Mortality in patients with COVID-19 and cancer is associated with general clinical and demographic factors, cancer-specific factors, cancer treatment variables, and laboratory parameters, according to two presentations at the European Society for Medical Oncology Virtual Congress 2020.
Two analyses of data from the COVID-19 and Cancer Consortium (CCC19) were presented at the meeting.
The data suggest that older age, male sex, more comorbidities, poor performance status, progressive cancer or multiple cancers, hematologic malignancy, and recent cancer therapy are all associated with higher mortality among patients with cancer and COVID-19. Anti-CD20 therapy is associated with an especially high mortality rate, according to an investigator.
Among hospitalized patients, increased absolute neutrophil count as well as abnormal D-dimer, high-sensitivity troponin, and C-reactive protein are associated with a higher risk of mortality.
Prior analyses of CCC19 data pointed to several factors associated with higher COVID-19 death rates, according to Petros Grivas, MD, PhD, of University of Washington, Seattle, who presented some CCC19 data at the meeting. However, the prior analyses were limited by weak statistical power and low event rates, Grivas said.
Clinical and Laboratory Factors: Abstract LBA72
The aim of Grivas's analysis was to validate a priori identified demographic and clinicopathologic factors associated with 30-day all-cause mortality in patients with COVID-19 and cancer. Grivas and colleagues also explored the potential association between laboratory parameters and 30-day all-cause mortality.
The analysis included 3,899 patients with cancer and COVID-19 from 124 centers. Most centers are in the United States, but 4% are in Canada, and 2% are in Spain. About two-thirds of patients were 60 years of age or younger at baseline, half were men, 79% had solid tumors, and 21% had hematologic malignancies.
Cancer-specific factors associated with an increased risk of 30-day all-cause mortality were having progressive cancer (adjusted odds ratio, 2.9), receiving cancer therapy within 3 months (aOR, 1.2), having a hematologic versus solid tumor (aOR, 1.7), and having multiple malignancies (aOR, 1.5).
Clinical factors associated with an increased risk of 30-day all-cause mortality were Black versus White race (aOR, 1.5), older age (aOR, 1.7 per 10 years), three or more actively treated comorbidities (versus none; aOR, 2.1), and Eastern Cooperative Oncology Group performance status of 2 or more (versus 0; aOR, 4.6).
In hospitalized patients, several laboratory variables were associated with an increased risk of 30-day all-cause mortality. Having an absolute neutrophil count above the upper limit of normal doubled the risk (aOR, 2.0), while abnormal D-dimer, high-sensitivity troponin, and C-reactive protein all more than doubled the risk of mortality (aORs of 2.5, 2.5, and 2.4, respectively).
Further risk modeling with multivariable analysis will be performed after longer follow-up, Grivas noted.
Treatment-Related Outcomes: Abstract LBA71
An additional analysis of CCC19 data encompassed 3,654 patients. In this analysis, researchers investigated the correlation between timing of cancer treatment and COVID-19–related complications and 30-day mortality.
Mortality was highest among cancer patients treated 1-3 months prior to COVID-19 diagnosis, with all-cause mortality at 28%, said Trisha M. Wise-Draper, MD, PhD, of University of Cincinnati, when presenting the data at the meeting.
Rates for other complications (hospitalization, oxygen required, ICU admission, and mechanical ventilation) were similar regardless of treatment timing.
The unadjusted 30-day mortality rate was highest for patients treated most recently with chemoimmunotherapy (30%), followed by chemotherapy (18%), chemoradiotherapy (18%), and targeted therapy (17%).
The mortality rate was "particularly high," at 50%, in patients receiving anti-CD20 therapy 1-3 months prior to COVID-19 diagnosis — the time period for which significant B-cell depletion develops, Wise-Draper observed.
An analysis of disease status among 1,449 patients treated within 3 months of COVID-19 diagnosis showed mortality risk increasing from 6% among patients in remission or with newly emergent disease, to 22% in patients with any active cancer, to 34% in those with progressing disease, Wise-Draper said.
Discussant Benjamin Solomon, MD, PhD, of Peter MacCallum Cancer Centre in Melbourne, made note of the high 30-day mortality rate seen in patients receiving anti-CD20 therapy as well as the elevated standardized mortality ratios with recent chemoimmunotherapy and targeted therapy.
"Although there are some limitations of this analysis, it provides the best data we have to date about the effects of treatment on early mortality in patients with COVID-19 and cancer. It points to a modest but heterogeneous effect of treatment on outcome, one which is likely to become clearer with larger cohorts and additional analysis," Solomon said.
This research was funded by the American Cancer Society, Hope Foundation for Cancer Research, Jim and Carol O'Hare Fund, National Cancer Institute, National Human Genome Research Institute, Vanderbilt Institute for Clinical and Translational Research, and Fonds de Recherche du Quebec-Sante. Grivas disclosed relationships with many companies, but none are related to this work. Wise-Draper disclosed relationships with Merck, Bristol-Myers Squibb, Tesaro, GlaxoSmithKline, AstraZeneca, Shattuck Labs, and Rakuten. Solomon disclosed relationships with Amgen, AstraZeneca, Merck, Bristol-Myers Squibb, Novartis, Pfizer, and Roche-Genentech.
SOURCES: Grivas P et al. ESMO 2020, Abstract LBA72; Wise-Draper TM et al. ESMO 2020, Abstract LBA71.
This article originally appeared on MDedge.com, part of the Medscape Professional Network.
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The scientific outcry over a proposal to use herd immunity to blunt the COVID-19 pandemic continues to grow. Today, an open letter signed by more than 80 biomedical experts states that the "renewed interest in a so-called herd immunity approach" is a "dangerous fallacy unsupported by scientific evidence."
The new letter comes in response to the Great Barrington Declaration, which was posted on October 4. That declaration, written by a group led by three epidemiologists, called for allowing COVID-19 to spread among less vulnerable groups while selectively protecting the vulnerable as a way to deal with the pandemic, a strategy they called "focused protection."
Since its publication, the declaration has drawn numerous cosigners and critics, as reported by Medscape Medical News.
The new letter is something of a counter manifesto. Called the "John Snow Memorandum" — presumably named for the London physician who started the science of epidemiology in 1854 by tracking the local spread of cholera — it was published online as an open letter in The Lancet.
Implementing the type of strategy promoted by the Great Barrington Declaration authors "would not end the COVID-19 pandemic but result in recurrent epidemics, as was the case with numerous infectious diseases before the advent of vaccination," the authors of the John Snow Memorandum write.
"Empirical evidence from many countries shows that it is not feasible to restrict uncontrolled outbreaks to particular sections of society," they continue.
What is needed instead are "effective measures that suppress and control transmission" and that are widely implemented. "Continuing restrictions will probably be required in the short term to reduce transmission and fix ineffective pandemic response systems," and "suppress SARS-CoV-2 infections to lower levels."
The authors, including corresponding author Deepti Gurdasani, MBBS, MD, PhD, from Queen Mary University of London, United Kingdom, acknowledge that lockdowns have been disruptive for the economy and difficult for individuals. But they also note that these effects have been worse in countries that have not established pandemic control systems."
The John Snow Memorandum cites Japan, Vietnam, and New Zealand as models of "robust public health responses," demonstrating that the steps these countries took "can control transmission, allowing life to return to near normal."
At the time of publication, the signatories included clinicians and researchers from numerous countries and regions, including Europe, North America, Asia, and the Middle East.
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Johnson & Johnson paused dosing and enrollment in all of its COVID-19 vaccine clinical trials due to an unexplained illness in a study participant, the company announced Monday.
Later in the day, Eli Lilly had to acknowledge a pause of a clinical trial of antibody treatment because of a "potential safety concern," The New York Times reported , citing emails U.S. government officials sent to researchers.
Eli Lilly had been testing the treatment on hospitalized COVID patients, all of whom also received remdesivir.
In a statement to the Times, Eli Lily spokesperson Molly McCully confirmed the pause in the trial and said, "Safety is of the upmost importance to Lilly. Lilly is supportive of the decision by the independent (safety monitoring board) to cautiously ensure the safety of the patients participating in this study."
But that wasn’t the only challenge facing Eli Lilly. Reuters reported late Monday that FDA inspectors found serious quality control problems at the Lilly plant where the antibody drugs are manufactured.
Inspectors in November found data on the company’s manufacturing processes at the New Jersey plant had been deleted and not correctly audited, Reuters reported, citing government inspection documents.
The FDA sent Lilly an "Official Action Indicated" notice as classified the problems as a serious level of violation, Reuters said.
Meanwhile, in the Johnson & Johnson trial, the patient’s illness is being reviewed and evaluated by an independent monitoring board and the company’s doctors that investigate safety data.
"Adverse events — illnesses, accidents, etc. — even those that are serious, are an expected part of any clinical study, especially large studies," according to the announcement.
Outside researchers running the trial received a document about the pause, which STAT news obtained and first reported on Monday. Johnson & Johnson confirmed the pause with STAT but didn’t share any additional details about the patient’s illness.
"We must respect this participant’s privacy," the company said. "We’re also learning more about this participant’s illness, and it’s important to have all the facts before we share additional information."
The pause allows the company to determine whether the illness is related to the COVID-19 vaccine and whether to resume the study.
In its announcement, Johnson & Johnson explained the difference between a study pause and a regulatory hold of a clinical trial. A study pause temporarily halts the dosing and recruitment of new patients so safety data can be reviewed, and a regulatory hold is an enforced stop to a trial by an outside regulatory health agency, such as the FDA. Study pauses are usually communicated with the researchers but not the public, whereas a regulatory hold is disclosed with the public.
For this study pause, the independent review board met Monday to review the case, STAT reported. The late-stage clinical trial began on Sept. 23, and 60,000 participants are set to be enrolled in the U.S. and other countries.
As compared with other COVID-19 vaccine candidates in late-stage trials, the Johnson & Johnson vaccine doesn’t need to be frozen and requires one dose instead of two.
Last month, AstraZeneca paused its COVID-19 vaccine trial to investigate an illness in a patient in the U.K. The study resumed about a week later in the U.K. and other countries but is still on hold in the U.S.
The study pause isn’t an immediate concern, Ashish Jha, MD, dean of the Brown University School of Public Health, told CNN.
"This is completely expected, and it’s just a reminder how ridiculous it is to try and meet a political timeline of having a vaccine before Nov. 3," he said.
"We want the vaccine to be safe and we’ve got to let the process play out, and it’s going to take a while," Jha said. "To me it’s reassuring that companies are acting responsibly and pausing when they need to."
The Johnson & Johnson announcement is a further setback for the company's timeline. The FDA announced last week that it wants drug makers to have at least two months of safety data before requesting authorization from the FDA to distribute the vaccine.
Previously, Pfizer CEO Albert Bourla has said that sufficient data could be ready by late October. The two-month requirement could make that no longer possible. Top leaders at Moderna, AstraZeneca and Johnson & Johnson have said their clinical trial timelines are longer. Full FDA approval would require more data and occur sometime in early to mid-2021.
Sources:
Article: Two Major COVID Trials Paused for Safety Issues
Johnson & Johnson: "Johnson & Johnson Temporarily Pauses All Dosing in Our Janssen COVID-19 Vaccine Candidate Clinical Trials."
STAT News: "Johnson & Johnson Covid-19 vaccine study paused due to unexplained illness in participant."
CNN: "Johnson & Johnson pauses Covid-19 vaccine trial after ‘unexplained illness.’"
Video: Coronavirus in Context: Getting the Message Right on a COVID Vaccine
John Whyte, MD, MPH. Chief Medical Officer, WebMD,
Tamara Coyne-Beasley, MD Endowed Chair in Adolescent Medicine, Children's of Alabama, UAB
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A 25-year-old man from Nevada and a 42-year-old man in Virginia experienced second bouts of COVID-19 about 2 months after they tested positive the first time. Gene tests show both men had two slightly different strains of the virus, suggesting that they caught the infection twice.
Researchers say these are the first documented cases of COVID-19 reinfection in the U.S. About two dozen other cases of COVID-19 reinfection have been reported around the globe, from Hong Kong, Belgium, the Netherlands, India, and Ecuador. A third U.S. case, in a 60-year-old in Washington, has been reported but hasn't yet been peer reviewed.
Until now, immunologists haven't been too concerned about these reinfections because most second infections have been milder than the first, indicating that the immune system is doing its job and fighting off the virus when it is recognized a second time.
Unlike most of those cases, however, the men in Reno, NV, and Virginia, and a 46-year-old man in Ecuador, had more severe symptoms during their second infections, potentially complicating the development and deployment of effective vaccines.
The U.S. cases are detailed in new studies published in The Lancet and the journal Clinical Infectious Diseases.
"Coronaviruses are known to reinfect people — the seasonal ones — and so it's not very surprising to see reinfections occurring with this particular coronavirus," said Akiko Iwasaki, PhD, an immunobiologist at Yale University who was not involved in either study. "And the fact that there is more severe disease the second time around. It could a be a one-in-a-million event, we don't know. We're just becoming aware of the reinfection cases, and they are just a handful among millions of people infected."
The Nevada man originally got sick on March 25. His symptoms included a sore throat, cough, headache, nausea, and diarrhea. A test taken at a community event held on April 18 confirmed COVID-19. His symptoms gradually subsided and he reported feeling better on April 27. He tested negative for the virus twice after he recovered.
About a month later, the man went to an urgent care center with a fever, headache, dizziness, cough, nausea, and diarrhea. They sent him home. Five days later, he went to the doctor again, this time with difficulty breathing and low blood oxygen. They told him to go to the ER. He was admitted to the hospital on June 5. Lung X-rays showed telltale patches of cloudiness, known as ground-glass opacities, and a nasal swab test confirmed COVID-19. Gene testing of the two swabs, from April and June, showed key changes to the genetic instructions for the virus in the second test, suggesting that he'd gotten a slightly different strain the second time.
The Virginia man — a military health care provider — was infected the first time at work. He tested positive in late March after getting a cough, fever, and body aches. He recovered after 10 days and was well for nearly 2 more months. In late May, however, a member of his family got COVID-19, and he then got sick again with a fever, cough, difficulty breathing, and stomach upset. A chest X-ray confirmed pneumonia. His symptoms were worse the second time. Gene testing of the virus from each of his swabs indicated slight changes, suggesting he was infected twice.
There are other possibilities, including that the virus somehow went silent in his body for a few weeks and then became active again. The study authors think this is unlikely because it would mean that the virus is changing at a much faster pace than has been seen so far.
They also can't tell whether the severity of symptoms the men experienced the second time were related to the virus or to how their immune systems reacted to it. Were they sicker because they got a larger dose of the virus? Was there something about the gene changes to the virus that made it more damaging when the men caught it again? Or could their first COVID-19 infections have somehow primed their immune systems the wrong way, leading to more severe infections the second time — a phenomenon called enhancement?
Scientists are racing to try to understand all those things and more — what reinfection means and how common it may be. If it happens frequently, that could complicate efforts to reach a level of community protection known as herd immunity. Vaccines may need to be tweaked to keep up with the virus as it evolves, and people may need regular boosters to maintain their protection.
"We need more research to understand how long immunity may last for people exposed to SARS-CoV-2 and why some of these second infections, while rare, are presenting as more severe," study author Mark Pandori, PhD, of the Nevada State Public Health Laboratory, said in a news release.
"So far, we've only seen a handful of reinfection cases, but that doesn't mean there aren't more, especially as many cases of COVID-19 are asymptomatic," he said. "Right now, we can only speculate about the cause of reinfection."
Researchers stress that everyone should protect themselves from COVID-19 infection, even if they're sure they've had it before, by wearing a face mask in public, staying at least 6 feet away from others, and washing and sanitizing hands often.
SOURCES:
Akiko Iwasaki, PhD, Waldemar Von Zedtwitz Professor of Immunobiology and Molecular, Cellular and Developmental Biology; Investigator, Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT.
The Lancet, Oct. 1, 2020.
Clinical Infectious Diseases, Sept. 19, 2020.
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Delays in colorectal cancer screening due to the COVID-19 pandemic could lead to higher rates of advanced-stage cancer and death, according to a new study.
When compared with a delay of less than three months, the longer delay seen this year may result in an 11.9% increase in death rates.
"Across the globe, healthcare systems are facing serious difficulties while dealing with COVID-19, and it is imperative that support is given to the public and patients throughout the crisis, including for high-impact diseases such as colorectal cancer," Luigi Ricciardiello, the lead study author and a professor at the University of Bologna in Italy, said in a statement.
Ricciardiello and colleagues presented their research on Monday at UEG Week Virtual 2020, an international conference for gastroenterologists. The study will be published in the UEG Journal .
The researchers created a model to forecast the effects of delayed cancer screening during 2020. A "moderate" delay of 7-12 months caused a 3% increase in advanced-stage colon cancer, and a long delay of more than 12 months caused a 7% increase in advanced cancer.
Based on a survival rate of 5 years for stage 3 or stage 4 colorectal cancer, the death rate would increase nearly 12% when screening is delayed for more than a year, as compared with less than three months of delay.
The research team found similar results when forecasting advanced-stage cancer and deaths earlier this year. In a paper published in Clinical Gastroenterology and Hepatology in early September, they projected that deaths could increase 12% if screening is delayed for more than a year.
Throughout the pandemic, screening programs have been delayed in many countries, particularly across Europe.
"Healthcare authorities need to act urgently on how they reorganise activities during COVID-19, without compromising the diagnosis of other high-impact diseases like this research shows," Ricciardiello said.
United European Gastroenterology, a professional medical organization for digestive health specialists, has called for policymakers to implement colon cancer screening programs across the European Union. Annually, more than 375,000 new cases are diagnosed across the EU, and more than 170,000 people die from colorectal cancer, according to a UEG report.
"Early-stage diagnosis of colorectal cancer is crucial — it's far easier to treat and enhances optimal patient outcomes," Ricciardiello said. "It is therefore essential that vital diagnosis tools, like screening programmes, continue and help to prevent mortality rates from rising even further."
Sources:
EurekAlert, "COVID-related delays to CRC screening causing 11.9% rise in death rates, research reveals."
UEG, "UEG Week Virtual 2020."
UEG Journal, "UEG Journal COVID Collection."
Clinical Gastroenterology and Hepatology, "Impact of SARS-CoV-2 pandemic on colorectal cancer screening delay: effect on stage shift and increased mortality."
UEG, "Coordinating European Action Against Colorectal Cancer."
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