Radiation Oncology/Breast/Early breast/BCT


 * Subpages
 * BCS +/- RT

Surgical Options

 * Radical Mastectomy
 * Introduced by Halsted in 1894
 * En bloc removal of the breast, overlying skin, pectoralis major, pectoralis minor, and Level I, II, and III lymph nodes
 * Typically requires a skin graft. Long thoracic and thoracodorsal nerves sacrificed, leading to atrophy of serratus anterior and latissiumus dorsi
 * Improved local control, but poor survival
 * Currently no absolute indications for this procedure
 * Extended radical mastectomy
 * Introduced in an effort for improved loco-regional control based on Halsted's progression of breast cancer
 * Radical mastectomy + dissection of axilla, infraclavicular, supraclavicular, and 2nd-4th intercostal spaces
 * Currently not used
 * Modified Radical Mastectomy
 * Complete removal of breast tissue, pectoralis major fascia, and Level I and II lymph nodes. Preserves pectoralis minor.
 * Intercostal brachial nerve sacrified, leading to numbness in medial aspect of upper arm
 * Survival equivalent to radical mastectomy
 * Total Mastectomy (Simple Mastectomy)
 * Removal of breast tissue only. Preservation of both pectoralis muscles and axillary lymph nodes
 * More commonly used with sentinel lymph node biopsy
 * Skin-Sparing Mastectomy
 * Resection of biopsy scar, skin overlying the tumor, and removal of breast parenchyma. Preservation of majority of breast skin for reconstruction
 * Comparable recurrence rates, as long as all breast parenchyma is removed
 * Nipple-Sparing Mastectomy
 * Skin-sparing mastectomy with preservation of the nipple-areola complex
 * Used in patients with peripheral and small tumors
 * Quadrantectomy
 * Complete removal of primary carcinoma, with 1.5-2.0 cm surgical margin. Portions of the overlying skin and deep muscular fascia also removed
 * Used in the pivotal Milan trial of radical mastectomy vs. BCS
 * Partial Mastectomy
 * Lumpectomy
 * Wide Local Excision


 * Absolute contraindications to BCS
 * Persistently positive resection margins after reexcision
 * Multicentric disease, with 2+ primary tumors in separate quadrants
 * Diffuse malignant-appearing mammographic microcalcifications, suggesting multicentricity
 * Prior RT to the breast or chest wall
 * Relative contraindications to BCS
 * Pregnancy, with possibly performing BCS in 3rd trimester and deferring RT after delivery
 * Connective tissues disorders, since these patients may tolerate RT poorly
 * Large tumor in a small breast, because cosmetic outcome may not be satisfactory

More Extensive Mastectomy vs. Less Extensive Mastectomy + RT

 * NSABP B-04 (1971-1974) -- radical mastectomy vs. total mastectomy + RT vs. total mastectomy alone
 * Randomized, 2 separate randomizations. 1665 women. For further information, please see page at Axilla
 * 1079 women with clinically LN-: Arm 1) radical mastectomy vs. Arm 2) total mastectomy + RT vs. Arm 3) total mastectomy alone
 * 586 women with clinically LN+: Arm 1) radical mastectomy vs. Arm 2) total mastectomy + RT
 * 10-years, 1985 PMID 3883168 -- "Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation." (Fisher B, N Engl J Med. 1985 Mar 14;312(11):674-81.)
 * Conclusion: Variations of local and regional treatment not important in determining survival
 * 25-years, 2000 PMID 12192016 -- "Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation." (Fisher B, N Engl J Med. 2002 Aug 22;347(8):567-75.)
 * No difference in DFS, RFS, DM, or OS
 * Conclusion: No advantage to radical mastectomy. Also no survival advantage to removing occult positive nodes at surgery or to RT


 * Denmark DBCG (1951-1957) -- extended radical mastectomy vs. simple mastectomy + RT
 * Randomized. 666 consecutive patients with untreated primary breast CA randomized, 425 patients underwent surgery (majority of those excluded were not surgical candidates). Arm 1) extended radical mastectomy (radical mastectomy + dissection of axilla, infraclavicular, supraclavicular, and 2nd-4th intercostal spaces) vs. Arm 2) simple mastectomy + RT. RT given with opposing tangential fields including internal mammary LN + anterior/posterior fields to axilla supraclavicular region. Energy 180 kV - 400 kV, dose 42-45 Gy given in 6 days/week
 * 50-years; 2008 PMID 18465331 -- "Extended radical mastectomy versus simple mastectomy followed by radiotherapy in primary breast cancer. A fifty-year follow-up to the Copenhagen Breast Cancer randomised study." (Johansen H, Acta Oncol. 2008;47(4):633-8.)
 * Outcome: 5-year OS ERM 1% vs. SM + RT 1% (NS); 30-year OS 11% vs. 9% (NS). 25-year DFS 18% vs. 14% (NS)
 * Predictors: Stage I better vs. Stage II-III; premenopausal better vs. postmenopausal. Excess mortality due to breast CA demonstrable up to 20-25 years after primary diagnosis
 * Toxicity: lymphedema ERM 12% vs. SM + RT 4%
 * Conclusion: Mutilating extended radical mastectomy can be safely substituted by simple mastectomy with radiation; no difference in OS or DFS

Mastectomy vs. BCS + RT

 * No difference in overall survival between mastectomy and breast-conservation surgery + radiation
 * No difference based on the size of the tumor itself, therefore choosing mastectomy vs BCT for large tumors should be based on anticipated cosmetic outcome, not control of the cancer (based on B-06)
 * Young age alone is also not a contraindication


 * Denmark (1983-1989)
 * Randomized. 908 patients treated with BCS (intent to get free margins) + RT vs. mastectomy. Axillary dissection for everyone.
 * 3-years, 1992 PMID 1627427 -- "Danish randomized trial comparing breast conservation therapy with mastectomy: six years of life-table analysis. Danish Breast Cancer Cooperative Group." (Blichert-Toft M, J Natl Cancer Inst Monogr 1992;(11):19-25.). Median F/U 3.3 years
 * 6-year outcomes: DFS: BCS 70% vs. mastectomy 66%. Survival 79% vs. 82%
 * EORTC 10801 (1980-1986)
 * Randomized. 868 patients, tumors <=5cm (80% 2-5cm). Treated with modified radical mastectomy vs. lumpectomy with 1cm margin, complete axillary clearance, and RT 50/25 with 25 Gy IR-192 boost. IM RT given if central/medial tumor or if lateral tumor and axilla positive (~45%). Margins not inked, re-excision only for macroscopic residual disease. Chemo CMF given if >55 years, or younger and axillary LN+
 * 10-years, 2000 PMID 10904087 -- "Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial." (van Dongen JA, J Natl Cancer Inst 2000 Jul 19;92(14):1143-50.). Median F/U 13.4 years
 * 10-years: LR mastectomy 12% vs. BCT 20% (SS). No difference OS (66% vs. 65%, NS) and DM (66% vs. 61%, NS)
 * QOL, 1998 PMID 9640214 -- "Quality of life of early-stage breast cancer patients treated with radical mastectomy or breast-conserving procedures: results of EORTC Trial 10801." (Curran D, Eur J Cancer. 1998 Feb;34(3):307-14.)
 * Comparison of Quality-of-life and cosmetic results at 2-3 years. 127 MRM and 151 BCT patients
 * Outcome: significant benefit in body image and treatment satisfaction in BCT group. No difference in fear of recurrence.
 * Cosmesis decreased over time
 * Conclusion: Similar survival rates, even with Stage II tumors.


 * NCI (1979-1987) -- Lumpectomy + ALND + RT vs. MRM + ALND
 * Randomized. 237 patients with Stage I-II. Treated with lumpectomy + complete axillary dissection + RT vs. modified radical mastectomy + complete axillary dissection. Negative margins not required. RT 45/25 - 50.4/28 whole breast, supraclav if LN+, internal mammary coverage by crossing midline if axilla LN+ or medial tumor, boost 15-20 Gy via IR-192 (81%) or electrons (19%). If LN+, chemo AC
 * 10-years, 1999 PMID 7877647 -- "Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer." (Jacobson JA, N Engl J Med 1995 Apr 6;332(14):907-11.). Median F/U 10 years
 * 10-year loco-regional recurrence: mastectomy 10% vs. BCS 5% (NS), after censoring recurrences treated by mastectomy
 * No difference in OS (mastectomy 75% vs. BCS 77%), or DFS (69% vs. 72%)
 * 18-years, 2003 PMID 12910512 -- "Eighteen-year results in the treatment of early breast carcinoma with mastectomy versus breast conservation therapy: the National Cancer Institute Randomized Trial." (Poggi MM, Cancer 2003 Aug 15;98(4):697-702.). Median F/U 18.4 years
 * 18-year LR: 22% in-breast in BCT arm vs. mastectomy 0%. 60% salvaged successfully. Failures througout follow-up
 * No difference in OS (mastectomy 58% vs. BCT 54%) or DFS (67% vs. 63%). No difference in contralater BCA (5%)
 * Conclusion: No difference in OS or DFS.
 * Comment: higher in-breast failure likely due to large tumors (10% >4cm, 80% T2) and not requiring negative surgical margins
 * NSABP B-06 (1976-84) -- Total mastectomy vs lumpectomy alone vs lumpectomy + RT
 * Randomized. 1851 patients. Stage I-II with tumors <= 4cm and LN +/-. If lumpectomy and SM+ (10%), underwent mastectomy but tracked under lumpectomy group. All had axillary lymph node dissection. XRT was 50 Gy to the breast only (not axilla) without a boost. Women with LN+ received melphalan + 5-FU. 62% were node-negative, 26% had 1-3 nodes, 12% had 4 or more nodes. Estrogen receptor status was available for 75%: 64% were ER+ and 36% were ER-. If breast recurrence after lumpectomy, not tracked as treatment failure because mastectomy patients were not at comparable risk but as "cosmetic failure"
 * 5 years, 1985 PMID 3883167 &mdash; "Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer." Fisher B et al. N Engl J Med. 1985 Mar 14;312(11):665-73.
 * 8 years, 1989: PMID 2927449 &mdash; "Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer." Fisher B et al. N Engl J Med. 1989 Mar 30;320(13):822-8.
 * 12 years, 1995: PMID 7477145 Full text &mdash; "Reanalysis and Results after 12 Years of Follow-Up in a Randomized Clinical Trial Comparing Total Mastectomy with Lumpectomy with or without Irradiation in the Treatment of Breast Cancer." Fisher B et al. N Engl J Med. 1995 Nov 30;333(22);1456-61.
 * Outcome: OS mastectomy 62% vs. lumpectomy 60% vs. lumpectomy + RT 62% (NS); DFS 51% vs. 48% vs. 50% (NS); IBTR lumpectomy 35% vs. lumpectomy + RT 10% (SS)
 * Conclusion: Lumpectomy followed by breast RT is appropriate for women with <=4 cm tumors and LN+ or LN-
 * 20 years, 2002: PMID 12393820 Full text &mdash; "Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer." Fisher B et al. N Engl J Med. 2002 Oct 17;347(16):1233-41.
 * Outcome: IBTR lumpectomy + RT 14% vs lumpectomy alone 39% (SS). Benefit regardless of LN status. Recurrence in the chest wall or scar was considered a local failure but ipsilateral breast failure in lumpectomy patients was NOT. LRR mastectomy 15% vs. lumpectomy alone 17% vs. lumpectomy + RT 8%
 * Timing of local failure: After lumpectomy - 73% within first 5 years, 18% 5-10 years, 8% after 10 years. After lumpectomy + XRT - 39% within first 5 years, 29% 5-10 years, 30% after 10 years. 63% (in all arms) suffered death or a first event.
 * First recurrences: local failure mastectomy 10% vs. lumpectomy 9% vs. lumpectomy + RT 3%; regional failure 5% vs. 9% vs. 5%; DM 22-26%; contralateral BCA 8-9%, second cancer in 5-7%, or death without cancer in 10%. 69% of any recurrence was detected within 5 years. 38% of contralateral breast cancers detected within 5 years, 30% 5-10 years, 32% after 10 years.
 * Survival: DFS 36% vs 35% vs 35% (NS). OS 47% vs 46% vs 46% (NS).
 * Comments: PMID 12584378


 * Milan (1973-1980) - Radical (Halsted) mastectomy vs. BCS + RT
 * Randomized. 701 women with BCA <=2cm. LN+ in 25% (but suspect 35% due to inadequate path at that time). Treated with radical (Halsted) mastectomy (349 pts) vs. quadrantectomy followed by RT (352 pts). RT 50 Gy + boost 10 Gy. After 1976, patients with LN+ received adjuvant CMF
 * 20-years, 2002 PMID 12393819 -- "Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer." (Veronesi U, N Engl J Med. 2002 Oct 17;347(16):1227-32.). Median F/U 20 years
 * Ipsilateral recurrence: mastectomy 2% vs. BCS+RT 9% (SS). This rate identical to rate of contralateral BCA, suggesting new primaries rather than recurrence. True in-quadrant recurrence was comparable to mastectomy (8 cases vs. 10 cases)
 * Other outcomes: no difference in contralateral BCA, DM, or second primary CA
 * 20-year OS: both groups 41%; disease-specific survival 76% vs. 74% (NS)
 * Comments: PMID 12584378
 * Conclusion : BCS is the treatment of choice for women with relatively small breast cancers. Also, RT does not appreciably increase risk of contralateral BCA


 * Gustave-Roussy (1972-1980)
 * Randomized. 179 patients, tumor <=2cm. Treated with modified radical mastectomy (91) vs. tumorectomy + RT. All had low-axillary dissection; if LN+ complete axillary dissection
 * 10-years, 1989 PMID 2652199 -- "Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. (Sarrazin D, Radiother Oncol. 1989 Mar;14(3):177-84.)
 * 15-years, 1996 PMID 8622072 -- "Conservative treatment versus mastectomy in early breast cancer: patterns of failure with 15 years of follow-up data. Institut Gustave-Roussy Breast Cancer Group. (Arriagada R, J Clin Oncol 1996 May;14(5):1558-64.)
 * Outcome: No difference in OS, DM, contralateral BCA, and LR recurrence

Age
 * British Columbia, 2007 (1989-1998) PMID 17275207 -- "Is mastectomy superior to breast-conserving treatment for young women?" (Coulombe G, Int J Radiat Oncol Biol Phys. 2007 Apr 1;67(5):1282-90.)
 * Retrospective. Women aged 20-49 with early BCA. Management with MRM (1597 patients) compared with BCT (801 patients). Median F/u 9.0 years
 * No difference in outcome (L, LR, BCSS) by modality; but outcomes worse for younger patients
 * For patients 20-39, difference at 10-year LR potentially (p=0.3) favored MRM, no difference in DRFS or BCSS
 * Conclusion: Young age not a contraindication to BCT

High Risk
 * University of Alberta; 2011 PMID 21670451 -- "Increased risk of locoregional recurrence for women with T1-2N0 triple-negative breast cancer treated with modified radical mastectomy without adjuvant radiation therapy compared with breast-conserving therapy." (Abdulkarim BS, J Clin Oncol. 2011 Jul 20;29(21):2852-8. doi: 10.1200/JCO.2010.33.4714. Epub 2011 Jun 13.)
 * Retrospective. 768 patients, T1-T2N0, triple-negative breast cancer. Treated with mastectomy and no radiation versus lumpectomy with radiation. Median follow up 7.2 years
 * Outcome: 5-year LRR-free survival breast conservation 96% versus mastectomy 90% (SS). Mastectomy only independent prognostic factor associated with increased LRR (HR 2.5, SS)
 * Conclusion: Women with T1-T2N0 triple-negative breast cancer treated with mastectomy and no RT have a significantly increased risk of locoregional recurrence compared to those with breast conservation therapy

BCS +/- RT

 * Please see detailed trial information
 * 18 randomized trials performed (13 published as full results, 2 published as abstracts, 3 not published). Please note that eligibility criteria and adjuvant tamoxifen/chemo varied significantly
 * Addition of RT decreases ipsilateral BCA recurrence by approximately 2/3; effect is much more pronounced in N+ patients and younger women, but persists even in low risk small widely resected tumors
 * EBCTCG analysis of individual patient data from 10 trials (PMID 16360786) suggests 5-year outcome benefits:
 * Overall LR: 26% vs. 7% (SS)
 * If LN- LR: 23% vs. 7% (SS)
 * If LN+ LR: 41% vs. 11% (SS)
 * BCA mortality at 15 yrs: 36% vs. 30% (SS)
 * This translates into preventing 1 BCA death for every 4 local recurrences prevented, at 15 years

Nomograms
 * IBTR! (Tufts/British Columbia/Mass General)
 * Web-based IBTR! nomogram: http://160.109.101.132/ibtr/
 * 2010 PMID 20048188 -- "Validation of a web-based predictive nomogram for ipsilateral breast tumor recurrence after breast conserving therapy." (Sanghani M, J Clin Oncol. 2010 Feb 10;28(5):718-22. Epub 2010 Jan 4.)
 * Nomogram development/validation. IBTR! version 1.0 used to model BCCA data on 7,811 patient set (median F/U 9.3 years), then validate on MGH 664 patient set (median F/U 9.4 years).
 * Outcome: Risk group 1 (2.2% vs 1.3%, NS), risk group 2 (3.8% vs 3.5%, NS), risk group 3 (6.7% vs 3.2%, p=0.05), risk group 4 (12.5% vs 8.7%, NS)
 * Conclusion: IBTR! v2.0 accurate in majority of patients; overestimates risk in minority of patients with high risk features
 * 2007 PMID 17921706 -- "Predicting the risk of local recurrence in patients with breast cancer: an approach to a new computer-based predictive tool." (Sanghani M, Am J Clin Oncol. 2007 Oct;30(5):473-80.)
 * Nomogram development. Data from randomized trials, meta-analyses and institutional reports of BCS alone vs BCS+RT used
 * Model developed using age, SM status, LVI, tumor size, grade, use of chemo, use of hormones
 * Conclusion: IBTR! a first attempt to model local recurrence risk in breast conservation therapy

Meta-analyses
 * Early Breast Cancer Trialists' Collaborative Group (EBCTCG) (a.k.a. Oxford overview) - Meta-analysis.
 * See also: Oxford overview of Chemotherapy or Hormonal therapy
 * 2011: PMID 22019144 -- "Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials", Lancet. 2011 Oct 19. [Epub ahead of print]
 * 10,801 women in 17 randomized trials of RT vs no RT after BCS; 77% were pN0.
 * 10 yr risk of any first recurrence (LR or distant) reduced from 35.0% to 19.3% (absolute: 15.7%); 15-yr risk of breast cancer death from 25.2% to 21.4% (absolute: 3.8%);
 * for pN0 subset: reduced any recurrence from 31.0% to 15.6% (abs: 15.4%) and death from 20.5% to 17.2% (abs: 3.3%). absolute 10-yr recurrence risk reduction depended on factors (age,grade,ER,tamoxifen,extent of surgery). These factors were used to predict large (&ge;20%), intermediate (10-19%), and lower (<10%) benefits. The reduction in 15-yr risk of breast cancer death in these categories was: 7.8%, 1.1% [CI -2.0 to 4.2], and 0.1% [CI -7.5 to 7.7].
 * for pN+ subset: reduced any recurrence from 63.7% to 42.5% (abs: 21.2%) and death from 51.3% to 42.8% (abs: 8.5%)
 * Overall, 1 breast cancer death was avoided for every 4 recurrences avoided. The reduction in mortality did not differ significantly between the pN0 and pN+ subsets.
 * 2005: PMID 16360786 &mdash; "Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials." Clark M et al. Lancet. 2005 Dec 17;366(9503):2087-106.
 * 42,000 women in 78 randomized trials of RT vs no RT, more vs less surgery, and more surgery vs RT.
 * For breast conserving therapy, 5-yr LR 7% (RT) vs 26% (no RT), and 15-yr breast cancer mortality risk of 30.5% vs 35.9% (S.S.).
 * 2000 Van de Steene - PMID 10869741 &mdash; "Adjuvant radiotherapy for breast cancer significantly improves overall survival: the missing link." Van de Steene J et al. Radiother Oncol. 2000 Jun;55(3):263-72.
 * Analysis of Early Breast Cancer Trialists' Collaborative Group study showed that there was a survival benefit (12% reduction) for recent trials, large trials, and trials using standard fractionation. Importance of reducing cardiovascular toxicity.
 * 2000: PMID 10832826 &mdash; "Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials." Lancet. 2000 May 20;355(9217):1757-70.
 * Meta-analysis of 40 trials. 10-year and 20-year results looking at cause-specific mortality. Half were node positive.
 * RT associated with 2/3 reduction in local recurrence (8.8% vs 27.2% at 10 years). Breast cancer mortality was reduced but other mortality increased. Overall 20-year survival was 37.1% (RT) vs 35.9%, p=0.06.
 * A criticism of these results is that it mostly analyzed older radiotherapy techniques which delivered a higher dose to the heart.
 * 1995: PMID 7477144 Full text &mdash; "Effects of radiotherapy and surgery in early breast cancer. An overview of the randomized trials." N Engl J Med. 1995 Nov 30;333(22):1444-55.
 * 1/3 local failures compared to surgery alone. 5% fewer deaths due to breast cancer (odds ratio 0.95) at 10 years. However, 24% increase in death due to other causes. Overall survival no different: 40.3% (RT) vs 41.4% at 10 years. Increase in deaths was greater for pts > 60 yrs


 * BCS Project, 2004 PMID 14734701 -- "Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality." (Vinh-Hung V, J Natl Cancer Inst. 2004 Jan 21;96(2):115-21.)
 * Pooled analysis. 15 trials of BCS +/- RT with published data, 9422 patients
 * IBTR: RR 3.0 (SS)
 * Mortality: RR 1.086 (SS) = 8.6% relative excess mortality if RT not given
 * Conclusion: RT associated with large benefit on IBTR and small benefit on mortality


 * McMaster University, 2000 (1967-99) PMID 10715291 &mdash; "Does locoregional radiation therapy improve survival in breast cancer? A meta-analysis." Whelan TJ et al. J Clin Oncol. 2000 Mar;18(6):1220-9.
 * Node positive cancers, received systemic therapy. 18 trials. 6,367 pts. Most were treated with modified radical mastectomy.
 * RT reduced any recurrence (OR 0.69), LR (OR 0.25), and mortality (OR 0.83).

BCS and Tamoxifen +/- RT

 * Austrian ABCSG 8A (1996-2004) -- <3cm, Arimidex/TAM vs. RT + Arimidex/TAM
 * 869 patients. Early breast cancer, <3 cm, G1-2, N0, ER or PR positive. Treated by lumpectomy with Arimidex or Tamoxifen. Randomized to whole breast RT 50 Gy (+/- 10 Gy boost) vs no RT. Median age 66 yrs.
 * 2005 ASTRO 2005 Plenary #3 (Abstract only) - No PMID Webcast &mdash; "Lumpectomy Plus Tamoxifen or Arimidex With or Without Whole Breast Irradiation in Women with Favorable Early Breast Cancer." Poetter R et al. IJROBP Volume 63, Supplement 1, 1 October 2005, Page S2.
 * Median f/u 3.5 years. LR 0.2% vs 3.1%. Overall recurrence 4.4% vs 6.7%.
 * 5-years, 2007 PMID 17363187 -- "Lumpectomy plus tamoxifen or anastrozole with or without whole breast irradiation in women with favorable early breast cancer." (Potter R, Int J Radiat Oncol Biol Phys. 2007 Jun 1;68(2):334-40. Epub 2007 Mar 23.). Median F/U 4.5 years
 * 5-year outcome: LR: RT 0.4% vs. no RT 5.1% (SS); Overall relapse 2.1% vs. 6.1% (SS); DM/OS NS
 * Conclusion: RT leads to significant reduction in local and overall relapse


 * CALGB 9343 (RTOG 97-02, ECOG) (1994-99) -- 70 years or older, T1N0, ER+ -- TAM. vs RT + TAM
 * 636 pts. Randomized to tamoxifen +/- RT. 56% >75 y/o. ALND 37%. RT 45/25 + boost 14/7
 * 5-years, 2004 PMID 15342805 &mdash; "Lumpectomy plus tamoxifen with or without irradiation in women 70 years of age or older with early breast cancer." Hughes KS et al. N Engl J Med. 2004 Sep 2;351(10):971-7. Median F/U 5 years
 * 5-yr outcome: LR tamoxifen 4% vs TAM+RT 1% (SS). No difference in rate of mastectomy, distant mets, or 5-yr OS (87% vs 86%)
 * Side effects:
 * Physicians: cosmesis, breast pain, edema, hyperpigmentation worse at 1 year; no differences at 4 years
 * Patients: breast pain, fibrosis worse at 1 year; breast pain, arm/shoulder stiffness worse at 4 years
 * Conclusion: lumpectomy + tamoxifen alone is acceptable for women 70 years or older with T1N0 ER+ tumors
 * 10-years, 2010 ASCO 2010 Abstract -- "Lumpectomy plus tamoxifen with or without irradiation in women age 70 or older with early breast cancer." (Hughes KS, Abstract #507) -- Median f/u 10.5 yrs
 * First recurrence local in 9% (Tam) vs 2% (Tam+RT) -- IBTR 8% vs 2%, Axilla 1% vs 0%. RT prolonged the time to first recurrence. 10-year freedom from mastectomy 96% vs 98%, freedom from DM 95% vs 93%. Breast cancer specific survival 98% vs 96%, OS 63% vs 61%. Only 7% of deaths were due to breast cancer.
 * Conclusion: RT results in absolute reduction of 7% in LR (6% IBTR + 1% Axilla). No impact on overall survival, cancer specific survival, breast conservation, or distant DFS.


 * Canada multi-institutional (1992-2000) -- >50, TAM vs. RT + TAM
 * 769 pts. Randomized to tamoxifen +/- RT. Median age 68. pN staging 83%. Almost all had positive receptors (81%) or unknown receptor status (13%). RT 40/16 + boost 12.5/5
 * 5-years, 2004 PMID 15342804 &mdash; "Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer." Fyles AW et al. N Engl J Med. 2004 Sep 2;351(10):963-70. Median F/U 5.6 years
 * 5-yr local: LR tamoxifen 7.7% vs TAM+RT 0.6% (SS); DFS 84% vs 91%. Planned subset outcome (T1 ER+): LR 5.9% vs 0.4% (SS).
 * 5-year regional: axillary relapse 2.5% vs. 0.5% (SS). No difference in DM or OS.
 * Conclusion: RT in addition to tamoxifen significantly reduces local and axillary recurrence


 * German GBSG (1991-1998) -- 45-75, 2x2 +/- RT and +/- TAM
 * Randomized. Stopped prematurely due to slow accrual. 2x2 factorial. 347 out of target 700 patients with pT1N0, ER+, Grade I-II, EIC-, LVI-, SM-, ALND with minimum 10 LNs. Age 45-75 (>=60 in 54%). Randomized to +/- RT and to +/- TAM. RT 50/25 + boost 10-12 Gy. TAM 30 mg x2 years
 * 10-years; 2009 PMID 19879131 -- "Radiation therapy and tamoxifen after breast-conserving surgery: Updated results of a 2x2 randomised clinical trial in patients with low risk of recurrence." (Winzer KJ, Eur J Cancer. 2009 Oct 28. [Epub ahead of print]). Median F/U 9.9 years
 * Outcome: 10-year ITBR BCS 34% vs. BCS+RT 10% vs. BCS+TAM 7% vs. BCS+RT+TAM 5% (SS); regional failure 0% vs 1% vs 0% vs 0%; 8-year EFS 48% vs. 78% (RR 0.36) vs. 78% (RR 0.33) vs. 78% (RR 0.32) (SS). No difference for DMFS
 * Conclusion: In patients with favorable prognosis, avoidance of RT and TAM increases local recurrence substantially. Not powered to distinguish between RT, TAM, and RT+TAM


 * NSABP B-21 (1989-1998) -- <1cm, TAM vs. RT vs RT + TAM
 * 1009 women. Tumors <=1cm. Lumpectomy + ALND. Randomized to RT, TAM, or RT + TAM. RT 50/25, boost at discretion
 * 8-years, 2002 PMID 12377957 -- "Tamoxifen, radiation therapy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less." (Fisher B, J Clin Oncol. 2002 Oct 15;20(20):4141-9.)
 * Local recurrence: TAM 16% vs. RT 9% vs. RT+TAM 3%; no difference in DM or survival
 * Contralateral BCA: no TAM 5.4% vs. TAM 2.2%
 * Conclusion: Even in tumors <=1cm, should consider RT and TAM

Surgical Margin

 * Memorial Sloan Kettering; 2010 (2005-2007) PMID 19847566 -- "What is an adequate margin for breast-conserving surgery? Surgeon attitudes and correlates." (Azu M, Ann Surg Oncol. 2010 Feb;17(2):558-63. Epub 2009 Oct 22.)
 * Retrospective. SEER data/pathology reports used to identify 418 surgeons of breast cancer patients. Response rate to questionnaire 75% (n=312)
 * Outcome: Wide variation in margin selection. If T1 invasive cancer, tumor not touching ink 11%, 1-2 mm 42%, &ge; 5mm 28%, >1cm 19% as precluding need for re-excision. On MVA, >50% breast surgery practice predicted smaller margins (SS). If DCIS without RT: 3%, 12%, 25%, and 61% of surgeons chose above margins.
 * Conclusion: Wide variation in BCS margin definition


 * EORTC Boost Trial: Pathologic Characteristics; 2009 PMID 19720914 -- "Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the EORTC boost versus no boost trial." (Jones HA, J Clin Oncol. 2009 Oct 20;27(30):4939-47. Epub 2009 Aug 31.)
 * Please see EORTC Boost Trial section for full information. Multivariate predictors for LR: high grade (SS), age <50 (SS), 16 Gy boost (SS). If high grade, no boost 19% vs. boost 9% (SS). If age <50, 19% vs. 11% (SS).
 * Surgical margin status (negative, close, or positive) was not a predictor for local relapse (criticism - only 3.4% of invasive cases had + margins)
 * Conclusion: Young age and high-grade most important risk factors for local relapse; margin status not important
 * Editorial (PMID 19720895): Surgical re-excision should continue to be performed based on strength of multiple other studies. Age and grade worthy of further study


 * Joint Center for Radiation Therapy; 2000 PMID 10764427 -- "Outcome at 8 years after breast-conserving surgery and radiation therapy for invasive breast cancer: influence of margin status and systemic therapy on local recurrence." (Park CC, J Clin Oncol. 2000 Apr;18(8):1668-75.)
 * 553 pts. Margins scored: negative (>1mm), close (<=1 mm), focally positive (margin involved in 3 or fewer low power fields), or extensively positive. Pts treated with RT to the whole breast with a boost dose to the tumor bed of at least 60 Gy. Doses were not adjusted according to margin status.
 * 8 yr LR: 7% (negative), 7% (close), 14% (foc. pos), and 27% (extens. pos)

Tumor bed boost
Randomized
 * Netherlands - Ongoing
 * Randomized. Whole breast 50 Gy + boost 16 Gy vs. boost 26 Gy in young women
 * 2006 PMID 16904837 -- "High-dose simultaneously integrated breast boost using intensity-modulated radiotherapy and inverse optimization." (Hurkmans CW, Int J Radiat Oncol Biol Phys. 2006 Nov 1;66(3):923-30.)
 * Description of simultaneous integrated boost technique. 31 fxs @ 1.66 Gy to whole breast and 31 fxs @ 2.38 Gy to boost


 * Budapest (Hungary)(1995-1998)
 * Randomized. 604 women, T1-2 N0-1 BCA, s/p BCS + ALND and whole breast RT 50/25. Arm 1) observation vs. Arm 2) tumor bed boost. Boost given as electron boost 16/8 (50% patients) or Ir-192 HDR brachytherapy with 3-9 needles to 12/3 initially and then 14.25/3 (50% patients)
 * 5-years; 2002 PMID 12426672 -- "Electron and high-dose-rate brachytherapy boost in the conservative treatment of stage I-II breast cancer first results of the randomized Budapest boost trial." (Polgar C, Strahlenther Onkol. 2002 Nov;178(11):615-23.) Median F/U 5.3 years
 * Outcome: LR no boost 15% vs. boost 7% (SS), tumor bed recurrence 12% vs. 4% (SS), CSS 90% vs. 82% (p=0.053). No difference between electron and HDR boost
 * Predictors for LR: age <40, close/positive SM, high mitotic activity
 * Toxicity: excellent/good no boost 91% vs. boost 86% (NS); but Grade 2-3 side effects 8% vs. 17% (SS). No difference between electron and HDR boost
 * Conclusion: Boost dose significantly improves local control and relapse-free survival; cosmetic outcome comparable


 * Lyon (France) (1986-92)
 * 1024 pts. Tumor <=3cm. Lumpectomy 82%/quadrantectomy 16%. N+ 27%. SM- 2%. Treated with 50/20 +/- 10/4 boost to tumor bed.
 * 5-years, 1997 &mdash; PMID 9060534 "Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France." Romestaing P et al. J Clin Oncol. 1997 Mar;15(3):963-8.
 * Local recurrence: 3.6% (boost) vs 4.5% (no boost)
 * Cosmesis: telangiectasia 12.4% vs. 5.9%, but no difference in self-assessment of cosmesis
 * Conclusion: boost provides significant benefit without much impact on cosmesis


 * EORTC 22881/10882, 2001 (1989-96) - boost vs no boost.
 * 5318 patients. Stage I-II. Lumpectomy + ALND + 50/25 Gy to breast. 21% N+. If SM-, randomized to +/- 16 Gy boost. Boost was to lumpectomy + 1.5 cm margin. If SM+, randomized to 10 Gy vs 26 Gy boost. 28% adjuvant systemic therapy
 * Cosmesis, 1999 PMID 10524422 -- "The influence of the boost in breast-conserving therapy on cosmetic outcome in the EORTC "boost versus no boost" trial." (Vrieling C, Int J Radiat Oncol Biol Phys. 1999 Oct 1;45(3):677-85.)
 * Panel evaluation of cosmesis (731 patient photographs), digitizer measurements of nipple displacement pre-RT (3000 patients) and 3 years later (1141 patients)
 * Pre-RT cosmesis: no difference
 * 3-year cosmesis: excellent/good results in 86% no boost vs. 71% boost (SS)
 * Conclusion: Boost had adverse effect on cosmesis
 * 5-years, 2001 PMID 11794170 Full Text &mdash; "Recurrence Rates after Treatment of Breast Cancer with Standard Radiotherapy with or without Additional Radiation" Bartelink H et al. N Engl J Med. 2001 Nov 8;345(19):1378-87.
 * 5-year LR: Overall Boost 4.3% vs no boost 7.3%. (reduction of 40%). Women <40 the most benefit (10% vs 20%). Women >60 minimal benefit (2.5% vs. 4%)
 * No difference in rate of metastases or OS.
 * Age effect, 2007 PMID 17126434 -- "Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882." (Antonini N, Radiother Oncol. 2007 Mar;82(3):265-71.). Median F/U 6.5 years
 * Local control increased with age; effect of boost does not depend on age
 * Expected benefit for RT: treating everyone 3.8%, treating <=60 4.4%, <=50 5.1%, <=40 6.1%, treating nobody (no boost) 6.9%
 * Predictive factors: age, tumor size, grade
 * Conclusion: Treatment threshold age 60 would result in 0.6% increase in LR, while sparing boost in 1/3 of patients
 * 10-years, 2007 PMID 17577015 -- "Impact of a Higher Radiation Dose on Local Control and Survival in Breast-Conserving Therapy of Early Breast Cancer: 10-Year Results of the Randomized Boost Versus No Boost EORTC 22881-10882 Trial." (Bartelink H, J Clin Oncol. 2007 Aug 1;25(22):3259-65. Epub 2007 Jun 18.)
 * 10-year outcome: LR: boost 6% vs. no boost 10% (SS); if age <40 24% vs. 13%; if age 41-50 12% vs. 8%; if age 51-60 7% vs. 4%; if age >60 7% vs. 4%. Salvage mastectomy reduced by 41%. Survival 82% in both arms (NS)
 * Toxicity: severe fibrosis boost 4.4% vs. no boost 1.6% (SS)
 * Conclusion: Improved local control in all age groups, but no difference in survival
 * 10-year summary; 2008 PMID 18760649 -- "The addition of a boost dose on the primary tumour bed after lumpectomy in breast conserving treatment for breast cancer. A summary of the results of EORTC 22881-10882 "boost versus no boost" trial." (Poortmans PM, Cancer Radiother. 2008 Aug 27. [Epub ahead of print])
 * LR Outcome: SM- subgroup: no boost 10% vs. 16 Gy 6% (SS). SM+ subgroup 10 Gy boost 17% vs. 26 Gy boost 11% (NS). No impact on OS
 * Toxicity: Severe fibrosis no boost 2%, 10 Gy 3%, 16 Gy 4%, 26 Gy 14%
 * Conclusion: Improved local control with 16 Gy; development of fibrosis dose-dependent
 * Fibrosis; 2008 PMID 18757193 -- "Predictors of the risk of fibrosis at 10 years after breast conserving therapy for early breast cancer: a study based on the EORTC Trial 22881-10882 'boost versus no boost'." (Collette S, Eur J Cancer. 2008 Nov;44(17):2587-99. Epub 2008 Aug 29.)
 * Nomogram developed to predict moderate/severe fibrosis. Median F/U 10.7 years
 * Outcome: Moderate/severe fibrosis no boost 13% vs. boost 27% (SS)
 * Predictors: increasing whole breast dose, concomitant chemo, post-op edema/hematoma. Lower if RT given with >6 MV photons
 * Positive Surgical Margin; 2009 PMID 18707785 -- "Impact of the boost dose of 10 Gy versus 26 Gy in patients with early stage breast cancer after a microscopically incomplete lumpectomy: 10-year results of the randomised EORTC boost trial." (Poortmans PM, Radiother Oncol. 2009 Jan;90(1):80-5. Epub 2008 Aug 15.)
 * Subset analysis. 251 of expected 660 patients with SM+, median age 54. Arm 1) low boost 10 Gy vs Arm 2) high boost 26 Gy. Median F/U 11.3 years
 * Outcome: 10-year local recurrence low boost 17% vs high boost 11% (HR 0.8, NS). No difference in OS
 * Toxicity: Severe fibrosis breast low boost 1% vs high boost 5%; boost area 3% vs 13%. Moderate fibrosis 24% vs 54%.
 * Conclusion: No statistically significant difference in local control with higher boost dose, fibrosis more frequent.
 * Comment: Trial underpowered due to low patient numbers and low number of recurrences
 * Pathologic Characteristics; 2009 PMID 19720914 -- "Impact of pathological characteristics on local relapse after breast-conserving therapy: a subgroup analysis of the EORTC boost versus no boost trial." (Jones HA, J Clin Oncol. 2009 Oct 20;27(30):4939-47. Epub 2009 Aug 31.)
 * Multivariate predictors for LR: high grade (SS), age <50 (SS), 16 Gy boost (SS). If high grade, no boost 19% vs. boost 9% (SS). If age <50, 19% vs. 11% (SS). Surgical margin status (negative, close, or positive) was not a predictor
 * Conclusion: Young age and high-grade most important risk factors for local relapse; margin status not important
 * Editorial (PMID 19720895): Surgical re-excision should continue to be performed based on strength of multiple other studies. Age and grade worthy of further study
 * 10-year LRR; 2011 PMID 21821304 Full Text -- "Nomogram to predict ipsilateral breast relapse based on pathology review from the EORTC 22881-10882 boost versus no boost trial." (Van Werkhoven E, Radiother Oncol. 2011 Jul;100(1):101-7.)
 * Model to estimate 10-year LR probability in includes histologic grade, DCIS, tumor diameter, age, tamoxifen, chemotherapy, and boost treatment
 * Presence of DCIS adjacent to the invasive tumor was associated with increased LRR (HR 1.96, p=0.001).

Retrospective
 * HERA Trial HER2+ PMID 32861819 -- "De-intensifying Radiation Therapy in HER-2 Positive Breast Cancer: To Boost or Not to Boost?" (Jaoude JA, Int J Radiat Oncol Biol Phys. 2020 Nov 15;108(4):1040-1046. doi: 10.1016/j.ijrobp.2020.06.078. Epub 2020 Aug 28.)
 * Posthoc analysis of HERA Clinical Trial. 1082 patients treated with BCS, adjuvant chemotherapy, and adjuvant radiation therapy, subsequently randomized to no trastuzumab vs 1 year vs 2 years of trastuzumab maintenance. Radiation boost in 41% vs no boost in 59%. Median F/U 11 years
 * Outcome: Local control boost 93% vs no boost 91% (NS), no difference by subset (age 40, or ER+ vs ER-)
 * Conclusion: Excellent local control, boost does not improve local control


 * Virginia/Tufts, 2006 (1983-1999) PMID 16614879 -- "Tumor bed boost omission after negative re-excision in breast-conservation treatment." (Arthur DW, Ann Surg Oncol. 2006 Jun;13(6):794-801.)
 * Retrospective. 205 with early-stage BCA required re-excision, and had no residual disease. Boost omitted. LN+ 24%. Median F/U 8.2 years
 * Recurrence: 4 at tumor site (2%), 5 away from tumor bed (3%). 15-year in-breast control rate 93%; freedom from true recurrence 97.6%
 * Conclusion: Post-lumpectomy RT can be tailored

Localization of the boost field:
 * PMID 8331000 (1993) &mdash; "Breast conserving surgery and irradiation: the importance of demarcating the excision cavity with surgical clips." Bedwinek J et al. Int J Radiat Oncol Biol Phys. 1993 Jul 15;26(4):675-9.
 * Clinical set-up based on scar or palpation misses tumor bed (as defined by clips) about 50% of the time.
 * PMID 1931770 (1991) &mdash; "Boost dosage to the excision site following conservative surgery for breast cancer: it's easy to miss!" Denham JW et al. Clin Oncol (R Coll Radiol). 1991 Sep;3(5):257-61.
 * PMID 11274557 (2001) &mdash; "Breast electron boost planning: comparison of CT and US." Smitt MC et al. Radiology. 2001 Apr;219(1):203-6.

Hypofractionation

 * ASTRO Fractionation Guideline
 * 2010 PMID 20638191 -- "Fractionation for Whole Breast Irradiation: An American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline." (Smith BD, Int J Radiat Oncol Biol Phys. 2010 Jul 15. [Epub ahead of print])
 * Equivalent outcomes with hypofractionation and conventional fractionation for patients &ge; 50, pT1-T2N0, no systemic chemotherapy and dose homogeneity +/- 7%. Favor dose 42.5/16, heart should be excluded, tumor bed boost is uncertain, use of hypofractionation for other patients is uncertain


 * MRC FAST Link (UK) ONGOING
 * Randomized. Whole breast 50/25 vs. 30/5 vs. 28.5/5; each arm over 5 weeks


 * MRC IMPORT HIGH Link (UK) ONGOING
 * Randomized. Simultaneous integrated boost for high risk patients with whole breast RT 36/15 and SIB (48/15 or 53/15) vs. control 56/23 (40/15 + 16/8 boost)
 * Eligibility: BCS at high relapse risk (<50, or T2, or GIII/III, or SM <2mm, or LVI+, or LN+, or no surgery). Target 840 patients. Endpoint breast induration

Randomized


 * ELIOT (Italy) (2000-2007) -- 50/25+10/2 boost vs IORT 21/1
 * Randomized. 1305 patients. Age 48-75, clinical tumor <2.5 cm and clinically node negative. Arm 1) WBRT 50/25 + 10/5 boost, Arm 2) Intraoperative electron therapy 21 Gy x 1
 * 10-years; 2021 PMID 33845035 - "Intraoperative irradiation for early breast cancer (ELIOT): long-term recurrence and survival outcomes from a single-centre, randomised, phase 3 equivalence trial" Orecchia R et al. Lancet Oncol 2021 Apr 9;S1470-2045
 * Median follow up 12.4 years
 * IBTR: WBRT 2% vs IORT 11% (SS). 10-year 1.1% vs 8.1% (SS); 15-year 2.4% vs 12.6% (SS). Overall survival 10 years 92.7% vs 90.7% (NS); 15 years 82.4% vs 83.4% (NS)
 * Higher rate of IBTR in IORT arm, a small subset (~10%) may be reasonable to offer per Discussion section


 * Ontario (Canada) (1993-1996) -- 50/25 vs. 42.5/16
 * Randomized. 1234 patients with invasive T1-2 N0 (by ALND), margins negative. Age <50 in 25%, tumors >2 cm in 31%, adjuvant TAM 42%, adjuvant chemo 11%. Treated with Arm 1) 42.5/16 (2.66 Gy/fx) vs Arm 2) 50/25; No boost.
 * 5-years; 2002 PMID 12165639 Full text &mdash; "Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer." Whelan T et al. J Natl Cancer Inst. 2002 Aug 7;94(15):1143-50. Median F/U 5.75 years
 * 5-year LRFS: No difference (97.2% vs 96.8%). No difference in 5-year DFS or OS.
 * No difference in cosmetic outcome (defined as good or excellent) or radiation morbidity.
 * Conclusion: shorter course acceptable
 * 10-years; 2010 PMID 20147717 -- "Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer" (Whelan TJ, 2010 Feb 11; N Engl J Med 362(6):513-20). Min F/U 10 years
 * Outcome: 10-year local recurrence: Hypo-fx 7.4% (invasive 6.2%) vs control 7.5% (invasive 6.7%) (NS). No difference in 10-year DFS or OS. Subgroup analysis - high grade tumors hypo-fx 16% vs. control 5% (SS). 10-year DSS both groups 87% (NS); OS both groups 84% (NS)
 * Toxicity: No Grade 4 toxicity. Grade 3 skin toxicity hypo-fx 2.5% vs. control 2.7% (NS); Grade 3 subcutaneous toxicity 2.5% vs 3.6% (NS). Grade 2 skin toxicity 6.4% vs. 5.0% (NS); Grade 2 subcutaneous toxicity 9.4% vs 6.8% (NS). Excellent/good cosmetic outcome hypo-fx 70% vs. 71% (NS)
 * Conclusion: Accelerated hypofractionated WBRT was not inferior to standard WBRT.


 * MRC START B (1999-2001) -- 50/25 vs. 40/15 over 3 weeks
 * Randomized. 2215 patients. Operable invasive BCA, pT1-3a N0-1, requiring RT after surgery. Surgery either BCS or mastectomy (8%). Arm 1) 50/25 vs. Arm 2) 40/15 over 3 weeks. Boost given at discretion (43%) 10/5. Regional RT 14%.
 * Concurrently, patients enrolled on photographic assessment substudy, QoL substudy and health economic studies.
 * 2008 PMID 18355913 -- "The UK Standardisation of Breast Radiotherapy (START) Trial B of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial." (START Trialists' Group, Lancet. 2008 Mar 29;371(9618):1098-107. Epub 2008 Mar 19.) Median F/U 6 years
 * Outcome: LRR 50 Gy 3% vs. 40 Gy 2% (NS); DM, DFS and OS all better (SS) in 40 Gy group
 * Toxicity: Lower rate of late toxicity in 40 Gy group (SS)
 * Conclusion: 40 Gy over 3 weeks has at least as favorable control and toxicity as 50 Gy over 5 weeks
 * Toxicity; 2010 PMID 20138809 -- "Comparison of patient-reported breast, arm, and shoulder symptoms and body image after radiotherapy for early breast cancer: 5-year follow-up in the randomised Standardisation of Breast Radiotherapy (START) trials." (Hopwood P, Lancet Oncol. 2010 Mar;11(3):231-40. Epub 2010 Feb 6.)
 * Prospective. 1079 patients accrued (88% BCS, 12% mastectomy). RT boost 51%. EORTC QLQ-C30 and BR23 questionnaires
 * Outcome: Significantly lower moderate/marked change in skin appearance in 40 Gy group (HR 0.76). 5-year breast symptoms, arm/shoulder symptoms (~20%), or body image problems (~40%) no difference between 40 Gy and 50 Gy.
 * Conclusion: Substantial proportion report breast/arm/shoulder symptoms, but no great difference between regimens


 * MRC START A (1998-2002) -- 50/25 vs. 41.6/13 vs. 39/13 over 5 weeks
 * Randomized. 2236 patients. Operable invasive BCA, pT1-3a N0-1, requiring RT after surgery. Surgery either BCS or mastectomy (15%). Arm 1) 50/25 vs. Arm 2) 41.6/13 vs. Arm 3) 39/13; all arms given over 5 weeks to eliminate treatment time variable. Boost given at discretion (61%) 10/5. Regional RT 14%.
 * Concurrently, patients enrolled on photographic assessment substudy, QoL substudy and health economic studies.
 * 2008 PMID 18356109 -- "The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial." (START Trialsists' Group, Lancet Oncol. 2008 Apr;9(4):331-41. Epub 2008 Mar 19.) Median F/U 5.1 years
 * Outcome: 5-year LRR 50 Gy 3.6%, 41.6 Gy 3.5%, 39 Gy 5.2% (NS).
 * Cosmesis: Lower rate of late adverse effects in 39 Gy, same in 41.6 Gy compared with 50 Gy
 * Alpha/beta estimate: tumor control 4.6 Gy, late breast changes 3.4 Gy
 * Conclusion: Breast cancer and normal breast tissues respons similarly to fraction size. No difference in local control
 * Comment: 60% had discretionary boost 10/5, 35% had chemotherapy and its interaction with fraction size unclear
 * Toxicity; 2010 PMID 20138809 -- "Comparison of patient-reported breast, arm, and shoulder symptoms and body image after radiotherapy for early breast cancer: 5-year follow-up in the randomised Standardisation of Breast Radiotherapy (START) trials." (Hopwood P, Lancet Oncol. 2010 Mar;11(3):231-40. Epub 2010 Feb 6.)
 * Prospective. 1129 patients accrued (78% BCS, 22% mastectomy). RT boost 71%. EORTC QLQ-C30 and BR23 questionnaires
 * Outcome: Significantly lower moderate/marked change in skin appearance in 39 Gy group (HR 0.63, SS), but not 41.6 Gy group (HR 0.83, NS). The 39 Gy group had improved breast hardness, oversensitivity, breast appearance, and skin appearance compared with 41.6 Gy. 5-year moderate/marked shoulder pain ~20%. 5-year breast symptoms, arm/shoulder symptoms (~20%), or body image problems (~40%) no difference between 40 Gy and 50 Gy.
 * Conclusion: Substantial proportion report breast/arm/shoulder symptoms, but no great difference between regimens


 * Royal Marsden (UK) (1986-1998)
 * Randomized. 1410 patients with T1-3N0-1 (max 1 positive node), treated with 1) 50/25, or 2) 39/13 (3.0 Gy/fx), or 3) 42.9/13 (3.3 Gy/fx) all over 5 weeks. Primary outcome late side effects; trial extended to allow power for LR evaluation but then stopped early due to start of START trial
 * RT: WBRT; 25% randomly assigned to no boost, 26% randomly assigned to boost, 50% boost at MD discretion (comparable in all 3 groups)
 * 2006 PMID 16750496 -- "Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: long-term results of a randomised trial." (Owen JR, Lancet Oncol. 2006 Jun;7(6):467-71.). Median F/U 9.7 years
 * 10-year IBTR: 12% vs. 14.8% vs. 9.6% (NS vs 50/25, but SS between 39/13 and 42.9/13)
 * Estimate of LR-based a/b = 4.0 Gy (and possibly as low as 3.0 Gy)
 * 2005 PMID 15878095 -- "Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: long-term results of a randomised trial." (Yarnold J, Radiother Oncol. 2005 Apr;75(1):9-17.) Minimum F/U 5 years
 * Long-term side effects equivalent among groups
 * Estimate of long-term side-effects a/b: 3.1 Gy


 * Egypt NCI, 2004 PMID 15959551 -- "Hypofractionation versus conventional fractionation radiotherapy after conservative treatment of breast cancer: early skin reactions and cosmetic results." (Taher AN, J Egypt Natl Canc Inst. 2004 Sep;16(3):178-87.)
 * Randomized. 30 patients with T1-2N0, treated with A) 50/25 vs. B) 42.5/16 (2.66 Gy/fx). Primary outcome early reaction and late cosmesis. Median F/U 22 months
 * Acute reactions: no difference, but group B 2 weeks earlier (3rd week vs. 5th week)
 * Late reactions: preliminary - no difference


 * Hopital Necker, France (1982-1984) -- 45/25 vs 23/4
 * Randomized. 230 patients (T1 22%, T2 61%, cN+ 28%), surgery in 79%, neoadjuvant chemo + RT 21%. Arm 1) 45/25 vs Arm 2) 23/4 over 17 days (D1, D3, D15, D17)
 * 1990 PMID 2254102 -- "The use of a specific hypofractionated radiation therapy regimen versus classical fractionation in the treatment of breast cancer: a randomized study of 230 patients." (Baillet F, Int J Radiat Oncol Biol Phys. 1990 Nov;19(5):1131-3.) Min F/U 4 years
 * Outcome: 5-year OS no difference. LRR hypofx 7% vs conventional 5% (NS)
 * Toxicity: hypofx 23% vs conventional 19%; fibrosis 18% vs 9%
 * Conclusion: No difference in effectiveness and rate of complications

Non-Randomized
 * Royal Marsden; 2008 (UK) PMID 18556186 -- "Acute Toxicity and 2-year Adverse Effects of 30 Gy in Five Fractions over 15 Days to Whole Breast after Local Excision of Early Breast Cancer." (Martin S, Clin Oncol (R Coll Radiol). 2008 Jun 13. [Epub ahead of print])
 * Pilot. 30 women, early BCA, >=50 years, tumor size <3cm, SM-, LN-, no chemo required. RT 30/5 over 15 days to whole breast, tangents. Median F/U 3.1 years
 * Outcome: Acute Grade 2 erythema 30%, no Grade 3+; moist desquammation 13% (Grade 1-2). Late (2 years) 0% marked change, 23% mild change, 77% no change from pre-treatment. No IBTR thus far
 * Conclusion: Further evaluation is justified, including regimen delivered in 5 days


 * NYU, 2007 (2003-2005) PMID 17470849 -- "Phase I-II Trial of Prone Accelerated Intensity Modulated Radiation Therapy to Optimally Spare Normal Tissue." (Formenti SC, J Clin Oncol. 2007 Apr 30; [Epub ahead of print])
 * Phase I-II. 91 patients. Stage I-II, allowed N1, SM-. Prone, IMRT 40.5/15 (2.7 Gy/fx) + concomitant boost 48/15 (3.2 Gy/fx). RT constraints: heart <=5% to >=18 Gy; <=10% ipsi lung to >=20 Gy. Median F/U 1 year
 * Acute toxicity: G1-2 dermatitis 67%, fatigue 18%
 * Conclusion: Accelerated whole breast IMRT with concomitant boost prone is feasible, and permits volume reduction for lung and heart


 * Fox Chase, 2007 PMID 17379430 -- "Four-week course of radiation for breast cancer using hypofractionated intensity modulated radiation therapy with an incorporated boost." (Freedman GM, Int J Radiat Oncol Biol Phys. 2007 Mar 20)
 * Phase II. 75 patients, normally eligible for standard RT. Neoadjuvant chemo in 44%
 * RT: IMRT and incorporated electron boost, whole breast 45/20 (2.25 Gy/fx) and lumpectomy bed 56/20 (2.8 Gy/fx)
 * Toxicity: Grade 0 12%, Grade 1 65%, Grade 2 23%. No Grade 3+
 * Conclusion: Feasible and acceptable acute skin toxicity and QOL


 * Hamburg, 2005 (1992-1994) PMID 16220400 -- "Late effects and cosmetic results of conventional versus hypofractionated irradiation in breast-conserving therapy." (Fehlauer F, Strahlenther Onkol. 2005 Oct;181(10):625-31.)
 * Retrospective. 129 patients (T1-2N0-1) treated with 1) 55/22 (2.5 Gy/fx) vs. 2) 55/28 (2.0 Gy/fx)
 * Late toxicity: fibrosis (57% vs. 16%, SS), telangiectsia (22% vs. 3%, SS), atrophy (31% vs. 3%, SS). No difference in breast pain. Cosmesis acceptable-very good (75% vs. 93%, SS)
 * Conclusion: Frequent late morbidity, and worse prognosis. No major impact on daily life


 * UK Practice Survey, 1995 PMID 8845316 -- "Non-surgical management of early breast cancer in the United Kingdom: radiotherapy fractionation practices. Clinical Audit" (Yarnold JR, Clin Oncol (R Coll Radiol). 1995;7(4):223-6.)
 * National Survey. 166 clinical oncologists treating breast.
 * 82% of respondents used either 50/25, or 45/20, or 40/15; remainder used other fractionation schemes
 * Boost use haphazard

Review
 * Royal Marsden; 2009 PMID 19243933 -- "Shorter fractionation schedules in breast cancer radiotherapy: clinical and economic implications." (Mannino M, Eur J Cancer. 2009 Mar;45(5):730-1. Epub 2009 Feb 23.)

Young Age

 * MD Anderson; 2009 PMID 18707822 -- "Ten-year recurrence rates in young women with breast cancer by locoregional treatment approach." (Beadle BM, Int J Radiat Oncol Biol Phys. 2009 Mar 1;73(3):734-44. Epub 2008 Aug 15.)
 * Retrospective. 652 patients, age <=35. BCT 30%, mastectomy 37%, mastectomy + RT 35%. Median F/U 9.5 years
 * Outcome: 10-year LRR BCT 20% vs. M 24% vs. M-RT 15% (p=0.05). If Stage I, no difference. If Stage II, 18% vs. 23% vs. 6% (SS). Worse LRR if mastectomy only or if Grade III disease. Chemo significant LRR benefit (13% vs. 28%, p=0.04)
 * Conclusion: Young women high rate of LRR. For Stage II disease, mastectomy + RT superior. For Stage I disease, no difference

Older Age

 * MD Anderson Cancer Center
 * Nomogram; 2012 (1992-2002) PMID 22734034 -- "Nomogram to predict the benefit of radiation for older patients with breast cancer treated with conservative surgery." (Albert JM, J Clin Oncol. 2012 Aug 10;30(23):2837-43. Epub 2012 Jun 25.)
 * Nomogram. Data from SEER database. 16,092 women, age 66-79, treated with conservative surgery. Medicare claims to identify receipt of RT and subsequent mastectomy. Median F/U 7.2 years
 * Outcome: 5-year mastectomy-free survival 98%, 10-year MaFS 95%. Nomogram developed, concordance index 0.66
 * Conclusion: Nomogram to predict mastectomy-free survival among older women with early breast cancer
 * Outcomes; 2012 (1992-2002) PMID 22890779 -- "Effectiveness of radiation for prevention of mastectomy in older breast cancer patients treated with conservative surgery." (Albert JM, Cancer. 2012 Aug 13. doi: 10.1002/cncr.27457. [Epub ahead of print])
 * Retrospective. SEER analysis. 7403 women, age 70-79, treated with conservative surgery. Medicare claims to identify receipt of RT and subsequent mastectomy. Median F/U 7.3 years
 * Outcome: 10-year risk of subsequent mastectomy if RT 3.2% vs no RT 6.3% (SS). Only group without benefit were 75+ with G1/G2 disease and pN0. All other subgroups experienced RT benefit ranging from 4.3% to 9.8% absolute reduction in mastectomy at 10 years.
 * Conclusion: Receipt of RT after BCS associated with greater breast preservation for most older women


 * CALGB 9343
 * Elderly Radiation PMID 23690420 -- "Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: long-term follow-up of CALGB 9343." (Hughes KS, J Clin Oncol. 2013.)
 * Randomized 636 women (age ≥ 70 years) who had clinical stage I (T1N0M0 according to TNM classification) estrogen receptor (ER) -positive breast carcinoma treated by lumpectomy were randomly assigned to receive tamoxifen plus radiation therapy (TamRT; 317 women) or tamoxifen alone (Tam; 319 women)
 * At 10 years, 98% of patients receiving TamRT (95% CI, 96% to 99%) compared with 90% of those receiving Tam (95% CI, 85% to 93%) were free from local and regional recurrences
 * No significant differences in time to mastectomy, time to distant metastasis, breast cancer-specific survival, or OS
 * At 10 years, OS was 67% with TamRT and 66% Tam (NS)


 * PRIME II Trial
 * Over 65 Radiation PMID 25637340 -- Between April 16, 2003, and Dec 22, 2009, 1326 women aged 65 years or older with early breast cancer judged low-risk (ie, hormone receptor-positive, axillary node-negative, T1–T2 up to 3 cm at the longest dimension, and clear margins; grade 3 tumour histology or lymphovascular invasion, but not both, were permitted), who had had breast-conserving surgery and were receiving adjuvant endocrine treatment, were recruited into a phase 3 randomised controlled trial at 76 centres in four countries. Eligible patients were randomly assigned to either whole-breast radiotherapy (40–50 Gy in 15–25 fractions) or no radiotherapy by computer-generated permuted block randomisation, stratified by centre, with a block size of four. The primary endpoint was ipsilateral breast tumour recurrence. Follow-up continues and will end at the 10-year anniversary of the last randomised patient. Analyses were done by intention to treat. The trial is registered on ISRCTN.com, number ISRCTN95889329. (Ian Kunkler and colleagues, The Lancet Oncology, 2015.)
 * 658 women who had undergone breast-conserving surgery and who were receiving adjuvant endocrine treatment were randomly assigned to receive whole-breast irradiation and 668 were allocated to no further treatment.
 * After median follow-up of 5 years (IQR 3·84–6·05), ipsilateral breast tumour recurrence was 1.3% (95% CI 0.2–2.3; n=5) in women assigned to whole-breast radiotherapy and 4.1% (2.4–5.7; n=26) in those assigned no radiotherapy (p=0.0002). Compared with women allocated to whole-breast radiotherapy, the univariate hazard ratio for ipsilateral breast tumour recurrence in women assigned to no radiotherapy was 5.19 (95% CI 1.99–13.52; p=0.0007). No differences in regional recurrence, distant metastases, contralateral breast cancers, or new breast cancers were noted between groups. 5-year overall survival was 93.9% (95% CI 91.8–96.0) in both groups (p=0.34). 89 women died; eight of 49 patients allocated to no radiotherapy and four of 40 assigned to radiotherapy died from breast cancer.
 * Similar results to CALGB 9343

Initial Treatment

 * Harvard; 2008 PMID 18413639 -- "Breast cancer subtype approximated by estrogen receptor, progesterone receptor, and HER-2 is associated with local and distant recurrence after breast-conserving therapy. (Nguyen PL, J Clin Oncol. 2008 May 10;26(14):2373-8.)
 * Retrospective. 793 pts 1998-2001 from DFCI/MGH, none received trastuzumab. Median F/U 70 months
 * Used receptors to divide pts into groups modeled after genetic subtype:
 * Luminal A (ERorPR+/HER2-), Luminal B (ERorPR+/HER2+), HER2 (ERandPR-/HER2+), Basal (Triple negative)
 * 5-year Local recurrence: Significantly worse for triple negative (7.1%) and HER2 (8.4%) vs. Luminal A (0.8%).
 * Conclusion: Triple negative subtype and HER2 type (without trastuzumab) have significantly higher risk of local recurrence.
 * Comment: Possible reason given for difference with Yale series: Harvard series had more modern patients with lower overall rate of local recurrence (1.8% vs. 17% for Yale series) which might have allowed the increased risk of LR among triple negative subtype to be more easily discerned.


 * Yale; 2006 PMID 17116942 -- "Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer." (Haffty BG, J Clin Oncol. 2006 Dec 20;24(36):5652-7.)
 * Retrospective. 117/482 triple negative patients. Median F/U 7.9 years
 * 5-year DMFS: triple negative 67% vs. all others (ER+ or PR+ or her2+) 82% (SS)
 * 5-year Local recurrence: no difference (17%)
 * Conclusion: higher risk of mets, but not at higher risk for local failure

After Recurrence

 * UMD New Jersey; 2008 PMID 18676094 -- "Prognostic value of triple-negative phenotype at the time of locally recurrent, conservatively treated breast cancer." (Parikh RR, Int J Radiat Oncol Biol Phys. 2008 Nov 15;72(4):1056-63.)
 * Retrospective. 47 IBTR specimens of patients who experienced an IBTR after conservative surgery and RT. Median F/U 7.5 years
 * Outcome: After IBTR, 5-year DMFS 83% and OS 91%. By subtype, 5-year DMFS tripple negative 49% vs non-TN 91% (SS). Univariate predictors of poor 5-year outcomes: tripple negative phenotype, time-to-recurrence <3 years, local recurrence
 * Conclusion: Although patients experiencing an IBTR have a relatively favorable prognosis, those with IBTR events of the TN phenotype had a rather poor prognosis despite receiving standard chemotherapy

BRCA1/BRCA2

 * See also page at Radiation_Oncology/Breast/Breast_overview


 * Multi-institutional; 2010 PMID 20411323 -- "Local therapy in BRCA1 and BRCA2 mutation carriers with operable breast cancer: comparison of breast conservation and mastectomy." (Pierce LJ, Breast Cancer Res Treat. 2010 Apr 22. [Epub ahead of print])
 * Retrospective. Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer. 655 women, BRCA1/2 mutations, diagnosed with breast cancer, treated with BCT (n=302) or mastectomy (n=353)
 * Local control: 15-year local failure BCT 23% vs mastectomy 5% (SS). For BCT patients, 30% same quadrant and same histology (true recurrence) vs 70% different quadrant and/or different histology (2nd primary), so true recurrence BCT 7% vs mastectomy 5%.
 * Outcome: Contralateral BCA 23%, same in both arms. BRCA1 had 1.8x higher risk than BRCA2. No difference in 15-year DM rate (11% vs 9%, NS), 15-year CSS (92% vs 93%, NS) or 15-year OS (87% vs 90%, NS)
 * Conclusion: Similar survival, however, elevated risk of 2nd in-breast event. Contralateral cancers very common

Lymphovascular Invasion

 * Nottingham, 2006 PMID 16377180 -- "Prognostic value of lymphovascular invasion in women with lymph node negative invasive breast carcinoma." (Lee AH, Eur J Cancer. 2006 Feb;42(3):357-62.)
 * Retrospective. 2760 women with N0 cancer. Two groups: 990 with no adjuvant therapy (1974-1988), 1765 with selective adjuvant therapy (1988-2000). Median F/U 13 and 6.8 years respectively.
 * LVI: 19% of tumors, associated with larger size, higher grade, younger age
 * Conclusion: LVI independent prognostic factor for survival

Survival

 * SEER Data -- T1a,bN0 (1988-2001)
 * 10-years; 2007 PMID 17971593 -- "Overall survival and cause-specific mortality of patients with stage T1a,bN0M0 breast carcinoma." (Hanrahan EO, J Clin Oncol. 2007 Nov 1;25(31):4952-60.)
 * Population study. 51,246 patients. Median age 65 (20-101). Median F/U 5.3 years
 * 10-year outcome: all-cause mortality 24%, BCA-specific mortality 4%
 * Worse outcome: age <50, high grade, ER-, PR-, <6 LN removed at dissection
 * Nomogram constructed

Follow-Up

 * University of Michigan, 2007 PMID 17568031 -- "Clinical practice. Follow-up of patients with early breast cancer." (Hayes DF, N Engl J Med. 2007 Jun 14;356(24):2505-13.)
 * Screening for metastatic recurrence: if asymptomatic - routine clinic visits, no specialized testing or screening. If symptomatic (bone bain, dyspnea, jaundice, neurologic symptoms), then work-up
 * Screening for loco-regional recurrence: same as contra-lateral breast
 * Screening for new primary cancers: breast - incidence 0.5-1%/year (2X normal), routine annual mammograms; high-resolution ultrasound and MRI controversial; other cancers - routine, age-appropriate screening for colon and cervical cancer
 * Symptom management reviewed: hot flashes, sexual dysfunction, cognitive dysfunction
 * Long term toxicity reviewed: osteoporosis, cardiovascular disease, venous thromboembolism
 * Frequency: visits every 4-6 months first year, then annually; mammograms annually; if on tamoxifen monitoring for uterine cancer

Ipsilateral breast tumor recurrence

 * Please see Breast/Recurrence for discussion of management option

IBTR vs New Primary

 * Royal Marsden; 2011 (1986-1998) PMID 20471183 -- "Ipsilateral breast tumor relapse: local recurrence versus new primary tumor and the effect of whole-breast radiotherapy on the rate of new primaries." (Gujral DM, Int J Radiat Oncol Biol Phys. 2011 Jan 1;79(1):19-25. Epub 2010 May 13.)
 * Retrospective. Data from whole breast randomized trials (PMID 15878095, PMID 16750496), 1410 women. IBTR classified as definite LR, likely LR, likely NP or definite NP. Definite LR if same quadrant, same histology, and same or higher grade. Definite new primary (NP) if different histology, lower grade and different quadrant. Median F/U 10.1 years
 * Outcome: IBTR 10.6% - definite/likely LR 79%, definite/likely NP 18%. Contralateral BTR 5%. Median time-to relapse 3.4 years. Crude rates of ipsilateral new primary 1.9% vs contralateral new primary 5%
 * Conclusion: Whole breast RT reduces rate of ipsilateral new primary tumors

Does IBTR cause distant metastases?

 * PMID 1677695, 1991 &mdash; "Significance of ipsilateral breast tumour recurrence after lumpectomy." Fisher B et al. Lancet. 1991 Aug 10;338(8763):327-31.
 * Analysis of NSABP B-06 reveals that IPTR is a marker for distant recurrence but is not a cause of distant recurrence. Thus, while mastectomy or RT after lumpectomy prevent the expression of this marker, they do not prevent the occurrence of distant disease.

Time course to local failure

 * See also: Patterns of failure


 * Recht, 1988 - PMID 2841261 &mdash; "Time-course of local recurrence following conservative surgery and radiotherapy for early stage breast cancer." Recht A et al. Int J Radiat Oncol Biol Phys. 1988 Aug;15(2):255-61.
 * 5-year and 10-year local failure rate was 10% and 16%. Risk of recurrence rose to be about 2%/year from 2-1/2 years to 5 years, then fell to 0.5%/year. Median time to recurrence is 38.5 months. Median time to "elsewhere" failures in the breast (i.e. other quadrants) was 64.5 months.