Like the eB catheter, Contura has a port for a vacuum to remove fluid or air around the lumpectomy cavity; the use of this vacuum port can improve tissue-balloon conformance. A recent study by Wilder et al. They observed incidence rates of acute toxicity with a Contura device similar to those with a MammoSite device [ 86 ]. Brown et al. Hybrid devices were developed to take advantages of the versatility and dosimetric conformity of multicatheter interstitial brachytherapy with the convenience and aesthetics of a single entry device.
The peripheral struts can be differentially loaded with a HDR source. The device is inserted in collapsed form through a small incision; once placed, it is then expanded to fit the lumpectomy cavity by clockwise rotation of a knurled knob at the proximal end of the expansion device, expanding the peripheral struts and providing a pressure fit [ 89 ]. The outward pressure exerted by the expanded struts pushes against the cavity walls securing the struts in place. Some tissue invagination between the struts has been observed during the course of the treatment.
Radio-opaque markers are present on three of the peripheral struts number 2, 4 and 6 for identification during the reconstruction process in treatment planning. The SAVI device is surgically implanted on an outpatient basis by the treatment radiation oncologist using ultrasound guidance with the patient under local anesthesia. A CT scan is acquired immediately following the implant surgery, both for the verification of the proper deployment of the device, and for treatment planning. It was recommended by Scanderbeg et al [ 89 ], that although the device does not move independently to the body, one should always try to attain a position as close to the planned patient position due to breast deformation.
They found a breast board to be best for patient setup because of its ease of setup and reproducibility. CP was developed to combine the advantage of balloon brachytherapy and multicatheter brachytherapy. The CP consists of both inner and outer catheters that expand by rotating a knob on the base of the device Figure 9 [ 67 , 90 ]. The CP device contains six outer expandable plastic tubes to displace the tissue. The radii of expansion of these tubes are adjusted at the base of the device and can be expanded to conform to a similar shape and size as a balloon device.
In the center of the expandable tubes is a central catheter surrounded by six additional catheters that allow the passage of an HDR Iridium source. In contrast to the SAVI device, the radiation source is not in direct contact with the breast tissue. In addition, after the device is placed in the patient, the rubber sleeve is sutured to the patient, and the base of the device is cut off. This leaves only the catheters exposed and visible external to the patient's skin [ 91 ].
Normally a cap is placed over the HDR channels. This could potentially lead to increased patient comfort by eliminating the dangling external catheters.
Accelerated Partial Breast Irradiation (2nd ed.)
CP is a relatively new device and hence no clinical outcome data have been reported. However, retrospective dosimetric analysis has been reported [ 90 , 91 ]. Dickler et al. Similarly, Beriwal et al. The technique uses four to five tangentially positioned non-coplanar beams Figure The tumor bed is defined by the computed tomography visualized seroma cavity, postoperative changes, and surgical clips, when available.
The clinical target volume CTV is defined as the tumor bed with a 1. EBRT has many potential advantages, over the other techniques [ 95 ]. The technique is non-invasive and the patient is not subjected to a second invasive surgical procedure or anesthesia, thereby reducing the potential risk of complications. The treatment can wait until completion of pathological analysis about the original tumor and the status of the resection margins are available.
The technique has potential for widespread availability since most radiation therapy centers already perform 3D-CRT for other cancers. It is likely that an external beam approach will be easier for radiation oncologists to adopt than brachytherapy techniques because the technical demands and quality assurance issues are much simpler. Treatment results with external beam may be more uniform between radiation oncologists because the outcome depends less on the experience and operative skills of the person performing the procedure than for brachytherapy especially using interstitial implantation.
It seems less likely that technical issues arising during external beam radiation therapy will require the procedure to be aborted as is not infrequently the case when brachytherapy techniques are used. External beam is intrinsically likely to generate better dose homogeneity and thus may results in a better cosmetic outcome when compared with bracytherapy techniques. These include breathing motion, treatment setups variation, and the fractionation scheme adopted.
The target may move during breathing and the patient may be positioned differently for different fractions. To avoid missing the planned target, a large treatment volume is used. A prone patient position has been suggested by Formenti et al. The prone position also provides exceptional sparing of the heart and lung tissues. Unfortunately, the prone position is not widely used because it requires a special immobilization device and is uncomfortable for some patients.
Also, 3D-CRT delivers higher doses to normal breast tissue since the PTV around the lumpectomy cavity is increased to account to breathing and setup errors [ 97 ]. LC determination is critical because treatment delivery is delayed after breast surgery. Furthermore, the GTV and CTV are generally defined as the contouring of a seroma within the lumpectomy cavity, expanded by some margin, usually 1 cm [ 93 ]. However, the delineation of the seroma could vary among different observers and even among experienced ones [ 98 ]. It has been suggested by Dzhugasvili et al.
As evident in Table 3 different doses and fractionation schemes have been reported in the literature. Rosenstein et al. Livi et al. However, Cuttino et al. Intra-operative radiation therapy IORT refers to the delivery of a single fractional dose of irradiation directly to the tumor bed during surgery. These techniques have been reviewed by Reitsamer et al. Older intra-operative radiation therapy devices were technically cumbersome, commonly relying on the transportation of the patient from the operating theatre to the radiation therapy unit during surgery, or require custom-built intra-operative radiation therapy theatres [ ].
These technical and financial limitations to delivery of intra-operative radiation therapy have prevented widespread use of the approach. Advances in miniaturization technology have enabled the development of mobile intra-operative radiation therapy devices. Intra-operative radiation therapy was first used in with a device called the Intrabeam, since then, two other mobile linear accelerators have become available the Mobetron and Novac-7 systems. These systems either generate megavoltage electrons Mobetron and Novac-7 or kilovoltage photons intrabeam.
The potential advantages of IORT include delivering of the radiation before tumor cells have a chance to proliferate. Furthermore, tissues under surgical intervention have a rich vascularization, with aerobic metabolism, which makes them more sensitive to the action of the radiation oxygen effect. Also, the radiation is delivered under direct visualization at the time of surgery. IORT could minimize some potential side effects since skin and the subcutaneous tissue can be displaced during the IORT to decrease dose to these structures, and the spread of irradiation to lung and heart is reduced significantly [ ].
IORT eliminates the risk of patients not completing the prescribed course of breast radiotherapy a well-recognized risk of conventional breast radiotherapy and allows radiotherapy to be given without delaying administration of chemotherapy or hormonal therapy [ ]. IORT has the potential for accurate dose delivery: by permitting delivery of the radiation dose directly to the surgical margins, IORT eliminates the risk of geographical miss in which the prescribed radiation dose is inaccurately and incompletely delivered to the tumor bed.
There is potential for decreasing healthcare cost because it is one fraction as opposed to 25 fractions. With IORT the final pathology reports arrives days post-festum. This has been one of the major criticisms of the technique. So recently a novel handheld probe Dune Medical Devices, Caesarea, Israel has been developed for intra-operative detection of positive margins [ ] Such a device can help reduce re-excision rate and improve acceptance of IORT technique.
The system is composed of a miniature, light-weight 1. The miniature X-ray source has a probe of 10 cm length and 3. Within this device, electrons are accelerated to the desired energy level and focused down the probe to strike a gold target. Various spherical applicators with a diameter ranging from 1. They are fixed to the end of the source and placed in the excision cavity to obtain a homogeneous dose distribution on the surface of the applicator and consequently on the surface of the tumor cavity.
When mounted onto the Intrabeam unit, each spherical applicator conforms the breast tissue around the radiation source to permit delivery of a uniform field of radiation to a prescribed tissue depth. Accurate and uniform dose delivery is further achieved by placement of "pursestring" sutures within the breast to hold the pliable breast tissue against the applicator surface [ ]. The mobile X-ray intraoperative radiation therapy device: The Intrabeam device intraoperative photon device.
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Various spherical applicators with diameters ranging from 1. The X-ray system produces low-energy photons 50 KVp with a steep dose fall-off in soft-tissue; no special shielding is therefore required in the room [ ]. Dosimetry varies by applicator tip size with the commonly used 3. Treatment time lasts for approximately 20 to 45 minutes, depending on the size of the lumpectomy cavity, the size of the selected applicator, and the prescribed dose.
Treatment can be carried out in unmodified operating rooms with minimal exposure to the staff and patient; rapid dose fall-off in the tissue around the applicator guarantees minimal exposure of the surrounding tissue such as the lung and cardiac tissue in the patient. The physics, radiobiology, dosimetry, and early clinical applications of this low energy x-ray device have been fully evaluated, and the device has received Federal Drug Administration approval for use in any part of the body since [ ].
The RBE for this low-energy x-rays have been estimated to be 1. Another potential advantage of Intrabeam is that, because normal tissues can repair their damaged DNA within a few minutes but cancer cells with poor DNA- repair machinery may be unable to repair quickly. So treatment given over a long time intrabeam is between minutes may have a higher therapeutic index than giving similar doses over 2 to 3 minutes [ ]. This trial compares single dose intraoperative radiation therapy targeted to the tumor bed to conventional whole breast external beam radiation therapy in early breast cancer.
Data accrual was closed in May and the results of this trial have recently been published by Vaidya et al. In this trial patients were randomly assigned to the targeted intraoperative radiotherapy group and allocated to the whole breast external beam radiation therapy group. From this, patients received targeted intraoperative radiotherapy, only received targeted intraoperative radiotherapy with external beam radiotherapy and patients in the external beam radiotherapy group receiving the allocated treatment. They observed at 4 years follow up, there were six local recurrences in the intraoperative radiotherapy group and five in the external beam radiotherapy group.
The Kaplan-Meier estimate of local recurrence in the conserved breast at 4 years was 1. The rate of recurrence between the two groups was not statistically significant. Similarly the total rate of major toxicities was similar in the two groups[ ]. This study presents the first level 1 evidence of the equivalence of APBI using IORT to WBI and confirms that targeted IORT allows the entire dose of radiation therapy to be administered in a single fraction at the time of breast-conserving surgery, thus avoiding the need for repeated radiation therapy treatments or placement of in dwelling radiation therapy devices.
The Mobetron system Figure 13a is composed of three separate units: the control console, the modulator and the therapy module [ ]. The control console which operates the accelerator during radiation treatment delivery is placed outside the OR so that the radiation treatment delivery is controlled remotely.
The modulator houses the electronic systems of the accelerator and energizes the accelerator to produce the electron. The therapy module houses the accelerator guide and control systems that generate and deliver radiation [ ]. The Mobetron uses two X-band 3 cm wavelength, 10 GHz frequency collinear accelerators. This design eliminates the need for a bending magnet thus affecting a reduction in photon leakage [ ].
The mobile electron intraoperative radiation therapy devices: a Novac7 b Mobetron intra-operative electron device reprinted with permission Beddar el al. The NOVAC-7 system Figure 13b Hitesys, Latina, Italy delivers electrons with the use of a mobile dedicated linear accelerator; its radiating head can be moved by an articulated arm that can work in an existing operating room.
It is based on a compact S-band standing wave electron beam linear accelerator utilizing a patented auto-focusing structure which eliminates the need of focusing solenoids. The accelerator is moved by six axis robotic arm. It delivers electron beams at four different nominal energies 3, 5, 7 and 9 Mev [ ]. A single dose of 21 Gy with energies up to 9 MeV, biologically equivalent to Gy in standard fractionation is applied to the tumor bed.
The electron energy used is determined from the depth of the tissue to be irradiated. The accelerators used have been designed to have a dose rate Gy per minute higher than conventional and can deliver 21 Gy in less than 2 min [ ]. The entire procedure last for about 15 to 20 minutes. Unnecessary radiation to the underlying normal tissue can be avoided by mobilizing the mammary gland during surgery and placing a lead plate for shielding on its dorsal surface. The costs of the mobile linear accelerator with a robotic arm, used in intra-operative radiation therapy, are prohibitive for poor countries.
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Frasson et al. A systematic review by Cuncins-Hearn et al. The current evidence base is however poor, making definitive assessment on IORT very difficult. They suggested that further research is required to clarify several issues such as identification of the most appropriate subgroups of patients for IORT, a comparison of the currently available mobile IORT technologies, establishing whether IORT is most appropriate as a boost replacement dose or replacement for all postoperative radiation therapy, the examination of how biological repair processes may differ between the two treatment modalities and determining precisely where local recurrences originate with respect to the original tumor site.
The IORT approach has the advantage of shortening the treatment course further, conveniently delivering the entire course of local therapy at the time of initial excision. However, IORT also presents significant technical challenges, not the least due to the need for accuracy of target definition and treatment delivery inherent in a single dose radiotherapy delivery. One issue is the accuracy of tumor bed definition when tissues are re-approximated following excision.
Another is the variable margin of normal tissue irradiated in the re-opposed tissues. IORT may be complicated in patients who are determined to have positive surgical margins and need re-excision. This may not have been a significant issue in the Versonesi studies [ ], as all patients received generous resections with quadrantectomies. The issue of the need and utility of APBI is highly debated within the medical community.
There are those of the school of thought that the current standard of care for early breast cancer works well.
So, the frame of mind is "if it is not broken why fix it? On the other hand, there are those who belief that APBI has a role to play in the clinical management of early stage breast cancer [ ]. If the proliferation of APBI techniques is anything to go by, there is indeed a high level of interest. As reviewed in this paper, there are several different approaches to APBI, each with their merits and limitations Table 5 , [ ].
Patient selection is critical to the successful application of APBI[ ]. In a recent review, Polgar et al. Similarly in a recent study by Chen et al. These failures highlight the need to better define the subset of patients for whom APBI is most appropriate. Various societies have now published recommendations of patient selection criteria for APBI.
However, less restrictive criteria could be applied to patients who enrolled in a clinical trial. It also worth noting that these recommendations were determined from a systematic review of the APBI literature. The groupings were based primarily on an analysis of the characteristics of patients most frequently included in trials of APBI and not on data that identified subsets of patients with higher rates of ipsilateral breast tumor recurrence IBTR when treated with APBI. One concern regarding APBI is the proliferation of approaches; this inherently makes it difficult to elucidate the generic effect of APBI from the specific effect of a particular technique.
As described within this review, many dosing schemes have been used; the different fractionation schemes and different BED make it possible for a failure to occur due to inappropriate dosing rather than the fact that only a partial region of the breast had been irradiated using APBI. Taking the 3D-CRT approach as an example, see Table 3 many dosing schemes have been reported; for example, in the ELIOT studies, three different dose levels were used: 20 Gy seven patients , 22 Gy 20 patients , and 24 Gy 20 patients [ ]. Further, the use of soft x-rays as in Intrabeam and Xoft approaches introduce another concept of relative biological effectiveness; thereby introducing another variable when trying to determine the effectiveness of the dosing.
The basic tenet of radiation therapy is the delivery of a tumorcidal dose to the clinical target volume. In terms of applying APBI, there are questions of the appropriate target volume; is 1 cm or 2 cm enough margin for the irradiation of residual tumor? Depending on the particular technique, the delineation of this target can be problematic.
It has been well documented that inappropriate target delineation will result in under dosing of the tumor or irradiating excessive volumes of normal tissues and organ at risk [ ]. For non-brachytherapy techniques, substantial differences in delineation of the lumpectomy cavity have been observed, even by dedicated breast radiation oncologists [ 98 ]. The definition of the CTV is influenced by clinical features in the breast such as dense breast parenchyma, benign calcifications, low seroma clarity score, small volume and proximity to the pectoralis muscles [ ]. To facilitate the contouring, surgically placed clips after lumpectomy have demonstrated strong radiographic surrogates of the lumpectomy cavity [ 99 , ].
Also, written guidelines for contouring CTV have been shown to significantly reduce the inter-observer variability and minimize the volumes for radiation [ ]. Vicini et al. More recently, Polgar et al. The other techniques have shorter follow-up, with no local recurrence rates at 5 years follow up for MammoSite brachytherapy MSB [ 73 ], no reported recurrences in 10 to 28 months with single institution studies of 3D-CRT and 1.
It is now accepted that critical evaluation of clinical studies is appropriately done in terms of evidence based medicine. There are a few methodologies for reviewing the quality of the evidence including SORT strength of recommendation taxonomy [ ], Grade grades of recommendation, assessment, development and evaluation [ ] and CEBM center for evidence based medicine. This critical evaluation is usually done under the umbrella of a systematic review and meta-analyses. The present review was not designed as a systematic review, but as a detailed analysis focussed towards providing the details and nuances of the different techniques.
Nonetheless, an evaluation of a particular technique will not be complete without some assessment of its clinical validity. However, not all of these studies met the SORT recommendation of quality, quantity and consistency. The YBCG Yorkshire Breast Cancer Group [ ] and Christie Hospital[ ] trials lack consistency in terms of patient selection and appropriate target definition, So, these two trials only provides level 3 evidence of efficacy.
Accelerated Partial Breast Irradiation
The Hungary trial [ 63 ] lacks the sample size to detect a difference. Case control studies provide level 3 evidence of efficacy and validity. Hence clinical community awaits the results of the other ongoing trials for more data on the long-term effectiveness of these techniques. These trials have been examined in great details recently by Mannino and Yarnold [ 27 ] identifying the differences between them. These trials differ in patient selection criteria, radiotherapy technique used in the experimental APBI arm, radiation dose and fractionation scheme [ 27 , ].
The sample size also varies with the different trials. A larger sample size as required in the NSABP trial increases the power to detect smaller differences. In addition, a larger sample size makes it possible to study subgroups of patients with statistical power to detect a difference. If these trials accrue to target, almost women will be followed, hence providing level I evidence for or against the application of APBI in women with early stage breast cancer. Breast Conservation Therapy BCT in the Asia region has not observed the level of interest and growth observed in the western countries.
In Hong Kong, the limited usage of BCT has been associated with limited number of radiation therapy facilities [ ]. However, because of the increasing local experience in the administration of BCT, increasing numbers of young patients in the population and increasing efforts to promote breast cancer awareness in recent years, the use of BCT is steadily increasing [ ].
However, there is another issue in the application of APBI to the Asian population which is breast size. Asian women generally have smaller breast compare to European. Some of the APBI techniques might be challenging to apply to this patient group. In Japan for example, excision involving 2 cm free margin from the tumor is most commonly performed.
In many cases mammary gland tissue does not remain on the dermal or pectoralis muscle sides of the tumor. The target of irradiation is only the lateral stump [ 23 ]. Hence APBI techniques like the Mammosite will not be very applicable in the Asian population, because of potential excessive radiation dose to the skin. However, treatment results have not yet been published. When irradiation is performed in the supine position, flat extension of the breast reduces the distance between the target of the irradiation and the skin, leading to excessive exposure of the skin. The coverage of the target varies depending on the technique.
There are limited studies evaluating multiple techniques [ ]. Dosimetrically, the best partial breast irradiation technique appears to depend on the clinical situation. In addition to local control, improved survival and better cosmesis, quality of life is also an important variable in evaluating treatment technique for breast cancer patients; with limited studies evaluating QOL aspects of breast cancer treatment.
Reports evaluating QOL for the different APBI have not been reported to date; although patients undergoing Mammosite have been reported to be very satisfied with their outcome [ ]. In the age of rapidly increasing health care costs, evaluation of techniques has to include cost effectiveness. Cost comparisons have been reported by Suh et al. The cost of HDR treatment delivery was primarily responsible for the increased direct medical cost.
APBI approaches in general were favored over whole-breast techniques when only considering costs to patients. Similarly, Sher et al. Unless the quality of life after MSB proves to be superior, it is unlikely to be cost-effective [ ]. As eluded in this review, there are still a few unanswered questions including optimal technique, patient selection and target volume definition. As reviewed herein, there are quite a variety of techniques available for APBI, but with insufficient clinical and dosimetric data to determine the optimal technique.
It is worth noting that none of the current RCT will address this issue since a direct comparison of the technique is not part of any of the current trials. So research is required to determine a what is the optimal technique? Breast size and location of the lumpectomy cavity might dictate which technique to use. For example, small breasted patients might be best suited for IORT, while larger breasted are best served by balloon based brachytherapy techniques such as the MammoSite.
There is yet to be a consensus in terms of which patients characteristics are suitable for APBI. Different societies have come up with varying patient selection criteria. Current data analysis shows that these recommendations might not be optimal. Therefore there is a need for a definitive clinical and pathological criteria for APBI patient selection. As reviewed herein, the volume of breast tissue irradiated varies with the technique used.
Empirical and pathological studies are required to determine the level and degree of spread of micro-calcification. This will give a definitive guidance on how much tissue needs to be irradiated. There is growing evidence that the linear quadratic model LQM may not be appropriate for modeling high dose per treatment[ , ]. It has been suggested that LQM consistently overestimates cell killing at high single doses because it predicts a survival curve that continuously bends downward, whereas the experimental data are consistent with a constant slope D0 at high doses.
Furthermore, high-dose radiotherapy is achieving higher local control than could be explained by our current knowledge of radiation killing of cancer cells in a tumor. Proper radiobiological modeling is required to determine the optimal dose for APBI and fractionation scheme for the different techniques. The impact of the radiation energy used in determining the dosing also has to be investigated. For example, the dose for low energy x-rays will be different from the dose needed for high energy x-rays.
The role of imaging in the management of most diseases is unquestionable. This is also true for breast cancer management.
The success of APBI depends highly on the ability to identify patients at low risk of multi-centric disease. Hence, the appropriate imaging technique has to be determined. For example, the value of adding a preoperative breast MRI to conventional mammography remains controversial[ ]. Hence, an imaging technique is required to increase the specificity and sensitivity of multi-centric disease diagnosis. The interest in APBI is evident from the proliferation of approaches and devices. However, studies are required, not only to evaluate the efficacy of APBI, but also to assess the safety and toxicity of the various techniques and dosing schedules.
Furthermore, it is hoped that more research will be carried out to determine the strengths and weaknesses of the different techniques; thereby creating a consensus and identifying where each technique may be best applied. Whole Breast Irradiation WBI as part of Breast Conservation Therapy has well established results in terms of disease control, good cosmesis, and low toxicity. The acceptance of APBI as a standard of care therefore rides on its ability to match or better WBI in terms of efficacy, quality of life outcomes, and cost-effectiveness.
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