring

27. First treated patient
 High risk
 Male, 70s, HTN, asthma, BMI 44
 CRP 16.2, required 5L after
rem/dex
 CRP remained 15, increased
ferritin, glucose, ALT/AST
 Required 6L by time of RT
 Randomized to 100 cGy
 Used prior 2014 CT chest to plan
(sped up treatment)
 Set up <15 minutes
 Treatment 12 seconds
AP
Lat

28. Using Diagnostic Imaging
 Prior CT, CXR can help pre-define radiation field
 Treatment planning can prepare before patient
arrives
 Treatment planning time: 20 minutes

29. Views of 100 cGy Dose Distribution
Treatment planning time: 20 minutes before patient arrival
Time for arrival to departure from department: 40 minutes
Beam on time: ~12 seconds (600 MU/min, 56 MU each field)
Lung Dose Dmax = 110.5%
Dmin = 82.9%
Dmean = 99.7%

30. Admitted Patients in Lowell
 All patients requiring oxygen receive remdesivir (R) and
dexamethasone (D) on admission, no plasma or other
therapies
 Seems to have differing clinical trajectories during
hospitalization
 Rapid progression – in ICU on ventilator in 24 hours
 Gradual progression – building, slower pace to ICU
 No response to R+D
 Partial response to R+D
 Stable
 Quick response

31. Admitted Patients in Lowell

32. Questions re: LDRT
 If we are so concerned about late effects of LDRT,
why do we still treat breast DCIS?
 No survival benefit
 Cosmetic benefit, decreases future surgery need in next
10 years
 If we believe it’s reasonable to improve cosmesis
to risk second malignancy, why not trials in LDRT
that may lessen risk of
 Mechanical ventilation?
 Prolonged hospitalization?
 Potential mortality?

33. Reasons to take LDRT Seriously
 Immediate risks to staff, cancer patients low with
vaccination and infection protocols
 We treat patients with other MRSA, VRE, C. Difficile
 Risk of late effects is low, potential benefit high if
you conduct trials in highest risk cohorts (65+ years
old)
 Don’t assume low dose late effects data from atomic
bomb/space whole body exposure data applies
 Common for prior areas of scientific inquiry to be
dropped but later relevant to current problems seen
in a new light

34. Summary
 Immediate risks to staff, cancer patients low with
vaccination and infection protocols
 We treat patients with other MRSA, VRE, C. Difficile
 Risk of late effects is low, potential benefit high if
you conduct trials in highest risk cohorts (65+ years
old)
 Don’t assume low dose late effects data from atomic
bomb/space whole body exposure data applies
 Common for prior areas of scientific inquiry to be
dropped but later relevant to current problems seen
in a new light