DOI: 10.31038/IMCI.2019214

Abstract

Introduction: Electrochemotherapy (ECT) is a locally enhanced chemotherapy that combines the administration of chemotherapeutic drugs with well-dosed electric pulses for cell membrane Electroporation (EP). As opposed to thermal ablation, cell death with ECT is primarily induced using electrical energy: electrical pulses disrupt the cellular membrane integrity, resulting in cell death while sparing the extracellular matrix of sensitive structures such as the bile ducts, blood vessels, and bowel wall. This article reports the successful non-thermal ablation treatment of a hepatic recurrence of lung cancer as an individual treatment in order to achieve loco-regional tumor control.

Case Presentation: 50-year-old Caucasian woman was referred for interventional treatment of the largest of the hepatic metastases of lung cancer (6.0 × 4.8 cm), located in the left hepatic lobe and close to the left suprahepatic vein. Due to the size and the immediate proximity to the left suprahepatic vein the patient could neither undergo ablation treatments (RFA or MWA) neither TACE because of tumor size and the high risk of thermal sinks (“heat-sink effect”) potentially resulting in reduction of complete treatment of the target lesion. Due to its ablation mechanism, electrochemotherapy with use of bleomicin was deemed to be the best therapy option for the patient as loco-regional disease control.

Conclusions: Due to its more selective and non-thermal ablation effect , percutaneous ECT is a novel, potentially very effective treatment option in minimally invasive oncologic treatments, especially for hepatic metastases. We showed in this case report that a large hepatic metastatic lesion adjacent to the left suprahepatic vein can be widely ablated by ECT with ablation of a large infiltrating tissue volume.

Keywords

Electrochemotherapy, Reversible Electroporation, Hepatic Metastases.

Introduction

Electrochemotherapy (ECT) is a locally enhanced chemotherapy that combines the administration of chemotherapeutic drugs with well-dosed electric pulses for cell membrane electroporation (EP) [1].

Tissue electroporation is a novel approach to introduce molecules and genes into the cells of specific areas of the body. It employs the ability of certain electrical fields to reversibly permeabilize the cell membrane in a process known as reversible electroporation [2].

The exposure of biological membranes to a sufficiently high external electric field can lead to a rapid and large increase in electric conductivity and permeability, called membrane EP. While applying an electric field on cell membranes, their surface tension will be destabilized and nonpermanent molecules can diffuse into the cytosol. According to the theory of aqueous pore formation, pores are able to form spontaneously, when the bilayer is exposed to an electrical field (>50 V) [2,3].

Mass transfer can now occur through these channels (pores), which in reversible electroporation persist for a period of a few seconds. Typically, in reversible electroporation, the permeabilization pulses are delivered on a time scale of microseconds, and the pores reseal on a time scale of seconds. Macromolecules in the extracellular space can enter the cells by diffusion during the time the pores are open [4].

When electric pulses are applied to cells, 2 different phenomena are observed: reversible EP and irreversible electroporation (IRE), both used in clinical practice. Reversible EP will increase cell membrane permeability and open an access route for molecules that are too big to cross the cell membrane (DNA, RNA) or facilitates cell enter by hydrophilic molecules (bleomycin [BLM], cisplatin) [5–7]. These molecules once crossed the cell membrane exert their effect in the resealing and intact cells. In contrast, IRE (>600 V/cm) is used as non-thermal form of soft tissue ablation in clinical routine [8]. The IRE of cell membranes leads to a disturbance of the cell homeostasis and thus ultimately to apoptosis in the treated tissue [9–11].

Electrochemotherapy is a promising method to locally treat tumors regardless of its histological type with minimal adverse side effects and a high response rate [12,13].

The efficacy of ECT treatment is well demonstrated for cutaneous and subcutaneous melanomas, and the technique can be applied in a variety of malignant lesions [14,15]. The range of applications can be divided into 3 groups: (1) treatment of cutaneous and subcutaneous metastases located in head or neck, melanoma, non-melanoma skin cancer, or breast cancer metastases to the skin [14, 16–19]; (2) treatment of non-cutaneous metastases located in bone, liver, or Soft Tissue Sarcoma (STS) [20–22]; and (3) clinical trials for the treatment of primary tumors, such as ovary or colon cancer [23,24].

Its applications were described by Neumann et al nearly 3 decades ago when electrical fields were used to temporarily create pores in cell membrane to facilitate gene transfer into mouse lyoma cells [25]. The use of electroporation to increase the permeability of the cell membrane in tissue was introduced by Okino and Mohri in 1987 [26] and by Mir et al in 1991 [27], who described that combining an impermeant anticancer drug with reversibly permeabilizing electrical pulses greatly enhanced the effectiveness of the treatment compared with either therapy alone.

The liver is an organ of particular current research interests in ECT. Besides established ablation modalities like microwave ablation [28] or RFA [29] and IRE [30] there is need for a controlled non-thermal ablation modality that enhances the efficacy of chemotherapeutic agents. The benefit of non-thermal ablation, like IRE, is the ability to treat lesions without thermonecrosis. This enables the ability to ablate near-sensitive structures like vessels and nerves, as no heat will be produced which spread around the treated area. An already established loco-regional method is TACE. During TACE, embolizing agents and chemotherapeutics will be administrated via catheter to obtain tissue-specific necrosis. As both therapy concepts are based on loco-regional application of cytostatic in hepatocellular parenchyma, a similar response rate of ECT by liver lesions can be possible. Similar to TACE, ECT allows for a controlled loco-regional additional chemotherapy without marked systemic side effects. As the chemotherapeutics applied during ECT are membrane impermeant, even better results might be possible [1].

First trials of ECT by hepatic tumors were conducted in animal models. Electrochemotherapy was shown to be effective to reduce the volume of hepatic metastases of colorectal cancer in the rats [31].

Electrochemotherapy of solid organs has been evaluated in phase I and II trials in humans [21, 32]. A significant reduction of viable tumor tissue in ECT-treated metastases was observed. Infarct-like necrosis occurred presumably caused by the cytotoxic and vascular-disrupting effect on tumor cells and small tumor blood vessels [32,33].

Histopathological analysis of colorectal liver metastases after ECT treatment revealed necrotic and fibrotic changes of tumor and normal tissue in the treated area, whereas 3 months later, regeneration was observable. The analysis also revealed that after ECT treatment, most vessels (>5 mm) and biliary structures were preserved [34].

In a small clinical trial, patients received an open approach of ECT for the treatment of unresectable colorectal liver metastases. The obtained response rates 4 weeks after ECT were 55% as complete response and 45% stable disease [35].

A recent study by Gasljevic et al. [34] Demonstrated regressive changes in the whole ECT-treated area of the liver. It confirmed that ECT could be proposed for the therapy of metastases near major blood vessels in the liver to provide a safe approach with good antitumor efficacy.

The successful establishment of ECT as hepatic lesion treatment can offer an additional minimally invasive treatment in the case of malignant lesions with decreased systemic side effects.

This article reports the successful non-thermal ablation treatment of a hepatic recurrence of lung cancer as an individual treatment in order to achieve loco-regional tumor control.

Case Presentation

 A 50-year-old Caucasian woman was referred for treatment of one of the liver metastases of lung cancer. After initial diagnosis of lung cancer with multiple bone metastases and a single hepatic lesion in 2013, a systemic chemiotherapy was performed with subsequent radiotherapy with the initial result of partial tumor remission. The hepatic lesion was treated with microwave ablation and was obtained a great loco-regional tumor control.

Under systemic chemotherapy (denosumab and navelbine), after a partial remission and subsequent disease stability, in 2018 a systemic progression was observed with appearance of peritoneal carcinomatosis, multiple lymphadenopathy, brain metastases and numerical and dimensional increase of bone and hepatic metastases.

The largest of the hepatic lesions was located in the left hepatic lobe and close to the left suprahepatic vein. The tumor size was 6.0 × 4.8 cm in axial section at the abdominal CT scan (Figure 1).

Figure 1. Contrast-enhanced axial CT scan demonstrating the large hepatic metastases (6.0 × 4.8 cm ) located in the left hepatic lobe and close to the left suprahepatic vein prior to ECT procedure. CT indicates computed tomography; ECT indicates electrochemotherapy.

The patient’s case was discussed at the multidisciplinary tumor board for therapy options: due to the size and the immediate proximity to the left suprahepatic vein the patient could neither second ablation treatments (RFA or MWA) nor TACE because of tumor size and the high risk of thermal sinks (“heat-sink effect”) potentially resulting in reduction of complete treatment of the target lesion. Electrochemotherapy with use of bleomicin was deemed to be the best therapy option for the patient as loco-regional disease control.

The concept of ECT is based on the aforementioned properties of reversible EP combined with therapeutic efficacy of chemotherapeutic agents. Due to the increased permeability of the cell membrane, chemotherapeutic agents can pass into cells and induce cell death mitosis in the targeted tissue. Electrodes located around or inside the tumor will deliver defined electric pulses which enables diffusion of otherwise membrane nonpermeant anticancer drug into the target cells [1]. This – in contrast to thermal ablation techniques like Radiofrequency Ablation (RFA) or Microwave Ablation (MWA) – potentially allows tumor cell ablation without concomitant destruction of connective tissue, blood vessels and nerves.

Due to this potentially selective cell ablation technique, ECT was offered as a therapy option because it provided the opportunity of tumor mass reduction and decrease of tumor burden with reduced risk of impairment of surrounding blood vessels. The procedure with risks and benefits was discussed with the patient and informed consent was obtained.

 The patient was put under general anesthesia and neuromuscular blocking to prevent arrhythmia. The procedure was performed using a commercially available RE system. Due to the large tumor volume a total of five needles were placed into the target area (Figure 2). The percutaneous placement of the electrodes was guided by ultrasound using a multifrequency probe (1 to 5MHz). As recommended by the manufacturer and recorded by the RE generator the following parameters were used: number of electrodes: five; type of electrodes: monopolar; distance of electrodes: 0.5m (minimum), 1.5cm (maximum); impulses per electrode: 80; voltage: 500V (minimum), 3000V (maximum); maximum deliverable current: 50A. An intravenous administration of an anticancer drug (BLM) was done so it could evenly distribute over the vascular system and extracellular space of the tissue. After that, electrodes located around or inside generated the electric pulses for a time of 8 minutes with consequent diffusion of otherwise membrane nonpermeant anticancer drug into the target cells. After a short time, a few seconds to several minutes after exposure to the electric field, the membrane permeability would return to its initial state and the specific chemotherapeutics would cause multiple DNA breaks (BLM) in the abnormal tumor cells. A stepwise ablation procedure with replacement of two electrodes at the level of the caudal portion of the lesion was performed.

Figure 2. Percutaneous placement of five electrode needles for hepatic lesion treatment.

During the electrochemotherapy the patient did not have any cardiovascular events, in particular no supraventricular tachycardia and no atrial fibrillation. Complications, especially post-interventional bleeding, were not observed.

Follow-up imaging, after one week, showed good response to the treatment of the hepatic lesion in absence of remaining viable tumor tissue. Contrast-enhanced CT scan at 3 and 6 months after electrochemotherapy procedure showed a complete necrosis of the tumor and reduction of tumor volume (Figure 3).

Figure 3. Follow-up imaging post-ECT procedure: contrast-enhanced axial CT scan (a) at one week demonstrating no residual or recurrent tumor; (b) at 3 and (c) 6 months showing a complete necrosis of the tumor and reduction of tumor volume. CT indicates computed tomography; ECT indicates electro chemotherapy.

Discussion

The majority of patients who are diagnosed with liver malignancies are not eligible for resection or transplantation due to inadequate functional liver function, multifocal or advanced disease, prohibitive tumor location or the presence of medical co-morbidities. In some highly selective scenarios resection appears to remain superior in terms of disease recurrence rates and overall and disease-free survival. For curative intentions in term of local tumor control there are reports of equivalent results following local-regional ablation treatments when compared to resection in selected patients [36–38].

Image-guided tumor ablation techniques have significantly broadened the treatment possibilities for primary and secondary hepatic malignancies. A tumor resection leads to immediate absence of tumor tissue, in contrast (thermo)ablative procedures will induce necrotic damages whereas chemoablative procedures induce cell apoptosis [1].

 Monopolar RFA is an established technique for the treatment of tumors that are limited in number (3 or less) and size (3 cm or less) and are located 1 cm or more from critical structures and vessels. MWA appears to have the potential to improve the rate of complete ablation achieved with RFA in tumors that are larger than 3 cm or when multiple and seems to have the potential to overcome the limitations of RFA in the treatment of tumors in perivascular locations [39].

 A new ablation technique, Reversible Electroporation (RE) with use of chemiotherapy (as BLM), is recently added to the treatment armamentarium. As opposed to thermal ablation, cell death with ECT is primarily induced using electrical energy: electrical pulses disrupt the cellular membrane integrity, resulting in cell death while sparing the extracellular matrix of sensitive structures such as the bile ducts, blood vessels, and bowel wall. The preservation of these structures makes electrochemotherapy attractive for liver metastases that are unsuitable for resection and thermal ablation owing to their anatomical location. In contrast to chemoembolization techniques, ECT relies on membrane non-permeant chemotherapeutics, which need EP for cell uptake. Improvements need to be done to achieve homogeneous EP in the treated area, as well as steady concentrations of cytostatic drug in big lesions [1].

The establishment and expansion of ECT in deep-seated tumors (eg, liver, bone metastases) will open up new opportunities for minimally invasive treatment of metastases and carcinomas. Even if only few experiences have been published for colorectal liver metastases treated by ECT, considering the proven safety and the promising results, this treatment option deserves further attention. ECT can induce tumor volume shrinkage, suggesting an implementation in clinical routine as neoadjuvant treatment to enhance future tumor resection. In most cases, it is used in treatment of advanced neoplastic lesions in which radical surgical treatment is not possible (eg, due to lesion location, size, and/or number) [1].

Even though percutaneous ablation techniques are used as possibly curative therapies, palliative tumor ablation can be useful to achieve loco-regional control of tumor growth, pain relief or pain control, especially in patients with unresectable tumor manifestations [40]. Indeed, electrochemotherapy is usually applied in palliative settings for patients with unresectable tumors, resulting in amelioration of quality of life.

Electrochemotherapy allows treating tumor nodules in the proximity of important structures like vessels and nerves and the safety profile of ECT is favorable. Due to heat dissipation to adjacent structures there is an inherent risk of thermal damage of adjacent organs, blood vessels and nerves. Thus, lesions close to adjacent structures with high risk of unintended heat destruction still pose a challenge for percutaneous thermal ablation techniques [41]. In particular, ECT – in contrast to thermal ablation – would allow tumor cell ablation without concomitant destruction of connective tissue, blood vessels and nerves, which means ablation of tumor cells in those areas where thermal ablation was not possible before. In the proximity of larger blood vessels thermal ablation techniques are also hindered by the heat-sink effect. Due to its cooling effect blood flow is an important determinant as much as a limiting factor of thermal ablation techniques [42,43]. ECT seems to be unaffected by the blood flow and conversely does not potentially affect the macro vascularization of the ablation zone.

Most of the observed adverse events are local and transient, including moderate local pain, erythema, edema, and muscle contractions during ECT. No serious adverse events or deaths related to ECT have been reported. Limitations of ECT are the need for interventional individual electric pulse generating systems, individual electrode needles, and complex preinterventional planning. As the success of difficult interventions in deep-seated tumors will rely on accurate needle placement, robotic navigated systems as well as image guidance improve successful ECT treatment and minimize reintervention [1].

Conclusion

Percutaneous ECT of solid organs is a novel, potentially very effective treatment option in minimally invasive oncologic treatments, especially for hepatic metastases.

Due to its more selective and non-thermal ablation effect ECT widens the field of minimally invasive treatable lesions. We showed in this case report that a large hepatic metastatic lesion adjacent to the left suprahepatic vein can be widely ablated by ECT with ablation of a large infiltrating tissue volume.

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DOI: 10.31038/IMCI.2019213

Abstract

Objective: While the use of intraoperative laser angiography (SPY) is increasing in mastectomy patients, its impact in the operating room to change the type of reconstruction performed has not been well described. The purpose of this study is to investigate whether SPY angiography influences post-mastectomy reconstruction decisions and outcomes.

Materials and Methods: A retrospective analysis of mastectomy patients with reconstruction at a single institution was performed from 2015–2017. All patients underwent intraoperative SPY after mastectomy but prior to reconstruction. SPY results were defined as ‘good’, ‘questionable’, ‘bad’, or ‘had skin excised’. Complications within 60 days of surgery were compared between those whose SPY results did not change the type of reconstruction done versus those who did. Preoperative and intraoperative variables were entered into multivariable logistic regression models if significant at the univariate level. A p-value <0.05 was considered significant.

Results: 267 mastectomies were identified, 42 underwent a change in the type of planned reconstruction due to intraoperative SPY results. Of the 42 breasts that underwent a change in reconstruction, 6 had a ‘good’ SPY result, 10 ‘questionable’, 25 ‘bad’, and 2 ‘had areas excised’ (p<0.01). After multivariable analysis, predictors of skin necrosis included patients with ‘questionable’ SPY results (p<0.01,OR:8.1,95%CI:2.06 – 32.2) and smokers (p<0.01,OR:5.7,95%CI:1.5 – 21.2). Predictors of any complication included a change in reconstruction (p<0.05,OR:4.5,95%CI:1.4–14.9) and ‘questionable’ SPY result (p<0.01,OR:4.4,95%CI:1.6–14.9).

Conclusion: SPY angiography results strongly influence intraoperative surgical decisions regarding the type of reconstruction performed. Patients most at risk for flap necrosis and complication post-mastectomy are those with questionable SPY results.

Background

In recent years, intraoperative laser (SPY) angiography has been shown to be effective in identifying areas of ischemic tissue and predicting skin or nipple areolar necrosis during mastectomies [1–5]. One of the most significant complications following a skin or nipple sparing mastectomy with reconstruction is flap necrosis [6,7]. Consequently, SPY angiography has been found to be a useful adjunct to clinical assessment in identifying and potentially preventing complications such as skin necrosis [2].

While studies have demonstrated the ability of SPY angiography to predict mastectomy flap necrosis, none have investigated the impact of SPY angiography on intraoperative decision making, such as changing the type of reconstruction performed. In order to identify the independent predictive value of SPY angiography for postoperative complications, prior studies have not allowed SPY results to impact intraoperative reconstruction decisions [1]. Other studies have described the usefulness of SPY in identifying areas of flap ischemia intraoperatively so that compromised skin could be excised, resulting in decreased complication rates compared to those who did not use SPY [4]. To date, there are no studies describing whether SPY angiography affects surgical decision making regarding the type of breast reconstruction performed. Nor are there studies evaluating whether SPY angiography results can predict other complications, such as seroma or infection. These complications can result from skin necrosis, but independent predictive values have not been evaluated.

Our study aims to describe the impact of SPY angiography on intraoperative decision making regarding type of breast reconstruction. Additionally, we aim to investigate the utility of SPY in predicting other postoperative complications.

Materials and Methods

Patients

After receiving institutional review board approval, a retrospective analysis was performed of a single institution breast care center from 2015–2017. Adult female patients age 18 or older who underwent Nipple Sparing Mastectomy (NSM) or Skin Sparing Mastectomy (SSM), with or without sentinel lymph node biopsy (SLNB) and/or Axillary Lymph Node Dissection (ALND) were identified. The study included patients with a diagnosis of breast cancer and patients undergoing prophylactic surgery. All mastectomies were performed by one of three breast surgical oncologists at our institution. All patients underwent immediate reconstruction with Tissue Expander (TE) or fixed volume implant during the same procedure by one of three plastic surgeons, and all had intraoperative indocyanine green (ICG, standard dose of 2.5mg/ml with 4ml) SPY angiography using the SPY Elite System to evaluate skin perfusion prior to reconstruction.

Variables

Preoperative patient variables including age, smoking status (defined as current smoker at the time of surgery), diabetes, obesity (BMI >/= 30kg/m²), breast weight, and exposures (history of chest wall radiation or chemotherapy) along with intraoperative variables including type of surgery (NSM vs SSM) and ALND were compared. SPY results were defined as described by the plastic surgeon in their operative report as ‘good,’ ‘questionable,’ ‘bad ’or‘ areas excised.’ Documentation of planned reconstruction was noted in the preoperative clinic note and the performed reconstruction was identified in the final operative report. A change in intraoperative reconstruction was either placement of an expander rather than implant, minimal expansion of an expander, or no reconstruction at all. Complications assessed included necrosis (full or partial flap or Nipple-Aerola Complex (NAC) necrosis, dehiscence, or those requiring reoperation), infection (abscess, cellulitis or sepsis), seroma (requiring aspiration or surgical intervention), or explantation of implant within 60 days of surgery. These outcomes were compared between those who had SPY results that changed the type of reconstruction performed and those who did not.

Statistics

Univariate analyses were performed using chi-square tests, Fisher’s exact test, independent sample t-tests, and F-tests in ANOVA for categorical and quantitative variable analysis, respectively. A change in reconstruction was used as the predictor variable with each outcome of interest being the dependent variable tested for significant univariate association. Patient demographics and intraoperative variables were tested for univariate association with our predictor variable to identify possible confounders. These variables were adjusted for in multivariable logistic regression models when the respective univariate p-value was less than 0.1. Covariates in the final multivariable logistic model were considered statistically significant if the p-value was less than 0.05. All statistical analysis was done using SAS version 9.3 (Cary, NC).

Results

Of the 267 mastectomies identified, 42 breasts from 25 patients (15.7%) underwent a change in the type of reconstruction intraoperatively due to SPY results. Of the 42 changes in reconstruction type, 6 breasts had ‘good’ SPY results, 10 had ‘questionable’ SPY results, 25 had ‘bad’ SPY results, and 2 breasts ‘had areas excised’ (p<0.0001) (Table 1). Of the patients who underwent a change in reconstruction, 39 of 42 breasts (92.8%) had a TE placed instead of implant or a TE placed with lower volume, while 3 breasts (7.1%) did not undergo any reconstruction based on intraoperative assessment.

Table 1. SPY results and frequency of intraoperative decision change.

The patient demographics that were statistically significant on univariate analysis in relation to those who had no change versus those who had a change in reconstruction included smoking (p<0.001), obesity (p<0.01), and breast weight (p<0.0001). Age, diabetes, and history of chemotherapy or chest wall radiation were not statistically significant (Table 2). Patients who did not have a change in reconstruction were more likely to have undergone a SSM versus a NSM (p<0.01) and have a ‘good’ SPY result (p<0.0001) compared to those who underwent a change in reconstruction (Table 2). There was a statistically significant increase in complications including necrosis (p<0.01), infection (p<0.01), and seroma (p<0.0001) for patients who had a change in reconstruction based on SPY results compared to those who did not (Table 3).

Table 2. Demographic and intraoperative variables for patients with no change in reconstruction compared to change in reconstruction.

Table 3. 60-day outcomes for no change in reconstruction compared to change in reconstruction.

A multivariable analysis was performed adjusting for significant co-variates including preoperative factors and intraoperative factors if a variable produced a p<0.1. Predictors of necrosis within 60 days of surgery included those who had a ‘questionable’ SPY result (p<0.01 OR: 8.1 95% CI 2.1–32.2) and current smoker (p<0.01 OR: 5.7 95% CI 1.5 – 21.2) (Table 4). Predictors of infection included those who underwent a change in reconstruction (p<0.01 OR: 34.6 95% CI 2.7 – 448) and obesity (p<0.001 OR: 79 95% CI 6.1 – 1000) (Table 5). Predictors of seroma included those who underwent a change in reconstruction (p < 0.05 OR: 4.3 95% CI 1.2–14.7) (Table 6). There were no significant predictors of explantation after multivariable analysis (Table 7). Predictors of one or more complications were significant for patients who had a change in type of reconstruction (p<0.05 OR: 4.5 95% CI 1.4–14.9) and those who had a “questionable” SPY result (p<0.01, OR: 4.4 95% CI 1.6 – 12.1) (Table 8). There were no mortalities within 60 days.

Table 4. Multivariable logistic regression model predicting necrosis within 60 days of surgery.

Table 5. Multivariable logistic regression model predicting infection within 60 days of surgery.

Table 6. Multivariable logistic regression model predicting seroma within 60 days of surgery.

Table 7. Multivariable logistic regression model predicting explantation within 60 days of surgery

Table 8. Multivariable logistic regression model predicting any complication within 60 days of surgery.

* = significant, p < 0.05
** = 3 decimal places needed to accurately show OR and CI
OR = odds ratio
CI = confidence interval
SSM – skin sparing mastectomy, ALND – axillary lymph node dissection

Discussion

To date, this has been the first study describing how SPY angiography impacts intraoperative decision making with respect to reconstruction after mastectomy. In this study, nearly 20% of patients underwent excision of compromised tissue and 16% had a change in reconstruction due to findings on SPY angiography (Table 1). Our study also found that SPY results strongly affected the plastic surgeon’s intraoperative decision making, where 100% of ‘bad’ SPY results resulted in a change in type of reconstruction and 40% in the ‘questionable’ SPY group (Table 1). Furthermore, a change in reconstruction type was predictive of infection, seroma, and any complication, while established risk factors such as smoking and obesity increased risk of necrosis and infection. Interestingly, ‘questionable’ SPY results were an independent risk factor for postoperative necrosis and other complications while ‘bad’ results were not.

Studies have shown that Immediate Breast Reconstruction (IBR) has increased complication rates compared to delayed reconstruction with flap necrosis being reported as the most common complication [8–10]. Flap necrosis rates after IBR have been noted to range anywhere from 3.8% up to 42% [8,9,11]. However, morbidity rates for IBR have decreased over time even with nipple sparing technique [12]. This improvement is likely multifactorial and has been largely attributed to increased surgeon experience and technique modification. Our study found a necrosis complication rate of 8.9% for all patients undergoing mastectomy with reconstruction, which is consistent with prior studies [8,9,11]. While preoperative risk factors for complications have been well studied, the intraoperative evaluation for necrosis with SPY angiography is the next potential area of intervention to reduce morbidity [13].

Our study found that 15.7% of breasts with planned IBR ultimately underwent a change in reconstruction intraoperatively based on SPY results either by undergoing TE placement rather than implant, TE with less volume, or no reconstruction at all. While patients who had a change in reconstruction were at increased risk of a complication on univariate analysis, our study also shows that patients who are smokers or had a ‘questionable’ SPY result are at greater risk for necrosis on multivariate analysis (Table 4). Smoking has been established as a known independent risk factor for skin and flap necrosis [7,10,13]. This was seen within our patient population as well and stresses the importance of SPY for these smokers who undergo IBR. Those patients with a ‘questionable’ SPY were more likely to have necrosis compared to those with a ‘good’ result, while those with a ‘bad’ or ‘had areas excised’ result were not. This is likely because excision of skin for a ‘questionable’ spy was not performed. This confirms the utility of SPY intraoperatively in identifying ischemic areas that can be excised in order to reduce postoperative complications and suggests that a more aggressive approach for ‘questionable’ areas should be taken. After multivariable analysis, patients with SPY results that were not clearly identified as “under-perfused/bad” or “well-perfused/good” were at the greatest risk for necrosis complications.

The objective methods by which SPY can be reported have varied in the literature, with studies investigating anatomic blood flow patterns and the quantitative measurements of perfusion including intensity of fluorescence (also known as absolute perfusion or relative perfusion.) [3,5,14] These studies were limited by small sample size, and because SPY angiography is an “instantaneous index of perfusion” it can be impacted by variations in blood pressure or possibly during the operation [1,3,4,5,14]. In addition, because images are black and white with shades of gray defining areas of perfusion, SPY angiography may be subject to user interpretation and operator experience.⁶ Overall, most studies have made a consensus that SPY should be used in conjunction with clinical assessment to assess perfusion [3–6,14]. Our study confirms SPY is helpful in assessing flap perfusion but there continues to be a need for standardization of perfusion measurements. While 100% of patients with a ‘bad’ SPY result underwent a downgrade in reconstruction, only 40% of those with a ‘questionable’ SPY result had a change, suggesting that surgeons should be more vigilant in downgrading reconstruction options, delaying reconstruction for patients, or excising areas of skin that are compromised with a questionable SPY result. This is further supported by the finding that intraoperative change in reconstruction was not an independent risk factor for necrosis (Table 4).

Obesity is another known risk factor for postoperative complications [10]. In this study, obesity and a change in reconstruction were independent risk factors for infection. Those who underwent a change in reconstruction were at higher risk for infection as well as seroma formation (Table 4, Table 5). The increased risk of infection in those who underwent a change in reconstruction may have been related to ischemia or necrosis while the increased risk for seroma formation may have been due to placement of a TE with minimal expansion instead of placement of an implant.

SPY angiography continues to be an important adjunct in assessing tissue perfusion and can guide intraoperative decision making including excision of ischemic tissue and change in reconstruction options. While changing reconstruction may result in increased seroma formation, it may reduce other complications when there is indeterminate or ‘questionable’ SPY imaging result. There are multiple limitations to our study. The single institution and retrospective nature of our study are limitations as well as the small sample size. As with many other studies, the subjective nature of a SPY result interpretation by the surgeon continues to be present. Since SPY was introduced at our institution in 2014, operator experience may have affected our study as other studies have demonstrated that there is a learning curve for surgeons [6]. In addition, long term and oncologic outcomes were not assessed. Further prospective studies using a standardized measurement to assess tissue perfusion with SPY angiography are needed.

Conclusions

SPY angiography can influence intraoperative decision making for reconstruction, and whether direct to implant reconstruction is possible or expanders are necessary. The patients who were at greatest risk for flap necrosis or other complications in this study were those with ‘questionable’ SPY results as interpreted by the surgeon. Further studies are needed using a SPY angiography standardized perfusion measurement to identify patients who are at risk for post-mastectomy complications.

References

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