 Surgical Science, 2013, 4, 464-468 http://dx.doi.org/10.4236/ss.2013.410091 Published Online October 2013 (http://www.scirp.org/journal/ss) Evaluation of an in Situ Polymerizing Hydrogel Applied in Tumor Excision Cavities during Breast Conservation Surgery M. Korell1, F. Brassel2, G. Bilir3, J. Pagels3 1Department of OBGYN, Johanna Etienne-Krankenhaus, Neuss, Germany 2Department of Radiology, Klinikum Duisburg, Duisburg, Germany 3Department of OBGYN, St. Josef Krankenhaus, Moers, Germany Email: m.korell@freenet.de Received September 14, 2013; revised October 12, 2013; accepted October 20, 2013 Copyright © 2013 M. Korell et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. ABSTRACT Study Objective: To evaluate the imaging characteristics and healing following application of an absorbable biocom- patible hydrogel into the excision cavity following breast conservation surgery. Design: Non-randomized study evalu- ating hydrogel application feasibility, post-operative hydrogel imaging characteristics, cavity healing following hy- drogel absorption and the resulting breast cosmesis. Setting: Teaching hospital University of Essen, Germany. Patients: Seven (7) patients underwent unilateral or bilateral breast conservation surgery to remove cancerous or benign tumors. Interventions: All patients received hydrogel application following primary tumor excision. Imaging performed in the first postoperative week included ultrasound, MRI and CT. Breast cosmesis scores were obtained at one and three months following surgery. Measurements and Main Results: While preliminary, a relationship between percent cavity filling and drainage was observed, with 30% or more cavity filling resulting in decreased drainage. Additionally, the hydrogel was readily visible under ultrasound, MRI and CT imaging modalities. Finally, patients were satisfied and surgeons felt that patient cosmesis was improved relative to their prior experience. Co nclusion: Initial data suggest that hydrogel filling may reduce excision cavity drainage, which may reduce seroma or hematoma formation. Additionally, these gels may improve cavity visibility and stability, furthering the use of partial breast irradiation. Finally, while more studies are required, these materials may have a role in improving long term patient cosmesis. Keywords: Lumpectomies; Breast Radiation; Seroma Prevention; Breast Cosmesis 1. Introduction The current standard of care for the surgical treatment of patients diagnosed with breast cancer is breast conserva- tion surgery (BCS, frequently called lumpectomy) whenever it is possible. The BCS procedure involves removal of the breast cancer along with a margin of normal breast tissue, followed routinely by whole breast radiation therapy (WBRT) to eliminate potential tumor cells beyond the resected margins. In addition to pre- serving much of the patient’s breast tissue, this technique has been shown to be as efficacious as mastectomy, with similar survival rates over 15 years of follow up [1-4]. For further reduction of local breast cancer recurrence, a radiation boost is applied to the tumor bed, which is guided by using metal clips as marker. This approach is justified since cancer recurrence is highest near the exci- sion site, with 86% of recurrences in the same quadrant as the excision, as shown in one multicenter study [5]. However, unlike many other radiation oncology targets (i.e. prostate), the margins of the excised cavity are often difficult to visualize following surgery, as demonstrated by large inter-observer differences while attempting to delineate and contour the cavities [6-8]. Surgical clips are often used to mark discreet points within the cavity, but the vast majority of the cavity margins remain unmarked, and often difficult to delineate. Frequently seromas and/or hematomas form within the excision cavities fol- lowing surgery, assisting in cavity visualization, but se- roma formation is an unpredictable complication of BCS and therefore is not a reliable aid for visualization. Further complicating cavity targeting is the change in cavity volume due to seroma absorption in the months following surgery. Several researchers reported changes in mean excision cavity volumes during radiation therapy C opyright © 2013 SciRes. SS
 M. KORELL ET AL. 465 ranging from 22.5% to 54% [9-13]. Cavity volume change during radiation can result in movement of nor- mal tissue into the radiation treatment volume, or worse, movement of the cavity margins, potentially containing residual tumor cells, out of the radiation treatment vol- ume. A marker that allows for improved post-operative identification and localization of the excision cavity margins while preserving the cavity volume through the course of radiation therapy would overcome a number of the challenges related to partial breast irradiation. Further, stable and visible cavity margins would facilitate accel- erated partial breast irradiation (APBI), which has been reported to be about half the cost of WBRT [14]. The aim of this study is to gather initial clinical data on the use of in situ polymerizing polyethylene (PEG) hydrogel instilled into lumpectomy cavities to facilitate postoperative cavity visibility via ultrasound, MR and CT imaging. Additional study endpoints include patient comfort and tolerance of implant, breast drainage, physi- cian scored cosmesis at 1 and 3 months following im- plantation, and collection of adverse events experienced by patients. 2. Materials and Methods Following institutional Ethics Committee protocol ap- proval and receipt of Informed Consent, a total of 7 pa- tients were enrolled in this evaluation. Patient ages ranged from 19 to 75 years (mean = 47 years), and 4 of the patients had benign disease, while 3 patients had been previously diagnosed with breast cancer. 6 of the patients had unilateral procedures, while one patient had bilateral lumpectomies, resulting in 8 hydrogel instillations. Tu- mor volumes ranged from 1 to 165 cc, with a mean vol- ume of 63 cc. Following completion of tumor excision and confir- mation of cavity hemostasis, one drainage catheter was tunneled into the cavity, and one silicone instillation catheter was introduced into the excision cavity via the surgical incision. With the drainage catheter clamped to prevent plugging, between 4 to 20 ml of hydrogel (mean = 14 ml) was instilled via the silicone catheter, which was withdrawn from the cavity prior to hydrogel polym- erization (Figure 1). All but one of the cavities were par- tially closed with sutures prior to injection, and depend- ing on incision location, half of the skin incisions (4 of 8) were mostly closed prior to hydrogel injection to prevent loss of liquid hydrogel precursor while the hydrogel po- lymerized. The hydrogel used in this evaluation was a polyethyl- ene glycol (PEG) based hydrogel initially approved in Europe for use as a dura mater sealant, but subsequently approved for use on the lung, in vascular surgery and for the prevention of peridural adhesions following spinal Figure 1. Injection of hydrogel precursors into the lumpec- tomy cavity, where they polymerized forming a soft, ab- sorbable hydrogel. surgery (Confluent Surgical, Bedford, MA, USA). Fol- lowing mixing of the two precursor solutions, a reaction between end-functionalized PEG and trilysine results in polymerization, or creation of a soft, solid hydrogel, within seconds without producing measureable heat. The resulting hydrogel contains hydrolysable linkages at each PEG-trilysine junction, causing the hydrogel to break down over time and be absorbed. For this application both precursors were diluted 1:1 with sterile saline prior to applicator assembly using a commercially available mixing Y-connector (Micromedics, Inc. St. Paul, MN, USA). This dilution slightly slowed down the polymeri- zation rate reducing the likelihood of applicator plugging during instillation, and reduced the absorption time to within 1 month (as demonstrated by prior testing in 37˚C PBS). While the relatively short persistence of this mate- rial will not make it an ideal candidate for partial breast radiation targeting, it will still provide valuable informa- tion regarding hydrogel visualization, injection feasibility, patient tolerance, cosmesis, and could potentially benefit the patient by reducing drainage and the likelihood of problematic seromas. Following surgery ultrasound (US) images of cavities were obtained within 2 days, and drains were removed between 1 and 5 days (mean = 3 days), with the total drainage recorded. In addition to US images, magnetic resonance (MRI) or computed tomography (CT) images were obtained within one week of surgery. At the 1 month postoperative visit the surgeon queried patients regarding postoperative pain, and scored both postopera- tive pain and treated breast cosmesis as either worse than expected (score of −1), as expected (0) or better than expected (1, relative to hospital experience). At 3 months following surgery the treated breast cosmesis was scored as before, along with a patient´s estimation of breast cosmesis score using the visual analogue scale (VAS), with a range from 0 (completely unsatisfied) to 10 (very satisfied). All three of the breast cancer patients received postop- Copyright © 2013 SciRes. SS
 M. KORELL ET AL. 466 erative chemotherapy and whole breast radiation. 3. Results The course of healing for all patients was normal, al- though one patient experienced a superficial wound in- fection that resolved within three weeks without further treatment. Overall the postoperative pain was scored as either less than normal, or normal to the surgeon’s clini- cal experience. Breast drainage ranged from 5 to 180 ml (mean = 59 ml, median = 8 ml). Of note, 94% of the total study drainage came from the three patients with the largest lumpectomies. In the other breasts drainage averaged 6 ml. A sharp drop in drainage was noted when the gel volume was greater than 30% of the cavity volume (Fig- ure 2). In every patient the hydrogel was readily apparent un- der US imaging. Initially the hydrogel had a hypointense appearance, like water. Over time gel absorption was observed (Figure 3). The gel was found to be readily visible using MR im- aging, as seen in Figure 4. The gel is most conspicuous using T2 with fat suppression, although it is visible under all modalities. In cases with low drainage the cavity had a much more uniform density, suggesting a better cavity fill and less fluid collection (as seen in Figure 4(a)). In a patient that exhibited 180 ml of drainage (with 12% cav- ity filling), different densities are visible within the cav- ity suggesting both fluid and gel collections, as seen in Figures 4(c) and (d). The hydrogel was also visible under CT imaging at one week following implantation, with a good agreement between US and CT cavity shapes (Figure 5). Patients satisfaction with the outcome at 3 months postoperatively was high: mean = 8.8 (min 8 – max 9.5). Surgeon scored breast cosmesis at one and three months following surgery was scored as “Better than expected” (50%, 62.5%), “As expected” (50%, 25%) and “Worse than expected” (0%, 12.5%), respectively. Using the scoring method outlined earlier, this represents a 50% Figure 2. Postoperative drainage was observed to drop when the gel volume was at least 30% of the lumpectomy cavity volume. (c) (b) (a) Figure 3. Hydrogel appearance under ultrasound imaging in a single patient at 1 day (a), 1 week (b), and at 14 weeks (c) following implantation. (a) (b) (d) (c) Figure 4. Six days following implantation the gel is clearly visible under MRI using fat suppression with both T2 (a), and T1 with contrast (b). Differing densities within the cav- ity of one patient suggested both fluid and gel collections at 7 days with T2 and fat suppression (c), and with T1 and no fat suppression (d). Scale = 1 cm. improvement in cosmetic outcome at both time points, relative to prior surgeon experience (Figure 6). 4. Discussion Some of the patient care challenges following breast conservation surgery include 1) avoiding the formation of symptomatic seroma or hematoma, 2) accurate identi- fication of the tumor cavity margins for targeted radio- therapy during either PBI or boost procedures, 3) the change in cavity volume over time, also limiting the po- tential use of PBI, 4) the long term cosmetic result due to Copyright © 2013 SciRes. SS
 M. KORELL ET AL. 467 (a) (b) Figure 5. Close agreement between ultrasound image (a) and CT image (b) in patient one week following surgery. Scale = 1 cm. Figure 6. Surgeon scored breast cosmesis one and three months following surgery show ed a 50% improvement rela- tive to prior surgeon experience. volume loss and scar tissue retraction, and 5) impact on tissue visualization during subsequent diagnostic imaging procedures (mammography) due to scar formation. The hydrogel used in this evaluation has been ap- proved and used as a sealant and adhesion barrier in dif- ferent areas of the body. As such, these features may have a role in improving outcomes following BCS. These materials have the potential to reduce the incidence of postoperative seroma and hematoma formation by both acting as a cavity filler, and by sealing the cavity walls to prevent fluid migration into the cavity. While limited in sample size, the data from this preliminary study suggest that when at least 30% of the cavity volume is replaced with hydrogel that seals the cavity margins, postoperative drainage, and presumably postoperative seroma forma- tion, may be reduced. Additionally, while the hydrogel utilized for this evaluation will likely not last long enough for PBI, it may provide adequate cavity delineation and stability for accelerated PBI. Imaging with both MRI and CT demon- strated hydrogel visibility, leaving open the possibility of contouring the hydrogel during radiation treatment plan- ning. Indeed, recent studies in cadavers with similar cav- ity filling hydrogels demonstrates that these materials can be contoured with CT, and if a 15 mm treatment margin is utilized due to improved cavity visibility, then the total radiation dose to the normal breast tissue, heart and lungs can be reduced [15]. Another potential benefit of hydrogel excision cavity fillers is an improvement in patient cosmesis. Permanent fillers could result in long term volume replacement, preventing contour deficits. Absorbable fillers, while not providing long term volume replacement, may also im- prove cosmesis by allowing tissue filling of the cavity during absorption, or by reducing the scar formation and subsequent scar retraction which can lead to scar invagi- nation. While this evaluation is very preliminary, it does demonstrate some of the potential advantages on excision cavity filling with hydrogels at the time of surgery. These materials have the potential to reduce seroma formation, improve cavity visualization and delineation, and to im- prove long term patient cosmesis. These results warrant further clinical research of this technique. 5. Acknowledgements The authors would like to thank Alex Norbash, MD for assistance in interpreting the MR and CT images. REFERENCES [1] W. C. Dooley, “Breast Cancer: Surgical Therapy,” In: J. L. Cameron, Ed., Current Surgical Therapy, 3rd Edition, Mosby, St. Louis, 1995. [2] B. Fisher, S. Anderson, C. K. Redmond, et al., “Reanalysis and Results after 12 Years of Follow-Up in a Randomized Clinical Trial Comparing Total Mastectomy with Lum- pectomy or without Irradiation in the Treatment of Breast Cancer,” New England Journal of Medicine, Vol. 333, No. 22, 1995, pp. 1456-1461. http://dx.doi.org/10.1056/NEJM199511303332203 [3] B. Fisher, M. Bauer, R. Margolese, et al., “Five-Year Results of a Randomized Clinical Trial Comparing Total Mastectomy and Segmental Mastectomy with or without Radiation in the Treatment of Breast Cancer,” New England Journal of Medicine, Vol. 312, No. 11, 1985, pp. 665-673. http://dx.doi.org/10.1056/NEJM198503143121101 [4] J. A. Jacobson, O. N. Danforth, K. H. Cowan, et al., “Ten-Year Results of a Comparison of Conservation with Mastectomy in the Treatment of Stage I and II Breast Cancer,” New England Journal of Medicine, Vol. 332, No. 14, 1995, pp. 907-911. Copyright © 2013 SciRes. SS
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