# Radiation Oncology/Breast/Partial breast irradiation

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* NSABP trials
Partial Breast Irradiation

## Anatomical studies

* Rationale for APBI is that majority of local recurrences occur in close proximity to tumor bed, and <20% appear "elsewhere" in the breast. Absolute number of "elsewhere" failures is quite low (<<1% per year) and is similar to rate of new contralateral tumors
* Holland - Classic paper that justified the need for whole breast RT. Evaluated mastectomy specimens. 42% of extensive intraductal component (EIC) negative breasts had residual carcinoma; 74% of EIC+ had residual carcinoma. Most carcinoma was intraductal type. Most tumors were large and clinically detected.
    PMID 2153190 — "The presence of an extensive intraductal component following a limited excision correlates with prominent residual disease in the remainder of the breast." Holland et al., 1990.
* Vaidya - A paper that paradoxically justified the rationale for partial breast irradiation. Multicentric foci were plotted in an abstract 3-D space and the conclusion was that although 63% (same result as Holland) of otherwise occult cancers were present in mastectomy specimens, over 79% of them were in other quadrants. This was in contrast with the results of breast conserving surgery trials in which early local recurrence occurred most commonly (>90%) of the time in the area around the primary tumor, thus justifying the approach of TARGeted Intraoperative radioTherapy [TARGIT]
    PMID 8795588 — "Multicentricity of breast cancer: whole-organ analysis and clinical implications." Vaidya JS, Vyas JJ, Chinoy RF, Merchant N, Sharma OP, Mittra I. 1996.
* 3D studies of duct-lobular system
** PMID 8630874 — "Intraductal extension of primary invasive breast carcinoma treated by breast-conservative surgery. Computer graphic three-dimensional reconstruction of the mammary duct-lobular systems." Ohtake et al. 1995.
    20 pts studied, all had quadrantectomy. Ductal anastomoses are present, and may be a risk for spread to other ductal-lobular systems. Maximum distance of spread, 11.9 mm.
** PMID 11413514 — "Computer-assisted complete three-dimensional reconstruction of the mammary ductal/lobular systems: implications of ductal anastomoses for breast-conserving surgery." Ohtake et al. 2001.
    3D reconstruction of a single entire breast
* PMID 11072782 Full Text — "Relationship between the morphological and biological characteristics of intraductal components accompanying invasive ductal breast carcinoma and patient age." Imamura et al. 2000.
    Median extension of intraductal component 9 mm. Related to patient age, with older patients having less extension.
* PMID 15465188 (2004) — "Defining the clinical target volume for patients with early-stage breast cancer treated with lumpectomy and accelerated partial breast irradiation: a pathologic analysis." Vicini et al. Int J Radiat Oncol Biol Phys. 2004 Nov 1;60(3):722-30.
    Recommend 10 mm margin around tumor bed

## Dosimetry

* MD Anderson; 2012 PMID 22884255 -- "A new paradigm for calculating skin dose." (Gifford KA, Brachytherapy. 2012 Aug 8. [Epub ahead of print])
** Evaluation of skin volumetric models. Literature review showed average breast epidermal thickness 1.68 mm. Clinical plan developed with 2 mm skin contour, as contraction of the external surface contour, to estimate epidermis thickness. Second plan 5 mm expansion of the external contour
** Outcome: median difference for Dmax (01. cc) skin -2 mm vs skin +2 mm was 12% (SS), maximum was 24% (SS)
** Conclusion: Surface model for skin may underestimate dose delivered to epidermis by as much as 24%
* Dose Homogeneity Index, Tufts; 1988 PMID 3352544 --"A dose homogeneity index for evaluating 192Ir interstitial breast implants." (Wu A, Med Phys. 1988 Jan-Feb;15(1):104-7.)
** Dose homogeneity index defined as DHI = [V(TDR)-V(HDR)]/V(TDR), where V(TDR) denotes the total treatment volume enclosed by the prescribed treatment dose rate (TDR) and V(HDR) denotes the volume enclosed by high-dose rate (HDR), which is 1.5 X TDR or greater. Also can be written as (V100% - V150%)/V100%

## APBI vs. Whole Breast RT Overview
### Ongoing

* NSABP B-39/RTOG 0413 -- ONGOING
** Randomized. Whole breast vs. APBI for stage 0, I and II patients
** Technique: multi-catheter brachytherapy (34 Gy), MammoSite (34 Gy) or External Beam (38.5 Gy)
* Ontario RAPID NCT00282035 -- ONGOING
** Randomized. Whole breast 42.5/16 vs 3D-CRT APBI 38.5/10 BID.
** Inclusion criteria: >=40, DCIS or invasive carcinoma, SM-, LN-
* MRC IMPORT LOW Trial -- ONGOING
** Randomized. 40/15 to index quadrant vs. 40/15 index quadrant + 36/15 remaining quadrants vs. 40/15 to center of breast (whole breast control). No boost.
** Eligibility: Low risk early stage BCA (>50 and BCS and T1 and invasive ductal and unifocal and GI-II/III and SM > 2mm and LVI- and LN- and DM-)
* University of Florence (ONGOING) -- WBRT 50/25 vs APBI 30/5
** Randomized. Ongoing. 259 patients out of planned 520. Arm 1) WBRT 50/25 using conventional tangents vs Arm 2) IMRT APBI 30/5. Mean CTV 44 cm3, mean PTV 123 cm3, mean PTV/breast volume 21%
** 2009 PMID 19700248 -- "Accelerated Partial Breast Irradiation with IMRT: New Technical Approach and Interim Analysis of Acute Toxicity in a Phase III Randomized Clinical Trial." (Livi L, Int J Radiat Oncol Biol Phys. 2009 Aug 21. [Epub ahead of print])
*** Toxicity: Skin toxicity Grade 2 WBRT 19% vs. IMRT 1%
*** Conclusion: APBI is feasible, with very low acute toxicity
* Milan ELIOT -- ONGOING?
** Randomized. Intraoperative electron RT vs. whole breast RT
| Organization | Year | Arm 1 | Arm 2 | Status |
| TARGIT-A | 2000-2009 | WBRT 45-56 | IORT 20/1 | IORT Non-inferior |
| Hungary | 1998-2004 | WBRT 50/25 | HDR 36.4/7 | Similar control, better cosmesis with HDR |
| Yorkshire | 1986-1990 | WBRT 40/15 | EBRT 55/20 | WBRT superior |
| Christie | 1982-1987 | WBRT 40/15 | Electrons 42.5/8 | WBRT superior |

### Meta-Analysis

* Heraklion University, Greece; 2010 PMID 20210799 -- "Partial Breast Irradiation or Whole Breast Radiotherapy for Early Breast Cancer: A Meta-Analysis of Randomized Controlled Trials." (Valachis A, Breast J. 2010 Feb 23. [Epub ahead of print])
** Meta-analysis. 3 trials with 1,140 patients.
** Outcome: No difference in OS (OR 0.9, NS), DM (OR 0.7, NS), or SCV recurrences (OR 1.4, NS). However, PBI increased risk of local recurrence (OR 2.1, SS), and axillary recurrence (OR 3.4, SS) compared with whole breast RT
** Conclusion: PBI doesn't jeopardize survival but issue of locoregional recurrence needs to be addressed
** Letter to editor (Polgar C, PMID 20127229): Inappropriate to include the 2 "old" British trials using inadequate patient selections criteria
* Aarhus, Denmark; 2009 PMID 18783840 -- "Accelerated partial breast irradiation as part of breast conserving therapy of early breast carcinoma: A systematic review." (Offerssen BV, Radiother Oncol. 2009 Jan;90(1):1-13. Epub 2008 Sep 8.)
* University College London; 2016 PMID 27478165 -- "Reduced Mortality With Partial-Breast Irradiation for Early Breast Cancer: A Meta-Analysis of Randomized Trials." (Vaidya JS et al, Int J Radiat Oncol Biol Phys. 2016 May 13. pii: S0360-3016(16)30200-0. doi: 10.1016/j.ijrobp.2016.05.008.)
** Meta-analysis. 5 trials for non breast cancer mortality (n=4489) and 4 trials for breast cancer mortality (4251)
** Outcome: The overall mortality was 4.9%. There was no detectable heterogeneity between the trials for any of the outcomes. There was no difference in the proportion of patients dying of breast cancer (difference, 0.000% [95% confidence interval (CI), -0.7 to +0.7]; P=.999). Non-breast cancer mortality with PBI was lower than with WBI (difference, 1.1% [95% CI, -2.1% to -0.2%]; P=.023). Total mortality with PBI was also lower than with WBI (difference, 1.3% [95% CI, -2.5% to 0.0%]; P=.05).
** Conclusion: Use of PBI instead of WBI in selected patients results in a lower 5-year non-breast cancer and overall mortality, amounting to a 25% reduction in relative terms. This information should be included when breast-conserving therapy is proposed to a patient.

### Retrospective

* Medicare claims analysis (MDACC) (2000-2007)
** Review of medicare claims; patients > age 66 with invasive breast cancer diagnosed 2000-2007, treated with surgery followed by standard whole-breast irradiation (WBI) or accelerated partial breast brachytherapy (APBI)
** 2011 Abstract only: No PMID Abstract San Antonio Breast Cancer Symposium 2011; Abstract #S2-1 "Partial Breast Brachytherapy Is Associated with Inferior Effectiveness and Increased Toxicity Compared with Whole Breast Irradiation in Older Patients." (Smith GL, Dec 7, 2011)
*** Use of APBI-brachytherapy increased over time: from <1% in 2000 to 13% of patients in 2007. At 5 yrs, cumulative incidence of subsequent mastectomy was significantly higher: 4.0% (APBI) vs 2.2% (WBI); HR = 2.14. Higher risk of hospitalization: 9.6% v 5.7% (O.R. 1.71), infection: 8.1% vs 4.5% (O.R. 1.85); rib fracture 4.2% vs. 3.6%; fat necrosis 9.1% vs. 3.7%; breast pain 14.9% vs. 11.7%. Lower incidence of pneumonitis: 0.1% vs. 0.8%.
*** Conclusion: APBI-brachy was associated with inferior effectiveness (as evidenced by increased utilization of mastectomy) as well as increased acute and late toxicities compared with WBI.

## APBI-Preoperative RT

* University of North Carolina; 2010 (2003-2007) PMID 20395062 -- "Cosmetic Outcomes for Accelerated Partial Breast Irradiation Before Surgical Excision of Early-Stage Breast Cancer Using Single-Dose Intraoperative Radiotherapy." (Kimple RJ, Int J Radiat Oncol Biol Phys. 2010 Apr 13. [Epub ahead of print])
** Phase II. 53 patients, age ≥ 48, IDC, <3 cm, cN0. Ultrasound driven treatment to select electron energy and cone size, target tumor + 1.5-2.0 cm circumferential margin and +1.0 cm deep margin. Dose 15 Gy electrons prior to segmental mastectomy. Additional WBRT in 20%. Median F/U 3.1 years (minimum 1 year)
** Toxicity: "Good or excellent" RTOG cosmesis physician 80%, patient 76%. Grade 1-2 acute toxicity 6%, no Grade 3-4 toxicities
** Conclusion: RT delivered to in-situ tumor feasible, with acceptable acute tolerance

## APBI-Intraoperative RT
### Randomized

* ELIOT (2000-2007) -- IORT 21/1 vs WBRT 50 Gy + 10 Gy boost
** Randomized, equivalence trial. Italian. 1305 patients, age 48-75, tumor <= 2.5 cm, eligible for breast conserving therapy
*** Patients received either intraoperative radiotherapy (21 Gy in 1 fraction) or whole breast radiotherapy (50 Gy in 25 fractions plus a 10 Gy boost)
** 2010 PMID 24225155 -- "Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised controlled equivalence trial" (Veronesi Lancet Oncol. 2013 Dec;14(13):1269-77.)
*** Outcome: 5-year IBTR was 4.4% with IORT versus 0.4% with WBRT (HR was 9.3). 5-year OS was similar (96.8% with IORT and 96.9% with WBRT).
*** Toxicity: Lower skin toxicity with IORT
*** Conclusion: Although the rate of IBTR with IORT was within the prespecified equivalence margin, the rate was significantly greater than with WBRT. Improved selection of patients could reduce the rate of IBTR with intraoperative radiotherapy with electrons.
* TARGIT-A (2000-2012) -- IORT 20/1 vs WBRT 40-56 Gy
** Randomized, non-inferiority. 11 countries. 3451 patients, age ≥ 45 (median age 63, ≥ 70 in 15%), IDC (ILC excluded), unifocal, breast-conserving surgery + SNB/ALND. Mostly T1 (86%), N0 (83%), and low/intermediate grade (84%). Allowed entry prior to surgical pathology results(66%) or post pathology results (34%). Arm 1) Intra-op RT with Intrabeam 50 kV device 20 Gy at surface vs Arm 2) WBRT (as per each individual center, typically 40-56 Gy with/without boost 10-16 Gy). Postop RT for predefined factors (e.g. LCIS, EIC, N+, LVI+ or others pre-defined per each individual center) done as WBRT without boost (a prior expected rate 15%, actual rate 15.2%). Primary endpoint local recurrence. Non-inferiority 2.5% absolute difference in LR.
** 2010 PMID 20570343 -- "Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial" (Vaidya JS, Lancet. 2010 Jul 10;376(9735):91-102.)
*** Outcome: 4-year LF IORT 1.2% vs WBRT 0.95% (NS)
*** Toxicity: Major toxicity (including skin breakdown) IORT 3.3% vs WBRT 3.9% (NS); Grade 3-4 toxicity 0.5% vs 2.1% (SS)
*** Conclusion: For select patients, single dose IORT should be considered an alternative to EBRT
*** Criticisms: PMID 21060332, PMID 20888981, PMID 20888982 -- Median f/u only 2 years (not directly stated in manuscript but inferred from figures), premature to draw conclusions from only 11 events in 2232 patients, 21% in APBI arm received mastectomy or WBRT, delivered only 5-7 Gy at 1cm from radiation source
** 2014 PMID 24224997 -- "Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial" (Vaidya JS, The Lancet, Early Online Publication, 11 November 2013). 5-year median F/U in 1222 patients, 4 year MF in 2020 patients, 2 year MF in 3451 patients
*** Outcome: 5-year LF TARGIT 3.3% versus EBRT 1.3% (p=0.04, NS). If concurrent with lumpectomy, 2.1% versus 1.1% (p=0.3, NS); if delayed after lumpectomy 5.4% versus 1.7% (p=0.07, NS but larger than the non-inferiority margin). Breast cancer mortality 2.6% vs 1.9% (p=0.56, NS); non-breast-cancer mortality 1.4% vs 3.5% (p=0.0086, significant); overall mortality 3.9% vs 5.3% (p=0.099, NS)
*** Toxicity: Wound-related complications same, Grade 3/4 skin toxicity lower 0.2% versus 0.7%
*** Conclusion: TARGIT concurrent with lumpectomy should be considered an option for eligible patients
*** Criticisms: PMID 24835608, PMID 24835610, PMID 24835611, PMID 24835612, PMID 24835609, PMID 24929161 -- The chairman of the Data Monitoring Committee for TARGIT, Dr. Cuzick, (but without the support of the rest of the DMC) suggested that 5-year estimates should be used for calculating non-inferiority; authors responded that their method using complete raw data was the standard method and 5-year estimates, being mere estimates would give misleading results. Analysis restricted to the patients randomised in the first 8 years of the trial - these patients had a median follow up of 5 years - had given the same results and met the non-inferiority criteria. The authors pointed out that although recurrences may occur after 5 years, the effect of radiation on local recurrence is only in the first 5 years and most of this is seen in the first 2-3 years, the period very adequately covered by the follow up period as published. A robust response to scientifically weak criticisms for use of TARGIT IORT during lumpectomy breast cancer, including a decision aid (figure 4) is given in the Red Journal.
** 2016 The full comprehensive report of the TARGIT-A trial (226 pages) was published in September 2016 PMID 27689969

### Non-Randomized

* Baton Rouge, LA; 2009 PMID 19945859 -- "Accelerated partial breast irradiation: Initial experience with the Intrabeam System." (Elliott RL, Surg Oncol. 2009 Nov 27. [Epub ahead of print])
** Retrospective. 67 patients, preop U/S diameter <3.5 cm. IORT with Intrabeam System
** Outcome: 4 patients required later total mastectomy, 11 whole breast RT. No local failures
** Toxicity: Good to excellent
** Conclusion: IORT with Intrabeam is feasible in the community setting
* Milan ELIOT study; 2008 (1999-2006) No PMID Full Text (PDF) -- "Full Dose Intraoperative Radiotherapy With Electrons (ELIOT) During Breast Conserving Surgery - Experience with 1246 Cases" (Veronesi U, ecancermedicalscience DOI 10.3332/eCMS 2008.65
** Prospective. 1246 patients, tumor <2.5 cm. Electron IORT 21 Gy single dose. Median F/U 2.2 years
** Outcome: Local recurrence 1.9%. 5-year OS 96%
** Toxicity: Severe breast fibrosis 0.5%, mild fibrosis 3%
** Conlusion: ELIOT is a safe method, with encouraging toxicity and local control

## APBI-Interstitial brachytherapy
### Randomized

* Hungary (1998-2004) -- partial breast RT vs WBRT
** Randomized. Trial stopped prematurely, since patients offered entry onto GEC-ESTRO Phase III APBI trial. 258 of expected 570 patients with T1N0-1mic, G1-2 nonlobular BCA, no EIC, SM-. WLE + ALND/SLND. Arm 1) WBI 50/25 vs. Arm 2) PBI 36.4/7 @ 5.2 Gy/fx BID multicatheter HDR (69%) or limited field electron PBI 50/25 if unsuitable for HDR (tumor bed + 2cm margin). Primary endpoint 5-year LR , noninferiority was 6% difference. Adjuvant chemo/hormones 72%
** 20-years; 2021 PMID 33186620 -- "Breast-Conserving Surgery Followed by Partial or Whole Breast Irradiation: Twenty-Year Results of a Phase 3 Clinical Study" (Polgar C, Int J Radiat Oncol Biol Phys. 2021 Mar 15;109(4):998-1006. doi: 10.1016/j.ijrobp.2020.11.006. Epub 2020 Nov 10.). Median F/U 17 years
*** Outcome: 20-year IBTR PBI 10% vs WBI 8% (NS), no difference in DFS (79%) or OS (59%)
*** Toxicity: Excellent/good result in 79% vs 59% (SS)
*** Conclusion: PBI provides good long term control with improved cosmetic results compared with whole breast RT
** 5-years; 2007 PMID 17531400 -- "Breast-conserving treatment with partial or whole breast irradiation for low-risk invasive breast carcinoma-5-year results of a randomized trial." (Polgar C, Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):694-702.). Median F/U 5.5 years
*** Outcome: 5-year LR WBI 3.4% vs. PBI 4.7% (NS); no difference in DFS or OS
*** Toxicity: excellent/good cosmesis WBI 63% vs. PBI 78% (SS); HDR 81% and EB-APBI 70%
*** Conclusion: Similar outcomes, better cosmesis with HDR APBI
** Fat necrosis; 2007 PMID 17524571 -- "Fat necrosis after partial-breast irradiation with brachytherapy or electron irradiation versus standard whole-breast radiotherapy-4-year results of a randomized trial." (Lovey K, Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):724-31.)
*** 4-year fat necrosis: overall WBI 32% vs. HDR 36% vs. EB-APBI 18% (SS); symptomatic 8% vs. 11% vs. 7% (NS)
*** Conclusion: asymptomatic fat necrosis common; symptomatic fat necrosis comparable after conventional WBI and APBI

### Non-Randomized

* National Institute of Oncology, Hungary; 2010 PMID 20181401 -- "Accelerated partial-breast irradiation using high-dose-rate interstitial brachytherapy: 12-year update of a prospective clinical study." (Polgar C, Radiother Oncol. 2010 Mar;94(3):274-9. Epub 2010 Feb 22.)
** Prospective. 45 patients, T1N0-N1mic, IDC, no EIC, SM-. APBI using interstitial HDR BT, 30.3/7 (n=8) or 36.4/7 (n=37) over 4 days BID, tumor bed + 1-2cm margin. Median F/U 11 years for surviving patients
** Outcome: IBTR 9%; 5-year IBTR 4.4%, 10-year IBTR 9.3%, 12-year IBTR 9.3%. Regional recurrence 4.4%. 12-year DFS 75%, CSS 91%, OS 89%.
** Toxicity: Grade 3 fibrosis 1 patient (2%), no Grade 3 telangiectasia, fat necrosis requiring surgery 2%. Excellent/good cosmesis 78%
** Conclusion: Continued excellent long-term local tumor control and cosmetic results
* Tufts/Brown U. (1995- ) - ASTRO 2005 Abstract #12 — "Accelerated Partial Breast Irradiation (APBI): An Analysis of Variables Associated with Late Toxicity after HDR Interstitial Brachytherapy." Kaufman S et al. IJROBP Volume 63, Supplement 1, 1 October 2005, Page S7.
** 75 pts. T1-2 N0-1 (0-3 nodes positive). Used HDR implant 34 Gy in 10 fractions BID over 5 consecutive days.
** Median f/u 73 mo. Excellent/good cosmesis in 67%/24% (91%). Poor cosmesis associated with higher V150 and V200 and poor dose homogeneity index.
* U. Wisconsin (2000-05) - ASTRO 2005 Abstract #13 — "Multi-catheter Breast Brachytherapy Following Lumpectomy in Select Early Stage Breast Cancer Patients: The University of Wisconsin Experience." Patel RR et al. IJROBP Volume 63, Supplement 1, 1 October 2005, Pages S7-S8.
** 268 pts (240 treated with interstitial, the rest with MammoSite).
** Median f/u 30 mos. IBTR in 1.4%. Symptomatic fat necrosis in 8.9%.
* RTOG 95-17 (1997-2000)
** Phase I-II. 99 pts. Brachytherapy with LDR (45 Gy in 3.5 - 5 days) or HDR (34 Gy in 10 fractions BID). Stage T1-2 (<3 cm), pN0-1
** Toxicity: PMID 16503383, 2006 — "Phase II trial of brachytherapy alone after lumpectomy for select breast cancer: Toxicity analysis of RTOG 95-17." Kuske RR et al. Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):45-51.
** Median f/u 2.7 yrs. Grade 3-4 acute toxicity in 3% (HDR) or 9% (LDR). Grade 3 late toxicity in 18% (LDR) and 4% (HDR).
* Ochsner Clinic, 2000 (1992-1993) PMID 11113440 -- "Long-term results of wide-field brachytherapy as the sole method of radiation therapy after segmental mastectomy for T(is,1,2) breast cancer." (King TA, Am J Surg. 2000 Oct;180(4):299-304.)
** Original Phase I-II. 50 patients, Tis-T2, <=4cm, N0-1, SM-. Retrospective comparison to EBRT during same time. Median F/U 6.25 years
** RT: Wide-field brachy (target volume 2cm peripheral and 1cm superficial/deep). Either LDR (45 Gy over 4 days) or HDR (32/8 in 4 Gy/fx BID) in blocks of 10 patients.
** Outcomes: No difference in toxicity, local/regional recurrence, or cosmesis
** Toxicity: 6% Grade 3 complications (3.8% LDR vs 7.7% HDR) - 2 severe fat necrosis on HDR requiring surgery (resulting in dosimetry adjustment) and 1 abscess from infected seroma. 56% Grade 2 complications (24% symptomatic fat necrosis, 12% telangiectasia, breast shrinkage, infection, pain, fibrosis). Fat necrosis worse if chemo (50% vs. 12%, SS), and if bad dosimetry gradient >30% (40% vs. 17%)
** Conclusion: Brachytherapy attractive alternative to EBRT
** Comment: Original fractionation scheme based on soft-tissue sarcomas, as per PMID 8407399

## APBI-SAVI

* Arizona Breast Cancer Specialists; 2011 PMID 20817617 -- "Dosimetric performance of Strut-Adjusted Volume Implant: a new single-entry multicatheter breast brachytherapy applicator." (Gurdalli S, Brachytherapy. 2011 Mar-Apr;10(2):128-35.)
** Phase II. 19 patients enrolled, 15 treated. PTV_eval defined as 1 cm expansion of excision cavity, less skin and pectoralis muscle Prescribed at 3.4 Gy x 10 fractions twice daily
** Outcome: Average D90 96%, average D100 91%. Average DHI 56%. Average skin distance 15 mm and skin Dmax 2.49 Gy/fx; average CW distance 23 mm and rib Dmax 1.99 G/fx.
** Conclusion: Able to optimize dose distribution to obtain clinically acceptable dose plans
* Multi-institutional; 2011 (2006-2009) PMID 20646847 -- "Initial clinical experience with the Strut-Adjusted Volume Implant (SAVI) breast brachytherapy device for accelerated partial-breast irradiation (APBI): first 100 patients with more than 1 year of follow-up." (Yashar CM, Int J Radiat Oncol Biol Phys. 2011 Jul 1;80(3):765-70. Epub 2010 Jun 18.)
** Retrospective. Arizone Oncology Services and UC San Diego. 102 patients treated with SAVI; none pulled prior to treatment completion. PTV = tumor bed + 1cm, minus CW/ribs/skin. 34/10 twice daily. Median F/U 1.7 years
** Outcome: V90 = 96%; max median skin dose 2.8 Gy. Local recurrence 1%
** Toxicity: grade 1 hyperpigmentation 10%, Grade 2 fibrosis 2%, telangiectasia 2%, fat necrosis 2%
** Conclusion: SAVE appears safe and increase eligibility for APBI over balloon brachytherapy

## APBI-Balloons
### Overview

* Usual dose: 34 Gy in 10 fractions (BID) over 5 consecutive days. Dose usually prescribed at 1 cm depth.
* Ideal dosimetric criteria (see PMID 20378268):
** PTV_EVAL: breast tissue bounded by expansion of balloon by 10 mm, limited to 5 mm from skin surface, and limited by posterior breast tissue extent (chest wall and pectoralis muscles are not included), less balloon volume
** 95% of prescribed dose covers 95% of PTV_EVAL
** Skin maximum: ≤ 125% prescribed dose
** Rib maximum: ≤ 145% prescribed dose
** Volume of breast receiving 150% of prescribed dose (V150): ≤ 50 cc
** Volume of breast receiving 200% of prescribed dose (V200): ≤ 10 cc

### Outcomes

* TRIUMPH-T Trial; 2019 PMID 30611839 -- "Three-Fraction Accelerated Partial Breast Irradiation (APBI) Delivered With Brachytherapy Applicators Is Feasible and Safe: First Results From the TRIUMPH-T Trial" (Khan A, Int J Radiat Oncol Biol Phys. 2019 May 1;104(1):67-74. doi: 10.1016/j.ijrobp.2018.12.050. Epub 2019 Jan 4.)
** Phase II multi-institutional trial. 200 patients, age >=45, unicentric invasive or DCIS, <=3 cm, ER+, pN-, surgical margin negative. Interstitial or SAVI or Contoura applicators. 22.5 Gy in 3 fractions. Minimum f/u 6 months
** Dosimetry parameters: PTV-eval 90%/90%, skin (surface) and rib dose <100% (<120% permitted), V150 <40cm3; V200 <15 cm3 (17 cm3 permitted); interstitial homogeneity >0.75. S
** Outcome: 97% good/excellent cosmetic outcome
** Conclusion: Ultrashort breast brachy dosimetrically feasible, and excellent short-term toxicity
* American Society of Breast Surgeons MammoSite Registry
** True recurrence; 2012 PMID 22836556 -- "Tumor bed control with balloon-based accelerated partial breast irradiation: incidence of true recurrences versus elsewhere failures in the American Society of Breast Surgery MammoSite(®) Registry Trial." (Beitsch PD, Ann Surg Oncol. 2012 Oct;19(10):3165-70. doi: 10.1245/s10434-012-2489-x. Epub 2012 Jul 27.)Randomized trials demonstrate that lumpectomy plus whole-breast irradiation (WBI) yields survival equivalent to mastectomy. Studies that use WBI, however, typically report higher tumor bed recurrence rates than elsewhere failures (EF) (historically considered new primary lesions). The rate of true recurrence (TR) versus EF was queried for a large patient cohort treated with accelerated partial breast irradiation (APBI).
*** Registry trial. 1449 cases, lumpectomy with MammoSite APBI (34/10 BID). Invasive 87%, DCIS 13%. Comparison of true recurrence (TF) versus elsewhere failure (EF). Median F/U 5 years
*** Outcome: IBTR 3.5%; 5-year invasive IBTR 3.6%, DCIS 3.4%. True recurrence 1.1% versus elsewhere failure 2.6%. ER- status associated with increased risk of IBTR and EF. No pathologic factors associated with TF
*** Conclusion: IBTR after balloon-based APBI is low, and similar (and potentially better) than whole breast irradiation
** Axillary recurrence; 2011 PMID 21537870 -- "Axillary Failure in Patients Treated with MammoSite Accelerated Partial Breast Irradiation." (Aburabia M, Ann Surg Oncol. 2011 May 3. [Epub ahead of print])
*** Registry trial. 1440 patients / 1449 cases treated with Mammosite (87% invasive, 13% DCIS). Median F/U 5 years
*** Outcome: 5-year axillary failure 0.8%, only risk factor high grade. 5-year OS 78%
*** Conclusion: Rate of axillary failure after MammoSite APBI is low and comparable to whole breast RT
** DCIS; 2010 (2002-2004) PMID 20577822 -- "Update on DCIS Outcomes from the American Society of Breast Surgeons Accelerated Partial Breast Irradiation Registry Trial." (Jeruss JS, Ann Surg Oncol. 2010 Jun 25. [Epub ahead of print])
*** Registry trial. 194 patients, DCIS, MammoSite registry. Placement at lumpectomy 45%, post-lumpectomy 55%. SLN 26%. SM negative 88%, <2 mm 11%, positive 1%. Grade 3 37%. Median F/U 4.5 years
*** Outcome: IBTR 3.1%, breast/axilla recurrence 0.5%, 5-year local recurrence 3.4%
*** Toxicity: Seroma 24%, associated with lumpectomy placement. Favorable cosmesis 92% (minimum 5 year follow-up)
*** Conclusion: APBI via MammoSite well tolerated for patients with DCIS
** ASTRO Unsuitable; 2010 PMID 20853036 -- "Five-year outcome of patients classified in the "unsuitable" category using the American Society of Therapeutic Radiology and Oncology (ASTRO) Consensus Panel guidelines for the application of accelerated partial breast irradiation: an analysis of patients treated on the American Society of Breast Surgeons MammoSite® Registry trial." (Beitsch P, Ann Surg Oncol. 2010 Oct;17 Suppl 3:219-25. Epub 2010 Sep 19.)
*** Retrospective. 176 patients (<50 age, SM+, LN+, tumor size/EIC >3 cm) of 1449 treated. Median F/U 4.5 years
*** Outcome: 5-year IBTR 5.2%. For comparison, all registry patients IBTR 3.9% (NS), non-unsuitable 3.6% (NS), invasive 3.9% (NS). Only predictor for IBTR was ER- status
*** Conclusion: ASTRO guideline did not differentiate patients with significantly worse rate of IBTR after MammoSite brachytherapy
* Beaumont Hospital
** 5 years; 2007 PMID 17826055 -- "Five-year results: the initial clinical trial of MammoSite balloon brachytherapy for partial breast irradiation in early-stage breast cancer." (Benitez PR, Am J Surg 2007 Oct; 194(4):456-62)
*** Prospective study of MammoSite therapy, enrolled 70 pts, implanted in 54 pts, 43 pts treated, 36 with long term f/u. Excluded 7% of treated pts due to death from metastatic disease.
*** Outcome: IBTR = 0%; Cosmesis improved with >= 7 mm from skin surface.
*** Complications: Infection 9%; Seroma 33%
** 12 years; 2011 PMID 21497927 -- "Twelve-year clinical outcomes and patterns of failure with accelerated partial breast irradiation versus whole-breast irradiation: Results of a matched-pair analysis." (Shah C, Radiother Oncol. 2011 Apr 15. [Epub ahead of print])
*** Retrospective. Matched-pair analysis, 199 patients WBRT vs 199 patient APBI.
*** Outcome: No difference in outcome. 12-year LR 3.8% vs 5.0% (NS), RR 0% vs 1.1% (NS), DM 10% vs 4% (p=0.05), DFS 87% vs 91% (NS), CSS 93% vs 95% (NS), OS 78% vs 71% (NS). After LR, no difference in DFS, CSS, OS
*** Conclusion: APBI produced equivalent outcomes to WBI
* University of Minnesota/SEER; 2011 (2000-2007) PMID 21287535 -- "Trends in the use of implantable accelerated partial breast irradiation therapy for early stage breast cancer in the United States." (Abbott AM, Cancer. 2011 Feb 1. doi: 10.1002/cncr.25927. [Epub ahead of print])
** Retrospective. SEER database. 127,257 women, Stage I-II. Evaluated proportion receiving implantable APBI
** Outcome: Proportion receiving implantable APBI 2000 0.4% to 2007 6.8% (SS), significant across all stage and age categories >40. Significant variation by region
** Conclusion: Marked increase since 2000, concerning, because large RCT have not demonstrated long-term effectiveness compared with whole breast RT
* Multi-Institutional; 2008 (2000-2004) PMID 18037585 -- "Multi-Institutional Experience Using the MammoSite Radiation Therapy System in the Treatment of Early-Stage Breast Cancer: 2-Year Results." (Cuttino LW, Int J Radiat Oncol Biol Phys. 2008 May 1;71(1):107-14. Epub 2007 Nov 26.)
** Retrospective. 483 patients from 9 institutions. 34/10 BID. Median F/U 2 years
** Outcome: 1% in-breast failure, of these 2/3 were remote from lumpectomy site
** Complications: infection 9%, but 5% if placement after lumpectomy. Predictors for acute toxicity: open cavity placement, skin spacing <6 mm, no prophylactic ABX, single dwell position
** Conclusion: MammoSite acceptable toxicity and cosmetic outcome
* U. Pittsburgh (2002-04) - ASTRO 2005 Abstract #11 — "Accelerated Partial Breast Irradiation: Single Institutional Experience of 100 Patients Using MammoSite Brachytherapy." Agarwal A et al.
** 100 pts. All surgical margins >= 2mm. Median age 64 (45-89). Cosmetic outcome excellent good in 56%/37% (93%). Palpable seroma beyond 6 months in 27%.

### Toxicity

* Dartmouth; 2013 (2003-2008) PMID 23830216 -- "Increased Rates of Long-Term Complications after MammoSite Brachytherapy Compared with Whole Breast Radiation Therapy." (Rosenkranz KM, J Am Coll Surg. 2013 Jul 2. pii: S1072-7515(13)00321-9. doi: 10.1016/j.jamcollsurg.2013.03.028. [Epub ahead of print])
** Retrospecitve. 71 MammoSite patients and 245 WBRT patients. Median F/U 4 years
** Toxicity: Palpable mass MammoSite 27% vs WBRT 7% (SS). Telangiectasias 24% vs 4% (SS). Either palpable mass or telangiectasias MammoSite 42%
** Conclusion: Palpable masses or telangiectasias frequent long-term complications after MammoSite
* WellStar Kennestone Hospital, Georgia; 2011 (2004-2011) PMID 22245195 -- "Factors associated with chest wall toxicity after accelerated partial breast irradiation using high-dose-rate brachytherapy." (Brown S, Int J Radiat Oncol Biol Phys. 2012 Jul 1;83(3):801-5. doi: 10.1016/j.ijrobp.2011.08.033. Epub 2012 Jan 13.)
** Retrospective. 89 patients, APBI 34/10 using single or multi-lumin device. Rib doses at D0.008cc, D0.5cc, D1cc, D2cc, D3cc Rib pain evaluated at F/U visit; no grade
** Outcome: Any rib pain 21.3%. Median point rib dose if pain 132% prescribed dose versus no rib pain 95% prescribed dose (SS)
** Dose statistics: D0.5cc mean 234% versus 324%, max 462% versus 485%; D2cc mean 178% versus 241%, max 367% versus 328%
** Conslusion: Incidence of chest wall/rib pain low, but attempt should be made to keep volume of rib to minimum

### Dosimetry

* US Multi-institutional Contura; 2011 PMID 20378268 -- "Improvements in critical dosimetric endpoints using the Contura multilumen balloon breast brachytherapy catheter to deliver accelerated partial breast irradiation: preliminary dosimetric findings of a phase iv trial." (Arthur DW, Int J Radiat Oncol Biol Phys. 2011 Jan 1;79(1):26-33. Epub 2010 Apr 6.)
** Phase IV registry trial. 144 cases. Contura multilumen catheter.
** Outcome: All dosimetric criteria met in 76%; skin dose met 92%, rib dose met 89%, target volume coverage 93%, homogeneity criteria (V150, V200) met 99%
** Conclusion: Contura MLB catheter provides means of achieving higher standard of dosimetric goals in majority of clinical scenarios

## APBI-EBRT
### Randomized

* RAPID Trial (2006-2011) -- Whole breast (42.5/16 (82%) or 50/25(18%); boost in 21%) versus APBI (38.5/10 BID; no boost)
** Randomized. 2135 patients. IDC/DCIS (invasive lobular excluded), SM-, pN0, age >40, tumor size >3 cm. Most patients were age >50, ER+, tumor <1.5 cm. Chemotherapy 15%
** Interim Cosmesis/Toxicity; 2013 PMID 23835717 -- "Interim Cosmetic and Toxicity Results From RAPID: A Randomized Trial of Accelerated Partial Breast Irradiation Using Three-Dimensional Conformal External Beam Radiation Therapy." (Olivotto IA, J Clin Oncol. 2013 Jul 8. [Epub ahead of print]). Median F/U 3.0 years
*** Toxicity: 3-year adverse cosmesis by trial nurse assessment APBI 29% vs WBI 16% (SS); 5-year rate 33% vs 13% (SS). By patient assessment 3-years 26% vs 18% (SS); 5-years 32% vs 21% (SS). Grade 3 toxicity rare (1.4% vs 0%), grade 1/2 toxicity worse with APBI
*** Conclusion: 3D conformal APBI increased rate of adverse cosmesis and late radiation toxicity compared with standard whole breast irradiation
* Yorkshire Breast Cancer Group (1986-1990) -- WBRT 40/15 vs PBI 55/20
** Randomized. Trial closed prematurely due to non-accrual. 174 out of expected 400 patients. pT1-T2, pN0-N1. SM-. Arm 1) conventional WBRT 40/15 vs Arm 2) APBI 55/20 (tangents, appositional Co-60 teletherapy, appositional Cs-137 teletherapy, electrons)
** 2005 PMID 16372487 -- "A randomised study of whole-breast vs tumour-bed irradiation after local excision and axillary dissection for early breast cancer." (Dodwell DJ, Clin Oncol (R Coll Radiol). 2005 Dec;17(8):618-22.)
*** Outcome: IBTR WBRT 4% vs. APBI 12% (NS). LRF 24% vs 9% (NS). No difference in DM and OS
*** Conclusion: Conclusions are limited due to failure to complete accrual
* Christie Hospital (1982-1987) -- electron tumor bed RT vs WBRT
** Randomized. 708 patients. Tumor <4cm, SM-. No ALND. No systemic therapy. Randomized to tumor bed electron RT (Dose 40-42.5/8, majority 10 MeV, majority 8x6 cm field) or 4 field whole breast with regional LNs, no IMN (40/15). No adjuvant therapy
** 5-years; 1993 PMID 8305334 -- "The Christie Hospital breast conservation trial: an update at 8 years from inception." (Ribeiro GG, Clin Oncol (R Coll Radiol). 1993;5(5):278-83.) Median F/U 5.4 years
*** Outcome: IBTR tumor bed for infiltrating ductal CA 15% vs. WBRT 11%, for infiltrating lobular CA 34% vs 8%, for extensive DCIS 21% vs 14%
*** Conclusion: Lumpectomy with limited field RT is feasible, albeit with higher breast recurrence rate. Later could be reduced by improved selection and refined technique
** Prognostic factors; 1996 PMID 8783398 -- "Prognostic factors for breast recurrence after conservative breast surgery and radiotherapy: results from a randomised trial." (Magee B, Radiother Oncol. 1996 Jun;39(3):223-7.)
*** Outcome: 8-year local recurrence tumor bed 25% vs. WBRT 13% (SS). Majority of recurrences within treated quadrant. 8-year DSS 72% vs 73% (NS). IDC 22% vs 12%; ILC 43% vs 17%. Axillary failure 24% vs 12% (SS), supraclav failure 6% vs 5%
*** Predictors for recurrence: field size, grade, LVI
*** Conclusion: Clear superiority for whole breast radiation therapy

### Non-Randomized

* Rocky Mountain Cancer Center, Colorado (2004-2007)
** Phase II. 136 patients, Stage 0/I, SM-. IMRT APBI, 38.5/10
** 4-year update; 2013 PMID 23824363 -- "Four-year clinical update from a prospective trial of accelerated partial breast intensity-modulated radiotherapy (APBIMRT)." (Lei Ry, Breast Cancer Res Treat. 2013 Jul;140(1):119-33. doi: 10.1007/s10549-013-2623-x. Epub 2013 Jul 4.). Median F/U 4.4 years
*** Outcome: 4-year IBTR 0.7%, distant failure 0.9%, OS 97%, CSS 100%
*** Toxicity: Excellent/good cosmesis patient-rated 88% vs physicians-rated 90%. Breast pain none/mild 97%. Telangiectasia 3.6%. Rib fracture 1.4%
*** Conclusion: Excellent local control, survival, cosmetic results and toxicity
** IGRT; 2010 PMID 19467799 -- "Clinical experience with image-guided radiotherapy in an accelerated partial breast intensity-modulated radiotherapy protocol." (Leonard CE, Int J Radiat Oncol Biol Phys. 2010 Feb 1;76(2):528-34. Epub 2009 May 19.)
*** Retrospective. 19 patients. APBI with IGRT using 3 fiducial markers around surgical cavity. Total 200 IGRT sessions
*** Outcome: Average vector displacement 4mm (2-7mm), SI 2mm (0-5mm), lat 2mm (1-4mm), AP 3mm (1-5mm)
*** Conclusion: IGRT can be successful in APBI
** Initial; 2007 (2004-2005) PMID 17234359 -- "Prospective trial of accelerated partial breast intensity-modulated radiotherapy." (Leonard C, Int J Radiat Oncol Biol Phys. 2007 Apr 1;67(5):1291-8.)
*** Prospective. 55 patients, Stage I BCA. IMRT 7 patients 34/10, then 48 patients 38.5/10. Median F/U 10 months
*** Outcome: no local or distant recurrences
*** Cosmesis: patient: excellent 73%, good 22%; physician: excellent 80%, good 18%. Pain: none 62%, mild 35%, moderate 4%. One telangiectasia. No significant edema
*** Dosimetry: compared to historical controls, reduced volume of breast within 100%, 75%, and 50% isodose
*** Conclusion: Feasible; deserves additional investigation
* Michigan
** Prospective Phase II. Trial closed prematurely due to unacceptable toxicity. 32 patients, age >40, Stage 0-I, breast conserving surgery. APBI 38.5/10 BID using IMRT at deep-inspiration breath-hold. PTV = cavity + 1.5 cm margin.
** 5-years; 2014 PMID 24613813 -- "Decline of Cosmetic Outcomes Following Accelerated Partial Breast Irradiation Using Intensity Modulated Radiation Therapy: Results of a Single-Institution Prospective Clinical Trial." (Liss Al, Int J Radiat Oncol Biol Phys. 2014 Mar 7. pii: S0360-3016(14)00061-3. doi: 10.1016/j.ijrobp.2014.01.005. [Epub ahead of print])
*** Median F/U 5 years
*** Outcome: 5-yera local control 97%
*** Cosmesis: Further decline in 5 women. Excellent 43%, good 30%, fair 20%, poor 7%. Fibrosis 3%
*** Conclusion: Excellent rate of tumor control. Cosmetic rates continued to decline over time, wit 27% having fair/poor cosmetic result
** 2010 PMID 19409733 -- "Unacceptable cosmesis in a protocol investigating intensity-modulated radiotherapy with active breathing control for accelerated partial-breast irradiation." (Jagsi R, Int J Radiat Oncol Biol Phys. 2010 Jan 1;76(1):71-8.) Median F/U 2.5 years
*** Toxicity: Unacceptable cosmesis in 20%. All but one plan adhered to requirements of NSABP trial. V50 and V100 correlated with cosmesis
*** Conclusion: The schedule and parameters used in the ongoing national trial may be suboptimal
* Tufts University; 2009 PMID 19395195 -- "Toxicity of three-dimensional conformal radiotherapy for accelerated partial breast irradiation." (Hepel JT, Int J Radiat Oncol Biol Phys. 2009 Dec 1;75(5):1290-6. Epub 2009 Apr 22.)
** Retrospective. 60 patients treated with APBI. Dose 38.5/10. Median F/U 15 months
** Toxicity: Moderate/severe late toxicity 10%. Fibrosis Grade 3+ in 8%. Cosmesis good/excellent 82%, fair 12%, poor 7%. Multiple dosimetric parameters correlated with development of fibrosis and cosmetic outcome
** Conclusion: 3D-CRT per B-39 protocol results in remarkably high rate of late normal tissue effects
* RTOG 0319 (2003-2004) PMID 19910132 -- "Initial Efficacy Results of RTOG 0319: Three-Dimensional Conformal Radiation Therapy (3D-CRT) Confined to the Region of the Lumpectomy Cavity for Stage I/ II Breast Carcinoma." (Vicini F, Int J Radiat Oncol Biol Phys. 2009 Nov 10. [Epub ahead of print])
** Phase I/II. 52 patients, Stage I-II BCA, lesion <= 3cm, SM-, LN1-3. (Median age 61, 46% <1cm, 87% IDC, 94% Stage I, 83% no chemo, 71% no hormones). CTV = 10-15 mm over surgical cavity, PTV 10 mm. 3D-CRT 38.5/10 BID, IMRT not allowed. Median F/U 4.5 years
** Outcome: 4-year ipsilateral breast failure 6% (4% in-field), ipsilateral nodal failure 2%, DM 8%, DFS 84%, OS 96%
** Toxicity: Grade 3 in 4% (1 patient fibrosis/telangiectasia, 1 patient dermatitis/myositis). Grade 2 pain 13%
** Conclusion: Initial efficacy and toxicity appears comparable to other experiences
* William Beaumont
** 2003 (2000-2001) PMID 12527042 -- "Accelerated partial breast irradiation using 3D conformal radiation therapy (3D-CRT)." (Baglan KL, Int J Radiat Oncol Biol Phys. 2003 Feb 1;55(2):302-11.)
*** Prospective. 16 patients (7 archived to develop technique, 9 on study), IDC <= 3cm, EIC-, SM-, ALND-, surgical clips in place.
*** Technique: CTV = lumpectomy cavity + 15mm. ITV +5 mm. PTV +5 mm. Noncoplanar 4-5 beam arrangement. Dose 35/10 BID patients, then 38.5/10 BID in 4 patients. Median F/U 8 months
*** Toxicity: No skin changes during treatment, mild hyperpigmentation/erythema at 4 week follow up
*** Conclusion: APBI feasible using 3D-CRT
** 2003 (2000-2002) PMID 14630258 -- "Ongoing clinical experience utilizing 3D conformal external beam radiotherapy to deliver partial-breast irradiation in patients with early-stage breast cancer treated with breast-conserving therapy." (Vicini FA, Int J Radiat Oncol Biol Phys. 2003 Dec 1;57(5):1247-53.)
*** Phase II. 31 patients, lumpectomy + 3D CRT PBI. Dose 34/10 BID (n=6) or 38.5/10 BID (n=25). CTV +10-15 mm. PTV +10mm. Median F/U 10 months
*** Toxicity: At initia 4-8 week visit: no toxicity 29%, Grade 1 toxicity 61%, Grade 2 10%, no Grade 3. Cosmesis good/excellent in all patients
*** Conclusion: 3D-CRT for PBI is feasible and acute toxicity is minimal
** 2007 (2000-2005) PMID 17967306 -- "Interim cosmetic results and toxicity using 3D conformal external beam radiotherapy to deliver accelerated partial breast irradiation in patients with early-stage breast cancer treated with breast-conserving therapy." (Vicini FA, Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):1124-30.)
*** Phase II. 91 patients. Lumpectomy + 3D-CRT APBI. Dose 38.5/10 BID. Median F/U 2 years
*** Outcome: No local failures.
*** Cosmesis: Good/excellent at 6 months 100%, 1 year 93%, 2 years 91%, and 3 years 90%. Grade 3 toxicity (breast pain) in 3%. Grade 1-2 fibrosis 18%, fat necrosis 9%
*** Conclusion: Minimal chronic toxicity with good/excellent cosmetic outcomes
** 4-years; 2009 PMID 19515514 -- "Four-Year Efficacy, Cosmesis, and Toxicity Using Three-Dimensional Conformal External Beam Radiation Therapy to Deliver Accelerated Partial Breast Irradiation." (Chen PY, Int J Radiat Oncol Biol Phys. 2009 Jun 8. [Epub ahead of print])
*** Prospective. 94 patients with Stage 0-II, tumor <=3cm (68% <1cm), SM-, LN-. Postmenopausal 88%. 3D-CRT 38.5/10 BID. Median F/U 4.2 years
*** Outcome: 4-year IBTR 1.1%, ipsilateral node failure 0%, contralateral breast failure 1%, DM 4%, DFS 95%, OS 97%, CSS 99%
*** Toxicity: Grade 3 in 4% (breast pain, fibrosis). Cosmesis good/excellent 89%
*** Conclusion: Efficacy, cosmesis, and toxicity appear comparable to other experiences

## APBI-Protons
### Non-Randomized

* Loma Linda; 2014 PMID 25084608 -- "Partial Breast Radiation Therapy With Proton Beam: 5-Year Results With Cosmetic Outcomes." (Bush DA, Int J Radiat Oncol Biol Phys. 2014 Jul 30. pii: S0360-3016(14)01959-2. doi: 10.1016/j.ijrobp.2014.05.1308. [Epub ahead of print])
** Phase II. 100 patients. Invasive, nonlobular carcinoma, max dimension 3 cm (average 1.3 cm). Negative SM and pN0. Dose 40/10 once daily x2 weeks. Median F/U 5 years
** Outcome: 5-year LRFS 97%; DFS 94%; OS 95%
** Toxicity: No grade 3 or higher skin toxicity. Telangiectasia grade 1 in 7%. Good/excellent cosmesis 90%
** Conclusion: PBT excellent control with minimal toxicity
* National Cancer Center, Goyang, Korea; 2013 PMID 23891102 -- "Phase II trial of proton beam accelerated partial breast irradiation in breast cancer." (Chang JH, Radiother Oncol. 2013 Jul 25. pii: S0167-8140(13)00284-3. doi: 10.1016/j.radonc.2013.06.008. [Epub ahead of print])
** Phase II. 30 paitnets, breast conservation surgery, proton beam APBI, single field or two fields. 30/6 CGE once daily. Median F/U 5.0 years
** Outcome: No IBTR, regional or distant mets. All alive
** Toxicity: good/excellent at end of RT 83%, at 2 months 80%, at 3 years 69%. In patients treated with 2 fields, good/excellent outcomes in all patients and time points but one. Breast retraction assessment (pBRA)increased for patients with single field but not two-field
** Conclusion: Proton beam APBI 30 Gy in 6 fractions daily can be delivered with excellent control and tolerable toxicity, particularly with multiple-field technique
* MGH; 2006 (2004-2005) PMID 17011445 -- "Accelerated partial-breast irradiation using proton beams: initial clinical experience." (Kozak KR, Int J Radiat Oncol Biol Phys. 2006 Nov 1;66(3):691-8.)
** Phase I/II. 20 patients, Stage I BCA. Proton 3D-CPBI 32 CGE/8 fractions BID over 4 days. PTV=lumpectomy + 1.5-2cm, but <5 mm from skin. 1-3 beams, inhomogeneity <15%. Median F/U 1 year
** Cosmesis: good/excellent 100% at 1 year; bt significant acute skin toxicity, moderate/severe skin color changes in 79% at 3-4 weeks, moderate/severe moist desquammation 22% at 6-8 weeks
** Conclusion: Significant acute skin toxicity, but good/excellent cosmetic outcome at 1 year

### Dosimetric

* MD Anderson; 2010 PMID 20708848 -- "External-Beam Accelerated Partial Breast Irradiation Using Multiple Proton Beam Configurations." (Wang X, Int J Radiat Oncol Biol Phys. 2010 Aug 12. [Epub ahead of print])
** Treatment plan comparison. 11 patients, APBI. Passive scatter proton (including Monte Carlo verification) multiple beams vs 3D-CRT photons
** Outcome: Protons reduced V100 by 3%, V90 by 9%, V75 by 12%, V50 by 18% and V20 by 24%. Skin similar V90. Reduced lung and heart dose
** Conclusion: APBI using multiple proton beams spares significantly more normal tissue
* Loma Linda
** 2007 PMID 17476139 -- "A technique of partial breast irradiation utilizing proton beam radiotherapy: comparison with conformal x-ray therapy." (Bush DA, Cancer J. 2007 Mar-Apr;13(2):114-8.)
*** Prospective. 20 patients. Technique described. 2-4 proton beams. 40/10 CGE. Comparison with conformal XRT
*** Plan comparison: Protons significantly less to ipsilateral breast, skin; eliminating dose to heart and lung
*** Acute toxicity: occasional radiation dermatitis Grade 1-2
*** Conclusion: Well tolerated, reproducible, with substantial normal tissue sparing
*** Editorial (PMID 17476135)
* MGH (2004-2005)
** 2006 PMID 16863934 -- "Dosimetric comparison of proton and photon three-dimensional, conformal, external beam accelerated partial breast irradiation techniques." (Kozak KR, Int J Radiat Oncol Biol Phys. 2006 Aug 1;65(5):1572-8.)
*** 24 patients, Stage I, treated with proton 3D-CPBI. Treatment plans also generated using photon-electron 3D-CPBI. PTV and prescribed dose held constant.
*** Outcome: PTV coverage: 95% received >90% of prescribed dose in all cases. Only one case >10% inhomogeneity. Significantly better volume of nontarget breast, lung, and heart for proton plans
*** Conclusion: Proton 3D-CPBI significantly reduces volume of irradiaated nontarget breast tissue
** 2006 PMID 16730137 -- "Accelerated partial breast irradiation using proton beams: Initial dosimetric experience." (Taghian AG, Int J Radiat Oncol Biol Phys. 2006 Aug 1;65(5):1404-10. Epub 2006 May 26.)
*** Retrospective. 25 patients. Tumor <=2 cm, N0. Proton 3D-CPBI 32 CGE/8 fractions BID over 4 days. 1-3 beams.
*** Dosimetry: Median PTV receiving >95% prescribed dose 100%. Dose inhomogeneity >10% in 1 patient (4%). Median volume of nontarget breast tissue receiving 50% of prescribed dose 23%. Median lung receiving 20 CGE 0%, 10 CGE 1%, 5 CGE 2%
*** Cost-analysis: modestly more expensive (25%) than whole breast RT
*** Conclusion: Technically feasible, excellent PTV coverage and normal tissue sparing

### Economics

* Sweden; 2005 PMID 15885828 -- "Economic evaluation of proton radiation therapy in the treatment of breast cancer." (Lundkvist J, Radiother Oncol. 2005 May;75(2):179-85.)
** Markov model simulation, 55 year old patient with left-sided BCA
** Outcome: Euro 67,000 cost per QALY gained; better if high risk cardiac patients treated
** Conclusion: Proton therapy for BCA can be cost-effective if appropriate risk groups are chosen

## Outcomes by patient subgroups

Invasive Lobular Carcinoma:
* William Beaumont; 2011 (1993-2010) PMID 21640491 -- "Clinical outcomes using accelerated partial breast irradiation in patients with invasive lobular carcinoma." (Shah C, Int J Radiat Oncol Biol Phys. 2011 Nov 15;81(4):e547-51.)
** 16 pts with ILC; compared with 410 pts with IDC. APBI technique was interstitial LDR or HDR, balloon, or 3D conformal.
** Median f/u 3.8 yrs for ILC pts, 6.0 yrs for IDC. ILC pts were more likely to have positive margins (20% vs 3.9%), larger tumors (1.4 cm vs 1.1 cm), less likely to be N+ (0% vs 9.5%) than pts with IDC. 5-yr LR was 0% for ILC and 2.5% for IDC. No differences in regional recurrence, DM, DFS, or OS.
** Conclusion: "Women with ILC had excellent clinical outcomes after APBI. No difference in local control was seen between patients with invasive lobular versus invasive ductal histology."

## Consensus Statements

* ASTRO Updated Consensus Statement (2016) PMID 27866865-- "Accelerated Partial Breast Irradiation: Executive Summary for the Update of an ASTRO Evidence-Based Consensus Statement" (Correa Candace, et. al. Practical Radiation Oncology 2016 Sep 17. pii: S1879-8500(16)30184-9)
Summary of updated 2016 consensus statement
| | "Suitable" | "Cautionary" | "Unsuitable" |
| Age | >= 50 years | 40-49 years if all other criteria for "suitable" are met  ≥ 50 if patient has at least one of the pathologic factors below and does not have any "unsuitable" factors. Pathologic factors:  Size 2.1-3.0 cm*  T2  Close margins (<2 mm)  Limited/focal LVSI  ER Negative  Clinically unifocal with total size 2.1- 3.0 cm†  Invasive lobular histology  Pure DCIS ≤3 cm if criteria for "suitable" not fully met  EIC ≤3 cm |  <40 years  40 – 49 years and do not meet the criteria for cautionary |
| BRCA 1/2 | Not Present | | Present |
| Tumor Size | <= 2 cm | 2.1-3.0 cm | >3 cm |
| T Stage | Tis or T1 | T2 | T3 or T4 |
| Margins | >=2mm | Close (<2mm) | Positive |
| Grade | Any | | |
| LVSI | No | Limited/Focal | Extensive |
| ER Status | Positive | Negative | |
| Multicentricity | Clinically unifocal, total size ≤2.0 cm Microscopic multifocality allowed, provided the lesion is clinically unifocal (by PE and MMG/US) and total lesion size (including intervening normal breast parenchyma) is ≤2.0 cm | Clinically unifocal, total size 2.1-3.0 cm Microscopic multifocality allowed, provided the lesion is clinically unifocal and total lesion size is 2.1-3.0 cm cm | Clinically multifocal or microscopically multifocal >3 cm in total size |
| Histology | Invasive ductal or other favorable subtypes | Invasive lobular | |
| Pure DCIS | Allowed if all of the below:  Screen-detected  Low to intermediate nuclear grade  Size ≤ 2.5 cm  Resected with margins negative at ≥ 3 mm | ≤3 cm and does not meet criteria for “suitable” | |
| EIC | Not allowed | ≤3 cm | >3 cm |
| Associated LCIS | Allowed | | |
| N Stage | pN0(i-,i+) | | pN1, pN2, pN3 |
| Nodal Surgery | SN Bx or ALND | | None performed |
| Neoadjuvant | Not allowed | | If used |
* ASTRO Consensus Statement (2009) PMID 19545784 -- "Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO)." (Smith BD, Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):987-1001.)
** see also Task Force Statement (2009) PMID 19545782 -- "Accelerated partial breast irradiation: caution and concern from an ASTRO task force." (Prosnitz LR, Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):981-4.)
Summary of consensus statement :
| | "suitable" | "cautionary" | "unsuitable" |
| Age | ≥60 y | 50-59 y | <50 y |
| BRCA1/2 | Not present | | Present |
| Tumor size | ≤2 cm | 2.1-3.0 cm | >3 cm |
| T stage | T1 | T0 or T2 | T3 or T4 |
| Margins | Negative by ≥2 mm | Close (<2 mm) | Positive |
| Grade | Any | | |
| LVSI | No | Limited/focal | Extensive |
| ER status | Positive | Negative | |
| Multicentricity | Unicentric only | | Multicentric |
| Multifocality | Clinically unifocal, total size ≤2.0 cm Microscopic multifocality allowed, provided the lesion is clinically unifocal (by PE and MMG/US) and total lesion size (including intervening normal breast parenchyma) is ≤2.0 cm | Clinically unifocal, total size 2.1-3.0 cm Microscopic multifocality allowed, provided the lesion is clinically unifocal and total lesion size is 2.1-3.0 cm cm | Clinically multifocal or microscopically multifocal >3 cm in total size |
| Histology | Invasive ductal or other favorable subtypes | Invasive lobular | |
| Pure DCIS | Not allowed | ≤3 cm | >3 cm |
| EIC | Not allowed | ≤3 cm | >3 cm |
| Associated LCIS | Allowed | | |
| N stage | pN0(i$^-$,i$^+$) | | pN1, pN2, pN3 |
| Nodal surgery | SN Bx or ALND | | None performed |
| Neoadjuvant therapy | Not allowed | | If used |
* American Society of Breast Surgeons (2008) Consensus Statement
** Inclusion criteria: Age >=45, IDC or DCIS, size <= 3cm, SM-, SLN-
* California Technology Assessment Forum (2008)
** CTAF link
** Recommendation: The use of breast brachytherapy does not meet Technology Assessment Criteria 4 or 5 for safety, effectiveness and improvement in health outcomes when used as primary radiation therapy following breast conserving surgery for localized breast cancer.
* American Brachytherapy Society Task Group (2007) Guideline
** Inclusion criteria: age >= 50, infiltrating ductal carcinoma, T1 and T2 <= 3cm N0M0
** Not yet fully evaluated: age <45, non-IDC, 1-3 nodes without ECE
** Relative contraindications: EIC, multifocal disease
** Absolute contraindications: inappropriate for standard breast conservation, autoimmune disorders, distant mets
* 3 German Oncology Societies (2007) PMID 17647249 -- "Accelerated partial breast irradiation: consensus statement of 3 German Oncology societies." (Sauer R, Cancer. 2007 Sep 15;110(6):1187-94.)
** "The authors expressly discourage the routine use of APBI outside clinical trials. Until definite results show that APBI neither impairs therapeutic outcome nor cosmetic results, WBRT remains the gold standard in the treatment of early breast cancer"
** Update (2009) PMID 19806329: "DEGRO expert panel recommends to refrain from APBI outside prospective studies as this would not only jeopardize the completion of the necessary clinical trials but also neglect the lack of data that are mature enough to permit definitive conclusions regarding long term tumor control, overall survival and cosmetic outcome of thousands of women"

## Review

* Royal Marsden; 2009 PMID 19178972 -- "Accelerated partial breast irradiation trials: Diversity in rationale and design." (Mannino M, Radiother Oncol. 2009 Apr;91(1):16-22. Epub 2009 Jan 27.)

## Pacemakers / ICDs

* Allegheny General, Pittsburgh
** Distance-dose estimate; 2012 PMID 22330105 -- "Pacemaker/implantable cardioverter-defibrillator dose in balloon high-dose-rate brachytherapy for breast cancer treatment." (Kim Y, Brachytherapy. 2012 Sep-Oct;11(5):380-6. doi: 10.1016/j.brachy.2012.01.001. Epub 2012 Feb 11.)
*** Retrospective. 3 patients treated with HDR APB. 34/10. Implants evaluated. Phantom study performed.
*** Dosimetry: Minimal balloon-device distance 10.9 cm, 18.4 cm, and 4.3 cm. Graph developed correlating dose to distance. To meet 2 Gy cummulative dose, minimum distance depended on fill volume: 35 cc - 10.5 cm, 60 cc - 12 cm, 80 cc - 12.5 cm, 100 cc - 13 cm, and 125 cc - 14 cm
*** Conclusion: The proposed distance-dose graph and/or table enable to approximately predict the maximal device dose based on the measurement of minimal distance between lumpectomy and the device before balloon implantation for the suitability of balloon HDR brachytherapy
** Dose assessment; 2011 (2007-2010) PMID 21607774 -- "Avoiding mastectomy: accelerated partial breast irradiation for breast cancer patients with pacemakers or defibrillators." (Croshaw R, Ann Surg Oncol. 2011 Nov;18(12):3500-5. doi: 10.1245/s10434-011-1784-2. Epub 2011 May 24.)
*** Retrospective. 8 patients treated with APBI (3 HDR with dose 34/10, 5 EBRT with dose 38.5/10). Mean F/U 6 months.
*** Dosimetry: HDR maximum dose 1.03 Gy, mean pacer-lumpectomy distance 9.1 cm. EBRT maximum dose 1.68 Gy, mean distance 9 cm
*** Toxicity: maximum grade 1; no adverse device events
*** Conlusion: APBI in patients with pacemakers/AICDs seems to be safe and reasonable
* ↑ Vaidya, Jayant S; Bulsara, Max; Wenz, Frederik; Joseph, David; Saunders, Christobel; Massarut, Samuele; Flyger, Henrik; Eiermann, Wolfgang; Alvarado, Michael; Esserman, Laura; Falzon, Mary; Brew-Graves, Chris; Potyka, Ingrid; Tobias, Jeffrey S; Baum, Michael; On behalf of the TARGIT trialists' group (7 April 2015). "Pride, Prejudice, or Science – attitudes towards the results of the TARGIT-A trial of targeted intraoperative radiotherapy for breast cancer". International Journal of Radiation Oncology*Biology*Physics. doi:10.1016/j.ijrobp.2015.03.022.