Unprecedented times call for novel solutions. The COVID-19 pandemic has placed tremendous burden on healthcare personnel, equipment, and supplies. Social distancing and other efforts to control spread of COVID-19 have led directly to the introduction of “pragmatic” policies that have temporarily but dramatically altered all healthcare in United States and the rest of the world. With regards to breast cancer, many prominent organizations such as The American Society of Breast Surgeons (ASBrS), the American College of Radiology (ACR), and the American Cancer Society (ACS) have recommended immediate postponement of routine mammography, ultrasound, and breast MRI in asymptomatic women for 6–12 months or until after the pandemic is over [1, 2]. It is well known that breast cancer screening is one of most important factors contributing to modern improvements in breast cancer survival. While allowance is made for the ongoing evaluation of patients with symptomatic breast problems, the recent closure or curtailment of work-hours of many breast imaging centers has made it increasingly challenging for women to complete assessments of existing breast problems.
A key driver of the moratorium on routine breast cancer screening is the widely applied hospital policy to postpone elective surgical procedures to preserve limited hospital resources and to minimize viral exposure during the pandemic. This policy has been endorsed by the American College of Surgeons (ACOS) and by an expert opinion Special Communication of the ASBrS, National Accreditation Program for Breast Centers, National Comprehensive Cancer Network, Commission on Cancer, and ACR which recommend at least a 1.5–4 month delay of surgery for most conditions that are not immediately life-threatening (designated Surgical Priority B and C), which include nearly every breast diagnosis, including cancer [1, 3]. In “Recommendations for Prioritization, Treatment and Triage of Breast Cancer Patients During the COVID-19 Pandemic,” the authors advocate expedited breast surgery only for breast conditions that are immediately life-threatening: abscesses and bleeding complications requiring surgical management (Surgical Priority A), prevention or management of wounds with compromised blood supply (Surgical Priority B1), and surgical management of women completing pre-operative chemotherapy for high-risk breast cancer (triple-negative or HER2/neu-positive breast cancer or breast cancers that show continued growth despite pre-operative systemic therapy) (Surgical Priority B1).
In lieu of surgery, the ACOS and the Special Communication recommend pre-operative endocrine therapy 6–12 months for most women with estrogen-sensitive breast cancer as a way of reducing cancer extent or preventing tumor growth (Surgical Priority B3, C1). For example, for women with stage I, node-negative, estrogen-sensitive, HER2/neu-negative breast cancer, the Special Communication recommends endocrine therapy while withholding surgery until after the pandemic has ended (Surgical Priority C1), which directly impacts 70% of women diagnosed with breast cancer in the modern era. This decision is further complicated by compliance concerns due to the side effects many woman experience with endocrine therapy. Women requiring or considering mastectomy are advised to forego breast reconstruction altogether or limit breast reconstruction options to implant-based reconstructions instead of tissue flap reconstruction (Surgical Priority C2) to avoid extended hospitalizations.
Although short surgical delays are unlikely to diminish patient breast cancer survival, an unfortunate consequence of these policies is the tremendous amount of anxiety that follows a patient’s consent to postpone surgery for several months. Anxiety may be created by the possibility of delay resulting in tumor growth or spread and may also be heightened by uncertainty about how long the pandemic will last. Will the pandemic be followed by another surge of viral infections that might further delay the scheduling of elective surgery nationally, regionally, or locally? When the pandemic ends, will the national backlog of elective surgical procedures impede the scheduling of breast cancer operations, and what will determine the order of patients in the queue awaiting surgery—date of diagnosis, tumor stage or biology, patient age, level of insurance, etc.? Will hospitals that have been financially strapped by the lack of elective surgery remain operational and sufficiently staffed to handle the backlog of elective cases? Assuming regional variations in access to surgery, will patients have the freedom of movement, financial means, and insurance coverage to travel from one location to another for breast cancer procedures that might not be available in their home community?
What distinguishes this pragmatic policy from the traditional use of pre-operative endocrine therapy is that neoadjuvant endocrine therapy is most often administered for a period of 6–9 months to increase the odds of lumpectomy in a patient who would otherwise require mastectomy due to large tumor size. Hence, the benefit of improved surgical outcomes helps to ease the anxiety of leaving the tumor in place for an extra 6–9 months. However, from an oncological and philosophical perspective, it’s difficult to rationalize delaying definitive treatment in patients with early stage breast cancer when the potential for surgical benefit is marginal. For example, a woman who is already a candidate for lumpectomy is unlikely to receive sufficient tumor response to neoadjuvant endocrine therapy to eliminate the need for surgery and will still ultimately require lumpectomy. Furthermore, there are insufficient data supporting the efficacy and safety of pre-operative endocrine therapy in pre-menopausal women .
Completely missing from the official discourse about the pragmatic management of breast cancer is percutaneous breast tumor ablation, specifically cryoablation or tumor freezing. Although cryoablation has yet to be established as a standard-of-care procedure for the management of breast cancer, unconventional times call for unconventional measures, just like the current moratoria on breast cancer screening and elective breast surgery that the co-authors of the Special Communication acknowledge are based on expert opinion and only limited prospective experience. By these standards, cryoablation warrants special consideration as a pragmatic, non-operative, resource-saving strategy for managing breast cancer.
Cryoablation has emerged as a minimally-invasive alternative to breast cancer surgery that reduces morbidity along with the psychosocial and cosmetic impact of breast cancer therapy. As an outpatient, office-based procedure performed under local anesthesia, cryoablation also reduces burden on the healthcare system by eliminating the need for an operating theater, an anesthesiologist and surgical team and decreasing the number of requisite personal protective devices (e.g., masks, face shields, and surgical gowns)—all important considerations in a pandemic where such resources are at a premium. Using a needle-like, handheld cryoprobe and liquid-nitrogen, tumors are typically ablated in two freeze–thaw cycles achieving a core temperature of – 180 °C. Breast masses ≦ 2 cm can be cryoablated in as little as 30–45 min compared to 2–3 h for lumpectomy or mastectomy. Patients are spared the cost, discomfort, and potential complications of general anesthesia and surgical resection. Skin injury is prevented by repeated injection of saline under the dermis to maintain separation between the skin and the underlying frozen mass. Short and long-term cosmesis and patient satisfaction would likely be superior since the incision is small (~ 3 mm) and there is no need for removal of breast tissue. The procedure is essentially painless due to the analgesic effect of the tumor freezing process, and post-procedure narcotic requirements are nearly nil. Most patients are able to return to non-strenuous activities the very next day.
Although surgical resection offers the advantage of complete tumor removal and margin assessment, apart from excess resource utilization, a major drawback of surgical resection is the cosmetic and functional impairment of the breast resulting from volume changes, scar formation, nipple displacement, sensation changes, and skin/scar retraction. Since cosmesis is a primary goal of breast conservation, and the major determinant of cosmesis is resection volume, cryoablation has the potential to expand the options for breast conservation by avoiding tumor resection altogether thereby reducing the need for more resource-intensive procedures like mastectomy, breast reconstruction, oncoplastic surgery, and contralateral breast symmetry procedures. Thus, cryoablation with a 1–2 cm ablation margin around the cancer might be the optimal compromise that balances the goals of early detection and treatment of breast cancer with the desire for a less invasive, less morbid, less resource-intensive approach to managing breast cancer. Unlike the average hospital outpatient surgical procedure which typically involves 15–20 patient-hospital personnel interactions, cryoablation achieves social distancing by limiting patient to 2–3 healthcare personnel interactions for the typical office-based procedure.
Breast cancer cryoablation builds on the significant body of preliminary data and historical experience in the use of cryoablation for the treatment of benign and malignant breast tumors, including multiple patient series that identified tumor characteristics most conducive to successful ablation . The largest published series was the American College of Surgeons Oncology Group (ACOSOG) Z1072 trial, a multicenter phase II study which sought to determine the rate of successful ablation in 99 women with early stage breast cancer managed initially with percutaneous cryoablation followed four weeks later by lumpectomy or mastectomy . ACOSOG Z1072 was limited to subjects with invasive ductal carcinomas measuring ≦ 2 cm and no extensive intraductal component, of which complete tumor resection was documented in 100% of tumors < 1 cm and 92% of lesions ≦ 2 cm when accounting for tumor multifocality. The findings of ACOSOG Z1072 influenced the design of the FROST Trial (currently enrolling, www.clinicaltrial.gov, #NCT011992250) and the Ice3 Trial (active, non-enrolling, www.clinicaltrial.gov, #NCT02200705), two U.S. non-randomized trials examining the outcome of a similar cohort of women treated with cryoablation without subsequent surgical removal. Interim results of both trials presented at the 2019 annual meeting of the ASBrS demonstrated 1.1% and 1.4% local recurrence rates with 1 year short-term follow-up. In Japan, a clinical trial at Kameda Medical Center (Kamogawa, Chiba, Japan) undertook a prospective investigation of cryoablation in a cohort of women with clinically node-negative, luminal A invasive ductal carcinomas measuring ≦ 1.5 cm managed with cryoablation, sentinel node biopsy, endocrine therapy, and whole breast radiotherapy without subsequent surgical removal. Although results of this ongoing study have yet to be published in manuscript form, an oral presentation at the 2019 ASBrS meeting reported a 0.98% local recurrence rate among 304 subjects of mean age 57 (31–83 years) with median follow-up of 6 years, which provides confidence in the ability of cryoablation combined with adjuvant therapy to maintain long-term local control in a well-selected patient population. As with breast conserving surgery, there remains a potential for local recurrence within or adjacent to the cryoablation site. The fact that unrecognized, clinically occult, microscopic disease might exist in the perimeter of the cryoablated tumor is why radiotherapy and/or adjuvant systemic therapy remain important in the multidisciplinary management of most patients treated with cryoablation. The same is also true for most patients treated with lumpectomy.
Besides cryoablation, several other methods of percutaneous ablation are currently under investigation, including MRI-guided radiofrequency ablation; ultrasound or MRI-guided high-intensity focused ultrasound; stereotactic, MRI, or ultrasound-guided LASER thermotherapy; and ultrasound-guided microwave ablation . However, data supporting alternate percutaneous ablation techniques are largely limited to small feasibility studies involving ablation followed by lumpectomy or mastectomy, without longer term follow-up of unresected tumors. Other limitations include the necessity to perform these procedures in the radiology department as well as the requirement for anesthesiology support for intravenous sedation which is generally required for pain control during these heat-generating ablation procedures.
In the context of percutaneous management of breast cancer, opportunities also exist for the non-operative management of the axilla. Since 2016, The Society of Surgical Oncology’s “Choosing Wisely” Campaign, an initiative of the American Board of Internal Medicine, has encouraged surgeons to avoid “routine sentinel node biopsy in clinically node-negative women ≥ 70 years of age with hormone receptor-positive, HER2/neu-negative invasive breast cancer .” This pragmatic recommendation is validated by the low estimated risk of axillary metastasis in this cohort as well as the low rate of axillary recurrence when axillary surgery is omitted among these patients. Whereas selective use of sentinel node biopsy is now widely accepted in women ≥ 70, withholding sentinel node biopsy is more controversial in younger women for whom the status of the axilla has remained a core factor in assessing the need for chemotherapy. However, the primacy of the axillary nodal stage as a prognostic and predictive factor has been gradually eroded by growing confidence in the prognostic and predictive ability of tumor genomic assays as a tool for assessing the benefit of chemotherapy, regardless of patient age or tumor size. For example, tumor gene expression profiling is now capable of identifying genomically low-risk patients that benefit little from chemotherapy despite the presence of high-risk clinical features, including positive axillary nodes, further reducing the need for surgical axillary staging and the use of related healthcare resources.
Since cryoablation intentionally eradicates tumor histology, it is critical to confirm that the diagnostic needle biopsy provided sufficient tissue samples for histological and genomic assays. Otherwise, additional tumor biopsies should be obtained immediately preceding cryoablation to provide tissue for determination of tumor prognosis and selection of adjuvant therapy.