Rationale for APBI
Although WBI remains the most common technique for delivery of radiation following BCS, APBI has been employed for many years, and interest surrounding its use continues to grow. The rationale for APBI stems from the observation that the majority of breast cancer recurrences occur near the primary tumor site.[23-26]Although multicentric disease can be found in a proportion of mastectomy specimens, the rate of breast cancer diagnosed outside the vicinity of the surgical cavity following WBI may not be significantly different than that for an unirradiated or contralateral breast.[27,28] Therefore, confining radiation to the area immediately surrounding the tumor may provide equivalent rates of primary tumor control, while sparing radiation to regions that are at low risk of harboring clinically relevant microscopic disease. APBI can also potentially minimize the dose to adjacent normal structures, including the heart, lungs, ribs, and soft tissues, which could reduce the risk of radiation-induced late complications.
Because less total tissue is irradiated, higher daily doses can be delivered over fewer fractions. Fewer treatment visits may improve patient satisfaction and quality of life by minimizing the psychological and physical strain associated with treatment.[29,30] Shorter courses of therapy could also improve compliance with radiation in elderly and geographically isolated patients, populations shown to have lower compliance with radiation following BCS.[31-33] Finally, some forms of APBI could improve efficiency and decrease the cost of treatment.[34,35]
APBI Techniques and Non-randomized Experiences
Several techniques have been developed to deliver APBI. Although the modalities vary significantly, all are designed to deliver therapeutic doses to the tissue near the surgical cavity that is believed to be at highest risk of recurrence.
External beam radiation techniques similar to those used for WBI have been adapted to deliver APBI. These techniques have the advantage of being noninvasive and can utilize many of the same treatment planning and delivery tools as WBI. Typical doses are 36 to 38.5 Gy in 10 fractions delivered twice daily over a period of 5 days. Conformal 3D-RT or IMRT planning can be used, and a variety of beam arrangements have been described. Early results from a number of institutional reports appear to be favorable.[36,37]RTOG 0319, a phase I/II trial with 58 patients, showed an IBTR rate of 6% (4% within the treatment field), and 2 patients with grade III skin toxicity at 4.5 years. Toxicity analysis of a randomized trial comparing conventional WBI vs IMRT-based APBI showed lower rates of acute skin toxicity in the APBI arm. No clear dose–toxicity relationship has been identified, and although initial results are promising, long-term follow-up is lacking.
Interstitial brachytherapy using multiple catheters and high-dose rate (HDR) or low-dose rate (LDR) sources was originally developed to deliver a boost dose to the surgical cavity following WBI, but has also been adapted to deliver APBI. The number and position of catheters are determined by the size and shape of the surgical cavity. Once inserted, the catheters are loaded at predetermined locations, to deliver the target dose to the breast tissue immediately surrounding the surgical cavity. Iodine-125 sources are typically used for LDR delivery and are prescribed to be delivered to a total dose of 45 to 50 Gy. Iridium-192 is the most common HDR source and is prescribed to 34 Gy, typically given over 10 fractions (twice daily for 5 days). Because of the steep dose falloff, interstitial brachytherapy allows for rapid delivery of high radiation doses to target tissues with nearly complete sparing of surrounding normal structures. However, due to the invasive nature of the procedure, infection, fat necrosis, or scarring can occur.
Several interstitial brachytherapy experiences in early-stage breast cancer have been published. RTOG 95-17 enrolled 100 stage I/II breast cancer patients who were treated with catheter-based HDR or LDR brachytherapy. IBTR rates for HDR and LDR techniques were 3% and 6%, respectively. A separate toxicity analysis revealed two grade 3-4 toxicities with HDR and three grade 3-4 toxicities with LDR. The 10-year cumulative incidence of IBTR in a series of patients treated with interstitial brachytherapy at William Beaumont Hospital was 5%, with a matched-pair analysis showing outcomes similar to those of patients treated with WBI. The 5-year rate of fat necrosis in these patients was 11%, but 95% to 99% of cosmetic outcomes were reported as good to excellent. However, 12-year results from a series of 50 patients treated with LDR interstitial brachytherapy showed six cases of IBTR (12%), somewhat lower rates of acceptable cosmesis (67% good to excellent results, 54% moderate to severe fibrosis), and more treatment-related toxicity with longer follow-up.
Intracavitary brachytherapy is an alternative brachytherapy technique that can be used to deliver APBI. The most commonly used intracavitary device is the MammoSite applicator, which was approved by the US Food and Drug Administraion (FDA) in 2002. The device is inserted into the lumpectomy cavity several days following surgery (after pathologic confirmation of margin status) and inflated. A CT scan is obtained for treatment planning, and iridium-192 is afterloaded into a single lumen in the center of the balloon to deliver the prescribed dose at the surface of the lumpectomy cavity surrounding the balloon. Alternate devices with multiple lumens are also available and allow for greater flexibility in treatment planning. A dose of 34 Gy is delivered in 3.4 Gy fractions given twice daily over a period of 5 days. Following treatment, the balloon is deflated and removed. Advantages of intracavitary brachytherapy include its ease of use compared with interstitial techniques and its reproducibility in delivery of radiation dose to the balloon surface. However, problems with dose homogeneity can occur when the surgical cavity is irregularly shaped, and treatment of superficial cavities can lead to higher skin dose and increased toxicity. The 5-year rate of IBTR in more than 1400 patients enrolled on the MammoSite registry is 3.8%, with good-to-excellent cosmetic results reported in 90.4%. Two-year data from a multi-institutional series of 483 patients treated using the MammoSite applicator show a 1.6% IBTR rate and 90% good-to-excellent cosmetic outcomes. A recent population-based retrospective analysis of 92,735 older women treated with WBI or brachytherapy-based APBI showed a significantly increased incidence of subsequent mastectomy as well as higher rates of post-operative complications, breast pain, fat necrosis, and rib fracture in patients treated with brachytherapy.
Intraoperative radiation is another technique for delivery of APBI, and is administered in a single fraction to the lumpectomy cavity immediately following tumor removal. One technique, TARGIT (TARGeted Intraoperative radioTherapy), employs low-energy x-rays emitted from a source located at the center of a spherical applicator placed within the surgical cavity. The prescription dose of 20 Gy at 0.2 cm depth and 5 Gy at 1 cm depth is delivered over a period of several minutes, after which time the applicator is removed and the surgical incision is closed. The technique has been criticized for not delivering adequate dose to a sufficient margin around the cavity. Another technique, ELIOT (ELectron beam Intraoperative radioTherapy), employs a dedicated linear accelerator in the operating room to deliver electron beam radiation. Although not widely practiced in the US, intraoperative radiation has the advantage of being completed in a single day and treats the operative bed in its native state prior to surgical closure. In a series of more than 1800 women treated with quadrantectomy followed by intraoperative radiation with electrons, the rates of local recurrence and new primary ipsilateral cancers at 36 months were 2.3% and 1.3%, respectively, while rates of fat necrosis and fibrosis were 4.2% and 1.8%, respectively. A disadvantage of intraoperative radiation is that pathologic information regarding margin status and lymph node involvement are not available at the time of treatment. If unfavorable pathologic features are found, subsequent WBI can be administered. When used as a boost prior to planned post-operative WBI, intraoperative delivery of 20 Gy to the surgical cavity was associated with a 5-year IBTR rate of 1.7%.