By Deborah Borfitz

May 12, 2020 | Oncology specialists working in pandemic hot spots around the world shared their experiences in treating COVID-19 infection in patients with cancer at the 2020 annual meeting of the American Association for Cancer Research, held virtually April 27-28. Among the major takeaways of their two-hour online talks were to avoid generalities across different cancer types, address widening disparities based on race and ethnicity and proceed with caution given the scarcity of randomized controlled trials to guide clinical decision-making.

First up was Li Zhang, M.D., Ph.D., a medical oncologist at Tongji Hospital in China, presenting a study suggesting cancer is associated with poor COVID-19 outcomes. Data were examined on 28 (2.2%) of the 1,276 COVID-19 patients being treated at three hospitals in Wuhan between January 13 and February 25 who also had cancer. Cancer incidence in the country’s overall population is considerably lower (0.29%).

Among the 28, lung cancer was the predominant cancer (25%), followed by esophageal cancer (14%) and breast cancer (11%), Zhang reports. Most were male (60.7%), with a median age of 65. More than a third (35.7%) had stage IV cancer. COVID-19 infection was assumed to be hospital-acquired for eight patients.

Severe events—defined as a condition requiring admission to an intensive care unit (ICU), use of mechanical ventilation or death—were seen in more than half (15) of the COVID-19-infected cancer patients and happened in a short seven days (median) after their COVID-19 diagnosis, says Zhang. The majority received oxygen therapy (22), antibiotics (23) and systemic corticosteroids (15). Twenty patients were also given one or more antivirals—arborol, lopinavir/ritonavir, ganciclovir or ribavirinent—all experimental agents, she noted.

As of April 4, half of the 28 cancer/COVID-19 patients had been discharged from the hospital after a median stay of 18.4 days, Zhang says. Eight (28.6%) had died, most commonly from acute respiratory distress syndrome (ARDS).

Anti-tumor treatment (i.e., chemotherapy, surgery and radiotherapy) within 14 days of patients’ COVID-19 diagnosis had “significant association” with severe events, as did the CT feature of patchy consolidation on admission, she adds.

Zhang says her lab followed 124 patients with cancer who were receiving immune checkpoint inhibitor treatment, among whom one developed COVID-19 infection. The patient was a 56-year-old man with bone and lung metastasis who experienced a mild course of the disease after being treated with the antiviral agent umifenovir and the antibiotic moxifloxacin.

Conclusion: Cancer patients with COVID-19 tend to have poor outcomes with a higher occurrence of severe events and having anti-tumor treatment within two weeks of the COVID-19 diagnosis increases the risk.

Birth of a Registry

Thoracic cancer—or more specifically, the newly created TERAVOLT (Thoracic cancERs interventional coVid 19 cOLlaboraTion) registry collecting data on thoracic cancer and COVID-19—was the focus of a presentation by Marina Chiara Garassino, M.D., chief of the thoracic oncology unit at the Istituto Nazionale dei Tumori Cancer Institute in Milan, Italy.

Initial reports out of China suggested that less than 1% of COVID-19 patients had cancer but others have since concluded the prevalence rate of the novel coronavirus is high among cancer patients compared to general population, and the majority of them have lung cancer, says Garassino. Multiple organizations have recently published guidelines for prioritizing treatment of such dually afflicted patients, including the American Society of Clinical Oncology, the European Society for Medical Oncology ESMO and the U.K.’s National Health Service.

The registry idea was born in mid-March, in the midst of the COVID-19 outbreak in Milan, says Garassino. Thanks to the efforts of Leora Horn and Jennifer Whisenant at Vanderbilt University in Nashville, an international committee was formed in a matter of days and cities around the world quickly began submitting data. TERAVOLT is currently receiving results of 70 new cases weekly, with 21 countries and every continent represented.

Data is being accepted on any thoracic cancer with COVID diagnosis, lab-confirmed with real-time polymerase chain reaction (PCR), she says, as are suspected cases when patients have symptoms such as fever and decreased oxygen saturation. Collectively, patients in the dataset have a median age of 68, 70.5% are male, most are current or former smokers and 73.5% have stage IV disease.

Non-small cell lung cancer (NSCLC) is the predominant diagnosis (75.5%), followed by small cell lung cancer (14.5%). Patients generally have at least one comorbidity (83.8%)—most often hypertension, chronic obstructive pulmonary disease (COPD) and cardiovascular disease—and 73.9% are on treatment. The patient population resembles what typifies daily practice, Garassino says, with a mixture of therapies (e.g., chemotherapy, immunotherapy, tyrosine kinase inhibitors) used alone or in combination.

Symptoms associated with thoracic cancer and COVID-19 have considerable overlap with those of lung cancer alone, including fever, cough and dyspnea, says Garassino. Pneumonia and pneumonitis affect 78.6% of those in the registry. More than three-quarters of them have been hospitalized and—notably—more than one-third (34.6%) have died.

Garassino says registry data indicate that the vast majority of patients (92.2%) are not offered ICU admission, which differs from what has been reported in JAMA, and only five patients have been on mechanical ventilation (possibly due to machine shortages). So far, no treatments have been associated with risk of death or hospitalization. Whether or not the most important risk factors for thoracic cancer patients mirror those for the general population (COPD, hypertension, gender and age) has yet to be determined.

Conclusion: Thoracic cancer patients with COVID-19 have unexpectedly high mortality and the cause of death for a large majority is SARS-CoV-2 and not the cancer; many are not offered ICU admission. To speed answers, investigators are urged to join the global registry rather than create their own datasets.

A View From Paris

The outcomes of cancer patients infected with COVID-19 and treated at Gustave Roussy, a cancer treatment center in the suburbs of Paris, was shared by lung cancer specialist Fabrice Barlesi, M.D., Ph.D. Contrary to other presenters for the plenary session, he concluded that both the incidence and outcomes of SARS-CoC-2 infection were comparable in cancer patients and the general population.

Overall, 12% of more than 1,300 patients have tested positive for the novel coronavirus as have 18% of healthcare workers, he says. Positive cases are therapeutically managed with antiviral, anticytokine therapy and steroids.

In an analysis covering a one-month period ending on April 14, Barlesi says 7,251 COVID-19 patients were managed by Gustave Roussy with 3,616 being hospitalized and 1,302 treated by a primary care physician. The analysis included 137 patients with cancer—median age 61, 58% female and 36.8% current or former smokers.

The majority (119 of 137 patients) had solid tumors, “very balanced across different types of cancers,” says Barlesi. Twenty-four patients were managed for hematological cancers. Roughly one-quarter (23%) had no COVID-19 symptoms and were diagnosed via screening. Symptoms at diagnosis usually included fever, dry cough, fatigue and dyspnea.

Median time to admission for the cancer cohort was four days, with three-quarters hospitalized for treatment and the remainder managed as outpatients. Forty-five patients were treated with antivirals, 10 with anticytokine therapy and the remainder steroids. One-quarter of patients had a clinical nurse manager and 11% were admitted to the ICU. Twenty patients (14.6%) died and the deaths were all COVID-related.

An exploratory analysis revealed clinical worsening (oxygen supplementation for more than an hour or death) in 35% of patients and improvement in 22%, Barlesi reports. Type of cancer and use of targeted therapy or immunotherapy had no impact on clinical worsening.

Conclusion: Patients who are frail, have hematological diseases or have been treated with cytotoxic chemotherapy within the last three months deserve special attention. Participation in clinical trials is critical.

Predictive Factors

The most promising news coming from Carlos Gomez-Martin, M.D., Ph.D., a medical oncologist at University Hospital 12 de Octubre in Madrid, Spain, is the response of onco-hematologic patients with ARDS being treated with tocilizumab. Nine out of 15 such patients were alive after treatment—most often initiated before they developed severe ARDS.

Safety precautions taken by the hospital as of March include on-site screening of patients and caregivers, limiting the number of outpatient visits to chemotherapy treatment, greater use of online consults and an isolation ward for suspected COVID-19 cases.

For the month ending April 19, COVID-19 test results were 74% negative. While the total number of admissions rapidly increase to 1,200, the number of admissions for oncology held steady at no more than 30 “through all months,” Gomez-Martin says.

The first 63 patients treated by the hospital’s medical oncology division most often had lung cancer (15), followed by gastrointestinal cancer (13) and breast cancer (10); 82% had metastatic disease and 40% had lung involvement. More than half of the patients were on active chemotherapy treatment, he says. Symptoms potentially related to COVID-19 included fever (almost 90%), malaise (70%), cough (66%), bilateral pneumonia (55%), diarrhea (50%) and rhinorrhea (18%).

The main outcome, for 25% of the 63 patients, was death with a mean overall survival of 12.4 days; 38% developed ARDS and, of those, 68% succumbed to it. Patients also had significant vascular comorbidities, says Gomez-Martin, noting a 15% risk of rethrombosis. “Three out of 13 patients on anticoagulants developed new disease.”

More than half of patients also developed some kind of respiratory failure that required supplemental oxygen therapy and 24 of those 34 patients had ARD, 16 of whom finally died. Gomez-Martin says the only clinical/lab parameters predictive of the development of respiratory failure was previous anemia and bilateral or multilobar radiology pattern.

Treatment regimens at the hospital shifted in response to study results published in the New England Journal of Medicine, he adds, noting that the lack of randomized controlled studies to inform drug choices.

Conclusion: Lung cancer, neutropenia, and acute respiratory distress syndrome demonstrated to be predictive factors for mortality regardless of other conditions. Follow the standard of care until data from randomized studies investigating cancer patients with the virus are released.

Managing Melanoma

An overview of clinical practice adaptations made in response to the COVID-19 pandemic was shared by Paolo A. Ascierto, M.D., a melanoma specialist at the Istituto Nazionale Tumori IRCCS Fondazione Pascale in Naples, Italy. Delaying surgery is acceptable for some patients and hasn’t been shown to influence survival, he says, although priority should be given to those with lesions 2 millimeters or larger. Wide excision may be sufficient for patients with especially small lesions.

Post-surgery follow-up can be done via telemedicine, Ascierto says, and in patients with no evidence of disease clinical visits can be postponed. Adjuvant care can be delayed for up to 12 weeks. For patients with BRAF-mutant melanoma (about half of all melanomas), combination therapy with BRAF and MEK inhibitors might be an ideal approach. When using checkpoint inhibitors, he recommends the longer dosing schedule.

Patients with metastatic disease are the highest priority and treatment delays should be a consideration, Ascierto stresses. Clinical trials not on hold are employing telemedicine, he notes.

Cancer patients receiving immune checkpoint inhibitors and showing signs of pneumonitis on CT scans should be tested for COVID-19 before being given steroids, advises Ascierto. Likewise, patients receiving BRAF/MEK inhibitors who have a fever that doesn’t resolve with treatment interruption need to be tested.

Ascierto likens inflammatory adverse events associated with immune checkpoint agents to the cytokine storm sometimes seen in COVID-19 patients and can result in lung inflammation—in fact, the severe immune overreaction is being treated by some of the same drugs used to treat pneumonitis, including tocilizumab, on an investigational basis. His clinic has investigated both tocilizumab and sarilumab, another IL-6 inhibitor, with mixed results, he reports.

Conclusion: Early diagnosis and treatment of cytokine storm is essential. Multiple other classes of oncology drugs beyond IL-6 inhibitors also warrant study in treating hyperinflammation in patients with COVID-19.

Facts Not Fear

Issues of racial and ethnic disparities are not novel, and oncologists (with the support of multiple professional societies) have been trying to address the inequalities in the diagnosis and outcomes of patients with cancer, says Louis P. Voigt, M.D., an intensivist at Memorial Sloan Kettering (MSK) Cancer Center. But the COVID-19 pandemic is widening disparities, as the patient experience in New York City (NYC) highlights.

Racial demographic data reveals stark disparities in COVID-19 deaths, with Hispanics and blacks bearing the brunt relative to whites and Asians, Voigt says. Similar trends are seen in infection and hospitalization rates.

MSK has collected data on 5,000 patients tested for COVID-19, he says. Of those, 327 have been hospitalized at MSK; 54% have been discharged and 14% have died at the hospital. In the ICU, 52 of 78 patients admitted have needed mechanical ventilation and 13 have been extubated.

Yet-to-be published data collected in NYC as well as in Seattle and the U.K. indicate a stark difference in mortality rate along patients receiving mechanical ventilation at MSK (27%) versus elsewhere (88%), which has raised many questions, says Voigt. Data is needed on whether prior immunotherapy serves as predisposing factors to COVID; if calibrated or reduced dose is a mitigating factor; and the impact of visitation policies, care delivered at home with daily remote monitoring for some patients, and patient characteristics to include socioeconomic status, race, ethnicity and English proficiency.

“When the healthcare system is overwhelmed, decisions are driven by fear and emotions rather than evolving facts,” says Voigt. “The most vulnerable will fall through the safety net if we don’t pay attention.”

Conclusion: Vulnerable populations are most impacted by deviations from standard care, and the healthcare system has an obligation to create a more robust safety net for them.

Defining Risk

The final speaker for the plenary session was Hongbing Cai, M.D., with the Zhongnan Hospital of Wuhan University, and she added to the growing body of evidence suggesting that COVID-19-infected cancer patients are at greater risk of severe illness. Like Zhang, she showed a link to metastatic disease and lung cancer and, like Barlesi, worse outcomes in patients with blood cancer.

Cai presented results of a multicenter study during the COVID-19 outbreak in China, which simultaneously published in Cancer Discovery (DOI: 10.1158/2159-8290.CD-20-0422), involving 105 cancer patients and 536 age-matched non-cancer patients confirmed with COVID-19. Results indicate those with both COVID-19 and cancer had higher risks of all severe outcomes—including rates of death, ICU admission, at least one severe or critical symptom and needing invasive mechanical ventilation.

Patients with hematological cancer, lung cancer, or with metastatic cancer (stage IV) had the highest frequency of severe events, says Cai, while those with non-metastatic cancer experienced a similar frequency of severe conditions to those observed in patients without cancer. Patients whose cancer was treated with surgery had the higher risk of severe events, but no significant differences were seen among those treated with only radiotherapy.

Outcomes were similar for cancer patients with COVID-19 whether they were or weren’t on active treatment for the former, Cai notes, suggesting equal attention should be paid to both groups.

When it comes to managing cancer patients during a COVID-19 outbreak, Cai recommends “self-protective isolation, strict in-hospital infection control and online medical services.” Individual treatment plans also need to be developed based on tumor type and stage, she adds, and clinicians should consider postponing surgery.

Two important questions yet to be addressed, Cai says, are whether early-stage cancer patients need to postpone their treatments during a COVID-19 outbreak and if immunotherapy aggravates severe outcome in COVID-19 patients. In her study, COVID-19 patients with cancer being treated with immunotherapy had a higher risk of dying and a higher chance of developing critical symptoms, but their number (six individuals) was too small to draw any definitive conclusions.

Conclusion: Risk factors for patients with cancer affected by the ongoing COVID-19 pandemic include cancer type (blood and lung), stage (metastatic) and treatment (surgery).