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Anti-cancer Therapy for Patients with COVID-19 Infection: Should cancer therapy be delayed in patients who are infected with COVID-19?
Patients receiving anti-cancer treatment and infected with influenza and other viruses are potentially at risk for serious complications such as pneumonia and hospitalization. Meta-analyses (Park et al, Acta Oncol; Zhang et al, J Natl Cancer Inst; Liu et al, Expert Rev Anticancer Ther, Yekedüz et al, Eur J Cancer; Liu et al, Cancer Med) have found no evidence of interaction for surgery, targeted therapy, and immunotherapy, but have mixed results with respect to chemotherapy and radiation therapy. All the meta-analyses have found substantial heterogeneity among the included studies.Until more definitive information emerges, decisions about interrupting anti-cancer treatment in patients with active COVID-19 should be based on a clinical benefit:risk assessment that considers the risk of interrupting cancer treatment versus the still poorly defined risk of adverse COVID-19 outcomes in patients receiving active cancer treatment.
It is unclear how long a delay after the infection has resolved may be necessary before initiating/restarting anti-cancer therapy, but, if the decision was made to interrupt treatment, it should not be resumed until symptoms of COVID-19 have resolved and there is some certainty the virus is no longer present (e.g., a negative SARS-Cov-2 test), unless the cancer is rapidly progressing and the risk:benefit assessment favors proceeding with cancer treatment. In the absence of cancer-specific information, the CDC has issued recommendations on discontinuing transmission-based precautions for patients with COVID-19; initiating/resuming anti-cancer therapy once transmission-based precautions are no longer necessary would be reasonable. The United Kingdom National Institute for Health and Care Excellence has published rapid guidance on the delivery of anti-cancer therapy that suggests treatment may be initiated or resumed after one negative SARS-Cov-2 test.
Therapy for Infection: Should antiviral therapy or other therapy to treat COVID-19 be considered?
- Prophylaxis – Currently, there is no evidence or published guidance on the use of prophylactic antiviral therapy for COVID-19 in immunosuppressed patients. This is an active area of research and evidence may be available at any time. Prophylactic antiviral therapy directed at other viral infections should be continued according to standard clinical guidelines and institutional practices. ASCO is aware that clinical trials are ongoing or have been reported in brief publications on the prophylactic use of potential antiviral medications (e.g. remdesivir, lopinavir) and anti-malarial drugs such as chloroquine with anti-viral properties, but to date, none of these trials have been specific to patients with cancer. The US National Institutes of Health (NIH) has published guidance that recommends against any pharmacological agents as pre- and post-exposure prophylaxis. The NIH reports that at least two randomized studies of post-exposure prophylaxis hydroxychloroquine have been conducted with neither trial finding any benefit. These guidelines are changing rapidly and should be reviewed prior to considering prophylaxis. CDC has information that describes the current state of research on therapy for COVID-19. Also, the American Society of Health-System Pharmacists (ASHP) has provided a resource that shows current evidence and known ongoing clinical trials of antiviral therapies.
- Treatment for Infection – The US National Institutes of Health (NIH) has published guidance on treatment of COVID-19 infection. Currently, the NIH recommends only dexamethasone, remdesivir, or the combination of those agents in patients who are hospitalized for COVID-19 and require supplemental oxygen. The recommendations in favor of remdesivir and dexamethasone are based on data from several randomized trials. They do not recommend any other specific therapy for hospitalized patients, and recommend against dexamethasone for patients who are not hospitalized, or who are hospitalized but do not require supplemental oxygen. NIH currently states that there are insufficient data to make a recommendation for or against the use of the monoclonal antibody agents (e.g. bamlanivimab or the combination of casirivimab and imdevimab) that have received emergency use approval in the United States for the treatment of mild to moderate COVID-19 in patients with positive results of direct SARS-CoV-2 viral testing and who are at high risk for progressing to severe COVID-19. These guidelines are changing rapidly and should be reviewed prior to considering therapy. The Reagan-Udall Foundation for the Food and Drug Administration’s page on COVID-19 provides information on clinical trials that are beginning or underway. The French Society for Oncology Pharmacy has published detailed information on the potential interactions of proposed COVID-19 therapies and anti-cancer agents that may be valuable in decision making around choice of both anti-cancer and anti-COVID-19 therapy (Slimano et al, Cancer Treat Rev).
The French Society for Oncology Pharmacy has published detailed information on the potential interactions of proposed COVID-19 therapies and anti-cancer agents that may be valuable in decision making around the choice of both anti-cancer and anti-COVID-19 therapy (Slimano et al, Cancer Treat Rev).
Surgery: Can/should surgery be cancelled or delayed? If surgery is delayed, should patients be started earlier on neoadjuvant therapy if that is an available option?
The CDC’s guidance for health care facilities suggests that “elective surgeries” at in-patient facilities be rescheduled if possible. The American College of Surgeons (ACS) has provided information as well and provides additional advice related to triage of patients for surgery relevant to cancer care. However, clinicians and patients will need to make individual determinations based on the potential harms of delaying needed cancer-related surgery; in many cases these surgeries cannot be considered “elective.” Also, if the surgery requires post-operative intensive care, the current capacity of the intensive care units available for that care should be considered as part of decision making. The Society of Surgical Oncology (SSO) has released information on surgery for cancer for several of different tumor types. Sud et al, Ann Oncol report on an analysis of a number of sources of data and estimated the increase in five-year mortality associated with a 6-month delay in surgery for various cancers at Stage 1, 2 or 3. They estimated substantial increases (>30%) in mortality for stage 3 disease of multiple types at all ages. The only situations in which little or no increase in mortality was estimated were stage 1 disease of several types (e.g. breast, melanoma) and prostate cancer at any stage in all but the oldest age groups. Johnson et al, Am J Surg have estimated overall survival hazard ratios for a 12 week delay in surgery for breast cancer [HR 1.46 (95% CI 1.28-1.65)], lung cancer [HR 1.04 (95% CI 1.02-1.06)] and colon cancer [HR 1.25 (95% CI 1.12-1.38)]. Ginsburg et al, J Urol reported on an analysis of the US National Cancer Database and found no association between delaying radical prostatectomy in patients with prostate cancer by up to 12 months and adverse outcomes. Fligor et al, J Gastrointest Surg have systematically reviewed the limited evidence regarding delay of surgery and impact on outcome in patients with colorectal and pancreatic cancer; they found a delay of colon cancer surgery of 30 to 40 days was associated with lower survival, but did not find any evidence of harms associated with delay in pancreatic cancer surgery. Rygalski et al, Ann Surg Oncol have estimated an overall survival HR of 1.189 (95% CI 1.122-1.261) for a delay in head and neck cancer surgery of 67 days.
In some situations (e.g. early-stage breast cancer) where neoadjuvant therapy is available but not routinely considered, it may be reasonable to consider neoadjuvant therapy instead of surgery or simply delaying surgery. The risks of tumor progression with delay in definitive surgery should be weighed against the potential added burden on hospital resources, case complexity, and patient risk of exposure to COVID-19. However, neoadjuvant therapy that requires clinic visits and clinician-patient contact or that itself is immunosuppressive is associated with risks to the patient that must also be considered.
Radiation: Can/should the initiation of radiation be delayed? Can radiation be interrupted or postponed if already in progress?
ASTRO has addressed this concern in part on its COVID-19 resource page. ASCO encourages clinicians to follow ASTRO’s current guidance. As noted by ASTRO, if hypofractionated schedules are considered clinically acceptable, they should be considered. ASCO recognizes the risks of delay in treatment for patients with rapidly progressing, potentially curable tumors may outweigh the risks of COVID-19 exposure/infection, but patients receiving radiation for symptom control or at low risk of harm due to alteration of schedule for radiation treatment visits could potentially be safely delayed. Patients should check with their radiation oncologist to determine the most appropriate course of action for their treatment. NICE has published rapid guidance on the delivery of radiation which may be of value.
Immunosuppressive Therapy: Can/should potentially immunosuppressive therapy (except allogeneic stem cell transplantation) be stopped, delayed, or interrupted?
There is no little direct evidence to guide decisions around changing or withholding immunosuppressive therapy in patients with cancer (see Russell et al, Ecancermedicalscience, for a systematic review of the currently available limited and indirect evidence). Therefore, routinely withholding critical anti-cancer or immunosuppressive therapy is not recommended. The balance of potential harms that may result from delaying or interrupting treatment versus the potential benefits of possibly preventing or delaying COVID-19 infection is very uncertain. Clinical decisions should be individualized and consider factors such as the risk of cancer recurrence/progression if therapy is delayed, modified or interrupted; the number of cycles of therapy already completed; and the patient’s tolerance of treatment.
However, the following practice points should be considered:
- For patients in deep remission who are receiving maintenance therapy, stopping chemotherapy may be an option.
- Some patients may be able to switch chemotherapy from IV to oral therapies, which would decrease the frequency of clinic visits but would require greater vigilance by the health care team to be sure that patients are taking their medicine correctly.
- Decisions on modifying or withholding chemotherapy should include consideration of the indication for chemotherapy and the goals of care as well as where the patient is in the treatment course and their tolerance of treatment. For example, the risk/benefit assessment for proceeding with chemotherapy in patients with untreated extensive small cell lung cancer is different from that for patients on maintenance pemetrexed for metastatic non-small cell lung cancer.
- If local transmission affects a particular cancer center, reasonable options may include giving a chemotherapy break for two weeks, arranging infusion at an unaffected satellite unit, or arranging treatment with another facility that is not affected.
- Consider whether home infusion of chemotherapy drugs is medically and logistically feasible for the patient, medical team and caregivers.
- In some settings, delays or modifying adjuvant treatment may pose a higher risk of compromised disease control and long-term survival than in others.
- Prophylactic growth factors as would be used in high-risk chemotherapy regimens as well as prophylactic antibiotics may be of potential value in maintaining the overall health of the patient and make them less vulnerable to potential COVID-19 complications.
- In cases where the absolute benefit of adjuvant chemotherapy may be quite small, and where non-immunosuppressive options are available (e.g. hormonal therapy in ER+ early-stage breast cancer), risk of infection with COVID-19 may be considered as an additional factor in weighing the different options available to the patient.
Stem Cell Transplantation: Can/should allogeneic stem cell transplantation be delayed?
In some cases involving patients at high-risk for COVID-19, delaying a planned allogeneic stem cell transplant may be reasonable, particularly if the patient’s malignancy is controlled with conventional treatment. Until further data are available, clinicians are encouraged to follow the recommendations provided by the American Society of Transplantation and Cellular Therapy (ASTCT); and the European Society for Blood and Marrow Transplantation (EBMT) recommendations with respect to stem cell transplantation. NICE has released rapid guidance on stem cell transplantation as well.
The following practice points may be considered:
- It may be prudent to test potential donors for COVID-19 even in an absence of evidence of transmission by blood transfusion.
- As a general precaution, visitation post-transplant may need to be limited and visitors may need to be screened for symptoms and potential exposure.
Immune Checkpoint Inhibitors: Can/should treatment with immune checkpoint inhibitors (e.g. ipilimumab, nivolumab) be delayed or interrupted? Are any special precautions or actions needed with respect to their use?
There are mixed data regarding the impact of immune checkpoint inhibitors (ICI) on COVID-19 infection in patients with cancer. The largest (1,545 patients, 20,418 controls) study reported to date by Klebenov et al, Oncologist found no significant relationship between risk of infection or risk of mortality between COVID-19 infection and ICI use. However, smaller studies (Robliotti et al, Nat Med, Bersanelli et al, Ther Adv Med Oncol, Mandala et al, J Immunother Cancer, Rogiers et al, J Immunother Cancer) have reported significantly worse infection rates and mortality.
It may be appropriate to adjust to less frequent dosing intervals when different schedules are considered reasonable options and/or are approved in your jurisdiction for the patient’s indication. However, there is preclinical evidence of cytokine storm and/or potentially increased inflammatory reactions and complications such as pneumonitis for some immune checkpoint inhibitors and CAR T-cell therapy agents. These agents may cause immune-related serious adverse events and immunosuppression may be necessary as a treatment for those events. The potential harms and benefits of therapy should be carefully considered for each patient. Where possible, COVID-19 testing prior to therapy with these agents is reasonable.
Immune Compromise in Survivors: How should care of survivors of cancer with long term immune suppression (e.g. hypogammaglobulinemia) be altered?
ASCO recognizes that patients with long term immune suppression may be at increased risk of infection. However, at this time no recommendations can be made to alter care for these patients beyond the care they would normally receive. These patients should follow all of the general measures (e.g. social isolation) advised by the CDC to minimize their exposure to potential infection. Patients who receive intravenous immunoglobulin should continue to receive it at the prescribed dose and schedule.
Other Therapy: Are there any other therapies that should be delayed, interrupted, or stopped?
At this time, ASCO cannot provide specific information on any other form of cancer therapy. As more data becomes available, this information will be updated. In general, however, any decisions to postpone, discontinue or modify necessary systemic cancer therapy should consider the overall goals of treatment, risks of cancer progression if treatment is postponed or interrupted, patient tolerance of treatment, and the patient’s general medical condition. Each decision requires an individualized risk/benefit assessment.
Impact of Concomitant Medications on COVID-19 Outcomes: Are there any concerns or issues surrounding concomitant medications for patients with cancer?
In addition to the guidance presented below, the NIH has guidance on concomitant medications that may be relevant to patients with cancer. It is changing rapidly and should be reviewed frequently.
- Cardiac medications – NIH recommends at this time that treatment with ACE inhibitors be continued. In addition, three recently published papers in the New England Journal of Medicine did not find any evidence of increased harms from ACE inhibitor therapy; see Jarcho et al, N Engl J Med for an editorial summary and links to the papers.
- G-CSF – G-CSF should be used judiciously and in accordance with ASCO guidelines. Prophylactic use with highly myelosuppressive immunotherapy would still be justified to avoid neutropenia or myelosuppression which may put the patient at higher risk of infection with COVID-19. In the case of patients with active COVID-19 requiring GCSF for neutropenic fever or neutropenia, there are limited or no data. Judgment needs to be exercised depending on the clinical situation. NCCN has published information on the use of G-CSF and ESA (Griffiths et al, J Natl Compr Canc Netw). See section below on neutropenic fever and neutropenia for additional information.
- Other medications – ASCO will provide information as it becomes aware of it to help clinicians and patients make decisions about other medications. See Russell et al, Ecancermedicalscience, for a systematic review of the currently available limited and indirect evidence on several medications that are used in patients with cancer.
Neutropenic Fever and Neutropenia: How can/should care for patients experiencing potential neutropenic fever and neutropenia be affected by the ongoing COVID-19 pandemic?
ASCO recognizes there are three aspects to care of patients with potential neutropenic fever in relation to COVID-19: prophylaxis and acute care.
- Prophylaxis – It may be reasonable for patients at risk for neutropenic fever to be prescribed growth factor for treatment regimens at a lower level of expected risk (e.g. >10% risk) in order to minimize the risk of neutropenic fever and the potential need for emergency care, with instructions for neutrophil count monitoring and regular contact with their health care team.
- Acute care for potential neutropenic fever – It may be reasonable in the current situation to evaluate the potential for neutropenic status in the febrile patient by telemedicine or by phone to determine whether a patient should be evaluated in the clinic or sent to the emergency department.
- Acute care for known neutropenic fever – Standard guidelines for care of neutropenic patients, including isolation, should be followed regardless of COVID-19 status. Rapid COVID-19 testing should be used, if available, to determine level of PPE necessary for caregivers and appropriate location in the facility for continued care. In the absence of rapid testing, manage the patient for neutropenic fever per standard guidelines under the presumption of COVID-19 infection.
Cancer-related Anemia: How can/should care for patients at risk for or experiencing cancer-related anemia be affected by the ongoing COVID-19 pandemic?
- Prophylaxis – Considerations should be given to erythropoietin-stimulating agents, where serious and/or symptomatic cancer/treatment-related anemia is anticipated, and the agents are deemed to be safe. Prophylactic transfusion in asymptomatic patients based on laboratory values should be avoided if possible.
- Acute care – Transfusion should be given where serious and/or symptomatic cancer/treatment-related anemia occurs in accordance with usual practice. The American Society of Hematology’s (ASH) previously issued Choosing Wisely statement recommends not transfusing more than the minimum number of red blood cell (RBC) units necessary to relieve symptoms of anemia or to return a patient to a safe hemoglobin range (7 to 8 g/dL in stable, non-cardiac in-patients). When considering transfusion, the specific patient circumstances (e.g. elderly, congestive heart disease) should be considered and may warrant a higher hemoglobin threshold, particularly for patients on ventilatory support with diminished oxygen-carrying capacity. As blood donation may be affected by community public health measures, the local blood supply must be considered as part of decision-making. Consideration should be given to simultaneously initiating erythropoietin-stimulating agents where they are deemed safe.
Central Venous Catheters/Ports: How can/should the central venous catheters/ports be maintained? Can flushing be delayed?
There is evidence that flushing can occur at frequencies as long as every 12 weeks with no notable increase in adverse events or harms. If patients can flush their own devices, that should be considered, although the process of training may itself be a source of exposure and access to sterile supplies at home may be limited.
Advance Care Planning: Should we discuss code status with patients on active treatment?
Proactive advance care planning is important for all cancer patients, especially now with the additional risk of COVID-19. This discussion has become more urgent than ever in this pandemic with the risk that your patient may be admitted emergently to the hospital and cared for by another team without your ability to participate, advise, and guide an end of life discussion. ASCO urges oncologists to engage in advance care planning discussions with their patients and encourages the use of advance directives or other expressions of end of life preferences, as well as clear documentation of these conversations.
The following resources are available from the Center to Advance Palliative Care™ and Respecting Choices®:
For cancer patients with COVID-19, who are at increased risk of needing mechanical ventilation or ICU care, a POLST conversation is appropriate. See National POLST for more information.