Low-dose Lung Radiotherapy for COVID-19-related Pneumonia: Preliminary Results of the Italian Mono-institutional COLOR-19 Trial

Abstract

Aim: To evaluate the feasibility and tolerability of low-dose radiotherapy (LDRT) delivered to both lungs in the treatment of SARS-CoV-2-immune-mediated pneumonia in the COLOR-19 study (NCT0437747).

Patients and Methods: From May 2020 to April 2021 at Brescia University Radiation Oncology Department, three patients with COVID-19-related pneumonia were treated with LDRT according to the COLOR-19 protocol. All patients were treated with a single fraction at the average prescription dose of 0.7 Gy to both lungs.

Results: Three patients were enrolled (two males and one female, aged 61-81 years) and underwent LDRT. Despite LDRT being safely performed without significant side-effects, two patients died (one 81-year-old male due to septic shock secondary to Escherichia coli infection and one 79-year-old male, already in poor condition, due to worsening of COVID-19). The remaining female patient (61 years old) underwent LDRT for less severe COVID-19: her clinical condition and chest X-ray improved, and she was discharged home completely asymptomatic 27 days after hospital admission. Blood levels of C-reactive protein and ferritin generally decreased after LDRT.

Conclusion: Early results of the COLOR-19 study demonstrate the feasibility of LDRT for therapy of COVID-19-related pneumonia; no conclusions on the efficacy have been reached due to poor accrual.

The Brescia District was one of the regions in Italy most severely affected by novel Coronavirus Disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1,2). A multitude of clinical trials have evaluated the use of several drugs, notably for the treatment of severe presentations [reviewed in (3)]. However, most studies to date have not shown a clear benefit of any drug, or led to controversial results (4,5) and currently only remdesivir, steroids and tocilizumab are approved for the treatment of hospitalized patients with severe COVID-19 (6-9). As one of the main pathogenetic mechanisms leading to severe COVID-19 is the uncontrolled release of inflammatory molecules (10), different drugs with anti-inflammatory action have been tested. However, most studies were inconclusive and some of these drugs are burdened by high price and limited availability [reviewed in (11)]. Since low-dose radiotherapy (LDRT) has been widely and effectively used for decades in the treatment of various inflammatory diseases (12), we developed a clinical protocol with the aim of assessing its effect in the treatment of severe forms of COVID-19 through the use of modern techniques. In this article, we report the preliminary results of the first enrolled patients.

Patients and Methods

A pilot study COLOR-19 (COVID-19 Pneumonitis Low Dose Lung Radiotherapy; NCT0437747) started recruiting in May 2020. This study was approved by Spedali Civili of Brescia Ethic Board (approval number NP4097). The study was conducted in agreement with the Declaration of Helsinki and all patients provided written informed consent before enrollment and consent for publication of their data.

Three patients were treated with LDRT to both lungs. Patients underwent a single session of LDRT at the average prescription dose of 0.7 Gy, as per protocol. Dose constraints included a maximum dose of 0.55 Gy to vertebral bodies and 0.9 Gy to both lungs.

The irradiation was planned using the treatment planning system and performed by means of antero-posterior (AP) postero-anterior (PA) opposing fields with beamlets: the principal AP field was conformed with multileaf-collimator to the whole lungs plus 2 cm, then, with a field-in-field technique, we defined two beamlets to treat each individual lung minus vertebral body and sparing the contralateral lung. PA fields were specular (a fourth beamlet was added, if necessary, to decrease the dose to the most cranial vertebral bodies). Planning dose prescription was 70 cGy as the mean lung dose (Figure 1). We performed cone-beam computed tomography to verify the patient set-up. The overall required time for plan simulation and delivery was less than 30 minutes. All the enrolled patients required supplemental oxygen, which was safely continued during radiotherapy using portable oxygen sources or the medical gas supply available.

Figure 1. A: Dose distribution and radiation fields of planning computed tomography -scan of patient 2, highlighting the sparing of the vertebral body. B: Dose-volume histogram for the same patient. C: Digitally reconstructed radiographs of the antero-posterior postero-anterior opposing fields, with the principal antero-posterior field conformed with multileaf-collimator to the whole lungs plus 2 cm and two beamlets (field-in-field technique) to treat each single lung minus vertebral bodies.

Inclusion criteria were: age ≥50 years; confirmed diagnosis of SARS-CoV-2 infection by polymerase chain reaction (PCR); Brescia Covid Respiratory Scale score 2-3; radiological findings of SARS-CoV2-induced pneumonia [evaluated by Brixia chest X-ray score (BS)]; at least three of the following laboratory criteria (C-reactive protein >5 times the maximum limit of normal, lactate dehydrogenase >2 times the maximum limit of the normal value, D-dimer >3 times the maximum limit of normal, aspartate aminotransferase >2 times the maximum limit of normal, total lymphocytes <1,000/ml, ferritin >500 ng/ml). Exclusion criteria were: age <50 years; active autoimmune disease; positive pregnancy test.

Brescia Covid Respiratory Scale (13) and BS (14) are scales developed during the first COVID-19 outbreak to classify clinical and radiological severity of COVID-19 easily. The primary outcome was the evaluation of the feasibility of LDRT with the purpose of a subsequent phase II study. Secondary outcomes were: modification of the chest X-ray according to BS at days 3, 6 and 10 after LDRT; evaluation of the safety and tolerability of LDRT according to Common Terminology Criteria for Adverse Events 5.0 (15).

Descriptive statistics were used to summarize patient’s features. All statistical calculations were performed using SPSS Software version 25.0 (IBM, Armonk, NY, USA).

Results

Patients’ characteristics are summarized in Table I, main parameters regarding COVID-19 evolution are given in Table II and trends of biochemical blood tests are reported in Table III.

Table I. Clinical features, comorbidities, and ongoing chronic treatments at COVID-19 diagnosis.

AAA: Abdominal aortic aneurysm; EVAR: endovascular aneurysm repair; PTCA: percutaneous transluminal coronary angioplasty; SCC: squamous cell carcinoma.

Table II. Main parameters regarding the clinical course of COVID-19 in the study patients.

BS: Brixia score for chest X-ray; CPAP: continuous positive airway pressure; CRP: C-reactive protein; HGS: hemo gas analysis; KPS: Karnofsky performance score; SpO2: peripheral capillary oxygen saturation.

Table III. Main parameters regarding biochemical trends of circulating molecules and radiological findings.

AST: Aspartate aminotransferase; CRP: C-reactive protein; LDH: lactate dehydrogenase; NA: not assessable; WBC: white blood cell count.

Patient 1 was an 81-year-old man with multiple comorbidities (hypertension, dyslipidemia, coronaropathy treated with percutaneous transluminal coronary angioplasty, abdominal aorta aneurysm treated with endovascular repair) who tested positive by PCR for SARSCov-2 on October 19, 2020, through a naso-pharyngeal swab (NPS) performed for fever and dyspnea. He presented for worsening dyspnea at the Emergency Room of our Hospital on October 21^st. Chest X-ray resulted in a BS of 14 and he was thus admitted to a dedicated COVID-19 ward. He started treatment with remdesivir with an initial improvement of chest X-ray (BS 5 on October 27^th) but his clinical condition worsened, requiring non-invasive ventilation with continuous positive airway pressure. He started oral dexamethasone at 20 mg/day, enoxaparin 6000 UI/day and intravenous morphine with transitory benefit, but then his radiological (BS 10 on November 2^nd) and general condition further deteriorated. He was thus enrolled to undergo whole-lung LDRT, which was performed on November 3^rd. Treatment was well tolerated and at follow-up 3 days after LDRT, chest X-ray improved (BS 8) and ferritin and PCR load were slightly reduced. Nonetheless, on the same day, the patient developed septic shock due to systemic Escherichia coli infection, treated with intravenous antibiotics. Computed tomography excluded pulmonary embolism. At 6 days post LDRT, inflammatory indices further declined and SpO₂ was 96% despite a reduction of continuous positive airway pressure at 2 sessions/day alternated with a Venturi mask (10 l/min 50%). Unfortunately, the patient developed right heart failure and, despite hemodynamic support, his condition precipitated and he died on November 19^th.

Patient 2 was a 79-year-old male with several comorbidities (hypertension, diabetes mellitus complicated with retinopathy, prostatic adenocarcinoma treated with radical radiotherapy in 2008) evaluated for esophageal cT2N1M0 squamous carcinoma of the middle third of the esophagus and in already poor general condition (Karnofsky score 60%) who was diagnosed with SARS-Cov-2 infection at a screening NPS on March 12^th, 2021, while undergoing radical radiotherapy as an inpatient in our ward. Treatment was thus halted after 15 fractions of 2.3 Gy but 2 days later he manifested mild fever and dyspnea and his condition gradually worsened, requiring supplemental oxygen (Venturi mask 6 l/min, SpO₂ 99%) despite administration of 6 mg/day dexamethasone. He also developed a urinary infection, treated with meropenem and vancomycin. On March 22^nd, chest X-ray revealed a BS of 10, PCR was 196.7 mg/l and ferritin 5998 μg/l. He underwent whole-lung LDRT on March 23^rd. However, notwithstanding a slight reduction of the PCR load, his clinical, respiratory and radiological (BS 12 on March 25^th) condition declined, and he died on March 26^th.

The third patient was a 61-year-old female in good general condition with a cT2N0M0 squamous carcinoma of the vulva and no other comorbidities. She started radical radiotherapy (prescribed dose 59.4 Gy/33 fractions) on February 25^th with concomitant 5-fluorouracil and mitomycin therapy (one cycle started on March 1^st). On March 19^th, she tested positive for SARS-Cov-2 at a screening NPS and 3 days later, she developed fever and mild dyspnea, chest X-ray showed BS 1. In the following days, she required supplemental oxygen and treatment with dexamethasone (6 mg/day) and enoxaparin (4,000 UI/day) was started. On March 29^th, chest X-ray worsened to BS 7, and she was thus enrolled for whole-lung LDRT, performed on March 30^th. The treatment was well tolerated and, despite no change in her chest X-ray, her respiratory function improved; D-dimers increased to over 35,000 μg/l, but embolic processes were ruled out. Supplemental oxygen was gradually reduced, and PCR load also decreased, but the chest X-ray remained unchanged; D-dimers sharply diminished. On April 9^th, PCR was 1.6 mg/l and SpO₂ of 98% was achieved with nasal cannula at 1 l/min; she was finally weaned from oxygen on April 12^th. April 14^th, she completed radiotherapy at the prescribed dose; on the same day, the chest X-ray had improved to BS 6. She was discharged from hospital on April 16^th with no respiratory symptom; she continued isolation at home until she received a negative NPS on April 23^rd and she is still asymptomatic.

Discussion

Although our results support the feasibility of LDRT for COVID-19-related pneumonia, several factors limit the reliability and the reproducibility of the data: the limited sample size, the extreme variability of patients’ baseline characteristics and COVID-19 severity, and timing from the onset of symptoms to the administration of LDRT. Moreover, the study protocol did not exclude pharmacological treatment, hence patients were referred to our Department after the failure of previous medical treatments. Nevertheless, the results of this small trial may provide some interesting data in this field and be useful for future studies including LDRT. Indeed, proper patient selection and timing of LDRT emerged as the main critical aspects in exploiting the anti-inflammatory efficacy of LDRT. Patient 1 received a partial benefit from LDRT, with an initial reduction of chest X-ray BS, inflammatory indices, and necessity for respiratory support; unfortunately, he died due to septic shock from Escherichia coli infection. The poor general condition and the severity of pneumonitis were likely the reasons for LDRT failure in patient 2. Patient 3 was probably an ideal candidate for LDRT: hyper-inflammation was properly intercepted at the right time; the severity of the COVID19-induced pneumonia was acceptable (as demonstrated by the initial low BS and the minimum need for supplemental oxygen). No patients were transferred to the Intensive Care Unit and patient 3 was discharged after 27 days of hospitalization. Several aspects remain to be clarified regarding the use of LDRT for COVID-19-related pneumonia, including a) Ideal timing, likely before hyper-inflammation peak as suggested by our experience and the available literature (16-19); b) optimal radiotherapy technique; and c) dose and fractionation of LDRT, as multiple schedules have been used (including 2-fraction regimens and doses up to 1.5 Gy) (16-19). Although a small-cohort randomized double-blind study reported no clinical benefit of LDRT for COVID-19 (20), enrolled patients were all on mechanical ventilation (thus possibly beyond the ‘window of opportunity’) and the adopted technique implied a large dosimetric inhomogeneity throughout the target volume (0.5 to 1 Gy).

In conclusion, although the issue is controversial (20,21), our results support the feasibility of LDRT for treatment of COVID-19-related pneumonia. Accurate planning and delivery are feasible in a reasonable time. No conclusions regarding effectiveness could be drawn, due to the small sample size. Larger trials are required to demonstrate clinical benefit and optimal timing, technique, and schedule of LDRT.

Conflicts of Interest

The Authors have no conflicts of interest to disclose.

Authors’ Contributions

Conceptualization: SMM, DT, EF, EMF, RM, MB and LS. Formal analysis: SMM, DT, NS, AEG, LT, RB, DG, LP, SLM, ER, GV, RM, MB and LS. Methodology: SMM, DT, NS, AEG, LT, RB, DG, LP, SLM, ER, GV, RM, MB and LS. Investigation: SMM, DT, EF, EMF, NS, AEG, LT, RB, DG, LP, SLM, ER, GV, RM, MB and LS Data curation: DT, EF, EMF, NS, AEG, LT, RB, DG, LP, SLM, ER and GV Supervision: SMM, DT, NS, AEG, LT, RB, RM, MB and LS. Writing – original draft: SMM, DT, NS, AEG, LT, RB, RM, MB, LS. Writing – review and editing: SMM, DT, EF, EMF, NS, AEG, LT, RB, DG, LP, SLM, ER, GV, RM, MB and LS.