Interstitial Accelerated Partial Breast Irradiation

The interstitial brachytherapy technique had traditionally been used for boost after WBI before the introduction of electron beams on linear accelerators and thus was the first technique used for APBI as monotherapy. A prospective Hungarian trial (1996–1998) with 12-year follow-up used the high-dose-rate (HDR) interstitial multicatheter technique as monotherapy for APBI and demonstrated a 9.3% rate of IBTR in a series of 45 patients with early-stage disease (tumor <2 cm, negative margins, negative nodes [N1mi allowed], low-grade). Toxicity rates were low with a 2% rate of grade 3 fibrosis and a 2% rate of fat necrosis, with 78% of patients having excellent/good cosmesis. This prompted a randomized trial comparing partial breast irradiation (PBI) and WBI in women with early-stage breast cancer (T1N0-1mi, grade 1–2, nonlobular histology, negative margins). Radiation on the partial breast arm was delivered with interstitial brachytherapy (HDR: 7 × 5.2 Gy) or electrons (50 Gy/25 fractions). At 10 years, no difference in the rate of local recurrence was noted (5.9% PBI vs. 5.1% WBI) with no difference in disease-free, cancer-specific, or overall survival noted as well. PBI was associated with improved cosmetic outcomes (81% vs. 63% excellent/good cosmesis). Similarly, a matched pair analysis (matched for age, size, nodal status, estrogen receptor status, hormonal therapy) from William Beaumont Hospital comparing 199 patients receiving interstitial APBI with 199 patients receiving WBI found no difference in 12-year outcomes including local recurrence (3.8% WBI vs. 5.0% APBI), which was confirmed by a second matched pair analysis from Washington University (3.8% WBI vs. 3.0% APBI). These outcomes were recently validated by the Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology trial; this multiinstitutional phase III noninferiority trial randomized 1184 patients to interstitial APBI with HDR/pulsed-dose-rate (PDR) implants or WBI with a boost after BCS. Five-year outcomes demonstrated no difference in local recurrence with interstitial brachytherapy (0.9% WBI vs. 1.4% APBI), along with no difference in survival. With respect to toxicity, APBI was associated with a reduction in breast pain and a trend for reduced late grade 2 to 3 skin toxicity (5.7% APBI vs. 3.2% WBI).

Radiation Therapy Oncology Group (RTOG) 9517 was a Phase II trial evaluating interstitial brachytherapy with both low-dose-rate (LDR; n = 33, 45 Gy in 3.5–5 days) and HDR (n = 66, 34 Gy in 10 fractions twice daily) multicatheter implants. Five-year local recurrence rates of 3% and 6% were noted for the HDR and LDR cohorts respectively. With regard to toxicity, 13% developed grade 3 skin toxicity with 66% to 68% rates of excellent/good cosmesis. These findings have been confirmed by other single-institution prospective studies as well as retrospective studies that have documented low rates of recurrence and toxicity with high rates of excellent/good cosmetic outcomes that remained stable over time. With respect to dose and fractionation, the majority of studies have used 34 Gy/10 fractions twice daily or 32 Gy/8 fractions twice daily, whereas the Hungarian randomized study used 36.4 Gy/7 fractions twice daily. In cases in which LDR is used, 45 to 50 Gy over 3 to 5 days has commonly been administered. A summary of selected multicatheter interstitial APBI studies are presented in Table 51.1 .

Applicator Accelerated Partial Breast Irradiation

Interstitial brachytherapy represented a technique that allowed for the delivery of APBI with excellent clinical outcomes. However, due to the technical complexity associated with inserting the catheters, it has been limited to a small number of centers. However, with the introduction of single-entry applicators whose insertion is less technically demanding, brachytherapy-based APBI became more widely available for patients and is used at a growing number of centers. The initial clinical studies, after US Food and Drug Administration approval in 2002, were performed using the single-lumen MammoSite (Hologic, Bedford, MA) applicator. Benitez and colleagues published results from the initial study of 43 patients with no local recurrences at 5 years and 83% excellent/good cosmesis. Toxicity rates were low including a 9.3% rate of infection and 12% symptomatic seroma rate. Importantly, a skin spacing target of 7 mm was identified to reduce skin toxicity, such as telangiectasias, and improve cosmetic outcomes. The success of this study led to the prospective American Society of Breast Surgeons (ASBS) MammoSite Registry, which enrolled 1449 patients from 2002 to 2004. With a median follow-up of 63 months, the 5-year IBTR rate was 3.8% and excellent/good cosmesis was seen in more than 90% of cases. Toxicity outcomes showed a 9.6% rate of infection, 2.5% rate of fat necrosis, and 13% rate of symptomatic seromas. Similar results have been seen by multiple prospective, multiinstitutional, and single-institution studies.

Although the initial applicator studies used a single lumen device, advances in design allowed for the development of multilumen applicators providing for more dosimetric degrees of freedom. Multiple dosimetric studies have been performed demonstrating improvements in target coverage as well as reduction in dose to the chest wall, normal breast tissue, and skin, even in cases with limited skin distance. Mature data beyond 5 years are limited with this technique, but initial studies have demonstrated low rates of toxicity and excellent clinical outcomes. A multiinstitutional series with 3-year outcomes found the local recurrence rate to be 2.2% in a series of 342 patients, with a 4.4% rate of persistent seromas and 8.5% rate of infection. Excellent/good cosmesis was noted in 88% of patients with these findings substantiated by additional studies. Table 51.2 presents a summary of selected applicator APBI studies.

Two observational studies evaluated brachytherapy based APBI compared with WBI and found higher rates of mastectomy as well as higher rates of toxicity (infectious and noninfectious). The limitations of these studies include the design of the study (observational), missing data in the databases used especially regarding use of radiation, short follow-up, failure to control for relevant patient and disease characteristics as well as lack of information for evaluating the reason for the difference in mastectomy rates, and use of billing codes rather than medical records, all of which makes their findings hypothesis generating in light of mature phase III data failing to corroborate their findings. With the continued evolution of brachytherapy APBI to include multilumen applicators, it is expected that toxicity rates will continue to decline. The most common dose and fractionation scheme is 34 Gy/10 fractions twice daily; however, shorter courses (e.g., 28 Gy/4 fractions twice daily) are being investigated.

External-Beam Accelerated Partial Breast Irradiation

APBI delivered with external-beam techniques is an appealing option for many patients because it eliminates the need for another procedure after surgery. Although older series have evaluated this technique, with the advent of computed tomography simulation, 3D planning, and image guidance, external-beam APBI can be delivered in multiple techniques with greater accuracy of target volume delineation and treatment delivery. Several institutional studies have suggested increased toxicity or poorer cosmesis with 3D conformal radiation therapy (CRT) APBI external-beam techniques, potentially related to larger volumes of normal breast irradiated or specific techniques utilized. However, publication of two randomized trials evaluating external-beam APBI has provided level I data regarding the technique and support the continued study and utilization of the technique.

The 3D-CRT technique was developed at William Beaumont Hospital with initial dosimetric studies and outcomes demonstrating its feasibility. A 5-year update (205 patients) from the institution demonstrated no recurrences and reasonable rates of chronic toxicity with a 7.5%/7.6% rates of fibrosis/telangiectasias and 81% of patients having excellent/good cosmesis. Similar results were noted in several studies including a subset analysis of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39, which demonstrated low rates of fibrosis (grade 2 < 12%, grade 3 < 3%, grade 4/5 0%), and an analysis of 100 patients treated with external-beam radiation therapy APBI at New York University using the prone technique, which demonstrated an 89% rate of excellent/good cosmesis at 5 years. Also, a small randomized trial from Spain demonstrated no recurrences at 5 years with improved acute toxicity with 3D-CRT APBI. However, other single-institution studies raised concerns regarding toxicity (fibrosis) and poor cosmetic outcomes. Findings from the University of Michigan (which used intensity modulated radiation therapy [IMRT] and active breathing control) and Tufts series were confirmed in part by long-term follow-up of RTOG 0319, a phase II trial that demonstrated deterioration of cosmetic outcomes from 82% excellent/good cosmesis at 1 year to 64% at 5 years with a 5.8% rate of grade 3 toxicity. The RAPID trial randomized women after BCS to external-beam APBI (3D-CRT) or WBI (standard/hypofractionated). The trial accrued more than 2100 women, and with median follow-up of 3 years, APBI was found to have higher rates of grade 1 and 2 toxicity (telangiectasias, induration, breast pain, fat necrosis) with no difference in the rates of grade 3 toxicity (1.4% vs. 0%). Cosmetic outcomes were inferior with 3D-CRT APBI. An alternative to 3D-CRT APBI is to use IMRT; initial outcomes from this technique were promising with a phase II study of 136 patients from Lei and colleagues demonstrating a 4-year IBTR rate of 0.7% with 88% to 91% excellent/good cosmesis and low rates of toxicity noted. A randomized study from Florence compared IMRT APBI with WBI delivered with IMRT (standard fractionation); at 5 years, no difference in rates of local recurrence were noted and acute toxicity was improved with APBI (0% vs. 6.5%), as was excellent/good cosmesis (95.1% vs. 89.6%). The dose and fractionation most commonly used is 38.5 Gy/10 fractions BID; however, recent data have demonstrated excellent clinical and toxicity outcomes with 30 Gy/5 fractions every other day. Similarly, an abstract of the IMPORT-LOW trial demonstrated that with 5.8 years of follow-up that once daily fractionation (40 Gy/15 fractions) to the partial breast was noninferior to WBI or WBI with a simultaneous integrated boost (0.5% vs. 1.1% vs. 0.2%) with respect to recurrences as well as toxicity. Table 51.3 provides a summary of selected external-beam APBI series.

Proton therapy represents an alternative external-beam technique compared with 3D-CRT and IMRT ( Table 51.4 ). This technique has undergone continued refinement because of initial concerns regarding toxicity; a study from Massachusetts General Hospital demonstrated 79% of patients having moderate to severe skin color changes at 3 to 4 weeks after treatment and 22% moderate to severe moist desquamation at 6 to 8 weeks. A subsequent update from MGH compared outcomes of 19 patients treated with protons (32 Gy/8 fractions BID) with 79 treated with photons or mixed photons/electrons. With 7-year follow-up, proton therapy was associated with worse cosmesis (62% vs. 94% excellent/good, p = .03) as well as higher rates of skin toxicity including telangiectasias, pigmentation changes but no difference in the rates of breast pain, edema, fibrosis, fat necrosis, rib fracture, or skin desquamation. Also, although not statistically significant there was a higher rate of local recurrence noted (11% vs. 4%). An update of the Loma Linda proton experience (40 Gy/10 fractions daily) was recently published with 5-year outcomes; 100 patients were enrolled with a 3% IBTR and no grade 3 or higher acute skin toxicity. Patient and physician assessed cosmesis was 90% excellent/good cosmesis with no change noted over time. Chang and colleagues reported outcomes of a phase II trial including 30 patients treated with protons (30 CGE/6 fractions daily). With a median follow-up of 59 months, no recurrences had been identified with 69% excellent/good cosmesis at 3 years. Breast retraction was noted to increase during follow-up across all patients.

TABLE 51.4

APBI Proton Studies

Institution	Patients (n)	Follow-Up (months)	Outcomes
Massachusetts General Hospital	19	82.5	7-year local recurrence 11%; 62% excellent/good cosmesis, increased late skin toxicity compared with photons
Loma Linda University Medical Center	100	60	5-year local recurrence 3%; 90% excellent/good cosmesis
Seoul National University	30	59	5-year local recurrence 0%; 69% excellent/good cosmesis

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