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COVID-19: Considerations in patients with cancer

COVID-19: Considerations in patients with cancer
Authors:
Robert G Uzzo, MD, MBA, FACS
Alexander Kutikov, MD, FACS
Daniel M Geynisman, MD
Section Editors:
Michael B Atkins, MD
Larissa Nekhlyudov, MD, MPH
Richard A Larson, MD
David I Soybel, MD
Deputy Editors:
Sonali Shah, MD
Sadhna R Vora, MD
Literature review current through: Jun 2022. | This topic last updated: Jun 29, 2022.

INTRODUCTION — At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in Wuhan, a city in the Hubei Province of China. It rapidly spread, resulting in an epidemic throughout China, followed by an increasing number of cases in other countries throughout the world. In February 2020, the World Health Organization designated the disease COVID-19, which stands for coronavirus disease 2019 [1]. The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

The rapidly expanding COVID-19 pandemic impacted all areas of daily life, including medical care. In particular, delivering care for patients with cancer or suspected cancer during this crisis has been challenging given the competing risks of death from untreated cancer versus serious complications from SARS-CoV-2, and the likely higher lethality of COVID-19 in immunocompromised hosts [2,3].

Issues related specifically to cancer care during the pandemic are discussed here. Other topics discuss more general issues related to diagnosis and management of COVID-19, and vaccination against SARS-CoV-2.

(See "COVID-19: Diagnosis".)

(See "COVID-19: Outpatient evaluation and management of acute illness in adults".)

(See "COVID-19: Management in hospitalized adults".)

(See "COVID-19: Vaccines".)

CANCER SCREENING AND SURVEILLANCE — Delays in cancer screening during the pandemic led to delayed diagnoses, a higher rate of patients diagnosed in an emergency setting, more diagnoses of later-stage cancers with higher tumor burden, and delays in effective treatment for patients with newly diagnosed malignancies [4-11].

Observational data suggest that cancer-specific mortality was higher during the COVID-19 pandemic when compared with prepandemic levels. In the United States, the number of cancer-related deaths increased by 3 percent between 2019 (prior to the pandemic) and 2020 (during the pandemic), with higher cancer mortality rates observed during the times when health care capacity was most challenged by the pandemic [12]. Delays in cancer screening and surveillance during the pandemic may also continue to impact future cancer mortality [13].

Because of these concerns, many screening programs have resumed in areas where infection has been relatively controlled. Specific recommendations about cancer screening and diagnostic/surveillance testing should be based on the extent of community transmission of COVID-19 as well as the availability of resources. In locations with high rates of ongoing viral transmission, any clinic visits that can be postponed without risk to the patient generally should be postponed. In areas where infection has been controlled, screening programs and clinic visits may be resumed, with clinicians maintaining full adherence to guidelines for limiting the spread of SARS-CoV-2 infection.

TESTING FOR COVID-19

Symptomatic or exposed individuals – Patients with cancer with symptoms concerning for COVID-19 (eg, fever, cough, dyspnea, hypoxia, etc), or those with an exposure to someone with confirmed COVID-19 should be offered testing, as for patients without cancer. A discussion of the various tests available for SARS-CoV-2 testing is available separately. (See "COVID-19: Diagnosis", section on 'Specific diagnostic techniques' and "COVID-19: Diagnosis", section on 'Whom to test'.)

The diagnosis of COVID-19 is made primarily by direct detection of SARS-CoV-2 RNA by nucleic acid amplification tests (NAATs), most commonly reverse-transcriptase polymerase chain reaction from the upper respiratory tract (table 1). (See "COVID-19: Diagnosis", section on 'NAAT (including RT-PCR) to diagnose current infection'.)

Antigen tests, which can be performed rapidly at the point of care, can be a useful alternatives to NAATs for individuals with symptoms of SARS-CoV-2 infection (algorithm 1). This is discussed in detail separately. (See "COVID-19: Diagnosis", section on 'Antigen testing as an alternative to NAAT'.)

Asymptomatic individuals – Depending on community levels of viral transmission, it may be appropriate to test asymptomatic patients prior to cancer surgeries or highly immunosuppressive systemic therapies, eg, oxaliplatin plus irinotecan and short-term infusional fluorouracil (FU) and leucovorin (FOLFIRINOX) for advanced colorectal cancer, or anti-CD20 monoclonal antibodies for hematologic malignancies, which are associated with B-cell depletion. Notably, these conditions/treatments are also associated with a suboptimal response to COVID-19 vaccination, and an approach to testing should apply to individuals irrespective of vaccination status. (See 'Safety and efficacy' below.)

Given the risk of transmission from patients with asymptomatic infection, some institutions in areas of high viral transmission are routinely testing all cancer patients prior to all immunosuppressive therapies [14-17], in accordance with guidelines from the Infectious Disease Society of America [18]. According to these guidelines, immunosuppressive procedures are defined as cytotoxic chemotherapy, solid organ or hematopoietic cell transplantation, long-acting biologic therapy, cellular immunotherapy, or high-dose corticosteroids. However, this is not a widespread practice, and it is not supported by guidelines from the American Cancer Society, American Society of Clinical Oncology, and the European Society for Medical Oncology [19,20].

Testing in patients who have undergone laryngectomy is discussed below. (See 'Laryngectomized individuals' below.)

CANCER TREATMENT IN UNINFECTED PATIENTS — The approach to cancer treatment in patients uninfected by SARS-CoV-2 is influenced by the rates of viral transmission in the area, which can fluctuate based on prevalent COVID-19 variants. The Centers for Disease Control and Prevention defines specific levels for transmission rates based on total new cases and the percentage of positive tests for COVID-19 over time. Global distribution and case counts for COVID-19 are also available. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Geographic distribution and case counts' and "COVID-19: Epidemiology, virology, and prevention", section on 'Variants of concern'.)

Cancer treatment in areas of low viral transmission — In areas where viral infection rates are low, cancer care proceeds largely along the lines of prepandemic standards. However, for individuals with a known SARS-CoV-2 exposure, particularly those who are not up to date on COVID-19 vaccination or are expected to have an inadequate immune response to vaccination, it is generally recommended to hold treatment until it is clear that the patient will not develop COVID-19 from that exposure. However, an exception to holding therapy may be made for patients receiving low-risk cancer therapies, such as hormonal treatments. (See 'Cancer therapy in infected patients' below.)

Precautions to prevent transmission during routine cancer care are appropriate. (See "COVID-19: General approach to infection prevention in the health care setting".)

Cancer treatment in areas of high viral transmission — The following sections will focus on issues related to surgery, radiation therapy, and systemic anticancer treatments in locations with high rates of ongoing viral transmission during active phases of the pandemic. All these issues are less relevant in areas where infection is less prevalent. (See 'Cancer treatment in areas of low viral transmission' above.)

Tools to guide whether treatment can be delayed — Delays in treating cancer can result in adverse oncologic outcomes, depending on the type of cancer and the stage. Nevertheless, in areas of continued high viral transmission, the risks of delayed cancer treatment have to be weighed against the burden on hospital resources and the patient’s risk of exposure to COVID-19 [21-23].

A framework by which to consider immediate versus delayed cancer treatment, according to disease, type of treatment, and patient age, has been published (figure 1).

The online tool OncCovid has been developed to help clinicians estimate the risks of delayed surgical and/or chemotherapy treatment for individual patients with a nonhematologic cancer. It was developed using data from three separate datasets obtained prior to the availability of effective vaccines against COVID-19 [24-26]. By providing input on 47 individualized patient-, disease-, and treatment-specific variables, as well as geographic location, clinicians can use the tool to estimate five-year mortality, cancer-specific mortality, the hazard ratio of treatment delays of various intervals, and the risk of contracting and dying from COVID-19 within six months.

Cancer surgery — Most cancer-related surgeries are time sensitive and cannot be considered "elective." Some experts have distinguished a subset of nonemergency cancer surgeries as being "essential cancer surgery," including surgical management of brain tumors, as well as breast, colon, stomach, pancreas, liver, bladder, kidney, and lung resections [27]. These are generally cancers that cannot wait two to three months, and patients have a significant chance of benefiting from the surgery. (See "COVID-19: Perioperative risk assessment and anesthetic considerations, including airway management and infection control", section on 'Preoperative evaluation during the pandemic'.)

However, in other cases, neoadjuvant therapy has been used as a means of delaying surgery, for example, in the neoadjuvant management of breast cancer. (See "General principles of neoadjuvant management of breast cancer".)

Specific guidance for decision-making for time-sensitive cancer surgery on a disease-by-disease basis during the active phase of the pandemic is available from expert groups. (See "Society guideline links: COVID-19 – Surgical care".)

Radiation — In areas where viral infection is not yet controlled, the decision to initiate or to continue with established radiation treatment plans requires careful consideration of indications, dose already delivered, and risks and benefits of alternative strategies.

Where available, alternative radiation therapy (RT) regimens (eg, hypofractionation) should be offered, if appropriate [28]. Hypofractionation uses higher daily RT doses per fraction with fewer total fractions, which reduces the total number of treatment visits. For patients receiving RT, this approach may reduce their risk of potential community exposure to SARS-CoV-2 and lessen the burden on hospital resources. As an example, an international expert consensus statement has recommended that neoadjuvant short-course RT be preferred over long-course chemoradiotherapy for patients with locally advanced rectal cancer during the pandemic [29]. (See "Neoadjuvant chemoradiotherapy, radiotherapy, and chemotherapy for rectal adenocarcinoma", section on 'Short-course radiotherapy'.)

Randomized trials also support deferring RT across a multitude of cancers by placing systemic therapy first in the treatment sequence [30]. Examples include initial androgen deprivation therapy for intermediate- to high-risk prostate cancer [31], induction chemotherapy for nasopharyngeal carcinoma, and upfront chemotherapy for some grade 2 or 3 gliomas. (See "Initial management of regionally localized intermediate-, high-, and very high-risk prostate cancer and those with clinical lymph node involvement", section on 'Sequencing and duration' and "Treatment of early and locoregionally advanced nasopharyngeal carcinoma", section on 'Induction chemotherapy' and "Treatment and prognosis of IDH-mutant, 1p/19q-codeleted oligodendrogliomas in adults", section on 'Order of therapy'.)

For those receiving RT for symptom control, or for whom an alteration of schedule is unlikely to significantly impact outcome, treatment should be delayed or adjusted. If hypofractionated schedules are appropriate for a given condition, they should be considered [32,33].

Systemic therapy

Chemotherapy — Administration of chemotherapy in locations with high rates of ongoing transmission should be determined on a case-by-case basis. In general, adjuvant or metastatic therapy with curative intent should likely proceed. For patients receiving palliative therapy for metastatic disease, the decision to continue requires careful consideration of indications, response to treatment already delivered, the risks and benefits of continued treatment, available resources for supportive care, and patient preferences.

Considerations for chemotherapy treatment during active phases of the COVID-19 pandemic set forth by the American Society of Clinical Oncology (ASCO) include the following:

For patients in deep remission who are receiving maintenance therapy, stopping chemotherapy may be an option.

For those in whom the benefit of adjuvant chemotherapy is expected to be small and where nonimmunosuppressive therapies are available (eg, hormone therapy for hormone receptor-positive early breast cancer or prostate cancer), it may be reasonable to omit chemotherapy in consideration of the risks of COVID-19. It may also be reasonable to alter the chemotherapy schedule so that fewer visits are needed or to arrange infusion at a less affected cancer center.

In regards to home administration of treatments:

Oral chemotherapy may be an option for some. Low-risk drugs that require subcutaneous or intramuscular administration (eg, fulvestrant, gonadotropin-releasing hormone agonists) can be safely administered at home [34].

Home administration of intravenous chemotherapy (aside from what is typically administered via an infusional pump) is typically not offered; however, it may be appropriate in some cases, as long as coordination with the oncology team is present to ensure that patients are taking their treatments correctly [35].

Supportive care, such as hydration or antiemetics, may be administered at home.

Immunotherapy — Considerations regarding immune checkpoint inhibitor (ICI) immunotherapy in the setting of active phases of the COVID-19 pandemic include the following:

Although there is a theoretic concern that immune checkpoint blockade may lead to worsened outcomes should a patient contract SARS-CoV-2, limited data suggest this is not the case. In a single-center observational study of 69 outpatients with lung cancer with confirmed COVID-19, severity of COVID-19 was comparable among those who had received a programmed cell death 1 (PD-1) inhibitor and those who had not [36,37].

There is a diagnostic dilemma posed by ICI-related pneumonitis, which may mimic COVID-19 [38,39]. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Pneumonitis'.)

Moreover, there are risks associated with viral spread, with any treatments requiring in-person evaluation and administration. As such, less frequent drug administration may be an option for patients with indications for ICIs:

Pembrolizumab can be administered less frequently at 400 mg every six weeks, which is approved by the US Food and Drug Administration. This schedule has similar efficacy and safety as a previously approved dose of 200 mg every three weeks. (See "Systemic treatment of metastatic melanoma lacking a BRAF mutation", section on 'Dosing considerations'.)

A less frequent dosing option (1500 mg fixed dose every four weeks) for durvalumab, an anti-programmed cell death ligand 1 (PD-L1) monoclonal antibody, has also been approved by the FDA for patients with unresectable stage III non-small cell lung cancer who weigh more than 30 kg. The previously approved weight-based dose was 10 mg/kg every two weeks. (See "Management of stage III non-small cell lung cancer", section on 'Incorporation of immunotherapy'.)

Decisions regarding whether it is appropriate to use combination versus single-agent immunotherapy will need to be individualized. The risks of immune-related adverse effects associated with ipilimumab-containing combination regimens (or other immunotherapy combinations), including the risks of hospitalization and associated COVID-19 exposure, should be weighed against the diminished efficacy of single-agent therapy in each particular setting. Other considerations are similar as to those receiving chemotherapy. (See "Toxicities associated with checkpoint inhibitor immunotherapy".)

Other treatments

Anti-CD20 monoclonal antibodies – Lymphopenia seems to be a specific risk factor for adverse outcomes from COVID-19 and other coronaviruses [40-46]. This has led some expert groups to recommend critical re-evaluation of the need for drugs that inhibit B cells, such as anti-CD20 monoclonal antibodies, during the active phase of the pandemic, particularly optional treatments such as maintenance therapy for follicular lymphoma [47]. Some have discontinued maintenance rituximab, especially in older patients and in younger patients with low immunoglobulin levels.

By contrast, ibrutinib and other inhibitors of Bruton tyrosine kinase (BTK) may reduce the incidence and severity of COVID-19 among patients with chronic lymphocytic leukemia. (See 'Cancer therapy in infected patients' below.)

Supportive care – ASCO has set forth several guidelines for supportive care during cancer therapy [48], including the following:

Flushing of ports can occur at intervals as long as every 12 weeks, and patients who are capable of flushing their own devices should be encouraged to do so.

It may be reasonable to offer prophylaxis against febrile neutropenia to more patients during the pandemic (eg, those with a >10 percent chance of febrile neutropenia rather than a >20 percent chance).

Although data are limited, we typically continue glucocorticoids in cancer patients with indications who are not infected with COVID-19, even if they reside in locations with high rates of ongoing transmission [49]. Discussion on the approach to withholding immunosuppressive therapies in cancer patients with COVID-19 is found below. (See 'Approach to cancer patients with COVID-19' below.)

APPROACH TO CANCER PATIENTS WITH COVID-19

COVID-19 outcomes among cancer patients and survivors — Most studies suggest a higher risk of severe COVID-19 in adult patients with active cancer [50-53], although data are mixed [54-56] and outcomes have improved with better COVID-19 therapy and earlier diagnosis [57]. Moreover, many studies were performed prior to availability of effective COVID-19 vaccines.

The risk likely varies by type and stage of cancer and treatment received. In particular, the following features have been associated with an increased risk:

Hematologic malignancies or lung cancer [58-66].

Advanced and/or progressive cancer [51,58,67-73].

Active chemotherapy treatment, particularly more myelosuppressive regimens, has also been described [74-76], although data are mixed [71,72,77-79]. By contrast, recent immunotherapy does not appear to worsen outcomes from COVID-19 [36,72,74,78,80-84], although data in this setting are also conflicting [85].

Older age [50,53-55,59,66,71,72,78,85] and comorbid conditions [46,50,53,55,58,59,67-71,77,78,85-104] that are independently associated with severe COVID-19 further contribute to the risk in patients with cancer.

Some data suggest that being a survivor of a prior cancer is also a risk factor for severe COVID-19, but the risk is lower compared with active cancer [58,92,105], while other studies have not found higher risks among survivors [71,106].

As an example of available data, in an analysis from the United Kingdom, including records of over 17 million individuals linked to over 10,000 deaths from COVID-19, multivariate analysis found that patients with nonhematologic malignancy diagnosed within one year prior to COVID-19 had a 1.8-fold higher risk of death relative to patients without cancer, and a hematologic malignancy carried a fourfold higher risk [58]. Relative to those diagnosed with cancer within the preceding year, the risks were lower for patients diagnosed with cancer 1 to 4.9 years prior to COVID-19, but still elevated compared with people without cancer; beyond five years, risks for death remained elevated for those with hematologic but not nonhematologic malignancies.

Management of COVID-19 infection — Overall, the management of COVID-19 disease infection in cancer patients is similar to the management used for the general population. However, cancer is considered to be a risk factor for progression to severe COVID-19 infection (table 2), which influences available treatment options.

Cancer patients in the outpatient setting – For cancer patients in the outpatient setting who are infected with COVID-19, available treatment options include monoclonal antibodies active against prevalent variants (table 3 and table 4) and antiviral agents, including nirmatrelvir-ritonavir, molnupiravir, and remdesivir. Further details on these agents and the approach to their use is discussed in separately. (See "COVID-19: Outpatient evaluation and management of acute illness in adults", section on 'Treatment with COVID-19-specific therapies'.)

Hospitalized cancer patients – The management of hospitalized cancer patients with more severe COVID-19 infection is the same as that used for the general population and is discussed separately (algorithm 2). (See "COVID-19: Management in hospitalized adults", section on 'COVID-19-specific therapy'.)

Thrombosis risk – Although both COVID-19 and cancer predispose towards hypercoagulability, available evidence suggests that cancer patients who develop COVID-19 are not at a higher risk of clotting from COVID-19 than those without cancer. As an example, in a small study in patients with COVID-19, patients with active cancer had a similar risk of thrombotic events as those without cancer (either arterial or venous) at 28 days (14 versus 18 percent) [107]. Issues surrounding anticoagulation for COVID-19 hypercoagulable state are addressed in detail separately. (See "COVID-19: Hypercoagulability", section on 'Management'.)

Cancer therapy in infected patients

General principles — In the event of a positive SARS-CoV-2 test result, decisions regarding anticancer therapy should be individualized. General principles are as follows:

Systemic therapy

For most patients, chemotherapy or immunotherapy should be interrupted, whether patients are symptomatic from COVID-19 or not [108,109]. Limited data also suggest worsened COVID-19 outcomes with administration of human granulocyte colony-stimulating factor [110].

Nonimmunosuppressive therapies such as hormonal therapies (eg, for breast and prostate cancer) and some oral targeted therapies typically may be continued [111]. Case reports have suggested safety with continuation of anaplastic lymphoma kinase (ALK)- and c-ROS oncogene 1 (ROS1)-targeted therapies among those with the relevant cancer genotypes and COVID-19 pneumonia [112].

Although data are limited, observational studies in chronic lymphocytic leukemia have suggested that Bruton tyrosine kinase (BTK) inhibitors may be associated with less severe infection [113-116], and continuation of this class of drugs should be considered on a case-by-case basis [117].

Decisions regarding systemic glucocorticoids must be individualized, depending on the dose and indication for the glucocorticoid. As an example, for those with an immunotherapy-related adverse event, it may be reasonable to continue treatment; by contrast, in a patient with nausea, glucocorticoids could be omitted or an alternative therapy provided. The role of glucocorticoids in COVID-19 management is discussed separately. (See "COVID-19: Outpatient evaluation and management of acute illness in adults", section on 'Therapies of limited or uncertain benefit' and "COVID-19: Management in hospitalized adults", section on 'Dexamethasone and other glucocorticoids'.)

Radiation therapy – Cancellation or delay in radiation may be appropriate for patients with COVID-19, after a reassessment of the patient's goals of care. Other potential options, such as modifications to the radiation therapy schedule (eg, hypofractionation), may be considered. (See 'Radiation' above.)

Surgery – The risks of perioperative morbidity and mortality are increased in patients with COVID-19, and the decision to perform surgery must balance this risk against the risks of delaying or avoiding the planned procedure.

When can cancer treatment be safely restarted? — For patients who have discontinued cancer therapy due to infection with COVID-19, we typically resume cancer-specific treatment once transmission-based precautions can be discontinued.

The duration of such precautions is often determined by regional and institutional protocol. As an example of one approach, the duration of precautions may be determined using a test-based strategy that includes at least two consecutively negative SARS-CoV-2 tests collected ≥24 hours apart, and the presence or absence of symptoms, which is consistent with guidelines from the Centers for Disease Control and Prevention [118]. If a test-based strategy is pursued, clinicians should be aware that nucleic acid amplification tests (NAATs) for SARS-Cov-2 may remain positive for several weeks in immunocompromised individuals due to persistent viral shedding, and cancer care should be delayed with caution in this setting. (See "COVID-19: Diagnosis", section on 'Specific diagnostic techniques'.)

However, clinical factors (such as the degree of immunocompromise and the severity of the cancer), as well as institutional policies, may also influence the appropriate duration of precautions and the decision to resume cancer therapy. Consultation with an infectious disease specialist may be helpful in determining the ultimate duration of precautions. More detailed information on discontinuing precautions in immunocompromised patients are presented separately. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Immunocompromised patients with confirmed infection'.)

SPECIAL CONSIDERATIONS

Differentiating lymphangitic spread, pneumonitis, and COVID-19 — Some systemic cancer treatments are associated with a risk of pneumonitis (eg, immune checkpoint inhibitors [ICIs], gemcitabine, mechanistic [previously referred to as mammalian] target of rapamycin [mTOR] inhibitors). In other cases, new infiltrates on radiographic imaging may reflect disease progression (eg, lymphangitic spread) or radiation pneumonitis [119]. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Pneumonitis' and "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents".)

Besides the fact that treatment-related pneumonitis might increase the risk of serious complications if the patient develops COVID-19, it may be difficult to distinguish therapy effect versus disease progression versus viral infection. In this setting, treatment should be held until it is clear that the diagnosis is not COVID-19. Testing for COVID-19 is appropriate in such circumstances, similar to the approach taken for patients with new respiratory symptoms.

Incorporation of telehealth — The benefits of virtual visits in oncology care include enabling care (including the maintenance of participation in clinical trials) during the pandemic while avoiding communicable disease exposure, increased patient access, and convenience. Accumulating data support mostly favorable outcomes in cancer patients [120-127]. Further discussion of telehealth is found separately. (See "Telemedicine for adults".)

Pre- and postexposure prophylaxis — The role of postexposure prophylaxis using monoclonal antibodies (table 4) in select asymptomatic individuals at high risk for severe COVID-19, and who have either not up to date on COVID-19 vaccination or are expected to have an inadequate immune response to vaccination, is discussed separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Post-exposure prophylaxis for selected individuals'.)

Pre-exposure prophylaxis has received emergency use authorization for individuals ≥12 years (weighing ≥40 kg) who may not have an adequate response to COVID-19 vaccination (table 5), or who cannot receive a full series of a COVID-19 vaccine because of a severe adverse reaction to the vaccines or their components. Solid organ and hematopoietic cell transplant patients and those receiving cellular therapies are among the patient populations who are prioritized for monoclonal antibodies (table 4). This is discussed in detail separately. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Pre-exposure prophylaxis'.)

Laryngectomized individuals — Some head and neck cancer survivors will have undergone permanent laryngectomy during treatment of their cancer. In general, such patients should wear a highly efficient heat and moisture exchanger over the stoma at all times, especially when around other people. In addition, they should wear a surgical mask (preferably an N95 respirator) over the stoma, and an additional surgical mask or respirator over the nose and mouth. (See "Alaryngeal speech rehabilitation".)

When carrying out COVID-19 testing in persons with a laryngectomy, swabbing and analysis from both the stoma and the nose may increase sensitivity [128,129]. At least one case report documents a laryngectomee who had a positive COVID-19 diagnostic test from the nasopharyngeal swab and a negative result from a tracheal swab [130].

COVID-19 VACCINATION

Whom to vaccinate

Vaccination recommended for cancer patients and survivors — We recommend that all individuals with active or prior cancer be up to date on COVID-19 vaccination to prevent SARS-CoV-2 infection. Immunocompromised patients may have attenuated immunogenicity to the COVID vaccines, but vaccination is still recommended in immunocompromised populations (figure 2). (See "COVID-19: Vaccines".)

If vaccine supply is limited, guidelines suggest prioritizing patients with active cancer who are either on or planning to start treatment (including hematopoietic cell transplant [HCT] and cellular therapies), and those within six months of treatment, except for those receiving only hormonal therapy. Additional factors linked to adverse outcomes from COVID-19, which may increase the priority for vaccination, include age, comorbidities, and sociodemographic factors (eg, poverty, limited access to health care, and under-represented minorities). (See 'COVID-19 outcomes among cancer patients and survivors' above.)

Assessment for potential vaccine contraindications — The Centers for Disease Control and Prevention (CDC) and Emergency Use Authorization (EUA) prescribing information for the COVID-19 vaccines indicates that a severe allergic reaction/anaphylaxis to a prior dose of the vaccine or any component of the vaccine is a contraindication to vaccination. The mRNA vaccines contain polyethylene glycol (PEG), which has rarely been implicated as an allergen in anaphylactic reactions to other PEG-containing medications, such as pegylated asparaginase (Pegaspargase), which may be used in the treatment of acute lymphocytic leukemia. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase'.)

While past anaphylaxis to PEG could be considered a contraindication to the administration of an mRNA COVID-19 vaccine, to date there is no confirmation that PEG allergy, including a history of infusion reaction to Peg-asparaginase, increases the risk for a reaction to COVID-19 vaccines [131]. Nevertheless, referral to an allergist may be needed in such cases prior to vaccination. This subject is discussed in detail separately. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Uncertain role of polyethylene glycol'.)

Thrombotic risks are not a contraindication — Although single-dose adenoviral vaccines have been associated with a rare risk of thrombosis with thrombocytopenia after vaccination, no risk factors for this have been identified. Therefore, a prior history of venous thromboembolism (VTE), or predisposition to VTE, is not a contraindication to vaccination with any type of vaccine. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)", section on 'Individuals with thrombotic risk factors, prior thrombosis, or prior HIT'.)

Safety and efficacy — Available data suggest that COVID-19 vaccination is safe in patients with cancer and reduces the risk of SARS CoV-2 infection [132,133]. As an example, one study found that the vaccine was 58 percent effective at preventing SARS-CoV-2 infections in patients with cancer, two weeks after the second dose [133].

However, studies also suggest that vaccine efficacy is reduced in those with active cancer relative to those without cancer, especially hematologic malignancies and particularly those on anti-CD20 antibody treatment [134-151].

In a registry study including 6860 partially or full vaccinated patients with an mRNA vaccine who developed COVID-19, including 1460 patients with cancer, cancer was associated with higher risks for breakthrough infection (odds ratio [OR] 1.1) and severe outcomes (OR 1.3) compared with not having cancer, after adjustment for other clinical factors [150]. Compared with solid tumors, hematologic malignancies were at increased risk for breakthrough infections (eg, adjusted OR for lymphoma, 2.1; and for lymphoid leukemia, 7.3). Breakthrough risks were lower for those who received a second dose of the vaccine, as well as for those who received the mRNA-1273 (Moderna COVID-19) rather than the BNT162b2 (Pfizer COVID-19) vaccination.

Immunogenicity studies also suggest decreased immune response among cancer patients, particularly those with hematologic malignancies [140,141,152-154]. As an example, in a study of 200 patients with cancer who had been vaccinated (with either two doses of the mRNA vaccines or one dose of the adenoviral vaccine), the seroconversion rate was 94 percent overall, 98 percent among those with solid tumors, and 85 percent in those with a hematologic malignancy [141]. Among those receiving anti-CD20 therapies or following HCT, the seroconversion rate was approximately 70 percent. This underscores the need to maintain appropriate precautions in all patients with cancer, and to not delay the timing of additional doses, if possible [155]. (See 'Three-dose primary series versus booster doses' below.)

There are limited studies directly comparing the available vaccines in cancer patients. Although most evaluated the use of mRNA vaccines (BNT162b2 [Pfizer COVID-19 vaccine] and mRNA-1273 [Moderna COVID-19 vaccine]), observational data in patients with solid organ or hematologic cancers suggest that one dose of the Ad26.COV2.S (Janssen COVID-19 vaccine) is associated with lower protective immune responses compared with two doses of the mRNA vaccines [136,139], which has been also seen in the general population. (See "COVID-19: Vaccines", section on 'Approach to vaccination'.)

None of these vaccines can cause SARS-CoV-2 infection, regardless of immunosuppression. In contrast to other vaccines that consist of live or attenuated virus, none of the currently available COVID-19 vaccines contain infectious SARS-CoV-2. Although Ad26.COV2.S (Janssen COVID-19 vaccine) uses an adenoviral vector platform, the adenovirus is nonreplicative. (See "Immunizations in adults with cancer", section on 'General approach' and "COVID-19: Vaccines", section on 'General principles'.)

Three-dose primary series versus booster doses — For individuals receiving immunosuppressive systemic therapy for cancer and those with any hematologic malignancy who received a two-dose mRNA vaccine series, a third primary dose of mRNA vaccine should be administered, at least 28 days after the second dose (figure 2). The third dose should be preferably the same vaccine that was administered previously, as part of the primary vaccination series. However, if the mRNA COVID-19 vaccine product given for the first two doses is not available, the other mRNA COVID-19 vaccine product may be administered. This is discussed in detail separately. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

A third vaccine dose has been shown to boost the neutralizing response against the Omicron variant in patients with cancer, but the benefit is less in patients with blood cancer compared with those with solid tumors [152,156,157]. In a prospective cohort study, among 79 patients with blood cancer, only 19 percent had detectable neutralizing antibodies (nAbs) against Omicron after two vaccine doses, while 56 percent had nAbs against Omicron after the third dose [156]. Among 100 patients with solid tumors, nAbs against Omicron were detectable in 37 percent after two vaccine doses; 90 percent had nAbs against Omicron after three doses. Further studies are necessary to determine how vaccine-induced nAbs predict clinical response to infection with the Omicron variant, especially in patients who are immunosuppressed [158-161]. (See "COVID-19: Vaccines", section on 'Efficacy against variants of concern'.)

Administering a three-dose primary mRNA vaccine series for certain immunocompromised patients is a distinct issue from booster vaccines following a primary series. Observational studies support the efficacy and safety of booster vaccination in cancer patients on active therapy [145,147,157,162-166]. Because of the possibility of waning immunity and decreased efficacy against certain variants [153,167,168], the US Food and Drug Administration (FDA) and the CDC have approved a booster dose for all adults 18 years or older, regardless of the vaccine or number of doses received. In the United States, a second booster dose with an mRNA vaccine four months after the first booster dose is recommended for individuals 12 years and older with moderately to severely immunocompromising conditions, including those on active treatment for solid tumor and hematologic malignancies (table 5 and figure 2) [169]. Immunocompromised individuals who received three doses of a primary mRNA vaccine series should also receive booster vaccines, as indicated. (See "COVID-19: Vaccines", section on 'Role of booster vaccinations/waning efficacy'.)

Timing

Relative to therapy — For patients receiving immunosuppressive therapy, our approach is to administer the vaccination between treatment cycles, when immunosuppression from treatment is minimized. However, for patients with marrow failure from disease and/or therapy who are expected to have limited or no recovery, as well as those receiving continuous treatment with targeted agents, vaccination should be administered when it is available. This approach is generally consistent with that from expert groups [170,171].

For those who received COVID-19 vaccination prior to HCT or chimeric antigen receptor modified T (CAR-T) cell therapy, the CDC recommends repeat vaccination with a full primary series at least three months after the transplant or CAR-T administration. (See "Immunizations in hematopoietic cell transplant candidates and recipients", section on 'COVID-19 vaccine'.)

Some expert groups recommend holding certain immunosuppressive agents around the time of vaccination or adjusting the timing of vaccination to account for receipt of such agents to try to optimize the vaccine response. As an example, for patients receiving rituximab, the American College of Rheumatology suggests scheduling vaccination so that the series is initiated approximately four weeks prior to the next scheduled rituximab dose and delaying administration of rituximab until two to four weeks after completion of vaccination, if disease activity allows [172]. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'Timing of vaccination'.)

Relative to radiologic imaging — Given the potential for interference with interpretation of radiologic imaging because of postvaccination axillary adenopathy, radiologic examinations (including mammography and positron emission tomography/computed tomography [PET/CT] scans) should be scheduled prior to the first dose of an mRNA-based COVID-19 vaccine (ie, BNT162b2 [Pfizer COVID-19 vaccine] or mRNA-1273 [Moderna COVID-19 vaccine]), or four to six weeks following completion of the primary series, provided that it does not unduly delay care. There is limited information as to whether these same concerns apply to Ad26.COV2.S (Janssen COVID-19 vaccine). Clinicians should take a history on vaccination details prior to obtaining these imaging studies.

Vaccine-associated lymphadenopathy — For cancer patients and survivors with an identified primary tumor site (eg, breast cancer, melanoma, head and neck cancer), it is preferable to administer the COVID-19 vaccine into the arm contralateral to the primary tumor to avoid confusing benign vaccine-associated adenopathy with malignant adenopathy on imaging studies [173-175]. By using this approach, lymphadenopathy that is detected after vaccination can often be observed for resolution, potentially reducing the need for further diagnostic imaging and biopsies.

Axillary swelling or tenderness has been reported in approximately 12 percent of patients after the first dose of mRNA-1273 and in 16 percent after the second dose [176]. Lymphadenopathy of the arm and neck has also been reported as an unsolicited event in 1 percent or fewer patients [177]. In available reporting, the lymphadenopathy generally developed within two to four days of vaccination and lasted a mean of 10 days.

Reported rates and duration of lymphadenopathy in both trials were based upon clinical assessment, and therefore, the rates of subclinical adenopathy detected by radiologic imaging might be higher. However, available data are conflicting, and results may vary according to the type of imaging study and which vaccine was used [173,178,179]. Most of the cases have been identified on PET/CT [174] rather than physical exam or mammography.

In an analysis of 750 women who received at least one injection of COVID-19 vaccine <90 days prior to mammography, 3 percent had unilateral axillary adenopathy on imaging, most of whom were asymptomatic [178]. Adenopathy rates decreased as days from vaccination increased, with no cases among the 195 whose imaging took place beyond 28 days postvaccination. There were no reported differences according to vaccine administered.

A systematic review of 15 reports including over 2000 patients with palpable or imaging-detected lymphadenopathy following COVID-19 vaccination found 737 cases of vaccine-associated lymphadenopathy [180]. Most cases were identified during imaging for cancer staging or follow-up (89 percent), typically by PET/CT. Only 21 of cases (2.8 percent) were identified during breast screening imaging examinations. The incidence range for postvaccination lymphadenopathy was 14.5 (after a single dose) to 53 percent, and 29 percent of cases persisted beyond 21 days.

Impact of immune checkpoint inhibitors — An unanswered question for patients with cancer is whether vaccine safety and/or efficacy will be impacted by the use of immune checkpoint inhibitors (ICIs), which stimulate immune system function. Only limited data are available on COVID-19 vaccinations, but suggest that vaccination is tolerated in patients receiving ICIs [164,181,182]. Based on available data and the likelihood that benefits of vaccination outweigh potential risks, we do not consider use of ICIs to be a contraindication to vaccination.

Is there a way to assess for successful immunization? — There is no reliable way to confirm whether a vaccine has elicited a protective immune response, and guidance from expert groups on this issue states that antibody testing is neither necessary nor recommended to assess for immunity following vaccination. This is discussed separately. (See "COVID-19: Vaccines", section on 'Limited role for post-vaccination testing' and "COVID-19: Diagnosis", section on 'Testing following COVID-19 vaccination'.)

SUMMARY AND RECOMMENDATIONS

Cancer screening and surveillance – During the pandemic, specific recommendations about cancer screening and diagnostic/surveillance testing should be based on the extent of community transmission as well as the availability of resources. Many screening programs have resumed in areas where infection has been relatively controlled. (See 'Cancer screening and surveillance' above.)

Cancer treatment in uninfected patients

In areas of low viral transmission – In areas where viral infection rates are low, cancer care proceeds largely along the lines of prepandemic standards. However, for individuals with a known severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, particularly those who are not up to date on COVID-19 vaccination or are expected to have an inadequate immune response to vaccination, it is generally recommended to hold treatment until it is clear that the patient will not develop COVID-19 from that exposure. An exception may be made for patients receiving low-risk therapies, such as hormonal treatments. (See 'Cancer treatment in areas of low viral transmission' above.)

In areas of high viral transmission – In areas of continued high viral transmission, the risks of delayed cancer treatment have to be weighed against the burden on hospital resources and the patient's risk of exposure to COVID-19. (See 'Cancer treatment in areas of high viral transmission' above.)

Cancer patients with COVID-19

Risk factors – Most studies suggest a higher risk of severe COVID-19 in adult patients with active cancer, although data are mixed. In particular, hematologic malignancies, lung cancer, advanced or progressive cancer, active chemotherapy, older age, and comorbid conditions are risk factors for severe COVID-19. Prior cancer is also a risk factor, but the risk is lower compared with active cancer. (See 'COVID-19 outcomes among cancer patients and survivors' above.)

Management of COVID-19 infection – Overall, COVID-19 disease management is similar to the management used for the general population. However, cancer is considered to be a risk factor for progression to severe COVID-19 infection (table 2), which influences available treatment options. (See 'Management of COVID-19 infection' above.)

Cancer therapy in infected patients – For most cancer patients with COVID-19, chemotherapy or immunotherapy should be interrupted, whether patients are symptomatic from COVID-19 or not. We typically resume cancer treatment once transmission-based precautions can be discontinued; the duration of such precautions is often determined by regional and institutional protocol. (See 'Cancer therapy in infected patients' above.)

COVID-19 vaccination

Vaccination in cancer patients – We recommend that all individuals with active or prior cancer be up to date on COVID-19 vaccination to prevent SARS-CoV-2 infection (Grade 1B). Vaccination is recommended in immunocompromised patients, although COVID-19 vaccines may be less effective in this population (figure 2). (See 'COVID-19 vaccination' above and 'Safety and efficacy' above.)

-For individuals receiving immunosuppressive systemic therapy for cancer and those with any hematologic malignancy who received a two-dose mRNA vaccine series, a third primary dose of mRNA vaccine should be administered, at least 28 days after the second dose. (See 'Three-dose primary series versus booster doses' above.)

-Because of the possibility of waning immunity and decreased efficacy against certain variants, there is regulatory approval in the United States for a booster dose of vaccine for all adults. Immunocompromised individuals who received three doses of a primary mRNA vaccine series should also receive a booster dose. (See 'Three-dose primary series versus booster doses' above and "COVID-19: Vaccines", section on 'Role of booster vaccinations/waning efficacy'.)

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