COVID-19 and the Practice of Neuro-Oncology
As of this writing, globally, almost 3.7 million individuals have been confirmed as having been infected by the SARS-CoV-2 virus, with almost 260,000 deaths. This pandemic has caused untold harm and disruption to human life, and, in particular, the operational capabilities of most healthcare systems, hospitals, and clinics have been severely disrupted. A whole host of problems have disrupted routine provision of healthcare, which of course, has the potential for a substantially magnified impact on cancer patients. Measures such as social distancing and wide-scale shut downs have severely restricted transportation and access. In the context of neuro-oncology, elderly malignant glioma patients are often almost completely dependent on others for transportation needs, daily care, and even survival. Therefore, their ability to access healthcare has become severely compromised. Furthermore, most healthcare facilities have switched over to telehealth operations, which requires a certain degree of sophistication regarding the use of technology. Elderly patients, especially those with malignant gliomas, often find this to be severely limiting.
Routine hospital and clinical operations have been severely impaired in many places. For example, elective surgical procedures have been put on hold. Medical resources are being rationed. Personal protective equipment is in short supply. The risk of infection among healthcare personnel is substantial. The risk of transmitting infection to immunocompromised patients is also significant. These realities and others have led to dramatic alterations in the practice of routine neuro-oncologic care. In this context, two recent publications that focus on the impact on patients with gliomas are worth evaluating.
The publication by Tabrizi et al provides a quantitative framework for estimating COVID-19 risk in elderly GBM patients, allowing for personalization of therapeutic choices.1 The intent here is to identify the risk of infection posed to patients with glioblastoma, especially the elderly, as a consequence of their therapy, and the impact of the risk of infection on therapeutic choice. The authors evaluated five randomized trials that focused on the management of elderly GBM patients. They extracted individual patient-level data on 1321 patients. For these patients, the risk of mortality from COVID-19 was simulated using two parameters, the risk of SARS-CoV-2 infection per fraction of radiation received and the risk of death from COVID-19 for patients who become infected. It was assumed that the risk of infection per fraction of radiation received is constant, independent of prior fractions, and this may or may not be true based on the lymphopenic potential of the cumulative dose of radiation therapy. Furthermore, the model did not incorporate infection risk beyond the use of radiation; for example, steroids, temozolomide, and a host of other variables could modulate this risk.
Subsequently, the number of deaths caused by COVID-19 was simulated using a mathematical model. The model is highly dependent on a 5-day incubation period, and mean of 18 days from symptom onset to death. In reality, the incubation period can vary from 3 to even 15 days or more, and the mean time from symptom onset to death has been described to be as short as 3 to 4 days in certain high-risk populations and as long as 30+ days in other subpopulations. These variations can significantly disrupt the mathematical models, if elderly GBM patients substantially skew away from the modeled means. In this review, the median age of elderly glioblastoma patients was between 70 and 80 years, and estimates available from the literature suggest an infection mortality rate of approximately 4.3% in this age group. However, it is well-known that the case fatality rate in cancer patients is approximately 2.5 to 5 times higher than that in the general population.
With this mathematical background, the authors simulated scenarios that computed COVID-19 fatality rates reflecting the range of patients included in these trials. They assumed a fatality risk of 10% in a “low-risk” infection scenario, which was escalated to 20% and 30% for “medium” and “high” risk. Low-, medium-, and high-risk scenarios were defined as 1%, 5%, and 10% risk of COVID-19 infection per fraction of radiotherapy delivered. These risk levels were defined as follows: 1% daily risk of infection and 10% mortality (low risk), 5% daily risk and 20% mortality (medium risk), and 10% daily risk and 30% mortality (high risk). The median survival and associated hazard ratios for death in these various scenarios were computed. The overall results demonstrated that in low– and medium–COVID-19 risk scenarios, hypofractionated chemoradiotherapy over 3 weeks yielded the most favorable results, irrespective of MGMT methylation status. For sicker patients for whom single-modality treatment may be contemplated, as expected, MGMT methylation status guides therapeutic selection in the model. For patients with MGMT methylation, temozolomide produced less risk and more favorable survival compared with radiation therapy. In contrast in the MGMT-unmethylated patients, radiation therapy alone was found to be superior to temozolomide.
In a separate publication, Bernhardt and colleagues assembled a 16-person multidisciplinary expert team to propose practical management strategies to be considered in the context of this pandemic.2 The pandemic was subdivided into two phases, a “scale-up,” or early phase, and a later “crisis” phase. It was presumed that, in the crisis phase, there would be severe limitations to healthcare access as well as healthcare resources. Key take away recommendations from this expert panel included the following:
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Multidisciplinary decision-making and care: In the context of limited resources, interdisciplinary decision-making is even more critical and crucial even though in-person tumor boards have essentially been put on hold. Telehealth solutions have essentially replaced these universally and are strongly recommended.
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Surgery: Although elective surgical procedures have been put on hold in many institutions, resection of malignant gliomas is not considered elective, and maximal safe surgery is recommended as a priority. In the context of the crisis phase of the pandemic, the possibility of a biphasic approach, initially performing rapid debulking and subsequently deferring a more aggressive resection to a later time point can be considered.
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Molecular diagnostics: Molecular findings often drive therapeutic choice in the management of patients with glioma, and these are not generally constrained to a substantial extent in the current crisis and therefore should be pursued. Imaging: Imaging resources are indeed constrained and limited. Therefore, standard imaging as necessary for immediate decision-making is recommended, but follow-up imaging can be stretched out as clinically feasible. Also, the utilization of advanced imaging should be individualized and considered only for those cases where a substantial impact can be predicted.
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Radiotherapy: Short-course radiotherapy is recommended where feasible. In particular, for older patients or those with poor performance status, hypofractionated schedules should be prioritized. For younger patients with better performance status, standard chemoradiotherapy is recommended with the caveat that, in the crisis phase of the pandemic, hypofractionation may be considered even for these patients. If and when necessary, based on patient circumstances, an ultra-hypofractionated course of 5 fractions can also be considered.
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Chemotherapy: Withholding temozolomide from GBM patients with unmethylated MGMT is considered reasonable. Temozolomide monotherapy for elderly GBM patients with methylated tumors is considered a good option. This is recommended only if radiotherapy is unavailable or treatment completion would be put at risk. For elderly patients with unmethylated GBM, temozolomide may be withheld in favor of radiotherapy alone. Given the significant toxicities (including pulmonary fibrosis) and infection risk posed by PCV chemotherapy, consideration should be given to dropping the vincristine, or switching to temozolomide, as feasible.
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TTField therapy: Being non-immunosuppressive and effectively a therapy obtained in the in-home setting, in general, this should continue. However, it does require in-home assessment of technological feasibility, compliance, and skin-health management, which requires additional personnel and hence risk, and safe distancing and facial coverings are recommended during these interactions.
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Steroids: The immunosuppressive effects of steroids could increase risk of infection and therefore a rapid taper to the lowest necessary dose should be undertaken.
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Clinical trials: Access to these has started to become more limited, especially where long-distance travel is required. Further, trials that require substantial interactions for endpoints such as cognition, or for multiple blood draws, are becoming more difficult to conduct, and some have, in-fact, been put on hold. However, as and where available, clinical trials should still be offered.
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Management of the SARS-CoV-2–positive patient: This has to be individualized based on local policies and availability of personal protective gear; in general, continuation of radiotherapy is recommended.
These papers summarize general recommendations, all of which need to be interpreted and applied in the local context after thorough evaluation of available resources and the patient’s inclusion in the decision-making process.
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Additional Info
- Tabrizi S, Trippa L, Cagney D, et al. A Quantitative Framework for Modeling COVID-19 Risk During Adjuvant Therapy Using Published Randomized Trials of Glioblastoma in the Elderly. Neuro Oncol. 2020 Apr 27. doi: 10.1093/neuonc/noaa111. [Epub ahead of print.]
- Bernhardt D, Wick W, Weiss SE, et al. Neuro-oncology Management During the COVID-19 Pandemic With a Focus on WHO Grade III and IV Gliomas. Neuro Oncol. 2020 May 5. doi: 10.1093/neuonc/noaa113. [Epub ahead of print.]
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