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Impact of COVID-19 on breast cancer management:Insights on Chemotherapy, Radiation therapy and Surgery protocols

Priya Iyer1

1M.D. Associate Professor

Department of Radiation Oncology, Cancer Institute, Chennai

Email ID: priyaonc@gmail.com

Introduction

The worldwide global pandemic caused by COVID-19 from early March 2020 has had an unfavorable impact on the health care infrastructures.[1] Cancer centers were the worst affected since it was observed that COVID-19 caused worse outcomes among cancer patients.[2,3] Oncologists worldwide had to change existing protocols to deliver the best possible cancer care amidst the pandemic. With the advent of a global lockdown, more challenges were sent their way, making cancer treatments reach the inaccessible population in the country very difficult.[2,3] But as it is said, just like there is light at the end of every tunnel, cancer services found new dimensions and once again it was proven that 'Where there is a will, there is a way'. Using the triage system to categorize patients based on risk stratification and priority for treatments, high-quality cancer care at the right time was delivered to the majority of the cancer patients.[4,5]

This article highlights the measures taken to offer breast cancer patients optimum therapy based on the stage and prognosis of their disease.

Breast cancer is the most common malignancy among women worldwide.[6] With increasing awareness and improved diagnostic facilities, more women are being diagnosed at an early stage.[6,7] However, the main concern during the COVID-19 pandemic was that delay in accessing healthcare resulted in patients presenting in advanced stages, again.[8,9] The causes were multifactorial - fear of contracting COVID infection, lack of transport for people coming from remote towns, cancer centers being converted to COVID wards to manage the rising cases and limited knowledge among the oncologists regarding cancer management in COVID positive patients. It was a challenge for every individual starting from the patient to the health care workers. There was an urgent need to revise the existing oncology practices and protocols because it was soon evident that cancer does not wait for COVID to subside. It is a definite killer compared to COVID-19 infection.[9] Oncologists all across the globe came together to discuss and design methods by which they could ensure safe cancer treatments during this pandemic.

This article will briefly specify the safely incorporated changes during this pandemic to provide quality care and safe treatments for cancer patients.

Surgical Management of breast cancer
Overview

Surgery in breast cancer is the primary curative treatment for all stages (selected stage IV).[10]The goal of neoadjuvant therapy is to make inoperable locally advanced breast cancer patient operable.[10] It has a high impact on the patients' survival, hence deferring surgical management of breast cancer during the COVID-19 pandemic was not a feasible option. However, certain modifications and prioritization could be made based on the risk stratification of patients based on stage, histopathology, tumor grade, and prognostic marker study. The modifications mentioned below are compiled based on the Surgical Society of Oncology (SSO) and European society of medical oncology (ESMO) guidelines.[11,12]

1. Very high risk: Patients with progression on neoadjuvant chemotherapy, angiosarcoma of the breast and malignant phyllodes tumor should be operated upon immediately without any delay. Breast cancer during pregnancy is also very high risk and must be given priority for treatments.

2. High risk: Triple-negative and HER2/neu positive patients with stage II or III disease should begin neoadjuvant chemotherapy (NACT). Two cm, borderline T1/T2 tumors with triple-negative status can be considered for NACT after multi-specialty board discussion. These patients are high priority for surgery once the situation is considered safe. Post-NACT in these patients based on tumor response, surgery can be planned after waiting for 4-8 weeks. However, patients must be screened during the waiting time for progression and considered for surgery on a high priority basis. Excision or surgery of malignant recurrences also is considered a high priority for surgery.

3. Intermediate risk: Patients with Estrogen receptor (ER) positive stage III and IV tumors should be on neoadjuvant endocrine therapy or chemotherapy as per the hospital policy or after discussion in the multispecialty board. If patients have more than partial or complete clinical response, they can be started or continued on endocrine therapy for further 4-8 weeks till it is deemed safe for surgery. If the patient is ER-positive and HER2/neu positive, she can continue endocrine therapy and anti-HER2/neu therapy till surgery is considered.

4. Low risk: Patients with hormone receptor-positive ductal carcinoma in situ (DCIS) or atypia can be safely started on endocrine therapy for 3-5 months. They can be reassessed after 8-12 weeks for any new mass or blood-stained nipple discharge to detect progression. Patients with hormone receptor-negative DCIS or large volume DCIS can also be observed. However, they should be screened every four weeks to look for signs of progression. They should be considered for surgery as soon as it is considered safe by the health system or hospital. The screening can be done by tele-consultation. Estrogen receptor (ER) positive stage I and II breast cancers can undergo genomic testing if feasible or continue on endocrine therapy with screening every 4-6 weeks for 3-5 months. Excision of benign lesions and duct excision for conditions like fibroadenoma, papilloma and atypia are also considered low risk and can be postponed.

Patients after surgery should be preferably discharged the same day or after a 24-hour observation period. All postoperative consults should be via teleconsultation unless there is an acute surgical site complication or suture or drain removal. Regular surveillance should be done by telemedicine or delayed by 1-3 months if a screening mammogram is needed. All breast reconstructive procedures should be delayed for 3-6 months.

Systemic therapy considerations
Overview

Systemic therapy in breast cancer includes chemotherapy (injectable and oral), endocrine therapy and anti-HER2/neu therapy. Primary systemic therapy is used more frequently for locally advanced breast cancer (LABC) and early breast cancer to facilitate breast-conserving surgery.[13,14] During the COVID-19 pandemic, decision on primary systemic therapy or upfront surgery in early-stage breast cancers have to be decided by the health system or hospitals based on patient safety and convenience.

The concerns with chemotherapy during the pandemic are mainly due to immunosuppression which may enhance the risk of contracting COVID infection.[11] However, using three weekly regimens of chemotherapy and colony-stimulating factors to increase the white blood cell count, it is possible to deliver the intensity ofchemotherapy for advanced breast cancers.

Adjuvant systemic therapy is optimally delivered 2-4 weeks after surgery.[15] In selected cases, it can be delayed by 4-6 weeks too. However, a delay of 12 weeks and more is associated with inferior outcomes.[15]So whenever possible, adjuvant endocrine therapy should be initiated as early as possible in ER-positive cases, anti-HER2 therapy in HER2 neu positive and chemotherapy in triple-negative and high-risk subsets. Given below are the ESMO guidelines for systemic therapy based on stage and risk stratification.[11]

Early Breast Cancer

1. High priority: Adjuvant Chemotherapy in Triple-negative and HER2/neu positive subsets should be initiated as early as possible post-surgery. Adjuvant chemotherapy for high-risk ER-positive/HER2 negative cancers (four or more axillary nodes positive, more than 5 cm tumors) must also be considered.

2. Medium priority: Patients with low genomic scores should be given endocrine therapy preferably. Elderly patients with stage I, ER-positive and HER2/neu negative disease can be initiated on endocrine therapy alone, and surgery can be deferred or delayed. Adjuvant trastuzumab can be postponed for 6-8 weeks in patients with a high risk of contracting COVID infection.

3. Low priority: Follow up imaging, re-staging studies, ECG, echocardiograms post adjuvant systemic and anti-HER2/neu therapy, and bone mineral density studies can be postponed in the adjuvant setting.

Locally advanced breast cancer

1. High priority: NACT for Triple-negative and HER2/neu positive patients should be considered for tumor downstaging and feasibility of surgery. Patients with ER-positive/ HER2 negative tumors who have already been initiated on Chemotherapy should be continued till completion of planned chemotherapy. In the post neoadjuvant setting, the continuation of adjuvant capecitabine in high-risk triple-negative patients and continuation of the planned anti-HER2/neu therapy in HER2/neu positive patients should be considered.

2. Medium priority: Neoadjuvant endocrine therapy for locally advanced ER-positive/HER2/neu negative patients can be considered to reduce the risk of contracting COVID-19 infections.

3. Low priority: Reimaging studies, follow-up visits, ECG, Echocardiograms should be minimized and postponed wherever feasible. If needed, the blood tests and imaging studies can be scheduled near home. Patients who are continued on adjuvant endocrine therapy can be followed up through teleconsultation in cases of potential side effects.

Metastatic breast cancers

1. High priority: Early initiation of chemotherapy, endocrine therapy, and targeted therapies can improve outcomes in metastatic breast cancers. It is recommended to consider Chemotherapy with anti-HER2/neu therapy in metastatic HER2/neu positive breast cancers. The addition of CDK 4/6 inhibitors to endocrine therapy is also preferred in ER-positive/ HER2/neu negative tumors. Patients in visceral crisis must be considered for chemotherapy irrespective of prognostic marker status. Continuation of treatment of patients enrolled in clinical trials must be continued after multispecialty board discussions, especially if the treatment benefits can outweigh the risks associated with treatments.

2. Medium priority: Elderly patients with ER-positive/ HER2/neu positive metastatic breast cancer can be offered endocrine therapy alone without CDK 4/6 inhibitors in order to minimize the risk of neutropenia and immune suppression. The addition of mTOR or PI3KCA inhibitors can be delayed in elderly patients and patients with multiple co-morbidities. Second-line or third-line systemic therapies can be considered if there is clinical benefit and effect on survival outcomes.

3. Low priority: Bone therapy agents like bisphosphonates and denosumab can be delayed if patients cannot come to the hospital and when pain control is not a priority. Three monthly injections can be given whenever required. Similarly, long-acting luteinizing hormone releasing hormone(LHRH) analogues can be given to the patient every three months either in the hospital or by a nurse visiting the patient's home. Endocrine therapy does not need monitoring since it does not suppress the immune system. However, Fulvestrant needs monthly intramuscular injection and hence should be advised only if needed. Patients with triple-negative and HER2/neu positive disease should be considered for oral chemotherapy agents whenever there is no visceral crisis.

Metastatic breast cancer patients must be supported with the best possible home-based palliative care and symptomatic relief via teleconsultation. For well-palliated patients, the option of drug holidays, delayed or deescalated maintenance regimens should be considered after multispecialty board discussion.

Radiation therapy considerations
Overview

Radiation therapy is an essential component of breast cancer management in early breast cancers following breast conservation surgery and locally advanced breast cancer after mastectomy.[16,17] It not only reduces the risk of local recurrence but also impacts the overall survival and mortality of these patients.[16,17] Radiation therapy involves multiple sessions entailing frequent hospital visits.

Due to the COVID pandemic, it was difficult for patients to report to the hospital daily for radiotherapy sessions. The lockdown imposed during this time, made it difficult for people living in distant places to commute or get transport for visiting the hospital for treatments. This made it necessary for radiation oncologists to adopt hypo-fractionated short-course radiation therapy to treat breast cancers.

Hypo-fractionated radiation therapy of 40 Gy in 15 fractions is a well-established protocol for treating breast cancers.[16,17] During this pandemic, breast cancer radiation treatments were revised as per the age groups and risk features. Shorter courses of radiation treatments were opted for as per the recent trials. Given below are the changes in breast radiation treatments that were adopted during the COVID pandemic.[18-20]

1. For patients more than 65 years old or younger with co-morbidities, with a tumor size of 3 cm, grade 1-2 tumors, ER-positive, HER2/neu negative can be exempted from RT and be treated with endocrine therapy alone after surgery.

2. Use moderate hypo-fractionation of 40 Gy in 15 fractions over three weeks for all breast/chest wall and nodal RT.

3. Nodal RT can be omitted in postmenopausal women with T1 tumor, ER-positive, HER2/neu negative, grade 1-2 tumors following sentinel node biopsy with 1-2 macro-metastasis.

4. Boost to tumor bed following breast conservation surgery must be avoided in most patients 40 years or older to reduce the number of fractions of RT. If the boost is a must, it should be incorporated as a simultaneous boost to minimize the fractions as per the resources available.

5. As per the FAST and FAST Forward trials[18-20]data, five fractions of RT to the breast in node-negative patients must be adopted.

6. For palliative RT to metastatic sites, the fractionation should be minimum to achieve satisfactory palliation of symptoms.

The techniques used for the planning and delivery of radiation must be kept simple and less technical to facilitate quick planning and execution of treatment.

For few selected cases of early breast cancer who fulfil the criteria as per the current guidelines can be taken up for partial breast irradiation.

As per the ESMO guidelines, the risk stratification of patients requiring radiation therapy is as follows: [11]

1. High priority: Adjuvant postoperative radiation for high-risk breast cancer patients with features of inflammatory disease at diagnosis, high-grade tumors or node-positive disease, triple-negative or HER2/neu positive status, residual tumor post-surgery or following NACT must be considered. Palliation of spine or brain metastasis and bleeding or fungating tumors not responding to primary systemic therapy is also considered a priority.

2. Medium priority: Adjuvant postoperative radiotherapy for low or intermediate-risk patients (age less than 65, stage I/II, ER-positive status irrespective of nodal or margin status) can be considered using moderate hypo-fractionated regimens. Endocrine therapy can be started in the waiting period.

3. Low priority: Elderly patients with low-risk disease (70 years of age or more, stage I disease, ER-positive, HER2/neu negative status) can be initiated on endocrine therapy while safely postponing radiation therapy.

Since radiation is a daily treatment, patients and caregivers have to be educated about appropriate COVID behavior to be followed at all times. The radiation couch should be sanitized after every patient in order to minimize the risk of covid transmission.

Concluding remarks

The article summarizes the commonly followed protocols from the start of the COVID pandemic in March 2020 till date. With the advent of the vaccination drive across the globe and as we battle the second wave, it is believed that oncologists can successfully adapt to this pandemic situation and provide effective good quality cancer care, which has been going on successfully since the start of the pandemic.

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  • Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
    Editor-in-Chief - Dr. Padmaj Kulkarni
    Section Editor - Dr. Sneha Bothra
    Editorial Assistant - Devika Joshi