Children from lower- and middle-income countries, diagnosed with cancer prior to the COVID-19 pandemic, experienced a far greater risk of death from all causes than children from high-income countries, according to the first multi-center global cohort study to explore this problem.

Thirty days after the trial began, data collected from 91 hospitals and cancer centers based in 39 countries revealed that children with cancer from lower- and middle-income countries were 15.6 times more likely to die from all causes during the pandemic, when adjusted for confounding variables. After 90 days, the risk of dying from all causes among pediatric cancer patients from lower- to middle-class nations was 19.7 times greater than those in high-income nations.

Factors contributing to the stark mortality disparities included delays or alterations in treatment options stemming largely from measures taken to minimize COVID-19 mortality and morbidity.

"This pandemic has become the defining crisis of our generation, and its ramifications may stretch beyond the acute crisis and have far-reaching consequences for the study," researchers noted. "Understanding its true impact, taking on key lessons, and identifying vulnerabilities within health systems help to develop solutions, which will also prove critical on our path towards equitable global pediatric oncology care."

Despite being highly curable, delays in diagnosis and lack of access to effective treatment have made pediatric cancer the second-leading cause of non-communicable deaths among children worldwide. More than 90 percent of these deaths occur in lower- to middle-income countries, with a 5-year mortality for childhood cancer in these countries at about 80 percent compared to about 20 percent in high-income countries. The researchers believe the COVID-19 pandemic may have widened this pre-existing imbalance in pediatric outcomes that separate poorer from richer nations.

"I understand that this may not be a surprising observation, but just because it is not surprising doesn't mean it isn't astonishing," said Louis M. Weiner, Director of the Georgetown Lombardi Comprehensive Cancer Center, who moderated an AACR press briefing on this topic. "I think we have to be careful not to be complacent about this kind of information. There are children dying around the world who don't need to die."

Muhammed Elhadi, MBBCh, a medical doctor at the University of Tripoli in Libya, added that clinicians in many of the lower- and middle-income nations lacked sufficient training in pediatric oncology-surgery and chemotherapy-to provide optimal care for their patients. Also, more investments are needed for childhood cancer care, particularly for chemotherapeutic drugs. "Many of these countries may not be able to provide this treatment for these patients at the appropriate time," he noted. "So there needs to be more investment to provide these treatments, especially in these countries."

Study Details

Researchers from the Global Health Research Group on Children's Non-Communicable Diseases Collaborative, led by Kokila Lakhoo, PhD, and Noel Peter, BMedSci, recruited patients from 91 hospitals in 39 countries (16 high-income countries and 23 lower- to middle-income countries). Some 556 (33.5%) children under the age 18 with pediatric cancer were enrolled in the study from high-income countries, as well as 1,104 (66.5%) from low- to middle-income countries.

Patients were either newly diagnosed or undergoing active cancer treatment for acute lymphoblastic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, Wilms tumor, sarcoma, retinoblastoma, gliomas, medulloblastomas, or neuroblastomas.

Primary study outcomes were all-cause mortality at 30 days and 90 days from initial anti-cancer treatment, starting March 12 to December 12, 2020. Secondary outcomes included any alterations in pediatric cancer treatment decisions during the COVID-19 pandemic and changes in health care frameworks which led to these alterations. Only a minority of patients with pediatric cancer were diagnosed with COVID-19, according to the study.

Of the 1,660 patients recruited for the trial, 182 out of 219 children from low- to middle-income countries experienced changes or delays in their treatment resulting from the pandemic. These changes included delayed or cancelled surgery, radiotherapy, immunotherapy or chemotherapies; reduced or increased doses; shorter duration of treatment; or abandonment of treatment all together.

During the first 30 days of the trial, 45 patients from lower- to middle-income countries died compared to two patients from higher-income nations (4.3% vs. 0.4%, respectively). Ninety days after the study was initiated, 66 patients in the lower- to middle-income countries died compared to five patients from high-income nations (7.0% vs. 0.9%, respectively).

After controlling for confounding factors-including age, weight at admission, patient sex, tumor type, grade, stage, and diagnosis date-children with pediatric cancer from lower- to middle-income countries were at a 15.6-fold higher risk of dying from all causes after 30 days than children from high-income countries. After 90 days, the risk of overall death during the pandemic among children from lower- to middle-income countries was 19.7 times greater than those from high-income countries, according to results published in the BMJ Open Book (2022; doi: 10.1136/bmjopen-2021-054690).

Delayed or altered treatments were observed largely among patients needing surgery, the study found, likely stemming from new guidelines that cautioned against surgical procedures during the pandemic.

"The most common reason for children with cancer not being given their usual standard of care were changes in policy, lead clinician decision, or travel lockdown," the study's authors wrote. "Changes may have been driven by the desire to reduce transmission of COVID-19 among patients with pediatric cancer, despite the fact that patients with pediatric cancer are not particularly vulnerable to COVID-19, nor is there sufficient evidence that concurrent COVID-19 infection worsens outcomes. Given the response to the pandemic appears to have had a larger effect on care than direct effects of the pandemic itself, the impact of the pandemic on patients with pediatric cancer can be mitigated through policy changes occurring now."

Added Elhadi: "We need this crucial information to inform policy makers to implement some changes providing better cancer care, especially in low- and middle-income countries."

Study limitations included the fact that only children already diagnosed with cancer were recruited, with research suggesting that many cases of cancer were missed during the pandemic. If so, the true burden in lower- to middle-income countries might even be greater than the study reports. Also, the researchers did not have specific baseline survival data for all cancer centers involved in the study, as many had never participated in a large research study. Finally, some 18 percent of the patients were lost to follow-up at 90 days.

Researchers were not able to determine cause of death, whether it was COVID-19, their cancer, or other. Further analysis of the data from the first year of the pandemic is expected to determine primary causes of death, with updated results expected to be published in the near future.

Warren Froelich is a contributing writer.