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.
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
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
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
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