Despite the improvements in early detection of breast cancer and the availability of breast conservation treatments, many women choose mastectomy for both the prevention and treatment of breast cancer over breast-conserving surgery.1 Most women who undergo mastectomy are candidates for breast reconstruction. However, access to information and education varies, and up to 67% of women with a breast cancer diagnosis are not informed about options for reconstruction.2 As plastic surgeons are increasingly involved early in the process of care for these patients, and with many states legislating that physicians who care for breast cancer patients inform them about reconstruction options, more women are becoming informed about their choices for reconstruction.3
Prosthetic reconstruction of the breast, as a 2-staged procedure using tissue expanders followed by placement of permanent implants offers favorable aesthetic results with minimal additional surgical intervention. The procedure involves the placement of a saline tissue expander under the pectoralis major muscle and the remaining skin after mastectomy. The expander is gradually inflated over several months by periodic injections of saline, causing the overlying skin and muscle to stretch. Once adequate tissue is developed, the expander is removed and replaced by a permanent breast implant. Despite many advantages of this technique, most notably minimal additional surgical dissection and patient downtime, the outpatient process can be lengthy and onerous, involving months of office visits and discomfort from the bolus saline inflations.
Plastic surgeons recognize that a gradual, continuous expansion method can overcome the drawbacks associated with periodic saline injections. Continuous low-dose expansion has been shown by Bergé and others to be more rapid and well tolerated, thus reducing time burden and patient discomfort.4,5
The study sponsor (AirXpanders, Inc, Palo Alto, CA USA) has developed a technology that has the potential to improve the process of breast tissue expansion.6,7 The AeroForm Tissue Expansion System provides a needle-free alternative to saline expanders and allows women to participate in the expansion process under the guidance of their physician. With this new technology, women control the expansion process using a wireless remote control to activate the release of a small volume of CO2 into the expander. The dosage controller acts similarly to a patient-controlled analgesia device: dosing is programmed to prevent overinflation by allowing low-volume (10-mL) fills up to 3 times per day. These dosing limits were evaluated in feasibility studies and were well tolerated by the patients. Tissue expansion with the CO2 system eliminates the need for periodic bolus injections and may be performed at the patient’s convenience in her own home under the direction of the physician. The incremental release of CO2 on a daily basis has been shown to allow a more rapid method of tissue expansion.6
Our objective was the evaluation of clinical outcomes and effectiveness of the patient controlled tissue expander (AeroForm) system compared to saline expanders in a multicenter randomized clinical trial.
MATERIALS AND METHODS
This study was designed as a prospective, multicenter, randomized, controlled open-label clinical trial to compare the AeroForm System to saline tissue expanders in terms of primary outcome measures of performance and safety. Subjects who met the inclusion criteria and agreed to participate in the study were enrolled and randomized to either the investigational arm (CO2 tissue expander) or the control arm (saline tissue expander) using a 2:1 (CO2 to saline) permuted block randomization stratified by investigational center and procedure (unilateral or bilateral). If the subject had a bilateral procedure, the same type of expander was implanted in each side. Subjects in both study arms were followed in the same manner until explantation of the tissue expander(s) and exchange for permanent implant(s). Recruitment began in October 2011, and all women provided written consent and enrolled at 11 clinical sites throughout the United States.
All sites obtained local institutional or independent review board approval of the protocol. The study (ClinicalTrials.gov Identifier: NCT01425268) was and continues to be conducted in accordance with ICH guidelines for Good Clinical Practices, the US Code of Federal Regulations for conducting clinical studies, and other applicable local regulations related to the rights and welfare of human subjects who participate in medical research.
Potential study participants were self-referred or were referred by their breast surgeons to each study site. Study eligibility was determined by the following criteria: women between the ages of 18 and 70 years who required tissue expansion as part of breast reconstruction, who could provide informed written consent, and who were willing to comply with all study requirements. Prospective subjects were excluded for the following criteria: tissue integrity was unsuitable for tissue expansion; presence of residual gross tumor at the intended expansion site; current or prior infection at the intended expansion site; clinically significant fibrosis caused by previous radiation (except if the use of autologous tissue is planned); planned radiation therapy at the intended expansion site while the expander is implanted; a history of failed tissue expansion or of failed breast reconstruction; any comorbid condition (eg, severe collagen vascular disease or poorly managed diabetes) or concomitant medications (eg, prednisone) determined by the investigator to place the subject at an increased risk of complications; current participation in another investigational drug or device study; current tobacco smoker; obesity (BMI, >33 kg/m2); unwillingness to comply with air travel or altitude restriction of not exceeding 3300 ft (1000 m) from baseline during the time the CO2 expander is implanted; presence of an implanted electronic device, for example, a pacemaker, defibrillator, neurostimulator, or drug-infusion device); pregnancy or plan to become pregnant during the study period; history of psychological condition or drug or alcohol misuse, which could interfere with the subject’s ability to use the device safely. The most prevalent reasons for exclusion were age, BMI greater than 33 kg/m2, and planned radiation therapy at the expansion site.
The study device is a sterile product and consists of a textured outer shell (silicone elastomer), an inner CO2 gas barrier, a stainless steel CO2 reservoir, and an embedded antenna and electronics for communication with a remote dosage controller (Fig. 1). The CO2 reservoir has a microvalve that opens when activated to release a 10-mL dose of CO2. Pressing a button on the dosage controller activates the valve and the release of CO2 resulting in gradual expansion of the implant. The investigational tissue expander was designed to have an anatomic shape and was available in 3 sizes for the study participants (Table 1).
The dosage controller is a small, battery-operated, handheld remote that activates the expander to release CO2. The dosage controller is programmed to provide coded instructions to its paired implant. It has a single push button and a row of indicator lights and audible tones to provide position and CO2 delivery information to the patient or physician. The dosage controller permanently bonds with the identified expander when activated and does not function with other expanders. It is programmed to deliver one 10-mL dose with each push of the button with a lockout period of 3 hours and daily maximum dosing of 30 mL. The dosage controller tracks the timing and volume of dosing as well as estimates the CO2 volume in the expander. Once the controller determines that the expander is at full volume, it allows the patient to dose only the amount required to maintain the labeled volume.
The physicians provided additional volume when needed with the use of a physician master key, which was inserted into the dosage controller. Use of the master key by the investigator permitted testing the tissue expander in the operating room before implantation, filling the expander to the desired volume after placement of the implant during surgery, adding volume to the expander during office visits and, if needed, adding volume to the expander to maintain the volume. The key was not provided to the subjects.
The tissue expanders, whether saline or CO2, were placed similarly, with no limitation as to the type of adjunct procedure for tissue coverage (acellular dermal matrix or flap). After expander implant, each physician determined when the patient could begin the active expansion process. Subjects were followed until the removal of the tissue expander(s) and/or exchange to permanent implant.
The primary efficacy end point of the study was successful tissue expansion and exchange to a permanent breast implant unless precluded by a non–device-related event; the end point was analyzed per breast. Breasts in which the expander was removed and/or replaced due to a device-related adverse event or a device malfunction were counted as failures. Safety was described in terms of device-related failures and adverse events. Additional outcome measures included usability of the device in terms of the average number of days to achieve expansion and exchange for a permanent implant and physician and subject satisfaction.
The study was powered to show that the treatment success rate for the study device is not worse than the rate for the saline expander/control device by more than 10%. Assuming that the success rate for both expanders is 95%, at least 92 breasts implanted with the study tissue expander and 46 breasts implanted with a saline expander would needed for a statistical power of 80% so that the lower bound of the 1-sided 95% confidence interval for the difference in the success rates (πTreatment − πControl) is greater than or equal to −10%. Roughly 20% of women undergoing reconstruction were expected to have a bilateral procedure, resulting in the need for at least 78 analyzable investigative subjects and 39 analyzable control subjects. Assuming 15% of subjects are not treated or are lost to follow-up, at least 92 subjects had to be randomized to the investigative group and 46 subjects to the control group. Early data are reported for those patients who have completed reconstruction.
Of the 82 women receiving implants to date, 58 (39 bilateral and 19 unilateral; bilateral rate, 67%) were implanted with CO2 tissue expanders and 24 subjects (15 bilateral and 9 unilateral; bilateral rate, 63%) were implanted with saline expanders. The bilateral rate for the combined population was 66% with a total of 136 expanders implanted. Preliminary expansion results were available for 55 women: 34 subjects in the CO2 group (19 bilateral, 14 unilateral for a bilateral rate of 56%) and 21 subjects in the saline group (12 bilateral, 9 unilateral for a bilateral rate of 57%).
Available mean time for active expansion, that is, the time needed to complete expansion, in the CO2 group was 18.2 (9.2) days (median, 14.0; range, 5–39; number of expanders, 53), which was less than the mean time for active expansion in the saline group: 57.4 (33.6) days (median, 55; range, 5–137; number of expanders, 33) (Fig. 2). Available mean time from implant placement to exchange for a permanent prosthesis in the CO2 group was shorter [106.3 (42.9) days; median, 99; range, 42–237; number of expanders, 53) than for the women in the control group [151.7 (62.6) days; median, 140; range, 69–433; number of expanders, 33] (Fig. 3). Five subjects in the CO2 group (8 expanders) had adverse events that were not related to the device but which lead to failed exchanges: cellulitis (n= 4) and infection with wound dehiscence (n = 1). Two subjects in the patient-controlled expander group experienced device related adverse events underexpansion (n = 1) and erosion (n = 1).
When asked to rate their experience using the patient-controlled expander at home, 99% of the respondents reported that the process was “mildly to very convenient.” The convenience question referred to the use of the dosage controller at home; there was not a corresponding question regarding saline expanders. For the purpose of evaluating how an expander filled with CO2 feels compared to an expander filled with saline, the subjects were asked to rate the firmness of their expanders just before exchange. From the saline expander group, respondents stated that 93% (25/27) of the expanders were moderately to very firm. Likewise, from the AeroForm expander group, 93% (71/76) of the CO2 expanders were moderately to very firm. Finally, 94% of the AeroForm respondents would recommend the device for other women undergoing breast reconstruction. Figures 4 and 5 illustrate 2 patients’ successful paths to reconstruction with bilateral, small AeroForm expanders.
We describe the successful use of a novel breast tissue expander system based on patient-controlled CO2 inflation among a preliminary group of women diagnosed with breast cancer or with positive BRCA1/2 mutations and who were randomized to the investigative device. The AeroForm Tissue Expansion System provided patients with significantly earlier transition to exchange for a permanent prosthesis than did the saline expanders and obviated the requirement for painful weekly bolus injections. Incremental dosing on a daily basis provided a more gradual method of tissue expansion. The results provide preliminary evidence that the CO2-based tissue expansion system performs the same function as saline expansion devices without significantly altering the risk to the patient and that the device has the potential to make the expansion process faster and more convenient for both the patient and the physician.
Of the new cases of breast cancer diagnosed annually in the United States, approximately 80,000 women choose total mastectomy.8,9 Of these procedures, implants represent approximately 60.5% of both delayed and immediate reconstructions, with 62.2% and 76.6%, respectively, accounting for unilateral and bilateral reconstructions.10 Implant-based breast tissue expansion is not without pain caused by the bolus injections and stretching of the pectoralis major. Such discomfort can be mitigated with the use of analgesics. The novel expansion system potentially allows patients to administer expansion doses in the comfort of their home and to expand at their own pace within preset limits. Home expansion may also minimize reliance on physician and surgical office and staff resources. Last, the system obviates the unpleasantness of multiple needle injections to achieve expansion.
Device-related complications were evident in 2 patients: erosion, which can occur with traditional saline expanders, and underexpansion due to permeation of CO2. After the observation of these complications and feedback from the investigators, the sponsor made several midtrial modifications to the expander to decrease the bulk of the expander, increase the durability of the inner bag, and to minimize stress on the inner bag material to decrease permeation. The modification also included a slight decrease in implant projection. The remainder of the subjects enrolled in the study will receive the modified device.
Strengths of this study are its RCT design and comparison with current standard of care devices. The principal limitation of this article is the interim nature of the results. Also, there is not a large enough sample size to stratify the data based on surgical approaches, such as use of ADM, intraoperative expansion volume, and technique. Surgical approach and technique could, theoretically, affect and rate of complications and the degree of patient satisfaction.
The AeroForm expander offers needle-free, patient-controlled tissue expansion with shorter time to full volume and less time to change to a permanent implant compared to saline expanders. To date, complication rates are similar to published complication rates for other tissue expanders. On the basis of the interim results, there is no difference in subjects’ perception of firmness of the CO2 expanders compared to saline expanders. As the trial progresses to completion, we anticipate seeing continued shorter overall times to complete both expansion and reconstruction for those women using the CO2 tissue expander system compared to those using saline expanders as well as data supporting patient and physician satisfaction with the investigational device.
The authors thank Mimi Wainwright, who provided research, writing, and editorial support to Dr Zeidler for the development of the manuscript. The sponsor paid Wainwright Medical Communications (Los Gatos, CA) for the associated work.
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Keywords:© 2014 by Lippincott Williams & Wilkins
breast cancer; mastectomy; breast reconstruction; BRCA1; BRCA2; carbon dioxide tissue expander; saline tissue expander; breast tissue expansion