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hampered progress of clinical trials in oncology

The effect of the COVID-19 pandemic on clinical brain cancer trials

2020 evolved into an annus horribilis for everyone, manifested by physical distancing and social isolation, disrupted work routines and for many, tragic loss of livelihood and loved ones.

covid-19_effect_on_the_clinical_trial_bortem-17
COVID-19’s effect on the clinical trial BORTEM-17. As active PhD candidates and scientists with ongoing experiments, a sudden change to home office was difficult to manage. Closing of laboratories and teaching facilities sparked a tremendous effort from teaching staff to switch to digital lessons, while the microscope collected dust on the lab bench. Social distancing, fear of public transport and challenges with attending physical appointments resulted in a reduction in newly recruited patients for clinical trials. Ill./
Photo:
Victoria Smith Arnesen and James Christian Enger

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The coronavirus disease pandemic also heavily affected scientific productivity in many research disciplines worldwide. In particular, the COVID-19 pandemic severely hampered progress of clinical trials in oncology that were ongoing in the Norwegian hospitals.

The authors are a multidisciplinary research team consisting of PhD candidates, statistician, researchers, oncologists and brain tumour user representatives that are conducting the national multicentre phase IB/II clinical trial, BORTEM-17 (ClinicalTrials.gov, NCT03643549), that is funded by the Norwegian Cancer Society and Clinical Therapy Research in the Specialist Health Services, KLINBEFORSK, https://www.uib.no/rg/marthaenger

The clinical trial BORTEM-17

BORTEM-17 has the primary objective to improve the survival outcomes of patients suffering from aggressive brain cancer (Rahman et al., 2019), glioblastoma with unmethylated MGMT promoter. BORTEM-17 was initiated in September 2018, where patients with recurrent glioblastoma were recruited for evaluation of toxicity and tolerance of treatment dose escalation in phase IB. Doctors and nurses recruit, administer treatment and follow-up the patients, while the researchers collect patients’ tumour and blood samples that are investigated for toxicity, immunological responses to treatment and biomarker analysis for early indicators of treatment efficacy.

After successfully completing phase IB, the BORTEM-17 phase II trial has a goal of recruiting a further 53 patients from all four Norwegian health authorities.

During the pandemic

In 2020 the COVID-19 pandemic struck, leading to restrictions in clinical trial activity at all treatment centers, as a result of redirection of human resources, temporary halting of patient recruitment and restricted in-person visits to the hospital for nearly three months. Several waves of SARS-CoV-2 infections led to further societal restrictions during the autumn of 2020, which resulted in fewer patients recruited than anticipated from both Haukeland university, Oslo university, St Olavs and University of Northern Norway hospitals.  As flights were grounded and travel by public transport was discouraged by the public health authorities, some study participants from distant regions encountered great difficulties in getting to the hospital for planned treatment and examinations. It became increasingly complicated for new patients to seize the opportunity and hope provided by participating in a clinical trial, despite the life-threatening nature of their disease.

We asked our study patients about their fear of contracting SARS-CoV-2 infection during transport to- or during hospital visits.

Patients reported that they did not experience substantial fears since strict hygiene and infection preventative measures, such as use of personal protective equipment, masks and physical distancing were thoroughly enforced both during hospital appointments and travel. For one patient, the COVID-19 pandemic had not negatively impacted his treatment. Another patient was delayed treatment start in the BORTEM-17 trial because all clinical trials had been halted. His health subsequently deteriorated, and he could not wait for the study to reopen. He was administered a course of chemotherapy outside the study protocol. A month later when societal restrictions were lifted and clinical studies were reopened, he was recruited into BORTEM-17. He was very grateful to take part in the clinical trial. He said that the COVID-19 pandemic in general has given him little concern since he responded well to treatment. He has noticed however, that the community is less “accessible” as he could not participate in leisure activities with friends, which he previously derived much joy from. However, the availability of good internet-based social networks has helped against social isolation. The patient is lucky as he lives with his family, which research shows to raise the quality of life (Porter et al., 2014) and reduce the degree of isolation. However, we have also experienced that patients have declined participation in BORTEM-17 trial, especially when this entailed public transport and residing outside the home.
 

Changing priorities and reallocation of resources

A significant change in priorities and reallocation of clinical resources emerged in light of the COVID-19 pandemic. Hundreds of oncological clinical trials worldwide were delayed or cancelled while almost 5,000 new research studies and experimental treatments for COVID-19 were registered in ClinicalTrials.gov, where 29 were launched in Norway (GlobalData, 2021; Otmani, 2020; van Dorn, 2020). As researchers, we grappled with several challenges related to the pandemic. The University was abruptly closed to students and staff without special permission in March 2020, and all experiments were cancelled at short notice. Our doctoral student was in a critical phase of experiments when the shutdown began, and she unfortunately lost several weeks of her work and valuable time she may not get back in the form of extension of the PhD period. With such a narrow timeframe to complete a PhD thesis, this was incredibly stressful and difficult to handle. One of our senior researchers also has two young children who, like most, became home schooled on short notice. This further complicated balancing productive research activity while working from home office and simultaneously providing effective care and follow-up of bored and, at times, restless children. Even when the research institute reopened, work in shifts for researchers was necessary to maintain physical distancing, rendering scheduling of experiments difficult. Scientific protocols that were optimised to run in one day had to be altered to run over two days or be avoided altogether. Production and delivery of necessary research and development chemicals and biological materials were delayed, re-prioritized and critical reagents became unavailable altogether. Despite this, we have adjusted, are able to perform necessary laboratory experiments for our study participants in order to continue the clinical trial as planned.

It is highly likely that delayed progress of oncology clinical trials will continue due to the protracted COVID-19 pandemic. Despite major changes to our way of life as we know it, patient recruitment and treatment progressing slowly, we take this in our stride. We are actively engaged to recruit patients; analyse clinical samples and data we have available. Hopefully, now that nationwide vaccination is underway, a slow but sure reinstatement of normal societal activity will reciprocally lead to increase in patient study participation and that the results will show a positive therapeutic benefit of BORTEM-17 treatment.

For the Brain Tumour Association (Hjernesvultsforeningen), which has user representation in the clinical study, it is important that interventional oncology clinical studies remain a national priority. Patients diagnosed with glioblastoma are a group with few treatment options, and subgroups with unmethylated MGMT promoter who have little benefit of standard of care, Temodal chemotherapy, are among the cancer patients with the shortest life expectancy after diagnosis. The reality is that for this subgroup, no new effective systemic treatments have emerged in the last 40 years (Stupp et al., 2009; Walker et al., 1980). There is an urgent, unmet need for clinical research that provides breakthroughs and increased survival with a good quality of life and low disease burden.

 

Victoria Smith Arnesen MSc1,2, Mohummad Aminur Rahman PhD1,2, Jorunn Brekke MD2, Dorota Goplen MD; PhD2, Martha Chekenya PhD; Dr Philos1 og Rolf J. Ledal BSc3     

1University of Bergen, Department of Biomedicine, Bergen, Norway
2Dep. of Oncology and medical physics, Haukeland University Hospital, Bergen, Norway
3Hjernesvulstforeningen