After approval by an Ethics Committee, a prospective study was designed and initiated at La Milagrosa Hospital (Madrid, Spain) to treat COVID-19 patients with Ultra-LDRT. The main purpose of the study was to analyze the efficacy of LDRT, as an anti-inflammatory intention, in patients with SARS-Cov-2 pneumonia with a poor response to medical treatment and would otherwise have no other treatment except IMV, to which they were no candidates. Given the extremely unusual situation and poor prognosis of the disease if left untreated the study has been designed without a control arm, to evaluate security and efficiency of the treatment.
We reviewed the medical records of these patients to evaluate biographical data and medical history. Based on that, Charlson Comorbidity Index (CCI) (>or< 6 score) (11) was calculated for each patient. Previously to the treatment, diagnosis of COVID-19 was proven by polymerase- chain-reaction (PCR), as well as blood gas analysis was performed to calculate the Pa02 / Fi02 (>or< 300 mmHg). We measured the oxygen saturation status (>or< 93%) and the ventilatory support with oxygen therapy (from less to more: Nasal Cannula-NC-; Ventimask -VMK- and VMK with reservoir). Blood analysis was obtained to assess inflammatory and immunological parameters, such as lymphocytes, IL-6 , D-dimer, ferritin, LDH, C Reactive Protein (CRP) and fibrinogen (12,13).
All patients underwent a baseline thoracic computed tomography (CT) scan, in which we assessed the radiological involvement through the Total Severity Score (TSS) (14). This score values ranged from 0 to 20 according to the sum of the percentage of involvement of each 5 lung lobes, which were scored from 0 to 4 points. The same senior thoracic radiologist also estimated the lung involvement qualitatively (subjectively) as mild (TSS 0-5), moderate (TSS 6-15), or severe (TSS >15). A worsening of TSS during the hospital stay or score at admission > 5 was considered as inclusion criteria.
Additionally, Eastern Cooperative Oncology Group (ECOG) (15) (Status ≤ 3), life expectancy (> 1 month) at hospital admission for COVID-19 and previous thoracic RT (relative-criteria) or chemotherapy history, was assessed.
All the patients were provided and signed a written informed consent.
Treatment protocol:
Ultra-LDRT was administered for 6-MV photon beams by a Tomotherapy Hi-Art Accuray® under institutional safety procedures.
The simulation images were acquired by megavoltage CT (MVCT) in the Tomotherapy®. Immobilization was done in supine position with thorax board with arms support. Three radiopaque-marks were placed on the patient skin. The contouring was made in Pinnacle® station and dosimetry in Tomotherapy Hi-Art Planning Station®. The planning target volume (PTV) was defined as both whole lungs extended 1cm isotropically. No dose constraints were applied to surrounding organs. Regarding the target coverage, the 90% of PTV should receive 100% of the prescription dose and the maximum hotspots dose should be <110%.
Verification imaging was carried out using a MVCT limited to the central third of the thorax, to correct for any error. Total single dose administered was 0.8 Gy in a 3-minutes session.
Response evaluation:
The radiological response, assessed by TSS change, was evaluated from a thoracic CT scan 7 days and 4 weeks after the treatment. Radiological improvement was defined as mild (TSS decrease <3 points), moderate (TSS decrease 3-5 points), or high (TSS decrease >5 points) from the baseline CT.
The clinical response was evaluated by pulse-oximetry, blood gas analysis and labs at days 2, 5, 7, and at 4 weeks after Ultra-LDRT. Two months later, oxygen status and pulse-oximetry were evaluated again. Sat02>93%, descent of oxygen therapy support, Pa02 / Fi02 > 300 mmHg and the achievement of normal range value in one or more of the inflammatory and immunological parameters, was considered as clinical improvement.
Toxicity was assessed according to the NIH Common Terminology Criteria for Adverse Events (CTCAE v5.0) scale (16).
Cases report
After establishing our protocol, 4 patients with COVID-19 pneumonia were candidates for LDRT. One refused to participate and another died before receiving the treatment. The other two participants met the study criteria and are discussed below.
Patients´ clinical characteristics are summarized in Table 1.
Patient 1
An 80-year-old-man presented to the emergency department with a 3-day history of dyspnea, cough and chest pain. He showed 70% 02-Sat and tachypnea. Pulmonary auscultation revealed crackles predominantly in bilateral lower two-thirds. During hospitalization his evolution was torpid with a 87% 02-Sat needing of increased ventilatory support (50% reservoir, 15L of flow). The baseline CT showed bilateral pneumonia and extensive bilateral ground-glass opacities corresponding to an acute inflammatory stage. (Figure 1.A)
Patient 2
A 65-years-old-woman debuted with dry cough. A week after, she reported to the emergency department with persistent cough, fever, asthenia and dysgeusia, hence she was admitted. During hospitalization, radiological study showed pneumomediastinum, making her not a candidate to IMV. After 5 weeks of admission and several desaturation episodes her respiratory status evolved until support with VMK 40%. The CT scan ruled out the possibility of Pulmonary Embolism and showed a moderate pneumonia, bronchiectasis, and subpleural bands suggesting an advanced inflammation phase (Figure 1.D).
The medical therapy administrated to both patients consisted of lopinavir/ritonavir, hydroxychloroquine, azithromycin, piperazillin/tazobactam, prophylactic doses of low- molecular-weight-heparins (LMWHs), corticosteroids (methyprednisolone 250mg x 3 boluses) and Tocilizumab (single dose). Despite this pharmacotherapy, prone position and the oxygen support, the respiratory status and high inflammatory parameters of both patients kept worsening. At this point, their enrollment in the ULTRA-COVID study was decided and a single ultra-LDRT was administered on April 23rd, 2020.