key: cord-312340-hpuoren5
authors: Holstein, Sarah A.; Vose, Julie M.
title: Oncology Treatment in the Era of COVID‐19: We Cannot Afford to Hit the Pause Button
date: 2020-06-02
journal: Clin Pharmacol Ther
DOI: 10.1002/cpt.1920
sha: 
doc_id: 312340
cord_uid: hpuoren5

The COVID‐19 pandemic has far‐reaching ramifications for patients undergoing cancer treatment. Oncologists and institutions have adjusted treatment practices and, in many cases, significantly curtailed clinical trial conduct. Whether these adjustments mitigate the risk of COVID‐19 complications without jeopardizing treatment of the cancer is unknown. Given the expected duration of the pandemic, it is imperative that treatment of the patient's cancer remain the priority and that advances in drug development continue through appropriately designed clinical trials.

The COVID-19 pandemic has far-reaching ramifications for patients undergoing cancer treatment. Oncologists and institutions have adjusted treatment practices and, in many cases, significantly curtailed clinical trial conduct. Whether these adjustments mitigate the risk of COVID-19 complications without jeopardizing treatment of the cancer is unknown. Given the expected duration of the pandemic, it is imperative that treatment of the patient's cancer remain the priority and that advances in drug development continue through appropriately designed clinical trials.

This article is protected by copyright. All rights reserved Perspective:

The scope of the COVID-19 pandemic is unprecedented in modern history. Any citation of infection/mortality statistics is immediately outdated, but COVID-19 has become the number one cause of death in the United States (US). It is increasingly recognized that older individuals and those with comorbidities are at higher risk for mortality, including those with active malignancies. In the US, the median age of cancer diagnosis is 66 years (NCI SEER data) and, until the advent of SARS-CoV-2, cancer was the second leading cause of death. Cancer therapies include cytotoxic agents and/or targeted agents and/or immune modifying agents, all of which have the potential to alter the immune response to infectious pathogens. Many hematological malignancies utilize autologous or allogeneic stem cell transplantation (SCT) or cellular therapies (e.g., chimeric antigen receptor (CAR) T-cell therapy), all of which have profound impacts on the immune system.

Emerging data from China and the US highlight the increased risk of oncology patients for morbidity and mortality from COVID-19. A report from China described the outcomes of 1524 patients with solid tumors and noted a two-fold higher risk of SARS-CoV-2 infection compared to the overall community risk (1). These patients were more likely to require the intensive care unit or die, compared to those without cancer (39% vs 8%, p =0.0003) (1). Furthermore, patients treated with chemotherapy within a month of COVID-19 infection experienced a 5-fold risk of severe events compared to those with cancer who had not received recent treatment (1). A report of 218 oncology patients who became infected in New York City noted a case fatality rate of 28% (2).

The recognition that oncology patients are at particularly high risk for COVID-19 complications COVID-19, as well as the strain that the pandemic has placed on healthcare resources, has led to rapid adjustments in the management of these patients. There has been a concerted effort to minimize patient contact to decrease the potential exposure of patients, caregivers and healthcare providers to SARS-CoV-2 and, in some hospitals, to divert healthcare resources towards the care of COVID-19 patients. Numerous publications from societies and disease groups have made recommendations for how cancer care, including specific chemotherapy regimens, should be adjusted (or even held) during the pandemic. These recommendations are opinion-based but not evidence-based, as at this point it is too soon to know whether these adjustments protect patients from COVID-19 complications. For example, in a publication focused on the management of patients with multiple myeloma during the COVID-19 pandemic, it was suggested that daratumumab be administered every four weeks starting in cycle 3 instead of the standard every two weeks schedule (3). While

this practice change would result in fewer infusion center visits, there are no data that enable us to estimate the resulting impact on efficacy from a myeloma perspective, on degree of immunosuppression or on COVID-19 severity. Early in the pandemic, when it was predicted that the surge from the first wave would be swift, it was relatively simple to make treatment decisions such as holding some or all of a cycle of chemotherapy or postponing SCT if the intent was not curative. However, it is becoming evident that this approach cannot be continued indefinitely and therefore the risk:benefit calculation must incorporate not only the risk of potential SARS-CoV-2 infection, but also the long-term risks of making significant adjustments to standard of care chemotherapy practices. With multiple second waves now being predicted, we must learn to practice optimal oncology care including the added risks of COVID-19.

Clinical trials are a critical component of oncology care. It is estimated that only 5-10% of all patients with cancer in the US participate in therapeutic clinical trials (4) . Despite the barriers that lead to this low rate of participation, clinical trials remain the cornerstone for improving oncology patient outcomes through the development of new therapies. An analysis of accrual data for national cancer treatment trials revealed a correlation between trial enrollment and 5-year cancer-specific survival rates (4) . The conduct of clinical trials has become increasingly complicated in the era of COVID-19, significantly restricting access of clinical trials to oncology patients. Underlying factors include the desire to limit patient contact to decrease SARS-CoV-2 exposure, research personnel being required to work from home, travel bans, concern about the unknown impact of investigational therapy on severity of COVID-19, as well as healthcare resources being diverted to the management of patients with COVID-19. Industry sponsors and institutions have placed selected studies on hold and/or halted enrollment. A recent survey conducted by the American Society of Clinical Oncology (ASCO) revealed that almost sixty percent of respondents (from both academic and community-based programs) had halted screening and/or enrollment of clinical trials (5) . Some institutions have encouraged investigators to remove subjects from ongoing studies. In other situations, institutions have mandated that only standard of care procedures be allowed and that study-specific procedures cease. The ASCO survey revealed that half of respondents reported that their sites had stopped collecting research-only blood and/or tissue samples (5) . Some institutions have halted the internal regulatory process that is necessary for new studies to open. Some sponsors have halted the internal review process that evaluates new investigatorinitiated trial concepts. As a whole, these measures have led to significant changes in the clinical trial enterprise. Table 1 provides an overview of some key clinical trial practices, including the pre-COVID-19 era, the current COVID-19 era, as well as speculations about what the future might entail. Some of these practice

This article is protected by copyright. All rights reserved changes, including the use of telehealth visits, electronic informed consents and delivery of study medications to the home, will hopefully become permanent additions in the post-pandemic era, resulting in enhanced accrual and retention. There is opportunity to incorporate secure online consenting processes and remote monitoring (e.g., heart monitor patches, wearable sensors). In addition, as recently discussed by Tan et al., there is opportunity to develop a decentralized clinical trial model (6) . It should also be noted that some institutions have opened COVID-19 clinical trials in remarkably short time periods (i.e., in a matter of weeks), which raises the question as to why most oncology trials take 3-8 months to open at academic centers (7, 8) .

Protection of human subjects is always of paramount concern, however it is recognized that many patients participate in clinical trials because the studies represent their best therapeutic option. Furthermore, from a study perspective, failing to obtain pharmacokinetic data, perform correlative studies, electrocardiograms, or imaging or biopsies to document disease response could result in inaccurate conclusions about a novel therapy's safety profile, optimal dosing and/or efficacy. As noted by Saini et al., the long-term consequences of decreased trial accruals will affect drug development timelines and ultimately delay getting promising treatments to patients (9) . In this country, the actions of a few (i.e., those who participate in clinical trials) affect the outcomes of the many (i.e., the general oncology population) who benefit from the approval of new drugs and therapies.

The risk that COVID-19 poses for oncology patients cannot be underestimated and it is critical that the field gather as much information as possible to guide us in making treatment decisions. To this end, there are many groups, including ASCO and the American Society of Hematology, that have created registries in order to collect data on outcomes of oncology patients infected with SARS-CoV-2. The impact of COVID-19 on the immune system, even in immunocompetent patients is striking, and is somewhat reminiscent of the cytokine release syndrome associated with CAR T-cell therapy (10) . The degree to which oncology patients have impaired immune responses varies widely depending on the specific malignancy type and therapy. It is difficult to predict what the impact of various immunotherapeutic modalities such as CAR T-cells, immunomodulatory agents and immune checkpoint inhibitors will have on COVID-19 severity. It is imperative that comprehensive immune profiling studies be performed to evaluate the immune responses in these patient populations and that oncology patients be included in COVID-19 clinical trials. As COVID-19 testing (both for viral RNA and serology) become more readily available, there is an opportunity to begin rigorously assessing SARS-CoV-2 status prior to initiation of high-risk therapies. Finally, there is also significant Accepted Article opportunity to utilize clinical pharmacology principles and prospectively evaluate the impact of adjustments in dosing of chemotherapy during the pandemic.

It has been said that we should view the pandemic as a marathon and not a sprint, but the reality is that even marathons have a finish line. In contrast, there may not be an end in sight for COVID-19 and patients with malignancies. Even if an effective vaccine is identified, it is likely that the virus will not be eradicated, given the faction of society who will refuse vaccination. Herd immunity may be helpful to some extent, but will not eliminate SARS-CoV-2 infections. Those patients with malignancies, particularly those with a diminished ability to mount antibody responses, will remain vulnerable to COVID-19. The mortality rate due to SARS-CoV-2 infection may be relatively straightforward to monitor. However, it will be much more difficult to estimate the numbers of lives lost or shortened due to consequences of COVID-19 such as: delays in malignancy diagnosis or presentation at more advanced stages due to lack of screening or access to primary care, reduced access to comprehensive cancer centers and clinical trials, adjustments made to standard of care chemotherapy regimens that abrogate efficacy, lack of insurance because of unemployment and delays in drug development. The coming months to years will be incredibly challenging, but it is paramount that we continue to practice evidence-based medicine and optimize the conduct of clinical trials in order to mitigate the risk of COVID-19, thereby improving the outcomes of current and future generations of individuals diagnosed with cancer. 

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Accepted Article