Antineoplastics/antiretrovirals

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An event is serious (based on the ICH definition) when the patient outcome is:

• * death

• * life-threatening

• * hospitalisation

• * disability

• * congenital anomaly

• * other medically important event

A case report of three patients described three men, aged 64−79 years, who developed Coronavirus disease 2019 (COVID-19) following treatment with folinic acid, fluorouracil, irinotecan, pembrolizumab, rituximab or bendamustine for oesophageal cancer, lung squamous cell carcinoma or lymphoplasmacytic non-Hodgkin lymphoma. Additionally, one of these patients developed diarrhoea during off-label treatment with lopinavr/ritonavir for COVID-19 [not all routes, dosages and outcomes stated; durations of treatments to reactions onsets not stated].

Case 1: The 70-year-old man, who had been diagnosed with oesophageal cancer in July 2019 and treated surgically with oesophagogastric resection followed by intrathoracic oesophago-gastroplasty, experienced local, hepatic and osseous relapse in January 2020. In January 2020, he received the first cycle of FOLFIRI regimen comprising folinic acid, fluorouracil [5-fluorouracil] and irinotecan. He lived in Italy, and was admitted to the emergency department on 24 February 2020 with fever, asthenia, anorexia and dysphagia for 3 days. Physical examination showed scattered bilateral inspiratory rhonchi. The breath rate was 18 acts/minute and the blood oxygen saturation (SaO₂) was 96%. Laboratory tests revealed leucopenia, lymphopenia and increased CRP. Chest X-ray revealed the gastric tubulization that occupies the inner third of the right hemithorax, diffuse interstitial thickening in medium and lower pulmonary fields, and reticulonodular opacities in the left lower field. His nasal-pharyngeal swab tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay on 26 February 2020. Therefore, he received off-label therapy with oral lopinavir/ritonavir 400/100mg and oral hydroxychloroquine 200mg twice a day for 10 days. He also received antibiotic therapy with off-label IV ceftriaxone 1g daily for 10 days along with oxygen supportive therapy via nasal cannula. Due to the onset of vomiting and nausea associated with the development of cachexia, he received antiemetic therapy with metoclopramide and sedoanalgesia with fentanyl or tramadol, as needed. A RT-PCR assay of nasal-pharyngeal swab repeated 20 days later was also positive. At day 39 of hospital stay, he died due to COVID-19.

Case 2: The 64-year-old man, who had lung squamous cell carcinoma, had received neoadjuvant immunotherapy with pembrolizumab from January 2019 followed by left upper lobe lobectomy and mediastinal lymphadenectomy in September 2019. Then, he received adjuvant immunotherapy with pembrolizumab until January 2020. He lived in Italy, and was was exposed to a SARS-CoV-2 positive subject on 14 February 2020. On 28 February 2020, he was admitted to the emergency department with fever and dyspnoea for 5 days. Physical examination was normal. The breath rate was 22 acts/minute and the blood oxygen saturation (SaO₂) was 98%. Laboratory tests revealed lymphopenia and elevated CRP levels. Chest CT scan performed on the day of admission showed new onset of patchy peripheral ground-glass round opacities associated with focal opacities with "crazy-paving" aspect which is characterised by ground-glass superimposed by thickening of the interlobular septa in both lower lobes. His nasal-pharyngeal swab tested positive for SARS-CoV-2 on the real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay on 4 March 2020. Therefore, he received off-label therapy with oral lopinavir/ritonavir 400/100mg twice a day and oral hydroxychloroquine 200mg, both for 10 days. He also received antibiotic therapy with off-label oral azithromycin 500mg daily for 7 days and IV ceftriaxone 2g daily for 8 days along with supportive oxygen therapy via nasal cannula. Following resolution of fever and dyspnoea, he was discharged on day 12 of hospital stay to home isolation with supportive oxygen therapy. RT-PCR assays of nasal-pharyngeal swab repeated on day 21 and day 38 after hospital admission, were still positive for SARS-CoV-2; however, he was in good conditions. RT-PCR assays of nasal-pharyngeal swabs performed on day 53 and day 55 after hospital admission came negative.

Case 3: The 79 year-old-man had been diagnosed with lymphoplasmacytic non-Hodgkin lymphoma in December 2019. He received the first cycle of rituximab combined with bendamustine at the end of January 2020. He lived in Italy, and was admitted to the emergency department with fever for 4 days on 5 March 2020. He denied any contact with COVID-19 positive subjects. Physical examination did not show any significant findings. The breath rate was 20 acts/minute and the blood oxygen saturation (SaO₂) was 94%. Laboratory tests revealed lymphopenia, elevated CRP and normal WBC count. Chest CT performed on the admission day showed new onset of bilateral peribronchial and peripheral "crazy-paving" opacities, extended for 30−35% of all the lung volume, based on visual score. He refused the hospitalisation. Four days later, he presented again to the emergency department due to persisting fever and new onset of dyspnoea, after testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on the RT-PCR assay of nasal-pharyngeal swab, on 8 March 2020. At that time respiratory rate was 24 acts/minute and the SaO₂ was 89%. The lymphopenia and WBC count were substantially unchanged, but CRP levels were increased. Chest CT scan showed the increase in the infiltrates extension and the appearance of band-like peripheral consolidation in both inferior lobes superimposed on a prevalent crazy paving pattern. Therefore, he was treated with antiviral therapy comprising off-label oral lopinavir/ritonavir 400/100mg twice a day. However, he developed diarrhoea due to lopinavir/ritonavir. Therefore, lopinavir/ritonavir therapy was stopped after 2 days of therapy. Thereafter, he received off-label therapy with oral cobicistat/darunavir 800/150mg daily for 5 days. Additionally, he received off-label therapy with oral hydroxychloroquine 200mg twice daily for 14 days and antibiotic therapy comprising off-label IV ceftriaxone 2g for 8 days and off-label oral cotrimoxazole [trimethoprim/sulfamethoxazole] 160/800mg for 7 days. During the hospitalisation, he received high flow oxygen therapy via either nasal cannula and reservoir facemask. Despite treatment, he died of respiratory failure due to COVID-19, after 17 days of hospitalisation.