Although little evidence exists with regard to how to best treat patients with breast cancer during the COVID-19 pandemic, guidelines have been issued by organizations like ESMO to assist providers with making those decisions.
Sibylle Loibl, MD, PhD, co-chair of the German Breast Group and associate professor at the University of Frankfurt in Frankfurt, Germany
Sibylle Loibl, MD, PhD
Although little evidence exists with regard to how to best treat patients with breast cancer during the COVID-19 pandemic, guidelines have been issued by organizations like ESMO to assist providers with making those decisions. The most important thing to remember is to treat as closely as possible to standard evidence-based recommendations, and to mindfully adapt procedures to ensure patient safety, according to Sibylle Loibl, MD, PhD.1
“We should treat our patients with cancer as closely as possible to the standard of evidence-based medicine recommendations,” said Loibl, chair of the German Breast Group, University of Frankfurt/M, Centre of Haematology and Oncology, in Frankfurt, Germany, in the first keynote lecture during the 2020 ESMO Breast Cancer Virtual Meeting. “I would like to remind you that we need to mindfully adapt our procedures and we should not overreact; this is very important. Otherwise, we risk the patients’ safety and we risk the integrity of our clinical trials; this will have consequences later on.”
As of May 23, 2020, a total of 5,175,476 cases of COVID-19 have been reported since December 31, 2019, according to the European Centre for Disease Prevention and Control; this includes 338,039 deaths.2 In Europe, COVID-19 case counts continued to rise from late January until the end of February, according to Loibl, who added that the number of deaths associated with the virus appears to have recently plateaued.
In any new or unusual situation such as this one, providers must approach the challenge as follows: create a plan, do something, check what has been done, and then act. “[The plan portion of the theory consists of creating] guidelines and prioritization of our patients. We then need to triage the patients and treat them accordingly,” explained Loibl. “After that, we need to look at outcomes and check the workflow. Eventually, we need to discuss with our patients or amongst ourselves the outcome, or what we have seen, and adapt accordingly.”
In light of the COVID-19 crisis, the treatment of patients with cancer must be prioritized, according to Loibl. To this end, a conceptual framework for prioritizing the use of radiotherapy and systemic treatments during the pandemic across all tumor types was recently published, with patients with breast cancer falling within the middle category.3
“We have the high-risk patients with breast cancer with neoadjuvant or adjuvant indications who might derive a substantial benefit from their treatment,” said Loibl. “Then, we have some patients with palliative indications; they range from low priority to higher priority and it really depends on the stage of the metastatic breast cancer, the seriousness of their symptoms, and the type of underlying problems and conditions they have in addition to their risk of acquiring a COVID-19 infection.” For example, patients categorized to be very low risk may have bone metastases that are manageable with medications, are stable, and are appropriate for active surveillance.
In an attempt to develop guidance to mitigate the negative effects of the COVID-19 crisis, ESMO released recommendations specifically for the management and treatment of patients with breast cancer. Similar to the conceptual framework, the approach is organized by priority: high, medium, and low.
If a patient is categorized as “high” priority, their condition is considered to be immediately life threatening, clinically unstable, or an intervention could result in significant survival benefit or substantial improvement in quality of life. For a situation to be classified as “medium” priority, it is considered to be noncritical, with the understanding that a delay in treatment for longer than 6 months could impact outcome, or the benefit of intervention qualifies for intermediate priority. If a patient’s condition is stable enough that treatment can be delayed for the duration of the pandemic or an intervention would not result in survival gain, their situation is classified as “low” priority.4
Outpatient Visit Priorities
Patients with a post-operative, unstable clinical scenario should be seen as an outpatient in the clinic, irrespective of the risk to acquire infections, according to Loibl. For these “high” priority patients who do need to visit the clinic, many hospitals have put precautionary measures in place to protect them from exposure to COVID-19. Patients with breast cancer who are pregnant are also considered to be “high” priority.
“Medium” category scenarios include those who receive a new diagnosis of invasive breast cancer, those on treatment who experience new adverse events, those who receive a new diagnosis of non-invasive breast cancer, and certain patients without any complications who require post-operative visits.
Established patients without any new issues, survivorship follow-up, follow-up for those at high risk of breast cancer or at high risk of relapse, and psychological support visits, are all considered to be “low” priority scenarios.
“High risk, again, are those patients who have breast cancer surgery complications and complications of reconstructing surgery. Also, surgery in patients who have completed the neoadjuvant chemotherapy-based treatment [fall in this category], because we know those patients are not operated on within 3 to 4 weeks, and especially those with residual disease who have a higher risk of relapse when they are not operated on very soon,” explained Loibl.
“Medium” or “high and medium” priority scenarios include the excision of malignant recurrence, depending on the phenotype and extent; clinically low-risk primary breast cancer, and discordant biopsies expected to be malignant.
On the other side of the spectrum, excision of benign lesions and duct excision; surgery of non-invasive breast cancer, except for extended high-grade ductal carcinoma in situ; discordant biopsies likely to be benign; breast reconstruction; and prophylactic surgery for asymptomatic but high-risk patients are all considered to be “low” priority.
Radiation Oncology Priorities
With regard to radiation oncology, palliative treatment of bleeding or painful breast mass considered to be inoperable, when control of symptoms cannot be achieved pharmacologically, is determined to be “high” priority, along with patients who are already receiving radiation treatment. “The adjuvant post-operative radiotherapy for our high-risk patients is, of course, important and should not be postponed, [and] should not be adapted,” said Loibl.
Adjuvant post-operative radiotherapy for low- or intermediate-risk patients with breast cancer is considered to be “medium” priority, and the use of hypofractionated regimens should be taken into consideration as a means to decrease visits to the hospital.
“On the other side, we have the in situ carcinomas and we have the elderly patients, where it might be more helpful to start the adjuvant therapy, endocrine treatment, and maybe postpone radiotherapy, because they are at high risk of acquiring COVID-19 infection,” added Loibl.
Patients with triple-negative breast cancer (TNBC), especially those with higher risk of relapse, should receive treatment with neoadjuvant and adjuvant chemotherapy; their treatment should not be delayed, said Loibl. Likewise, patients with HER2-positive breast cancer should continue treatment with neoadjuvant and adjuvant chemotherapy in combination with targeted therapy.
Additionally, adjuvant capecitabine treatment in patients with high-risk TNBC, and ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with high-risk HER2-positive breast cancer should be considered, according to Loibl.
“We might have more options for delaying or adapting treatment in our medium-risk patients,” said Loibl. “We can use endocrine treatment, or can use adjuvant trastuzumab [Herceptin] alone, which can be postponed for some weeks.”
Additionally, if a patient is clinically asymptomatic or exhibit clinical signs of response in the neoadjuvant setting, follow-up imaging, restaging studies, echocardiograms, and bone density scans can be delayed.
Early Breast Cancer
For patients with early breast cancer, standard adjuvant therapy in the pre- and post-menopausal setting should be continued, and telemedicine should be utilized to address potential associated toxicities that are reported by the patient. Additionally, neoadjuvant endocrine therapy can be used in patients with estrogen receptor (ER)—positive, HER2-negative stage I or II disease to allow for surgery to be deferred by 6 to 12 months.
“We should think about providing more supportive treatment to avoid unnecessary toxicity, especially toxicity associated with higher infection like neutropenia. We can give G-CSF support as primary prophylaxis, or we can add on antibiotics. We might consider reducing the immune suppression, especially in the elderly population,” said Loibl. “LHRH agonists and analogs can be given every 3 months instead of monthly, but monthly at-home administration is actually the preferred recommendation for our patients, and the blood tests should be done near home to avoid unnecessary travel.”
Metastatic Breast Cancer
When chemotherapy is recommended for patients with metastatic breast cancer, oral options are preferred as a way to reduce visits to the hospital. It is recommended that the chemotherapy schedules be modified to an every-3-week dosing schedule rather than weekly dosing, when appropriate.
“LHRH [analogues can be given] every 3 months and bone agents can be given every 3 months. The incorporation of CDK4/6 inhibitors into endocrine treatments should align with recommendations and resource availability,” said Loibl. “We know there’s risk associated with neutropenia, but we don't know how often the neutropenia is actually associated with an infection. We need to discuss this risk with our patients.”
Elderly patients are at higher risk, and thus, providers might consider postponing the start of CDK4/6 inhibitors in this population. For patients with low-risk metastatic breast cancer, endocrine therapy should be started first and then the CDK4/6 inhibitor can be added later on.
“We have the checkpoint inhibitor as additional treatment for our patients with PD-L1—positive metastatic TNBC; that option can be considered,” added Loibl. “So far, we haven't seen a higher complication rate. However, we need to closely monitor symptoms—especially as they can be associated with pneumonitis or infection—and promptly withdraw the patient in case we have additional COVID-19 infection diagnosis.”
Modifying Measures in Clinical Trials
The COVID-19 pandemic has also significantly impacted clinical trials, resulting in temporary holds or deactivation. When the trial is examining a drug that is providing significant benefit for high-risk patients, investigators are working hard to ensure the research continues. In comparison, if a trial is being conducted purely from an academic standpoint, and patients need to make extra trips to the hospital, the research might be temporarily halted, according to Loibl.
It’s important that investigators mindfully adapt their procedures and avoid overreacting in this situation.
“A 5% to 10% decrease in survival in high income countries has been predicted [as a result of not mindfully adapting our cancer treatment], and this will account for hundreds of thousands of excess deaths—this [number] will dwarf those caused by COVID-19,” concluded Loibl.