Recommendations for Managing Patients With Lung Cancer During COVID-19 Era

Antonio Passaro, MD

World Lung Cancer Day, which is a global initiative for raising awareness of lung cancer, the leading cause of cancer-related deaths in the United States, strikes differently this year in light of the coronavirus disease 2019 (COVID-19) pandemic. COVID-19 has made a strenuous impact on the healthcare system, and managing patients with lung cancer, in particular, has become a major challenge in the field.

Patients with lung cancer are at a greater risk of developing COVID-19, which will also put them at greater risk of experiencing comorbidities or mortality. Very minimal research is available on how to adjust standard-of-care treatments in patients with lung cancer during this unprecedented pandemic.

“World Lung Cancer Day [is] a great opportunity for all of us to raise awareness about lung cancer in a historic time characterized by Sars-Cov-2 infection,” Antonio Passaro, MD, told Targeted Oncology. “Despite the pandemic, we must continue to support the lung cancer community to raise awareness about lung cancer and its global impact, improving the understanding of lung cancer risks as well as early treatment around the world.”

In response, the European Society of Medical Oncology (ESMO) has published recommendations for the management of patients with lung cancer to maintain high-quality standards during the COVID-19 pandemic.1These guidelines have been developed through the consensus of an international panel of thoracic malignancies experts in Europe and demonstrate how to best manage patients with lung cancer from staging of the initial disease through to treatment.

“As the situation is rapidly evolving, practical actions are required to guarantee the best patient treatment while protecting and respecting their rights, safety, and well-being,” the study authors, led by Passaro, wrote. “In this environment, cancer practitioners have great responsibilities: provide timely, appropriate, compassionate, and justified cancer care, while protecting themselves and their patients from being infected with COVID-19.”

“During the COVID-19 pandemic, the management of lung cancer increased in complexity. We made hard choices in order to protect the health of our patients, limiting any way that they could get sick due to COVID-19,” said Passaro, an oncologist in the Division of Thoracic Oncology at the European Institute of Oncology-IEO in Milan, Italy, a country that has recently gotten the pandemic under control.

The ESMO guidelines are defined by 3 levels of therapeutic intervention: Tier 1, defined as high priority, focuses on immediately life-threatening cases, clinically unstable, and/or where the magnitude of benefit appears high priority, such as a significant improvement in overall survival or quality of life (QOL). Tier 2, defined as medium priority, includes non-critical situations where any more than a 6- to 8-week delay could impact the patient’s overall outcome or magnitude of benefit. Tier 3 is the lowest priority, which is defined as stable conditions that allow services to be delayed for the duration of the pandemic and/or when the intervention is non-priority, such as if there would be no survival benefit or a change/reduction in QOL.

“The prioritizations of resources and treatments is the only way to protect our patients with lung cancer in this historical period worldwide, but we do not forget that assuring our patients the care in a safe way is the most important think to follow in this time. Nobody needs to lag behind in screening, diagnosing, and treating lung cancer, but we all have to move forward safely to protect each other.”

Managing Patients With Lung Cancer in the Outpatient Setting

The guidelines recommend that the clinical situation and quality of care for a patient with lung cancer should not be changed, so all treatment plans should be discussed with a multidisciplinary team, and the implementation of a multidisciplinary team should not be considered negotiable in light of the COVID-19 pandemic and its challenges.

“Patients with lung cancer are more at risk of developing COVID-19, with high related morbidity and mortality as reported in our results of the international TERAVolt study,2 in which about 76% of enrolled patients were hospitalized and about 33% of these patients died, without admission to Intensive Care Unit (ICU),” Passaro said. “This dramatic scenario is characterized by a cumulative risk ratio, due to pathophysiological, clinical and treatment-related factors. Older age, significant cardiovascular and respiratory co-morbidities and smoking-related lung damage, are some of the most important risk factors that can predispose to more severe COVID-19 complications in patients with lung cancer.”

Before allowing patients to enter the hospital, all patients and should be triaged for potential COVID-19 symptoms via a questionnaire and temperature check. Patients visiting the hospital system in the outpatient setting should be reorganized so that patients with symptoms of or suspicion of a lung cancer diagnosis should be handled within standard pathways while protective measures are also put in place, such as proper hand hygiene, physical distancing, and personal protective equipment.

In the outpatient setting, patients visiting the hospital for psychological support are considered low priority and should be converted to telemedicine appointments. Patients with a new lung cancer diagnosis or suspicion of a diagnosis are considered medium priority. These patients should visit the hospital for follow-up if they are considered to be at high risk of relapse. Patients with new symptoms should be converted to telemedicine visits where possible. Patients with a newly diagnosed lung cancer or suspicion of invasive disease who are experiencing disease-related symptoms or have a suspicion of stage III or metastatic non–small cell lung cancer (NSCLC) or small cell lung cancer (SCLC) should visit the hospital for treatment administration.

Non-priority outpatient appointments should be converted to a telemedicine platform to limit the number of patients exposed to the hospital system. Telemedicine appointments are best suited for non-urgent scenarios, such as long-term follow-up of patients with low- to intermediate-risk of relapse. Radiological investigation can be delayed in asymptomatic patients unless new systems have occurred, which would make them a medium priority.

Any patients on active treatment that can be shifted to telemedicine should be, with blood tests administered in the home. However, the study authors noted that while telemedicine may represent a valuable tool for the hospital system during the pandemic, it should not entirely replace standard practice.

COVID-19 Impacts Surgical Approaches to Lung Cancer Treatment

Out of concern for the patients with lung cancer who are at a particularly higher risk of developing the virus, the capacity of surgery has been significantly reduced during the pandemic. Access to the ICU has also been significantly reduced.

Surgical oncology priorities considered low priority during the COVID-19 pandemic include patients with discordant biopsies that are likely to be benign, those with operable pure ground-glass opacity nodules of stage T1a, and patients with a diagnostic work-up and/or resection of all other nodules of incidental findings that include a solid nodule >500mm3 and known volume doubling time >600 days. The alternative for patients with no available surgical capacity would be stereotactic radiotherapy.

Medium priority in the surgical space would include those with discordant biopsies that are likely to be malignant, those with a diagnostic work-up and/or resection of nodules of incidental findings with either a solid nodule of >500 mm3, pleural-based solid nodule of > 0 mm, a known volume doubling time of <400 days, or a new solid component in a pre-existing non-solid nodule. The alternative in this patient population would also be stereotactic radiotherapy.

According to the guidelines, patients would be considered high priority for thoracic surgery if they have drainage with or without pleurodesis of pleural effusion, pericardial effusion, or tamponade risk; evacuation of empyema-abscess; T2N0, resectable T3/T4, or resectable N1/N2 tumors that have not received treatment or is following induction chemotherapy; resectable T3 or T4 tumors naïve of treatment or following induction chemotherapy; or operable NSCLC with T1AN0 disease. Diagnostic procedures such as mediastinoscopy, thoracoscopy, pleural biopsy, endoscopy, transthoracic investigations for diagnostic/staging workup are also considered high priority.

“For all the lung cancer stakeholders, it is highly important to strictly follow the social distancing rules and always use masks in the community,” Passaro noted. “Where feasible, testing patients before surgery of starting treatment could optimize and reduce the risk of community infections and dissemination.”

The common goal during the pandemic is to delay the perioperative morbidity and mortality of infection, but lung cancer is often a fast-growing cancer. Rapid surgical assessment should be prioritized and carried out if a delay in surgery could compromise the patient’s outcomes, as in the case of high priority cases.

Patients considered high priority by these guidelines should be given specific palliative surgical approaches, such as thoracentesis or stent insertion, as this may improve significant symptoms or the QOL and patient prognosis.

“Surgical indications must be individualized, and all decisions should be shared with the patients and their caregivers; assessing preference and managing expectations while informing on the pros and cons of any plan in the context of the COVID-19 crisis remains crucial,” the study authors wrote.

Treatment Recommendations Vary Among Lung Cancer Subtypes

Early-Stage NSCLC

A major challenge during the pandemic includes improving outcomes in the curative setting for patients with early-stage disease. Selection and prioritization of treatments in early-stage disease requires a long-term vision; overall survival should be the most important end point.

An absolute benefit of 5% to 6% has been observed with adjuvant platinum-based chemotherapy as treatment of patients with resected stage I through III NSCLC. However, tolerability and adherence to treatment are critical factors to consider when treating patients during the COVID-19 pandemic. Adjuvant chemotherapy should be reconsidered based on the patient’s priority, which is mainly impacted by the relative survival benefit and functional comorbidities.

Low priority includes patients with T1A-T2BN0 disease, where adjuvant chemotherapy is associated with negative prognostic features, and elderly patients or those with important comorbidities. Patients with T2B-T3N0 or pN1 NSCLC are considered medium priority, and adjuvant chemotherapy should be considered carefully in discussions with these patients. Adjuvant chemotherapy may also be used in patients of medium priority, such as younger patients below the age of 65 years with T3/4 or N2 disease.

High priority patients include those receiving concomitant chemoradiotherapy for stage I/II SCLC and neoadjuvant chemotherapy for stage II disease. Follow-up should be performed between 2 cycles of treatment if necessary and by telephone. A laboratory check should also be performed between 2 cycles if necessary, and at home if possible. Granulocyte colony-stimulating factor can be used for febrile neutropenia risk if considered to be more than 10% to 15%.

Physicians should thoroughly discuss the risk/benefit ratio of adjuvant chemotherapy with patients and the presence of negative prognostic features should be strongly considered. However, adjuvant chemotherapy should be withheld in elderly patients with significant comorbidities. It should only be proposed to patients who are young and fit with resected T3 or T4 disease, or those with pN2 disease.

Neoadjuvant chemotherapy should be top priority and can potentially be applied to all patients who are suitable for surgery of curative intent, such as young and fit patients who do not have comorbidities. The use of growth factors can be considered to both avoid and minimize neutropenia.

Locally Advanced NSCLC

Patients with stage III NSCLC are considered high priority, according to the guidelines. Given the significant curative potential, the use of neoadjuvant treatment in patients with potentially resectable stage IIIA and concomitant or sequential chemoradiotherapy in patients with stage IIIA/IIIB/IIIIC disease should be given high priority.

For patients with disease control after concomitant or sequential chemoradiotherapy, subsequent consolidation durvalumab (Imfinzi) should be given within 42 days of the completion of treatment. Durvalumab can be given via infusion every 3 weeks rather than the standard 2-week schedule whenever possible.

Metastatic NSCLC

In order to improve QOL and survival of a very aggressive malignancy, evidence-based approaches should retain priority during the COVID-19 pandemic. Although the virus can pose an immediate threat to patients with NSCLC, the disruption of cancer treatment could outweigh the number of deaths from COVID-19 in the coming years.

All frontline systemic treatment options should not be changed, which includes chemotherapy, immunotherapy, tyrosine kinase inhibitors (TKIs), and other combinations in an aim to improve the prognosis, cancer-related symptoms, and QOL, whenever possible. The same also holds true for second-line therapies for patients with symptomatic and progressive disease as a delay in treatment could compromise survival.

Immune checkpoint inhibitors should be modified or delayed to an every-4-weeks schedule compared with the standard 2- or 3-week schedules when appropriate to reduce the number of clinical visits. Delaying subsequent treatments for those who have received these treatments for 12 to 18 months can be considered, and discontinuation of immune checkpoint inhibitors after 2 years should be discussed with patients, bearing in mind the lack of evidence supporting optimal treatment durations in lung cancer.

TKI schedules should not be altered unless discontinuation is required for the clinical situation. Drug home delivery services should be used for those receiving oral TKIs to ensure access to treatment remains unchanged while limiting hospital access to reduce potential COVID-19 exposure.

With the use of oral chemotherapy agents, home delivery services should also be considered and are preferred when available to reduce hospital admission. Physicians are advised to take extra caution with systemic treatments that are less likely to impact the overall survival or QOL for a patient. Risk/benefit ratios should be discussed with patients on a case-by-case basis.

Temporary withdrawal of some interventions could be considered in an emergency situation, and antiresorptive bone-protective therapy should be withheld unless it is deliverable in the patient’s home.

SCLC

Treatment of SCLC should always be priority for patients who are suitable to receive frontline chemotherapy, either alone or with the addition of immune checkpoint inhibitors for metastatic disease, as well as for those with limited disease who are treated with concurrent therapy with chest radiotherapy. Second-line treatment in the symptomatic and/or platinum-refractory population should be discussed thoroughly with patients. Administration of prophylactic cranial irradiation should also be deferred in cases of limited-stage disease and can be replaced by MRI surveillance in patients with extensive-stage disease.

COVID-19 Impacts Research in Lung Cancer

In order to control the spread of COVID-19, many clinical research centers have reduced their activity, including the potential interruption or a permanent halt of clinical trials. However, clinical and translational research is important for providing the most optimal outcomes and care for patients with lung cancer.

Priority has been placed on clinical trials evaluating specific treatments for patients with COVID-19 at this time, but patients with lung cancer may be able to enroll in trials of targeted therapies or immune checkpoint inhibitors if feasible.

Imaging assessments and laboratory checks should be used for patients withdrawing from an optional trial procedure. Clinical trials that have a placebo arm should be suspended until the pandemic resolves as it cannot be justified exposing patients to the virus for treatment.

In order to optimally manage trials during the pandemic, the FDA and European Medicines Agency have issues guidelines for the safe delivery of treatment, as well as structural information for changes and protocol deviations.

Overall, the virus has strained the global healthcare system, but maintaining cancer care is a challenge that should be carefully considered. The risks of COVID-19 and optimal oncological standards should be considered for the treatment of patients with lung cancer.

“In Italy, the pandemic is under control, and it is improving, but for [countries like the] United States, Spain, and Brazil, the pandemic is not under control,” Passaro said. “Patients that require palliative or curative treatment that significantly could improve survival and quality of life should be highly prioritized as well as the use of different approaches: for example, the use of telemedicine or the home delivery of oral anticancer therapy and supportive medications, according to pharmacy department.”

To date, the data are minimal for understanding standard-of-care adjustments for patients with lung cancer during the COVID-19 pandemic. The ESMO recommendations here should serve as a guideline to ensure and maintain optimal standards for patients with lung cancer throughout this difficult time.

_References

1. _{Passaro A, Addeo A, Von Garnier C, et al. ESMO management and treatment adapted recommendations in the COVID-19 era: lung cancer. ESMO Open. 2020;5(Suppl 3):e000820. doi:10.1136/esmoopen-2020-000820}
2. _{Garassino MC, Whisenant JG, Huang LC, et al. COVID-19 in patients with thoracic malignancies (TERAVOLT): first results of an international, registry-based, cohort study. Lancet Oncol. 2020;21(7):914-922. doi:10.1016/S1470-2045(20)30314-4}