Background: Surgical removal of the tumour is the gold standard treatment for early stage invasive breast cancer. However, with a global ageing population, a larger number of diagnoses are occurring in women with comorbidities that render them unsuitable for surgery. Hence, it is of interest to explore alternative treatment strategies for this group of women. Summary: Our narrative review aims to explore two such techniques, cryoablation and external beam radiotherapy, providing a brief summary of the evidence behind each technique. Following this, we discuss which groups of patients would gain the most benefit from each technique. Factors favouring the use of radiotherapy include patients with larger tumours, more superficial tumours, and those with less well-demarcated tumours where there is uncertainty regarding tumour extent. Meanwhile, patients who may benefit more from cryoablation include those who desire a smaller number of treatment sessions, have concerns regarding cosmesis and skin pigmentation, or who have relative contraindications to radiotherapy such as scleroderma, systemic lupus erythematosus, reduced lung function, or cardiac comorbidities. Key Messages: Continued advancements in both cryoablation and radiotherapy technologies are taking place, in tandem with imaging technologies enabling greater certainty in tumour detection and delineation. These factors will help increase local control rates in this group of non-operable early stage breast cancer patients. Through this review, we hope to aid in the clinical decision-making process regarding the selection and referral of patients for each treatment.

Breast cancer is an increasingly common disease worldwide, making up nearly a quarter (24.5%) of all female cancers [1] with a lifetime risk of 1 in 8 among women in developed countries [2]. As the global population ages, a larger number of diagnoses will occur in women with comorbidities that render them unsuitable for surgery. Though surgical removal of the tumour remains the gold standard for early stage invasive breast cancer treatment, it is of interest to explore alternative means of treatment for the group of women who are at high operative risk. In this paper, we describe and compare 2 strategies, cryoablation and external beam radiotherapy, and analyse which group of patients may be more suited to receive either treatment. For our narrative review, we conducted a literature search of the electronic PubMed database. The search terms used included “cryoablation OR cryotherapy” AND “breast cancer OR breast adenocarcinoma,” as well as “radiotherapy OR radiation therapy” AND “breast cancer OR breast adenocarcinoma.” Studies with less than 5 years of follow-up (with the exception of interim analyses of phase 3 trials), and studies involving patients with metastatic breast cancer were excluded.

To date, the gold standard for treatment of early stage (T1–T2, up to 5 cm in size) node-negative breast cancer is surgical removal of the tumour, whether through wide excision with clear margins or mastectomy, together with sentinel lymph node biopsy [3]. For patients who undergo breast-conserving surgery, adjuvant radiotherapy is recommended in most cases; for patients aged 65 or older with hormone receptor-positive cancers compliant with endocrine therapy, radiotherapy may be omitted [4]. In patients with more aggressive subtypes such as triple-negative or HER2-positive tumours, neoadjuvant chemotherapy may be given [5]. For those not receiving neoadjuvant chemotherapy, chemotherapy following surgery may be recommended depending on factors such as HER2 expression or Oncotype Dx scores [6].

In patients being considered for surgical removal of their invasive breast tumours, preoperative risk stratification is essential. Various tools such as the American Society of Anaesthesiologists’ Physical Status Classification (ASA-PS), Physiological and Operative Severity Score for the enumeration of mortality and morbidity (POSSUM) score, and Revised Cardiac Risk Index (RCRI) [7], among others, are available to assess patients’ preoperative risk. In general, high-risk surgical patients are those with an individual mortality risk of greater than 5% [8]; these may include patients with a variety of comorbidities. For instance, cardiovascular conditions may include those such as unstable angina, congestive heart failure, previous stroke, or myocardial infarction within the last 3 months [9]. Patients with respiratory-related conditions such as chronic obstructive pulmonary disease or pulmonary fibrosis requiring oxygen supplementation may also be at higher perioperative risk [10]. Other conditions include history of poor wound healing due to poorly controlled diabetes or morbid obesity, resulting in a high anaesthetic risk. Frailty is a notable risk in an elderly population. Measurement scales of fraility include factors such as lean body mass, physical activity, and grip strength [11]; poorer scores are associated with greater post-operative complications and 30-day mortality [12]. In such situations, where the patient and surgeon deem the operative risk to be unacceptably high, alternative treatment strategies need to be considered. This paper discusses two such options, cryoablation and external beam radiotherapy.

External beam radiotherapy, utilising linear accelerator technology, has been commonly practised in the adjuvant and palliative settings for breast cancer. The cytotoxic effects of ionising radiation on rapidly dividing cancer cells result from the production of double-stranded breaks in DNA causing cell death, whether via apoptosis, necrosis, autophagy, replicative senescence, or mitotic catastrophe. Immunogenic effects may also contribute to the elimination of tumour cells both in the radiation field as well as distally [13]. Though recognised as standard treatment in the adjuvant or metastatic settings, the use of radiotherapy in the definitive treatment of breast cancer is less well described. Previous studies have used both conventionally fractionated and hypofractionated radiotherapy, and in more recent years, stereotactic ablative radiotherapy (SABR).

Classically, studies of radiotherapy for the radical treatment of breast cancer utilised multiple fractions over several weeks. For instance, Van Limbergen et al. [14] followed up on 221 patients with Tis-T3, N0-N1 breast cancer treated with definitive radiotherapy. The most common prescriptions were 40 Gy given over 4 weeks and 60–65 Gy given over 8–10 weeks to the whole breast, followed by a boost to the tumour site. The team reported a 75.4% local control rate after 15 years. Local failure risk increased by 8% per cm tumour diameter, and additional 10 Gy (T1 tumours) and 35 Gy (T2 tumours) doses of radiotherapy were needed to achieve local control similar to excision and radiotherapy. A larger study conducted by Arriagada et al. [15], involving 463 patients with breast cancer treated with radiotherapy alone, concluded that a dose increase of 15 Gy can result in a two-fold decrease in the relative risk of local recurrence. However, dose escalation beyond 75 Gy is limited by toxicity and poor cosmesis [16].

Recent advances in tumour delineation, such as via MRI planning and accurate radiotherapy delivery techniques, have led to an interest in accelerated partial breast irradiation after breast-conserving surgery for low-risk patients with early stage disease [17]; this allows the number of radiotherapy sessions to be significantly reduced while sparing a portion of the breast. Taking this one step further, SABR is also being explored for treatment of breast tumours. This technique is practiced commonly in the lung, prostate, and brain, allowing the definitive treatment of tumours without the need for surgery.

Several trials have investigated SABR for breast cancer; for instance, Bondiau et al. [18] conducted a phase I study using 5 dose levels for neoadjuvant breast cancer treatment. The pathological complete response rate was highest at 25.5 Gy/3#. Meanwhile, the Feasibility Study of Stereotactic Body Radiotherapy for Early Breast Cancer (ARTEMIS) study [19] aims to administer a dose of 40 Gy/5# every other day over 10–12 days, followed by lumpectomy. SABR-CaRe, a phase II randomised trial of preoperative SABR for early stage breast cancer, includes an arm with patients undergoing caloric restriction [20]. A good pathological response of tumours would support the option of definitive SABR for patients not able to undergo surgery. In addition, further advances in external beam radiotherapy techniques, such as proton therapy, may be successful in delivering higher doses with more tissue sparing. In a study investigating the dosimetric feasibility of early stage breast cancer treatment using both SABR and proton beam therapy by Lischalk et al. [21], overall target coverage of gross tumour and clinical target volumes was achieved while meeting dose constraints to vital structures such as the heart and lungs.

Cryoablation, a process where tumour cell kill is achieved via freezing, has also been explored for early stage breast cancer. It is a minimally invasive technique utilising one or more cryotherapy probes inserted under the skin under ultrasound or CT guidance, using local anaesthesia. Liquid nitrogen or pressurised argon gas is released, creating an ice ball that surrounds the tumour with a margin of at least 1 cm. During the subsequent freezing and thawing cycles, tumour cell death is achieved via ischaemia, cellular dehydration, coagulative necrosis, and apoptosis [22]. Separately, cryoablation can induce a systemic tumour-specific immunological response whereby cytokines released during cell death result in stimulation of cytotoxic lymphocytes, targeting microscopic metastases. In a murine model of breast cancer developed by Sabel et al. [23], cryoablation was shown to induce a tumour-specific T-cell response in surrounding lymph nodes as well as increased systemic NK cell activity. Low complication rates and overall favourable cosmetic outcomes have made cryoablation an attractive option for patients who are not candidates for surgical removal of their breast tumour [24].

Typical inclusion criteria for cryoablation include size of up to 2.0 cm, unifocality, ductal (rather than lobular) histology, absence of extensive intraductal component (EIC), and location greater or equal to 1 cm away from the skin surface [25]. Response to cryoablation can be determined either through subsequent surgical resection or imaging studies. An example of the former is found in the American College of Surgeons Oncology Group Phase II trial Z1072, where 86 evaluable patients with unifocal invasive ductal breast cancer smaller or equal to 2 cm underwent cryoablation. Surgical resection was performed within 28 days after cryoablation, and pathological examination showed successful ablation in 66 out of 87 lesions (75.9%). 100% of patients with tumours smaller than 1 cm in size had no residual invasive cancer on final pathology [26]. Likewise, an earlier study published in 2004 by Sabel et al. [21] showed the likelihood of success of cryoablation decreased with increasing tumour size. Among 27 patients undergoing cryoablation followed by surgical resection one to 4 weeks later, patients with breast tumours smaller than 1.0 cm had a 100% pathological response rate, but for the group of patients with tumours 1–1.5 cm, complete response was only achieved in those without a significant ductal carcinoma in situ (DCIS) component, and the authors concluded the technique was “not reliable” for patients with tumours >1.5 cm. Meanwhile, Machida et al.’s team [27] investigated serial imaging findings after cryoablation for early stage breast cancer, without surgery. Out of 54 patients, 7 showed suspicious areas on the first follow-up MRI, but these had resolved by the second follow-up MRI. 1 patient out of 54 experienced ipsilateral recurrence and underwent mastectomy.

Two phase 2 trials, ICE3 (NCT02200705) [28] and FROST (NCT01992250) [29], are in progress, aiming to evaluate response rates of cryoablation without surgery in patients with invasive breast cancer ≤1.5 cm. The FROST trial will evaluate residual viable invasive or in situ carcinoma via biopsy at 6 months post-procedure, while the primary outcome of ICE3 is ipsilateral breast tumour recurrence at 5 years. For the latter, a 3-year interim analysis was recently published in August 2021 [30]. At a mean follow-up duration of 34.83 months, the ipsilateral breast tumour recurrence rate was 4/194 (2.06%), with no severe adverse events and 95% of patients reporting satisfaction with their cosmesis.

Aside from cryoablation, several other ablative methods have been utilised for the treatment of non-operable early stage breast cancer [31]. For instance, radiofrequency ablation, high-intensity focused ultrasound, microwave ablation, and laser ablation all utilise heat-induced coagulation necrosis. Similar to cryoablation, most of these have been utilised for smaller tumours under 2 cm in size with minimal associated DCIS. Complications include pain, skin burns, and hyperpigmentation. Advantages of cryoablation compared to heat-based ablative techniques include better preservation of the tissue collagen matrix, resulting in better cosmesis; better tolerability due to the intrinsic anaesthetic effects of low temperatures [32]; and possible increased stimulation of the immune response [33].

Larger Tumours

Most trials utilising cryotherapy for early stage breast cancer have stipulated a maximum clinical tumour size of 2 cm as inclusion criteria. Some barriers to treating larger-sized tumours include technical limitations of ice ball formation with the cryoprobe, as well as uncertainty about the extent of EIC and ability to obtain adequate margins with larger tumours [34]. While Littrup’s team was able to treat tumours up to 5.8 cm with a multi-cryoprobe technique, the study team also recognised that accuracy of imaging using MRIs, as well as competent ultrasound-guided ablation were crucial to the success of the procedure; the 50% of patients with bulky tumours had additional CT guidance during the ablation procedure which may not be available in all centres [35]. Other available literature suggests that cryoablation is effective for tumours up to only 1.5 cm [36‒38]. Sabel et al.’s team showed a 100% pathological response rate at subsequent surgical resection for patients with tumours up to 1.0 cm but only a 71% response rate for tumours >1.5 cm. Taking these into consideration, the ICE3 [28] and FROST [29] trials take a conservative approach, including patients with tumours not larger than 1.5 cm.

In contrast, for tumours larger than 1.5 cm, radiotherapy can still be utilised effectively. In studies using conventional fractionation, the whole breast was included in the radiotherapy field, ensuring that the tumour received some dose coverage regardless of size or location within the breast. A boost dose was then added to the tumour itself, and this boost could be increased with increasing size of tumour, as long as doses to organs at risk were within constraints and side effects remained well tolerated for the patient. Van Limbergen’s team, investigating radical radiotherapy to the whole breast followed by tumour boost, was able to achieve control rates similar to surgery and adjuvant irradiation (95% at 5 years for T1 tumours and 90% at 5 years for T2 tumours) by utilising a correspondingly higher dose for T2 tumours [14]. Likewise, Arrigada et al. [39] showed that while larger tumour size was related to poorer local control, this could be compensated for by increasing tumour dose, and in fact, tumour dose was more significant than size in predicting local tumour control. More recently, larger breast tumours have been successfully treated by radiotherapy with the use of radiosensitization techniques. For instance, Shibamoto et al. [31] utilised two alternative radiosensitization techniques for tumours ≥2 cm in diameter: (1) hydrogen peroxide injections prior to whole breast radiotherapy, and (2) hyperthermia plus oral tegafur-gimeracil-oteracil potassium. Among a total of 45 patients, the majority of whom were stage I and II, good 5-year overall survival (97.3%) and local control rates (87.9%) were achieved. All in all, for larger tumours – greater than 1.5 cm, or T2 tumours, radiotherapy may be a more effective treatment compared to cryoablation due to the option of increasing prescribed radiotherapy dose with increasing tumour size, as well as the availability of radiosensitization methods.

Recent studies evaluating radiotherapy for the treatment of early stage breast cancer aim to give localised treatment with shorter fractionation schedules. Inclusion criteria are more generous in terms of size as compared to studies using cryoablation; for instance, the ABLATIVE study, evaluating single-dose radiotherapy for early stage breast cancer, has stipulated a maximum tumour size of 3.0 cm on diagnostic MRI. 20 Gy in a single fraction is prescribed, equivalent to 73.7 Gy equivalent dose in 2 Gy fractions [17]. Likewise, the SABR-care study [20], studying a 5-fraction, alternate-day, SABR procedure, includes breast tumours up to 3.0 cm on imaging. While results from these studies are still awaited, the technical feasibility of delivering stereotactic radiation to T2 breast tumours is certainly proven. Thus, for patients with tumours between 1.5 and 3.0 cm who are unsuitable for surgery, more options are available for enrolment on radiotherapy trials as compared to trials utilising cryoablation.

Superficial Tumours

Due to the ice-ball formation technique used in cryoablation and the requirement of ideally obtaining a margin of 1 cm around the tumour, patients with more superficial tumours are at higher risk of adverse hypothermia effects to the pectoralis muscle or skin, leading, in extreme cases, to necrosis [40]. As a result, most guidelines suggest that tumours should be located at least 1 cm below the skin surface [41, 42]. While teams such as Cazzato et al. [43] accepted patients with cancers located as close as 5 mm to the skin, saline solution was injected into subcutaneous tissue to create further separation between the ice ball and the skin. Toxicities included “haematoma coupled with skin retraction” as well as “skin burn.” Despite best efforts during the ultrasound-guided procedure to ensure the tumour is accurately treated, Pusceddu et al. [40] report that there is still “low capability of limiting the ablation area”; thus patients with more superficial tumours may not be good candidates for cryoablation due to higher risk of skin toxicity.

In contrast, more superficial breast tumours are more amenable to treatment with radiotherapy. While photons used in radiotherapy treatment are known to have a skin-sparing effect [44], lower-energy radiotherapy beams, for instance, 6 MV instead of 10 MV photons, can be utilised to obtain better dose coverage for superficial tumours [45, 46]. In some cases, an electron boost following photon radiotherapy can be given [47]. A bolus is often used to increase dose to the skin in patients undergoing post-mastectomy radiotherapy or with superficial chest wall lesions. However, with the availability of modern linacs using flattening filter-free photon beams, superficial dose can be further increased without the need for a bolus [48], thus minimising the risk of adverse skin side effects for patients with tumours in situ. Shibamoto et al. [49] delivered radical treatment utilising whole breast irradiation followed by IMRT boost to a patient with a tumour located just beneath the nipple; treatment was reported to be well tolerated. While the risk of acute dermatitis remains a possibility in radiotherapy, most cases can be managed with supportive treatment such as moisturisers [50]; on the other hand, the potential thermal injury and ulceration resulting from cryoablation-induced skin toxicity may require more intensive medical management and last for a longer duration [51].

Uncertainty regarding Extent of Tumour

Several factors, including multifocality, EIC, and invasive lobular histology, render it more difficult to determine the exact extent of the tumour. For patients with such tumours undergoing cryoablation, there is an increased risk of there being remnant disease outside of the ablation zone. For instance, in the Phase II ACOSOG Z1072 trial studying cryoablation of early stage breast tumours, successful ablation was achieved in 80 out of 87 patients (92.0%) when multifocality was not taken into consideration. However, 14 of these patients had residual foci of disease beyond the ablation zone, accounting for these patients, ablation success rate fell to 75.9%. The team concluded that multifocal disease may be a limiting factor in the effectiveness of cryoablation alone and suggested it should be combined with adjuvant radiation [26].

Meanwhile, Sabel et al. specified multifocal, non-calcified DCIS as “the most challenging issue” for ablative techniques. The authors recommended excluding patients with more than minimal calcifications, as the true size of DCIS is frequently underestimated by measuring the extent of microcalcifications on mammography alone. After patients in Sabel’s study underwent cryoablation and surgery, 4 out of 27 patients were found to have residual DCIS in the normal tissue around the cryoablation zone. When Sabel further stratified patients by histology, 3 patients with invasive lobular and 2 with colloid carcinoma underwent the cryoablation procedure; out of these 5, 3 had remnant invasive cancer, and initial ultrasound was shown to have significantly underestimated the final size of the tumour. Due to difficulty in measuring the true size of tumours on initial scans, patients with invasive lobular histology have typically not been candidates for ablation procedures [52].

On the other hand, radiotherapy can be used to treat breast tumours that are less “well-defined.” For instance, in a study [53] treating 38 patients radically with whole breast radiotherapy with stereotactic or IMRT boost, a local control rate of 92% was achieved at 3 years, with the caveat that chemotherapy and hormones were also allowed in the study. Patients with invasive lobular carcinoma, EIC, or multifocal tumours were not excluded and patients with lymph node metastases were also eligible. The Institut Gustave-Roussy study, treating breast cancer patients with radiotherapy alone, likewise did not specify limitations of histology or multifocality and even included patients with advanced, inflammatory tumours. While overall 5-year local control was poor at only 56%, patients with small tumours <4 cm, albeit unfit for surgery, had a much better 5-year local control rate of 85% [16]. One advantage of radiotherapy in treating more diffuse tumours is the presence of the dose gradient surrounding the target volume. This ensures the edges of the tumour will not experience a sharp dose fall off. Furthermore, the size of the clinical target volume and planning target volume can be expanded by the clinician during radiotherapy planning, if there is insufficient confidence regarding the tumour borders.

However, as the radiotherapy field moves towards using focal or SABR to treat early stage breast tumours in surgically ineligible patients, more caution needs to be taken, and different trials have varying inclusion criteria. For example, the prospective, single-arm ABLATIVE study, investigating single fraction MRI-guided radical radiotherapy treatment, excludes patients with EIC, pure lobular, and multifocal tumours [17]. However, the SIGNAL trial, investigating 21 Gy/1# versus 10 Gy/3# for early stage breast cancer followed by lumpectomy, has multifocality as an exclusion criteria, but lobular carcinoma are included and EIC is not mentioned [54].

At present, for surgically unfit patients with early stage breast tumours that fall into the “harder to demarcate” category – multifocal, invasive lobular tumours or those with EIC, we would recommend radiotherapy to the whole breast with a boost to the tumour using CT- or MRI-guided planning rather than partial breast or SABR, or cryoablation. However, this conclusion can be revisited in the future, assuming imaging techniques continue to improve, and it becomes easier to demarcate the extent of tumours with greater certainty.

Improved Cosmetic Outcomes

Side effects of cryoablation include skin or fat necrosis, infection, swelling, and pain; however, most resolve over the short term [40]. While few studies have specifically investigated cosmetic outcomes for patients receiving cryoablation for early stage breast cancer, results can be extrapolated from previous studies using the same technique to treat benign breast lesions; for instance, Kaufman et al. [55] treated 78 benign breast lesions with cryoablation, achieving patient satisfaction rates of 92% reporting “good to excellent”; no volumetric deficit was observed, and only a small scar was visible at the cryoprobe insertion area. Similarly, in a 3-year outcome report of the ICE3 trial, over 98% of treating physicians and over 95% of patients were satisfied with the cosmetic outcome [30].

On the other hand, radiotherapy sequelae such as hyperpigmentation and fibrosis tend to persist for the long term and can be permanent. Such effects can be worse for patients who receive higher doses of radiotherapy; for instance, Van Limbergen’s team reported a dose-response curve corresponding to increased radiation fibrosis with increased total dose from 40 Gy upwards, and for patients who received more than 80 Gy, only 15% had a good cosmetic outcome [56]. Likewise, Calle et al.’s [57] team delivered doses up to 85 Gy with only 38% patients reporting good cosmesis at 5 years. More recently, SBRT techniques have resulted in more sparing of normal tissue. However, with larger fraction sizes, risk of late-normal tissue toxicity increases. For instance, in the FAST-forward trial, the 27 Gy in 5 fractions arm showed increased toxicity compared to the slightly lower 26 Gy dose [58]; this study was done on patients receiving adjuvant radiotherapy after tumour excision; for non-operable patients with tumours in situ, a higher dose would be required for local control, leading to potentially worse cosmetic outcomes. In Shibamoto’s study of patients receiving radical whole breast radiotherapy with SBRT or IMRT boost, asymmetry of the breasts was reported as an adverse outcome [53]. Finally, should patients be eligible for and require surgery in the future, breast irradiation may lead to poorer post-operative outcomes such as delayed wound healing [59].

Reduced Number of Treatments

While external beam radiotherapy is non-invasive, it requires multiple visits by the patient; a simulation scan needs to be done, followed by the radiotherapy treatment sessions themselves. Using conventional fractionation to deliver a radical dose would necessitate around 5 or more weeks of daily treatment. With accelerated partial breast irradiation or SBRT, number of treatment fractions can be reduced, and treatment may be completed within a single week [60]. However, radiotherapy would still require more visits than cryoablation, which can typically be done within a single session as an outpatient procedure. After the simulation scan is performed, radiotherapy planning is done over several days, following which quality checks are done. In some cases, changes that occur in between simulation and the start of treatment, or during the course of radiotherapy treatment, may necessitate a repeat simulation and replanning process, such issues include weight loss, development of seromas, or difficulty reproducing the treatment position due to injury [61]. Thus, for patients who prefer to complete their treatment over a shorter period of time and avoid the more lengthy process of radiotherapy simulation, planning, and multiple visits for treatment, cryoablation may be the preferred option.

Patients with Relative Contraindications to Radiotherapy

A group of patients who may benefit more from cryoablation may be those with relative contraindications to radiotherapy, for example, patients with systemic lupus erythematosus. In a study conducted by the Mayo Clinic, 21% of systemic lupus erythematosus patients had acute radiotherapy-related toxicity of grade 3 or worse, while 40% had chronic toxicity of grade 3 or worse [62]. Meanwhile, case series of patients with scleroderma indicate greater risk of fibrosis of the breast that received radiotherapy [63]. In a study on scleroderma patients receiving breast RT in Johns Hopkins and Pittsburgh [64], between 48.4 and 54.6% of patients had skin thickening in the radiotherapy field, but no evidence of lung toxicity or disease flare was observed.

Other relative contraindications to radiotherapy include cardiac or pulmonary comorbidities. For instance, Van der Bogaardt et al. [65] found a 16.5% increase in coronary events for each Gy of mean heart dose, in patients treated with 3D conformal radiotherapy for breast cancer. Similarly, McGale et al. [66] reported a higher frequency of cardiac events – for example angina, pericarditis, myocardial infarction – in patients receiving radiotherapy to the left breast, in particular, patients with pre-existing cardiac comorbidities. This cardiac risk from radiotherapy, however, is mitigated somewhat if smaller volumes can be targeted (e.g., via SABR or partial breast irradiation).

Meanwhile, radiation pneumonitis may develop in 1–10% of patients receiving breast radiotherapy, most commonly occurring 3–6 months post-radiotherapy [67]. Menhati et al.’s [68] team found a drop in FEV1 at 3 and 6 months post-radiotherapy; though this did not manifest in significant increases in clinical symptoms, authors concluded that performing baseline pulmonary function tests could help identify patients at higher risk of pulmonary toxicity. Overall, studies show the risk of radiation pneumonitis and radiation-induced cardiac events increase in a dose-dependent fashion [69, 70]. For this cohort of non-operable patients, the dose required for radical treatment of breast cancer is correspondingly higher than that required in the post-operative setting; hence, for the portion of patients who are unfit for surgery due specifically to existing cardiac or pulmonary comorbidities, opting for cryoablation over radiotherapy may well be the safer option.

Finally, other circumstances whereby patients would be advised to choose cryoablation over radiotherapy would include patients who had received prior thoracic radiotherapy to the same area [71] or patients with DNA repair deficiencies, such as TP53 mutations, which increase the risk of secondary cancers following radiotherapy [72].

Ultimately, both radiotherapy and cryoablation have limitations for treatment of non-operable breast cancer, and not all patients are suitable for these techniques. For those lacking accurate imaging techniques, e.g., high-quality diagnostic mammography or MRI scans, biopsy site markers, or CT guidance during the procedure, success of cryoablation may be reduced [35]. For patients without access to radiosensitization techniques, tumours exceeding 3 cm may prove challenging to control with radiotherapy, without compromising cosmesis or acceptable tissue toxicity. For patients undergoing either treatment strategy, regular follow-up with clinical examination, annual mammograms, and/or breast MRIs is advisable. In addition, the treating physician should closely monitor for the potential development of nodal or distant metastases [73].

For the cohort of non-operable patients with early stage breast cancer, both cryoablation and external beam radiotherapy are valid options to consider. For patients with larger, less well-demarcated tumours, e.g., those with invasive lobular histology or a significant DCIS component, radiotherapy may provide better local control. On the other hand, for patients with cardiac or pulmonary comorbidities who are at risk of adverse effects from high-dose radiotherapy or for those who desire a smaller number of treatment sessions, cryoablation may be the preferred option instead. Cryoablation may provide a favourable cosmetic outcome with the option to repeat the procedure in the future, while external beam radiotherapy is a non-invasive procedure with the possibility of dose escalation, especially for larger tumours. Newer technologies, such as SABR or proton therapy, may enable greater sparing of normal tissues as well.

Continued advancements in both cryoablation and radiotherapy technologies are taking place, in tandem with imaging technologies enabling greater certainty in tumour detection and delineation; all in all, these may well help to increase local control rates in this group of non-operable patients unfit for definitive surgical excision of their breast cancer.

The authors have no conflicts of interest to declare.

No funding was received for this review.

All authors have made substantial contributions to the conception and writing of this manuscript.

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