Current Application and Research Directions for Partial-Breast Irradiation

Patient Selection

Accurate patient selection for APBI is critical to prevent locoregional failures. To date, the American Brachytherapy Society (ABS) and the American Society of Breast Surgeons (ASBS) have released similar versions of patient selection criteria for APBI, based mainly on single-institution, retrospective and prospective studies (Table 1).

The ABS criteria for patient selection include age older than 45 years, tumor ≤ 3 cm in greatest dimension, invasive ductal histology, negative lymph node status, negative marginal status (defined as "no tumor at ink"), applicator placement within 10 weeks of final lumpectomy procedure, and a postlumpectomy cavity with one dimension of at least 3.0 cm.[36] Very similar to the ABS recommendations, the ASBS recommendations include age older than 45 years, tumor ≤ 3 cm in greatest dimension, in situ or invasive ductal histology, negative lymph node status, and negative marginal status (defined as 2 mm in all directions). However, the criteria developed by these societies are based on data from small, nonrandomized studies from single-institution experiences. Prospective, randomized studies are needed to further elucidate patients that may or may not benefit from APBI.

The NSABP B-39/RTOG 0413 trial randomizing patients to WBI vs APBI uses the following criteria: age ≥ 18 years, in situ or invasive ductal histology, tumor size ≤ 3 cm, negative margins, a target lumpectomy cavity ≤ 30% of the breast volume, and, if invasive histology, 0 to 3 positive axillary nodes with a minimum of 6 sampled nodes, or negative sentinel node. This study will help to further refine selection criteria for APBI, including whether patients in younger age groups, patients with ductal carcinoma in situ, and patients with limited positive nodal status are suitable candidates. Given the survival benefit seen in patients with positive nodes after mastectomy and irradiation of the chest wall and regional nodal groups, inclusion of patients with positive nodes as candidates for APBI without regional nodal irradiation has been debated.[37,38] Other clinicopathologic features such as extensive intraductal component, invasive lobular histology, and lymphovascular invasion still need to be investigated.

The results of the NSABP/RTOG randomized trial, which includes patients with these features, may help to refine selection criteria for women considering APBI as an alternative to WBI. Until more data are available, it appears that the use of APBI per ABS or ASBS recommendations represents a reasonable cohort of patients to consider for partial-breast irradiation. However, we advise the enrollment of patients for APBI on clinical trials, to help to identify selection criteria, document patterns of recurrence as well as acute and long-term toxicities, and develop alternative technical approaches and fractionation strategies.

Current Techniques and Experience in APBI

The goal in APBI is to deliver a homogeneous dose of radiation in a short period of time to the tumor bed with additional margin. This may be achieved using several distinct radiotherapy techniques and include multicatheter interstitial brachytherapy, balloon catheter brachytherapy, 3D-CRT, and intraoperative radiotherapy (IORT), each of which is vastly different from one another in terms of degree of invasiveness, radiation delivery, operator proficiency, acceptance among radiation oncologists, and length of treatment. These techniques are able to deliver a homogeneous dose of radiation to the target area, which in theory is radiobiologically equivalent to conventional protracted whole-breast irradiation with respect to local tumor control, and acute and long-term toxicity.

A considerable amount of phase I/II data are available from investigations of APBI, with local control rates similar to those of WBI at 5 years. However, most of these data evolved from patients who received multicatheter interstitial breast brachytherapy, which is an intricate, labor-intensive procedure that requires skill on the part of the radiation oncologist. More recently, the MammoSite balloon catheter, external-beam radiotherapy (EBRT), and intraoperative radiotherapy have been investigated as alternative methods of APBI.

Multicatheter Interstitial Brachytherapy

Originating as a technique for delivering a tumor bed boost following WBI, the use of multicatheter, interstitial brachytherapy has been the longest-used method of APBI (Table 2). With this approach, flexible afterloading catheters are placed through the breast tissue in several planes, to ensure adequate coverage of the lumpectomy cavity with margin (Figure 1). Generally, these catheters are placed at 1- to 1.5-cm intervals in several planes, for a total of 10 to > 20 catheters, to ensure a homogeneous dose covering the target area.

Low-activity sources with dose rates in the range of 0.4 to 2 Gy/h are used in low-dose-rate (LDR) brachytherapy, while high-activity sources with dose rates greater than 12 Gy/h are used in high-dose-rate (HDR) brachytherapy. Medium-dose-rate (MDR) and pulsed-dose-rate (PDR) brachytherapy have also been investigated as alternative methods. With respect to APBI, LDR sources are implanted for approximately 2 to 5 days while the patient is admitted as an inpatient, whereas HDR brachytherapy allows for an outpatient treatment, fractionated over the course of a week, with a treatment time on the order of seconds to minutes. Implants are carried out using iridium (Ir)-192 sources of uniform or varying source activities. Remote afterloading with HDR brachytherapy allows for flexibility in treatment planning, given programmable dwell times for each catheter. Some critics of HDR brachytherapy have commented that although a homogeneous does is delivered to the treatment volume, the dose rate varies enormously during the course of treatment, which may have a differential effect on cell kill.[39]

• US Trials—Kuske et al investigated the use of LDR and HDR interstitial implants following lumpectomy in patients with DCIS or invasive ductal histology, with a tumor size < 4 cm, negative margins, and 0 to 3 positive axillary nodes.[40] They randomized 50 patients in block fashion to either LDR (45 Gy over 3.5-6 days) or HDR (32 Gy over 4 days in eight fractions). The target volume included the lumpectomy cavity with 2 cm of breast tissue. In their original report with a median follow-up of 75 months, there was only one breast recurrence (2%) and three regional nodal failures (6%), with only one nodal failure among the nine patients who had positive nodes upon study entry.

In a retrospective, case-control study, King et al identified patients who met the eligibility criteria for the brachytherapy trial but who received WBI.[41] They matched these patients according to characteristics including tumor size, breast size, and pathologic stage. Using this case-control cohort, they found no difference in breast recurrences (2% vs 5%) and locoregional recurrences (8% vs 5%) in patients treated with APBI and WBI, respectively. There was also a nonsignificant difference in terms of cosmesis rated as good or excellent at 20 months between the APBI and WBI groups (75% and 85%, respectively).

Vicini from the William Beaumont Hospital group has the largest experience using interstitial brachytherapy with the longest reported follow-up. In this study of 199 patients with early-stage breast cancer,[42] 80% were treated on institutional protocols with the following criteria: invasive ductal histology, tumor size < 3.0 cm, negative margins (≥ 2 mm), age > 40 years, and negative lymph nodes. The other 20% were treated with APBI for "compassionate" reasons and included patients with close margins, DCIS, participation in other studies, and timing of radiotherapy after lumpectomy. The median age was 65 years, and 12% of patients had one to three positive lymph nodes.

A total of 120 patients were treated with LDR brachytherapy, receiving 50 Gy over 96 hours, while the rest of the cohort underwent HDR brachytherapy, receiving either 32 Gy in 8 fractions or 34 Gy over 10 fractions.[42] The target volume included the lumpectomy cavity with a 1- to 2-cm margin for all patients. The group also included a matched-pair analysis to compare the rate of local recurrence between APBI and WBI. At 60 months, they reported a 1% local recurrence rate in both the APBI and WBI groups. There was also no difference in distant metastases, disease-free survival, cause-specific survival, or overall survival between the two groups. Furthermore, in patients with 60-month follow-up, 99% of patients reported their cosmesis to be good or excellent. At 10-year follow-up, the actuarial local recurrence rate is 3.6%, with 99% of patients still reporting a good or excellent cosmetic result (personal communication).

The RTOG conducted the first multi-institutional trial (RTOG 95-17) consisting of interstitial brachytherapy to treat early-stage breast cancer patients.[43] This was a phase I/II trial to determine the feasibility, reproducibility, toxicity, cosmesis, local control, and survival of patients treated with lumpectomy and axillary evaluation followed by APBI using intersitial brachytherapy. One hundred women were enrolled, and 99 were found to be eligible. Eighty-seven patients had T1 disease, and 20 patients had one to three positive lymph nodes. Thirty-three patients were treated using LDR (45 Gy over 4.5 days), and 66 using HDR (34 Gy over 10 fractions in 5 days).

With a median follow-up of 3.7 years, three patients developed an in-breast recurrence and three patients experienced a nodal failure. In a recent update presented at the American Society of Therapeutic Radiation Oncology (ASTRO) meeting in November 2006 with a median follow-up of 6 years, 3% and 6% of patients treated with HDR and LDR experienced an in-breast failure, with the majority of failures being classified as a true recurrence/marginal miss.[44] The authors conclude that "multicathether partial-breast brachytherapy on this trial experienced excellent in-breast control rates."

• European Trials—Several European groups have investigated the efficacy of multicatheter intersitial brachytherapy to deliver APBI. Many of the early studies were fraught with poor patient selection and outdated treatment planning modalities.[45-47] For the purpose of this discussion, we will focus on the more recent European studies, including one prospective, randomized controlled study comparing APBI using interstitial brachytherapy to WBI.

The National Institute of Oncology (NIO) in Budapest, Hungary, has much experience in the use of HDR interstitial implants to provide APBI.[48,49] They treated women of any age with pathologic T1 tumors (in situ carcinoma and invasive lobular carcinoma were excluded) with negative margins and pathologically negative axillary nodes (or micrometastases < 2 mm). Forty-five patients were treated to a total of 30.3 Gy (n = 8) or 36.4 Gy (n = 37) in seven fractions over 4 days. The authors of this study included a control group of patients who met the eligibility criteria during the same time period who were treated with WBI. With a median follow-up of 7 years, the actuarial ipsilateral failure rate was reported as 9% (n = 3) in the APBI group and 12% in the WBI group. All patients treated with APBI who experienced a recurrence were subsequently treated with lumpectomy followed by 46 to 50 Gy WBI, providing a 100% mastectomy-free recurrence rate.

The NIO then conducted a single-institution randomized study between 1998 and 2004 of patients over 40 years old with the same eligibility criteria as described above.[50] A total of 255 patients were randomized to 50-Gy WBI (n = 129) or APBI (n = 126) using HDR brachytherapy (36.4 Gy in seven fractions over 4 days). Patients who were not suitable for implantation received EBRT using an enface electron field of 50 Gy prescribed to the 80% isodose. With a median follow-up of 3 years, the local recurrence rates were reported as 1.3% and 1.9% for APBI and WBI, respectively (P = .99). The investigators found no difference in cause-specific survival, disease-free survival, and distant metastasis-free survival. However, they reported fewer grade 2/3 skin side effects in patients treated with APBI compared to WBI (3% vs 17%, P < .001). At 5 years, the actuarial rate of ipsilateral breast failure was 5.5% and 4.4% in the APBI and WBI arms, respectively (P = .65). The frequency of long-term cosmetic results rated as good/excellent was 79% and 59% in the PBI and WBI arms, respectively (P = .001).