Rating today’s evidence
Assistant Professor of Surgery, Mayo Medical School, Mayo Clinic
Assistant Professor of Surgery, Mayo Medical SchoolNicole
Multidisciplinary Breast fellow, Mayo Clinic, Rochester, MN
Early findings show APBI is feasible for some forms of early breast cancer, but ongoing studies are needed.
A 56-year-old woman with stage I infiltrating ductal carcinoma underwent breast conservation surgery. She had negative margins and her sentinel lymph nodes were negative. She lives in Hawaii and has limited access to a radiation treatment facility.
Accelerated partial breast irradiation (APBI) may be a good option for her. It concentrates the radiation to a partial volume of the breast over 1–2 weeks compared with the 6–7 weeks that conventional whole-breast irradiation (WBI) demands. Possible advantages of APBI include convenience, less toxicity, good cosmesis, and adequate local control.
FIGURE 1 Intraoperative radiotherapy
IORT is more popular in Europe. In this modality, a single-dose applicator is inserted into the lumpectomy cavity immediately after removal of the neoplastic tissue.
The promise of APBI
The principle of APBI is based on the rationale that most in-breast recurrences occur within centimeters of the original disease site. Although several PBI techniques are available, they all share the primary advantage of a shorter treatment schedule with improved convenience of treatment.
Early experience suggests APBI is a feasible treatment option for selected early breast cancer patients following breast-conserving surgery. However, this modality remains an investigational treatment with unknown long-term efficacy and complication rates until the current prospective trials mature. Whether APBI can truly deliver these promises is the subject of ongoing investigations. This article discusses the rationale for APBI, reviews the different techniques, and updates the prospective phase-III randomized trials.221
Rationale for APBI
Over the last 20 years, prospective randomized trials have demonstrated that survival for breast conserving therapy, or BCT, (which is lumpectomy followed by radiation to the entire breast) was equivalent to mastectomy.1-3 In the National Surgical Adjuvant Breast and Bowel Project (NSABP B-06 trial), women who had lumpectomy alone showed a local recurrence rate of 39% at 20 years. That decreased to 14% when radiotherapy was added.1
Postlumpectomy radiotherapy significantly reduces the risk of recurrence in the region of the tumor bed. The region at highest risk for microscopic residual disease and for in-breast recurrence is within 1–2 cm of the surgical bed.4
Recurrence rates away from the tumor bed are similar after lumpectomy alone or followed by whole-breast radiotherapy.2 Patients with new breast primaries have significantly better survival and lower metastasis rates than those with true recurrence. Treatment of the tumor bed can decrease the rate of local disease recurrence.5
Clinical and nonclinical influences
Factors the patient and physician must take into account when considering BCT versus mastectomy are daily access to a radiation facility for 5–6 weeks, transportation, geographic proximity, local toxicity, and employment status.6,7 Their relevance may explain why many American women who are candidates for BCT do not have that treatment.
Patient compliance with radiation is critical for the success of BCT. Only 36% of patients in one center completed the course of therapy and clinical follow-up.8
Ongoing prospective randomized trials
Numerous prospective randomized trials that compare whole-breast irradiation and accelerated partial breast irradiation are under way.18 These trials have been accruing rapidly, which attests to the desirability of APBI from a patient’s perspective. They include:
NSABP-39/RTOG-0413 trial, a randomized phase-III study enrolling women with stage 0, I, and II breast cancer. The eligibility criteria include stages 0-II carcinoma of 3 cm or less, histologically negative margins, no more than 3 positive axillary positive lymph nodes, age 18 or older, and a target lumpectomy cavity less than 30% of the breast volume. It excludes patients with extensive intraductal component, carcinoma of 3 cm or greater, and more than 3 positive nodes.
Those randomized to APBI may receive catheter-based interstitial brachytherapy, balloon-based brachytherapy using MammoSite, or 3D CRT. This study aims to identify selection criteria and document patterns of recurrence as well as acute and chronic toxicities. The NSABP/RTOG closed accrual to women 50 years or older with DCIS regardless of hormone receptor status, and women 50 years or older with invasive node-negative and hormone-receptor positive breast cancer. This was in response to concerns the trial population was skewed toward women at lower risk of ipsilateral breast tumor recurrence, perhaps due to radiation oncologists’ bias against the use of APBI in high-risk patients. The trial also increased the sample size by 1300 patients.
Veronesi’s group in Italy. A second major trial of APBI is under way involving 824 patients randomized to 60 Gy WBI or 21 Gy ELIOT for lesions less than 2.5 cm.
The University College of London trial. This study is comparing WBI to single-dose intraoperative-beam radiation therapy of 5 Gy in 1600 patients.
TARGIT, or Targeted Intraoperative Radiotherapy Trial. This phase-III international, randomized clinical trial is comparing targeted intraoperative radiotherapy and conventional WBI. Thirteen centers in 6 countries with 779 randomized patients have contributed to the study.19—ACD, JCB, NS
Is APBI the answer?
If local recurrences occur predominantly in the tumor bed, can one reduce the volume of radiotherapy along with treatment time and toxicity? APBI decreases the time required for radiotherapy, potentially reduces toxicity, and possibly improves patient quality of life.
APBI differs from WBI in these ways:
WBI involves administering a total dose of at least 50 Gy to the entire breast. This is usually delivered in 25 fractions of 2 Gy, 5 days a week, over approximately 6 weeks.
APBI delivers radiation therapy to the lumpectomy cavity plus a 1–2-cm margin after breast-conserving surgery in the patient with early stage breast cancer. The radiotherapy is completed in 4–6 days rather than over several weeks.
The four APBI techniques
Four techniques for APBI are available: interstitial brachytherapy, intracavitary brachytherapy, intraoperative radiotherapy, and 3D conformal radiotherapy.
Multicatheter brachytherapy is the oldest form of partial-breast irradiation. This treatment places 15–25 small hollow catheters about 1–1.5 cm apart in the surgical bed intraoperatively or shortly after tumor excision. A template guides the transcutaneous catheter, thus allowing uniform placement.
Low-dose rate (LDR) brachytherapy uses 0.4–2 Gy/hr while high-dose rate brachytherapy (HDR) uses dose rates greater than 12 Gy/hr. Studies of HDR reported good cosmesis and recurrence rates of 2% and 2.5% at median follow-up of 65 months and 7 years, respectively.9,10 Advantages of interstitial brachytherapy include:
Good control of radiation administration with the ability to tailor the dosing.
Limited toxicity to healthy tissues.
Short treatment sessions each lasting as little as 10 minutes over 5 days.
Disadvantages of this approach include the sophisticated planning required as well as the risks of infection and scarring from multiple skin puncture sites.
One advantage of interstitial brachytherapy is that it achieves good control of radiation with the ability to tailor the dosing.
Intracavitary brachytherapy offers technical simplicity. The devices may be placed intraoperatively or postoperatively. However, disadvantages of these modalities are infection, radiation dermatitis, and balloon conformation that may make it difficult to achieve adequate skin spacing to treat an asymmetric cavity.
In 2002, the FDA approved a balloon-tipped interstitial catheter for intracavitary brachytherapy (MammoSite Radiation Therapy System, Cytyc Corporation, Palo Alto, CA) (FIGURE 2).
FIGURE 2 Double-lumen catheter
The MammoSite device delivers high-dose radiation transcutaneously into the lumpectomy cavity either at the time of lumpectomy or postoperatively using US guidance (Courtesy Cytyc Company).
This is a double-lumen catheter with a central lumen that accommodates a high-dose radiation source (usually Ir-192). The catheter is placed transcutaneously with ultrasound guidance into the lumpectomy cavity either during the lumpectomy or postoperatively. The catheter and balloon must be positioned precisely: the balloon-to-skin distance is greater than 7 mm; the balloon conforms to more than 90% of the lumpectomy surface; and symmetry exists between the balloon and the center shaft.223
A registry trial of 1500 patients treated with the MammoSite device has reported ipsilateral breast recurrences in 1.2% with mean follow-up of 15 months, but the trial is ongoing until patients have completed 7-year follow-up.10,11 Excellent or good cosmetic results have been reported in 93%, with an overall infection rate of 8% (5.3% was device-related).10,11
Radiation dermatitis in study subjects correlated with the distance from the skin to the radiation device, with a rate of 19.7% in the group with device-to-skin distance of 7 mm or greater versus 64% in those with device-to-skin distance of 5–7 mm.12 The device was explanted in 9% for suboptimal skin distance, positive margins, and irregular cavity.9
Expandable bundle device
Another intracavitary brachytherapy device is the Strut Adjusted Volume Implant, or SAVI (Cianna Medical, Inc, Aliso Viejo, CA) that received FDA clearance in 2006 (FIGURE 3A). This device consists of an expandable bundle of catheters that surround a central lumen, allowing multicatheter treatments with a single-entry approach. Delivery of radiation through individual catheters allows better contour and control of dosing. It combines the tissue-sparing dosimetry of interstitial brachytherapy with the single-entry ease of intracavitary balloon brachytherapy.
A similar system, the ClearPath HDR device (North American Scientific, Inc, Chatsworth, CA), aims to address skin margin issues with the advantage of a continuous release form (FIGURE 3B). This device inserts I-125 strands to achieve continuous exposure, allowing the patient to return home during treatment. A fully shielded comfortable bra protects others in close contact with the patient.
FIGURE 3 Alternative brachytherapy devices
The Strut Adjusted Volume Implant, or SAVI, (A) consists of an expandable bundle of multiple catheters for a single-entry approach (Courtesy Cianna Medical).
The ClearPath device (B) applies continues exposure that allows the patient to return home during treatment (Courtesy North American Scientific).
This technique delivers a high single-fraction radiation dose directly to the tumor bed intraoperatively, immediately after removal of the neoplastic tissue (FIGURE 1). A radiation generator transportable to the operating suite delivers the single-fraction IORT. This modality is more popular in Europe than the United States.
The advantages of intraoperative radiotherapy are maximal treatment convenience for the patient and sparing of normal tissue.
The advantages of intraoperative radiotherapy are maximal treatment convenience for the patient and sparing of normal tissue. Disadvantages are the need for dosimetric quality assurance and dedicated equipment, and delivery of radiation without the benefit of pathologic confirmation.
Devices that provide mobile IORT include the Intrabeam (Carl Zeiss Surgical, Oberkochen, Germany) and the Mobetron System (Intraop Medical Corporation, Sunnyvale, CA).
The Intrabeam emits soft x-rays at 50 kV peak via a 3.2-mm-diameter probe that can be covered with different size applicators to match the cavity size. It delivers doses of 20 Gy at the surface of the applicator and 5 Gy at 1 cm over a 30-min period. The Mobetron emits MeV electrons via a collimator tube. A lead shield on the pectoralis fascia under the breast protects the lung.13224
Complications of electron intraoperative therapy include liponecrosis, hematoma, and mild fibrosis.
Electron intraoperative therapy (ELIOT) has been pioneered by Umberto Veronesi and colleagues in Milan, Italy.13,14 This technique delivers a dose of 21 Gy over 3 minutes via a collimator placed in the operative field under direct vision.
Complications among the 921 patients Veronesi’s group treated included liponecrosis (4.2%), hematoma (1.3%), and mild fibrosis (2.6%). The local recurrence rate was 1.6%. Veronesi’s group is now conducting a prospective trial comparing BCT with conventional radiotherapy and BCT with ELIOT of 21 Gy.
Three-dimensional conformal radiation therapy (3D CRT) is a noninvasive method of delivering APBI that requires computer planning and localizing techniques. This modality uses CT scanning to image the lumpectomy cavity and plan the target volume.6 Among the advantages 3D CRT offers are:
Increased dose homogeneity.
No need for catheter placement.
Utilization of equipment already present in the radiation suite.
Two reports of 3D CRT have been published.15,16 In the phase-I/II PBI trial of 95 patients, median follow-up at 10 months showed no observable effects of radiotherapy, no recurrences, and a 100% rating of good cosmesis.15
The Radiation Therapy Oncology Group (RTOG) study 0319, a phase I/II trial, showed the feasibility and reproducibility of delivering APBI via 3D CRT across multiple institutions.16 This study evaluated 58 patients with stage I or II invasive ductal carcinoma 3 cm in diameter or less with negative surgical margins. Each was treated with a total of 38.5 Gy in 10 fractions over 5 days.
Evidence-based recommendations for APBI
The rationale for accelerated partial breast irradiation (APBI) is based on the majority of local recurrences occurring in close proximity to the tumor bed. Level of evidence: 1b—individual randomized clinical trial with narrow confidence interval.
Patients with breast cancer less than 3 cm in size with histologically negative margins and no more than 3 positive axillary lymph nodes are the best candidates for APBI. Level of evidence: 2b—based on individual cohort study.
Multiple institutions are able to effectively perform similar interstitial catheter-based implants so there is a high degree of reproducible homogeneity. Level of evidence: 2b.
APBI appears to be equivalent to whole-breast irradiation in terms of local recurrence, failures elsewhere, cosmesis, and survival with a median follow-up of 5 years. Level of evidence: 2b.—ACD, JCB, NS
APBI concerns and contraindications
Investigators must address several concerns before APBI becomes widely used. Fore-most is the oncologic issue of local recurrence. Large-scale, longer-term follow-up is needed before the efficacy of APBI can be compared with WBI. Likewise, published data are limited on the long-term effects on cosmesis and local complications of acute and chronic toxicity, including fibrosis.
The studies that have been published have included patients with early stage disease, so only very early results regarding cosmesis and efficacy are available.11,12 Also, controversies surround the use of APBI for ductal carcinoma in situ (DCIS). APBI treats a limited field, whereas DCIS can be multifocal.17
The operator applies the intraoperative radiation without knowledge of final pathology and margin status, and concerns persist about the increased risk of axillary recurrence if PBI is pursued without axillary treatment fields in patients with 1–3 positive axillary nodes.
The authors have no affiliations to disclose.
CPT Advisor: Codes for APBI treatments
The following CPT codes may apply for breast cancer treatment:
Interstitial brachytherapy. The appropriate code depends on the number of radiation source applications. Choices are:
77776, Interstitial radiation source application; simple, is reported for the application of 1–4 sources.
77777, Interstitial radiation source application; intermediate, is for 5–10 sources.
77778, Interstitial radiation source application; complex, is reported for more than 10 source applications.
Intracavitary brachytherapy. Again, the appropriate code depends on the number of radioactive sources.
77761, Intracavitary radiation source application; simple, is reported for the application of 1–4 sources.
77762, Intracavitary radiation source application; intermediate, is for 5–10 sources.
77763, Intracavitary radiation source application; complex, applies for the intracavitary application of more than 10 sources.
Balloon-tipped catheter brachytherapy. Coding depends on the approach and type of catheter used.
19296, Placement of radiotherapy after loading balloon catheter into breast for interstitial radioelement application following partial mastectomy. This includes use of the MammoSite device with image guidance, and on a date separate from partial mastectomy.
+19297. Use this code concurrent with partial mastectomy (list separately in addition to code for primary procedure), in conjunction with CPT codes 19301 or 19302.
19298, Placement of radiotherapy after loading brachytherapy catheters (multiple tube and button type) into breast for interstitial radioelement application following (at the same time of or subsequent to) partial mastectomy. This also includes imaging guidance.
Other codes that may apply in the treatment of breast cancer are:
77300–77334, External beam radiation therapy (teletherapy).
77750–77799, Clinical brachytherapy. This modality may be used as a standalone treatment or in conjunction with external beam radiation therapy, surgery, or chemotherapy. Only the radiation oncologist supervises radioelements administration, dose prescription, and delivery. The radioactive material can be implanted permanently or temporarily via tubes, seeds, ribbons, or surface applicators.
77789, Surface application brachytherapy. This involves the application of sources placed directly on the skin or other external target surface.
John F. Bishop, PA-C, CPC
President, Bishop & Associates, Inc, Tampa, FL
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