Does partial expander deflation exacerbate the adverse effects of radiotherapy in two-stage breast reconstruction?

Tissue expander assisted two-stage breast reconstruction has been successfully utilized in many breast centers throughout the world [1, 2]. Furthermore, favorable results have recently been reported with the use of this approach in patients with locally advanced breast cancer requiring postmastectomy radiotherapy [3], leading to an increase in the number of patients in whom anatomical breast expanders are inserted at the time of mastectomy. However, the optimal protocol for expander volume adjustment with respect to the timing and application of radiotherapy (RT) remains controversial. While deflation of the expander at the time of RT helps to create a favourable geometry for dose planning, attempts to re-inflate after radiotherapy may cause extrusion through skin, complicating the reconstruction process [4, 5]. On the other hand, there are reports of successful outcomes with the application of RT whilst the expanders remained fully inflated [1, 6, 7].

In order to compare the effects of RT on pre-expanded tissues with different expander volume adjustments, we designed an experimental study with anatomically shaped breast expander implanted rabbits, in which RT was applied to pre-expanded tissues with expanders in an either fully inflated or partially deflated state. The changes in blood flow at different volume adjustments and the variations in the histopathological properties of the irradiated tissues including the skin, capsule and the pocket floor, were investigated.

This study was performed at the Institute for Experimental and Applied Medical Research of Istanbul University with permission of the Ethics Committee of the Istanbul University, Istanbul Faculty of Medicine.

Eighteen female New Zealand white rabbits (3.0-3.5 kg) were randomly divided into 3 groups (Table 1). The animals were anesthetized by intramuscular injection of ketamine (35 mg/kg) (Ketalar; Parke-Davis, Eczacibasi; Istanbul, Turkey) and xylazine (5 mg/kg) (Rompun; Bayer Istanbul, Turkey). Anesthesia was maintained by using the same two agents intraperitoneally.

The postoperative course was uneventful in each group. No animals were lost due to surgery or radiotherapy. There were no findings of postoperative infection, hematoma or expander extrusion. Seroma formation following radiotherapy was observed in 2/6 animals in Group II, whereas none developed in Groups 1 and Control (p = 0.45). No intervention was required and it resolved spontaneously following re-inflation in both cases. No expanders were lost in any of the groups.

Although nipple sparing and skin sparing mastectomy techniques mostly maintain the original dimensions of the breast skin envelope, a variable amount of skin resection is usually needed at the time of mastectomy, depending on the tumor site and the concerns on the marginal skin flap viability. Thus, immediate expander fill volumes usually fail to reach the final desired amount [8], and often several sessions are needed to expand the skin to its original size following mastectomy. Although, the classical effects of tissue expansion may not be observed in those cases in whom the expander serves solely to preserve the native breast skin, dermal and vascular structure changes accompany those cases where skin resection necessitates postoperative expansion to original breast size for optimum cosmesis.

The compatibility of tissue expansion and radiotherapy has been investigated in various studies. The results seem to vary according to the timing of delivery of radiotherapy and the execution of actual tissue expansion. Most of the studies that report on the adverse effects of radiotherapy have either placed the expanders in previously irradiated skin or begun the radiation therapy during the expansion period [9, 10]. However, according to an experimental study on rabbits, the effects of radiotherapy may not be as deleterious, when delivered on a pre-expanded field, with an actual increase in epidermal thickness and vascularity with increasing doses of radiotherapy [10]. This has been attributed to the probability of a better tolerance to radiotherapy after a period of tissue expansion and stabilization [10]. Having said this, it has not been investigated how this tolerance will change when radiotherapy is delivered to an expanded-deflated area and if subsequent re-inflation will change the tissue tolerance to the adverse effects of radiotherapy. In our study we looked into the chronic effects of radiotherapy, when delivered on a previously expanded, stabilized and partially deflated area and compared it with the effects of radiotherapy delivered on a fully inflated field. Previous studies on chronic effects of radiotherapy on implant sites, have underlined the presence of epidermal changes (either hyperplasia or atrophy), dermal edema and connective tissue degeneration, neovascularisation and vascular changes (dilatation, vessel wall proliferation, thrombi formation) as well as increase in fibrous capsule thickness [10‐12]. Our findings on the chronic effects on radiotherapy when executed at full expansion are compatible with the prior studies [10, 11]. However, we have further shown that, expander deflation, immediately prior to the delivery of radiotherapy, frankly exacerbates the adverse radiation effects.

Another point of interest related to the current study is the use of metallic port-integrated, anatomic tissue expanders, to better mimic the clinical situation. What we found with the use of such expanders was a variation in the region specific radiotherapy effects, i.e aggravated findings in the lower pole as compared to the sites neighboring the magnetic port. Previous ex vivo studies have shown that metallic port related dose attenuation is in fact present, albeit minimal and may be either overcome or overlooked in clinical practice [13, 14]. Our study findings of comparingly subdued RT effects over the magnet area in the deflated group, may indirectly be considered as concurrent with the aforementioned preliminary data [13, 14]. However, a relatively augmented, regional expansion-deflation effect due to anatomic expander configuration, may also have contributed to the aggravated findings in the lower pole.

Laser Doppler flowmetry (LDF), has been found to be a suitable method for the registration of reactions in dermal circulation, caused by tissue expander pressure changes [15]. A statistically significant association between the changes of the LDF values and the intraluminal pressure was observed [15]. The relationship between tissue expansion and cutaneous blood flow has also been studied by Goding et al [16]. Their study is unique due to its investigation of the effects of expander deflation on the pig skin circulation. Briefly, expanders were inserted into subcutaneous pockets in two experimental groups and a separate group with no expanders served as control. Controlled expansion followed by deflation was executed in Group I, while the expanders were kept non-deflated in Group II. According to their results, expander deflation following controlled tissue expansion causes an immediate increase in blood flow. However, this effect is reported to be temporary and furthermore, six days after deflation, skin expansion had a negative impact on cutaneous blood flow as compared to skin elevated without expander placement [16]. In our study, the LDF measurements were compatible with the reported results, confirming a significant early increase in the blood flow by expander deflation. Furthermore, in Group II, attempts for re-inflation two weeks after completion of radiotherapy, which is compatible with the expander re-inflation timing in the clinical setting [3], yielded a significant drop in skin blood perfusion, detected by the third LDF readings. This finding of relative skin ischemia may also help to explain the re-inflation related problems including expander extrusion and loss, reported in large clinical series by Kronowitz et al. [3].

Molecular oxygen is known to be a potent modifier of cellular radiation sensitivity and the biological effects of ionizing radiation on mammalian cells are reported to be aggravated under well- oxygenated conditions [17]. Thus, increased tissue perfusion and better oxygenation in the deflated state, may well account for the underlying etiopathology of the exacerbated adverse effects, observed in our study.

Clinically, when Kronowitz et al. first introduced the concept of delayed- immediate breast reconstruction, complete deflation of the expanders prior to radiotherapy was recommended, favoring a more effective addressing of the internal mammary nodes while avoiding adverse effects [5, 18]. Subsequently, due to high rates of expander loss during re-inflation, the protocol was revised and from then on, the expanders were kept partially deflated during the course of radiotherapy [6]. On the other hand, it has been clinically observed that even partial deflation may cause problems; Expander/skin dimpling and formation of a prominent inferior edge is one of the culprits that may lead to skin trauma facilitating exposure. Furthermore, deliberate dimpling of the expanded skin is reported to cause unacceptably high variations in terms of dosimetry [19] and dosimetric discrepancies greater than 10% of the original treatment dose are considered unacceptable in radiotherapy [20]. Since such unwanted variations have been attributed to changes in the size and shape of the underlying tissue expander [19], it may be a reasonable suggestion to stabilize the pocket with a fully inflated, taut implant and avoid fluctuations while executing RT.

In one study by Ascherman et al, it is stated that radiotherapy may be given before completion of expansion, to be continued following completion of radiotherapy [6]. In such cases, an increase in the complication rate was not observed. However, although it may be presumed that interrupted expansion does not cause as strong adverse effects as those under the hypervascular conditions that accompany a deflated expander after full expansion has been reached, cosmetic consequences of irradiating an insufficiently developed skin envelope and trying to expand it to the desired volume following radiotherapy may not be as satisfactory as those achieved with the irradiation of an already established skin envelope [7].

Expander deflation immediately prior to radiotherapy, increases adverse effects, potentially complicating the reconstruction process. To avoid radiotherapy-related problems, keeping the expanders in the fully inflated state may be an option. In those patients where optimum dose planning cannot be executed with full expanders, approximately one week wait period following partial deflation may be suggested before executing radiotherapy, in order for the hypervascular state in the tissues to be settled back to normal values.