Radiation Oncology/Breast/Regional Lymphatics

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Management of Breast Regional Lymphatics

PET staging

• Netherlands Cancer Institute; 2010 (2007-ongoing) PMID 20719497 -- "Detection of extra-axillary lymph node involvement with FDG PET/CT in patients with stage II-III breast cancer." (Aukema TS, Eur J Cancer. 2010 Aug 16. [Epub ahead of print])
  • Prospective. 60 patients, invasive BCA, T >3cm or pN+ (75%). Baseline U/S of ICV/SCV, followed by PET, before neoadjuvant chemotherapy. All visually PET+ nodes or SUVmax 2.5 were regarded as metastatic. Standard RT included IM and SCV lymph node coverage
  • Outcome: Extra-axillary LN+ 28% (breast 1%, pectoral 7%, IM 13%, IFC 7%, contralateral 5%. U/S found extra-axillary LN in 12% (vs PET 28%). RT treatment altered in 12%
  • Conclusion: PET may be usefula additional staging tool, with impact on adjuvant RT management

Axilla

Overview

• Historically, the axilla was managed with a full axillary lymph node dissection (ALND), either as part of modified/radical mastectomy, or as part of breast conservation surgery. Axillary dissection provides both treatment and information on nodal staging
• Two Japanese randomized trials showed that Level III dissection is not necessary, as it doesn't improve outcome and may result in worse side effects
• Adequate lymph node dissection is considered to be >=10 LNs
  • For PMRT trials, median # of nodes removed in Danish trial was 7, while median # of nodes removed in British Columbia trial was 11
• Sentinel lymph node biopsy has been developed as a means of axillary staging patients with early breast cancer, since their risk of positive axillary lymph nodes is low, in order to decrease morbidity associated with full ALND
  • Several smaller trials have shown SLN to be safe and effective. Clinical failure rate in axilla was essentially 0%
  • A large NSABP B-32 trial (5611 patients) showed 97% technical success rate, and a 10% false negative rate. In these patients (98% T1-T2, all cN0), 26% had positive SLN, and of these, 38% had additional positive lymph nodes on completion dissection. Thus, 74% had negative axilla and additional 16% only had one sentinel lymph node positive
  • The ALMANAC trial showed significantly better rates of lymphedema (5% vs. 13%) arm numbness (11% vs 31%), and overall quality of life scores for SLN the groups
• to be continued ...

Extent of Axillary Dissection

• Kyoto (Japan)(1995-1997) -- ALND Level I vs. Level III
  • Randomized. 522 patients. T1-3N0-1b. BCS or mastectomy. Randomized to Level I vs. Level III dissection. All oral 5-FU day 1 and tamoxifen x2 years
  • 10-years; 2006 "Ten-year follow-up results of a randomised controlled study comparing level-I vs level-III axillary lymph node dissection for primary breast cancer." (Kodama H, Br J Cancer. 2006 Oct 9;95(7):811-6.)
    • 10-year outcome: OS 77% vs. 74% (NS); DFS 90% vs. 88% (NS)
    • Toxicity: shorter surgery, less blood loss, no difference in edema or shoulder problems
    • Conclusion: Level III dissection not recommended

• Showa University, 2004 (Japan)(1991-1993) -- ALND Level II vs. Level III
  • Randomized. 1209 women with Stage II BCA. Mastectomy + Level II vs. Level III dissection.
  • 10-years; 2004 PMID 14716791 -- "Randomized clinical trial comparing level II and level III axillary node dissection in addition to mastectomy for breast cancer." (Tominaga T, Br J Surg. 2004 Jan;91(1):38-43.) F/U 10 years
    • 10-year outcome: OS 87% vs. 86% (NS); DFS 73% vs. 78% (NS)
    • Toxicity: Level II surgery shorter with less blood loss. No difference in patients' symptoms
    • Conclusion: Level III resection does not improve OS or DFS

SLB vs ALND

• NSABP B-32 (1999-2004) -- SLN + ALND vs. SLN alone
  • Randomized. 5611 women with operable invasive breast cancer and clinically negative axillary LNs (T1 80%, T2 18%; lumpectomy 86%). Arm 1) SLN followed by immediate completion ALND vs. Arm 2) SLN alone, if SLN-; full ALND if no SLN identified or if SLN+. Identification included technetium scan, blue dye, and clinically suspicious lymph nodes
    • 3989 had SLN-
  • Technical Outcomes; 2007 PMID 17851130 -- "Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial." (Krag DN, Lancet Oncol. 2007 Oct;8(10):881-8.)
    • Technical outcome: Technical success in 97%. Location in Level I/II in 99% (Level I 83%, Level II 16%, Level III 0.5%, IM 0.5%, SCV 0.1%. Mean number removed 2.1
    • Clinical outcome: SLN+ in both groups 26% (NS). If SLN- (74%), ALND- 96% and ALND+ 4% (false negative rate 10%). Overall accuracy 97%. If only one SLN removed, false negative rate 18%. In the 26% of SLN+ patients, 61% had no further LN disease on completion ALND
    • Conclusion: Success of SLN resection is high
  • Morbidity; 2010 PMID 20648579 -- "Morbidity results from the NSABP B-32 trial comparing sentinel lymph node dissection versus axillary dissection." (Ashikaga T, J Surg Oncol. 2010 Aug 1;102(2):111-8.)
    • Shoulder range of motion: deficit of 10% or more in 75% (ALND) vs 41% (SLND), peak at 1 week.
    • Arm volume: increase of 10% or more at 36 months in 14% vs 8%.
    • Sensory: numbness or tingling - peaked at 6 months - 49/23% (ALND) vs 15/10% (SLND)
    • Conclusion: Less morbidity for SLND
  • Survival; 2010 PMID 20863759 -- "Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial." (Krag DN, Lancet Oncol. [Epub ahead of print 2010 Sep 20])
    • OS, DFS, and regional control were statistically similar between groups.
    • Conclusion: SLND with no further ALND is appropriate therapy when SLN is negative

• Sentinella/GIVOM (Italy)(1999-2004) -- SLN vs. ALND
  • Randomized. Stopped early due to increasing preference for SLN. 697/1498 patients, breast cancer <=3 cm, clinically negative axilla. Arm 1) SLN + ALND vs. Arm 2) SLN alone, if SLN+ completion ALND. Radioactive tracer used. ALND was at least Level I-II. If BCS, adjuvant RT 50 Gy.
  • 5-years; 2008 PMID 18216523 -- "A Randomized clinical trial on sentinel lymph node biopsy versus axillary lymph node dissection in breast cancer: results of the Sentinella/GIVOM trial." (Zavagno G, Ann Surg. 2008 Feb;247(2):207-13.) Median F/U 4.7 years
    • Technical outcome: SLN identified in 95%. SLN+ in ALND 27% vs SLN 30%. False negative rate 17% (1 LN+ in 78%, 2 LN+ in 11%)
    • Clinical outcome: LR ALND 1% vs. SLN 5%. Axilla recurrence 0 patients vs. 1 patient. SCV recurrence 0 patients vs. 3 patients. 5-year DFS 90% vs. 88% (NS)
    • Toxicity: SLN group significantly less lymphedema, restrictions of shoulder mobility, and numbness. No impact on psychologic well-being
    • Conclusion: SLN is effective and well tolerated. Safety should be confirmed in larger randomized trials
  • Comment: Small size due to early stoppage, no formal training required for SLN, inclusion of small hospitals, which may explain high false positive rate, but may also be true of clinical practice

• ALMANAC (UK)(1999-2003) -- SLN vs. ALND
  • Randomized. Stopped early due to perceived loss of equipoise, with better QoL in SLN arm. 991/1260 patients, operable breast cancer, no size restriction, multicentric disease excluded. Arm 1) SLN, if SLN+ then delayed axillary surgery or axillary RT (depending on institutional practice) vs. Arm 2) standard axillary surgery (either full Level I-III ALND (75%) or 4 node sampling (25%), depending on institutional practice). Radioactive tracer and blue dye used. Primary outcome arm/shoulder morbidity and QoL
  • 2006 PMID 16670385 -- "Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC Trial." (Mansel RE, J Natl Cancer Inst. 2006 May 3;98(9):599-609.)
    • Technical outcome: SLN identified in 98%. SLN+ in ALND 23% vs. SLN 26%. If SLN+, delayed axillary clearance 69%, axillary RT 27%
    • Clinical outcome: Lymphedema SLN 5% vs. ALND 13% (SS), numbness 11% vs. 31% (SS). QoL and arm functioning scores significantly better for SLN group. No increase in anxiety level. 1-year axillary failure SLN 1 patient vs. ALND 4 patients
    • Conclusion: SLN is associated with reduced arm morbidity and better quality of life

• Milan SLN (Italy)(1998-1999) -- SLN + ALND vs. SLN alone
  • Randomized. 516/532 patients, T1-T2, breast conserving surgery. Multicentric cancer excluded. Arm 1) SLN + ALND vs. Arm 2) SLN alone, if SLN+ completion ALND; if no SLN identified, patient not eligible. ALND included Levels I-III. Radioactive tracer used. Adjuvant RT to ipsilateral breast 50 Gy + boost 10 Gy. Adjuvant chemotherapy as per institutional protocol (50% hormones, 7% chemotherapy, 40% chemotherapy + hormones, 3% none)
  • 4-years; 2003 PMID 12904519 -- "A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer." (Veronesi U, N Engl J Med. 2003 Aug 7;349(6):546-53. Median F/U 3.8 years
    • Technical outcome: SLN+ in ALND 32% vs. SLN 35% (NS). If SLN- (68%), ALND- 95% and ALND+ 5% (false negative rate 9%). Overall accuracy 97%. If LVI+, 70% had SLN+
    • Clinical outcome: Events ALND 8% vs. SLN 5% (NS). Axillary failure both groups 0%, SCV failure 1% vs. 0%, IBTR 0.5%, DM 4% vs. 2%
    • Toxicity: SLN patients less pain, numbness, better arm mobility, and less swelling
    • Conclusion: SLN is safe and accurate in women with a small breast cancer
  • 7-years; 2006 PMID 17138219 -- "Sentinel-lymph-node biopsy as a staging procedure in breast cancer: update of a randomised controlled study." (Veronesi U, Lancet Oncol. 2006 Dec;7(12):983-90.) Median F/U 6.6 years
    • Clinical outcome: Axillary failure ALND 0% vs SLN 0.004% (1 patient), SCV failure 0.008% (2 patients) vs. 0%, DM 5% vs. 4%. 5-year OS 96% vs. 98% (NS)
    • Conclusion: SLND allows patients with SLN- to avoid ALND, while reducing morbidity and cost of hospital stay

Predictive models:

• Mayo; 2010 (1997-2004) PMID 20429038 -- "Predicting four or more metastatic axillary lymph nodes in patients with sentinel node-positive breast cancer: assessment of existent risk scores." (Zendjas B, Ann Surg Oncol. 2010 Nov;17(11):2884-91. Epub 2010 Apr 29.)
  • Model evaluation. 3 models (Rivers, Chagpar, Katz) evaluated on 454 patients with N1 and cLDN
  • Outcome: 4+ LN+ in 19%. Discrimination score Rivers AUC 0.81, Chagpar AUC 0.73, Katz AUC 0.81 (SS)
  • Conclusion: Rivers and Katz models performed well

• Louisville; 2007 PMID 17096055 -- "Predicting patients at low probability of requiring postmastectomy radiation therapy." (Chagpar AB, Ann Surg Oncol. 2007 Feb;14(2):670-7. Epub 2006 Nov 10.)
  • Model. Prospective multicenter database (Breast Sentinel Lymph Node Study) 1133 patients. Predictive factors: tumor size, number of SLN+, proportion of SLN+. Points assigned: T2 = 1, #SLN+ = 1, 2, 3, proportion of SLN+ >50% = 1, H&E stain diagnosis (vs IHC) = 1, total = 6. Non-predictive variables histology, palpable primary
  • Conclusion: Patients with 1-2 point have low probability of ≥ 4LN+
  • Comment: Did not include ECE or LVI

• Michigan/MD Anderson (1995-2002) PMID 16378156 -- "Clinicopathologic features associated with having four or more metastatic axillary nodes in breast cancer patients with a positive sentinel lymph node." (Rivers AK, Ann Surg Oncol. 2006 Jan;13(1):36-44. Epub 2006 Jan 1.)
  • Model. 285 patients from 2 institutions. pN2+ disease in 14%. Predictors: tumor size, number of SLN+ (out of 3 total; if more removed, a proportion of SLN+ would be used), LVI+, ECE+. Non-predictive variable: size of metastatic focus, age, histology, grade, ER status
  • Outcome: Lookup table constructed with predicted probability (p=0.0-1.0). SLN micromets extremely low probability (1.3%) of extensive nodal disease
  • Conclusion: Predictive model developed

• Harvard
  • Nomogram; 2008 PMID 18445838 -- "Nomogram for the prediction of having four or more involved nodes for sentinel lymph node-positive breast cancer." (Katz A, J Clin Oncol. 2008 May 1;26(13):2093-8.)
    • Model. 402 patients, 1-3SLN+. N2+ disease in 22%. Predictors: histology, tumor size, number of SLN+, number uninvolved SLN+, LVI+, ECE+, met size. Validated on 206 patients previously published
    • Outcome: Nomogram developed
    • Conclusion: Patients with low probability of ≥ 4 positive LN can be identified
  • Retrospective; 2006 (1998-2003) - PMID 16488555 — "Factors associated with involvement of four or more axillary nodes for sentinel lymph node-positive patients." Katz A et al. Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):40-4.
    • Retrospective. 1133 patients, 224 of whom had completion axillary dissection for node-positive.
    • Factors associated with 4 or more involved axillary nodes were: lobular histology, LVI, increased number of involved sentinel LNs, increased size of SLN metastases.
    • Conclusion: pts with 1 or more involved SLN or LVI should be treated to the SCLV fossa if they do not undergo completion axillary dissection.

Comparison with complete ALND

• Nijmegen; 2007 (Netherlands)(1989-2002) PMID 17197151 -- "Survival after negative sentinel lymph node biopsy in breast cancer at least equivalent to after negative extensive axillary dissection." (Kuijt GP, Eur J Surg Oncol. 2007 Sep;33(7):832-7. Epub 2006 Dec 29.)
  • Registry study. 2561 patients (880 SLNB-, 1681 ALND-); Median F/U 3.6 years and 7.7 years
  • Outcome: 5-year OS SLNB 89% vs. ALND 85% (SS)
  • Conclusion: Survival after SLNB at least equivalent (if not better) to extensive ALND in N0 patients

Timing of SLND

• ACOSOG Z0010 and Z0011 PMID 18640934 -- "Impact of immediate versus delayed axillary node dissection on surgical outcomes in breast cancer patients with positive sentinel nodes: results from American College of Surgeons Oncology Group Trials Z0010 and Z0011." (Olson JA Jr, J Clin Oncol. 2008 Jul 20;26(21):3530-5.)
  • Retrospective. 1003 patients with SLN+ on 2 ACOSOG trials. Immediate ALND in 42%, delayed (second procedure) in 58%.
  • Outcome: median # of SLN and axillary LNs removed same. Immediate group worse axillary paresthesia, serom, and impaired extremity range early, no difference late; no difference in lymphedema
  • Conclusion: No significant difference in LN recovery or long-term complications between immediate and delayed completion ALND

SLN+: completion ALND vs no further dissection

• IBCSG 23-01 (2001-2010) -- completion ALND vs no further dissection
  • Randomized. 27 institutions. 931 patients, with tumor ≤ 5 cm and one or more micrometastases or isolated tumor cells(≤ 2 mm) in sentinel node, with no ECE. Arm 1) completion axillary dissection versus Arm 2) no further surgery. Primary endpoint DFS. Mastectomy 9%. In BCS group, 98% received adjuvant RT (28% intraoperative)
  • 2013 PMID 23491275 -- "Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial." (Galimberti V, Lancet Oncol. 2013 Apr;14(4):297-305. doi: 10.1016/S1470-2045(13)70035-4. Epub 2013 Mar 11.). Median F/U 5 years
    • Outcome: Local recurrence ALND 2.1% vs OBS 1.7%, regional recurrence 0.2% vs 1%, distant recurrence 7% vs 5%. 5-year DFS 88% vs 84% (NS)
    • Toxicity: ALND: one grade 3 neuropathy, three grade 3-4 lymphedema, three grade 3 motor neuropathy vs OBS one grade 3 motor neuropathy
    • Conclusion: Axillary dissection can be avoided in patients with limited sentinel node involvement

• ACOSOG Z0011 (1999-2004) -- completion ALND vs no further dissection
  • Randomized. Closed prematurely due to low accrual and low rate of events. Non-inferiority trial. 856 of expected 1900 patients, T1-T2, clinically N0, SNB+ (1 or 2 SNB+ on H&E, frozen section or touch prep; patients SNB+ by IHC were not eligible but ultimately 41% were micromets or ITCs). All underwent lumpectomy with SM- and tangents RT, but no dedicated axillary RT. Adjuvant systemic therapy 97% (hormones 46%, chemotherapy 58%). Arm 1) completion ALND (median 17 LN removed) vs Arm 2) no further dissection (median 2 LN removed).
  • 2010 PMID 20739842 Full text PDF -- "Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: the American College of Surgeons Oncology Group Z0011 randomized trial." (Giuliano AE, Ann Surg. 2010 Sep;252(3):426-32; discussion 432-3.) Median F/U 6.3 years
    • Outcome: Further involved nodes with cALND 27%. 5-year breast recurrence ALND 3.1% vs SNB 1.6% (NS); 5-year axilla recurrence 0.5% vs 0.9% (NS); 5-year OS 92% vs 92% (NS). No difference in LRR based on systemic therapy
    • Conclusion: No difference; SLND without completion ALND may be a resonable management options with tangent RT and systemic therapy
  • 2011 PMID 21304082 -- "Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node Metastasis: A Randomized Clinical Trial." (Giuliano AE, JAMA. 2011 Feb 9;305(6):569-75.) Median F/U 6.3 years
    • 5-yr OS 91.8% (ALND) vs 92.5% (SLND). 5-yr DFS 82.2% vs 83.9%.
    • Median # of nodes removed: 17 for ALND and 2 for SLND. Number of positive nodes (not including micromets) - median: 1 (ALND) vs 1 (SLND). However, 21% of ALND had ≥ 3 positive LN. Sentinel lymph node biopsy contained micromets: 37.5% (ALND group) and 44.8% (SLND). In ALND group, axillary dissection revealed additional metastases in 27.3%; 10% of ALND pts with micromets in SLN had additional positive (non-micromet) non-SLN lymph nodes.
    • Conclusion: among pts with limited positive SLN disease, treated with breast conservation +/- systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival.
  • 2014 Link - SABCS (no abst.) Abstract "Radiation field design on the ACOSOG Z0011 trial" (Jagsi R, San Antonio Breast Conference 2013, Poster Session: P5-14-19)

    See also: slides at link "SABCS Highlights 2013 Radiation Oncology" (Horst K, Powerpoint) -- see slides 31-36

    • Among 605 pts completed adjuvant RT, 89% were noted to receive whole breast RT. Of these, 89 patients (15%) were recorded as also receiving treatment to the supraclavicular region.
    • Detailed RT records available on 228 patients: 104/389 (26.7%) and 124/404 (30.7%) on the ALND and SLND arms, respectively.
    • 185 patients (81.1%) received tangent-only treatment: High tangent RT fields (with cranial tangent border within 2 cm of the humeral head) were used in 52.6% (40/76) patients randomized to the ALND arm and 50% (33/66) patients randomized to the SLND arm.
    • Of the 228 patients with records reviewed, 43 (18.9%) received directed regional nodal RT using ≥3 fields: 22 in the ALND and 21 in the SLND arm.
    • Those receiving directed nodal RT tended to have greater nodal involvement (p<0.001).

Review

• NSABP; 2010 PMID 20957459 -- "The Need for Axillary Dissection in Patients with Positive Axillary Sentinel Lymph Nodes." (Croshaw RL, Curr Oncol Rep. 2010 Oct 19. [Epub ahead of print])

SLN micrometastases:

• ICBSG 23-01 (2001-2010) -- randomized to +/- axillary dissection
  • 931 pts eligible if T<=5 cm + cN0, SLN Bx with 1 or more micrometastatic (2 mm or less) lymph nodes with no ECE. Non-inferiority trial design.
  • 2013 PMID 23491275 -- "Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23-01): a phase 3 randomised controlled trial." (Galimberti V, Lancet Oncol. 2013 Apr;14(4):297-305.)
    • Median f/u 5 yrs. 5-yr DFS 87.8% (no LND) vs 84.4% (LND); non inferior.
    • 91% were treated with BCS + RT.
    • Conclusion: "Axillary dissection could be avoided in patients with early breast cancer and limited sentinel-node involvement, thus eliminating complications of axillary surgery with no adverse effect on survival."

Rate of positive lymph nodes

Microinvasive or DCIS:

• MGH, 2006 (1998-2003)
  • PMID 16720145 — "Sentinel lymph node positivity of patients with ductal carcinoma in situ or microinvasive breast cancer." Katz A et al. Am J Surg. 2006 Jun;191(6):761-6.
  • Sentinel lymph node. 109 pts w/ DCIS, 21 pts w/ microinvasive (MIC).
  • DCIS: 3.6% pts positive on routine H&E, plus 3.6% positive only by IHC = 7.2% total positive
  • MIC: 4.8% (1/21) pts positive on H&E, plus 4.8% only by IHC = 9.6% total.
  • Conclusion: modest risk of nodal positivity

Tumor Burden in Axilla

• Karolinska University, Sweden; 2010 (2000-2004) PMID 20458033 -- "Breast Cancer Survival in Relation to the Metastatic Tumor Burden in Axillary Lymph Nodes." (Andersson Y, J Clin Oncol. 2010 May 10. [Epub ahead of print])
  • Prospective cohort. 3,369 women, pN0 2383 (71%), ITC 107 (3%), pN1mi 123 (4%), macromets 756 (22%). Median F/U 4.3 years
  • Outcome: 5-year CSS pN0 96.9% vs pN1mi 94.1% (SS). No difference between pN0 and ITC
  • Conclusion: Worse prognosis for patients with micrometastases, no difference if isolated tumor cells

Surgery vs Radiotherapy

• There are two randomized trials: NSABP B-04 and a French study, which did not evaluate axillary status.
• Currently ongoing AMAROS trial randomized patients with a positive sentinel lymph node to ALND or axillary RT

See also: Cuzick meta-analysis.

• EORTC Trial 10981-22023 (AMAROS) ("After Mapping of the Axilla, Radiotherapy Or Surgery") (2001 - ONGOING) -- SLN+, ALND vs RT
  • Randomized. Ongoing. Surgery, T1-T2 (<3cm), if SLN+ then Arm 1) completion ALND vs Arm 2) axillary RT 50/25. If ALND with 4+ lymph nodes, axillary RT allowed per institutional protocol
  • RT Quality Assurance; 2003 PMID 13129630 -- "Quality assurance of axillary radiotherapy in the EORTC AMAROS trial 10981/22023: the dummy run." (Hurkmans CW, Radiother Oncol. 2003 Sep;68(3):233-40.)
  • Chemo rates; 2010 PMID 20038733 -- "Role of axillary clearance after a tumor-positive sentinel node in the administration of adjuvant therapy in early breast cancer." (Straver ME, J Clin Oncol. 2010 Feb 10;28(5):731-7. Epub 2009 Dec 28.)
    • Subset analysis. First 2000 patients, 566 with SLN+. Patterns of adjuvant chemo use
    • Outcome: Chemotherapy ALND 58% vs ART 61% (NS); hormones 78% vs 76% (NS)
    • Conclusion: Absence of knowledge about extent of LN involvement doesn't impact administration of adjuvant chemo
  • SLN Outcomes; 2010 PMID 20300966 -- "Sentinel Node Identification Rate and Nodal Involvement in the EORTC 10981-22023 AMAROS Trial." (Straver ME, Ann Surg Oncol. 2010 Mar 19. [Epub ahead of print])
    • Subset analysis. First 2000 patients. SLN identification rate 97%
    • Outcome: SLN- in 65%; SLN+ in 34% (macromets 63%, micromets 25%, ITCs 12%). Further nodal involvement if macromet 41%, if micromet 18%, if ITC 18%
    • Conclusion: SLN procedure highly effective; further nodal involvement in patients with micromets and ITCs was 18%
  • Clinical Outcomes; 2014 PMID 25439688 -- "Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial." (Donker M, Lancet Oncol. 2014 November;15(12):1303-1310.)
    • Outcome: 5-year axillary recurrence ALND 0.43% vs RT 1.19%, underpowered to show non-inferiority (assumed 2% vs 4% with non-inferiority HR margin of 2). 5-year DFS ALND 87% vs 83% RT (NS). 5-year OS ALND 93% vs RT 93% (NS).
    • Morbidity: More lymphedema with ALND at 1, 3, and 5 years (5-year 23% vs 11%) (SS). Increased arm circumference at 5-year with ALND (13% vs 6%) (SS). But no difference in arm range of motion nor overall QoL.
    • RT: target all three levels of axilla and medial part of supraclavicular fossa to 50 Gy in 25 fractions
    • Conclusion: ALND and RT after SLN+ provide excellent and comparable control for T1-2, cN0. RT results in significantly less morbidity.

• NSABP B-04 (Fisher), 1977 (1971-4) - radical mastectomy (including axillary dissection) vs total mastectomy (no axillary dissection) + XRT to chest wall and lymphatics.
  • 1665 pts, operable, potentially curable cancer confined to the breast and axilla; nodes not fixed.
  • For clinically N+ pts, randomized to radical mastectomy vs total mastectomy + RT.
  • For clinically N- pts, randomized to radical mastectomy vs total mastectomy vs total mastectomy + RT. Pts treated without axillary dissection or regional RT who later developed biopsy-proven axillary disease then went on to axillary dissection. These pts were not considered to have a LR (unless the nodes were unresectable, only in 1 pt).
  • RT technique - dose was 50 Gy / 25 fx to chest wall, 45 Gy to SCLV and IM nodes (both @ 3cm), mid axilla boosted to 50 Gy with PAB; for LN+ pts, axilla boosted to additional 10-20 Gy by direct appositional field.
  • No systemic therapy was given.
  • Statistics: DFS, RFS, DDFS, OS. Local recurrence: in chest wall or scar. Regional recurrence: SCLV, subclavicular, IMN; or in ipsilateral axilla (in pts treated with RM or TM+RT). Pts who had TM alone and developed axillary recurrence that required axillary dissection were not considered to have a recurrence unless the nodes were unresectable (only in 1 pt).
    • DFS events: local, regional, or distant recurrence; contralateral breast ca, or any second primary tumor (other than a tumor in the breast); death.
    • RFS events: local / regional / distant recurrence; contralateral breast event that was judged a recurrence.
    • DDFS events: "distant recurrences that occurred either as the first recurrence or after a local or regional recurrence, contralateral breast cancers, and other second primary cancers"
  • PMID 3883168 — "Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation." Fisher B et al. N Engl J Med. 1985 Mar 14;312(11):674-81.
  • No difference in 10 year survival or axillary failure.
  • 25-year update (2002): PMID 12192016 Full text — "Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation." Fisher B et al. N Engl J Med. 2002 Aug 22;347(8):567-75.
    • 82% of pts had a event. Most common event was recurrence (57% LN+, 37% LN-) followed by death without evidence of cancer (25%) followed by second primary cancer (6%) and contralateral breast cancer (6%). Most recurrences (74%) were distant. 30% of LN- pts had a distant recurrence and 42% of LN+. 5% had local recurrence, and 4% had regional recurrence. Note the continued relapses even after 10 years.
    • Clinically negative axilla:
      • Axillary failure rate: 18.6% of LN- pts undergoing TM without RT eventually required nodal dissection for axillary recurrence. Median time to axillary failure was 14 months.
      • 40% of pts treated with radical mastectomy had occult positive lymph nodes.
      • Nodal recurrence as first recurrence event: 4% axillary dissection, 4% axillary RT, 6% no axillary tx

5 years   DFS DDFS OS RM 60 68 75 TM+RT 65 71 75 TM alone 56 65 74   p=0.08 p=0.3 p=0.9

10 years   DFS DDFS OS RM 47 58 58 TM+RT 48 57 59 TM alone 42 55 54   p=0.2 p=0.6 p=0.5

25 years   DFS RFS DDFS OS RM 19 53 46 25 TM+RT 13 52 38 19 TM alone 19 50 43 26

• • • Clinically positive axilla:

5 years   DFS DDFS OS RM 45 53 62 TM+RT 40 51 58   p=0.2 p=0.8 p=0.3

10 years   DFS DDFS OS RM 29 39 38 TM+RT 25 40 39   p=0.2 p=0.4 p=0.4

25 years   DFS RFS DDFS OS RM 11 36 32 14 TM+RT 10 33 29 14

• • Summary: No difference in DFS or RFS among the three LN- groups or among the two LN+ groups.
  • Additional publications:
    • Original results (1977): PMID 326381 Full text — "Comparison of radical mastectomy with alternative treatments for primary breast cancer. A first report of results from a prospective randomized clinical trial." Fisher B et al. Cancer. 1977 Jun;39(6 Suppl):2827-39.
    • Radiation compliance (1980): PMID 6992972 Full text — "Findings from NSABP Protocol No. B-04-comparison of radical mastectomy with alternative treatments for primary breast cancer. I. Radiation compliance and its relation to treatment outcome." Fisher B et al. Cancer. 1980 Jul 1;46(1):1-13.
    • Medial-central breast cancers (1981): PMID 7284980 Full text — "Findings from NSABP Protocol No. B-04: comparison of radical mastectomy with alternative treatments. II. The clinical and biologic significance of medial-central breast cancers." Fisher B et al. Cancer. 1981 Oct 15;48(8):1863-72.
      • Need for treatment of internal mammary nodes: no higher risk of distant metastases in pts with medial-central tumors (which have untreated IM nodes potentially harboring cancer cells). No evidence of beneficial effect of irradiating IM nodes.

• • Conclusion: Failed to show a benefit of axillary dissection for clinically node-negative pts (compared with a wait-and-watch approach).

• Institut Curie (France)(1982-1987) - lumpectomy + axillary surgery vs lumpectomy + axillary XRT
  • Randomized. 658 pts. Clinically N0, T < 3cm, randomized to axillary dissection or axillary XRT. All patients received lumpectomy + XRT to the breast, 55 Gy + 10-15 Gy boost (total 65-70 Gy).
    • Pts randomized to axillary surgery had axillary dissection (level I and lower level II nodes inferior to axillary vein) and had XRT to SCLV and IM nodes if they had positive axillary nodes, and IM node XRT if they had a central or medially located tumor.
    • Pts randomized to axillary XRT received RT to axilla and IMN. Dose to axilla was 50 Gy; dose to SCLV and IM nodes was 45 Gy.
    • 21% of the surgery group had LN+. Pts with more than one positive LN were allowed either hormonal therapy or CMF chemotherapy; some pts in XRT group received chemo. Chemotherapy in ~5% of surgery group, 3% of XRT group. Tamoxifen was allowed. Hormonal therapy given in 3-5% of patients (more in surgery group).
  • 5-years, 1999 PMID 1349666 — "Value of axillary dissection in addition to lumpectomy and radiotherapy in early breast cancer. The Breast Carcinoma Collaborative Group of the Institut Curie" (Cabanes PA et al. Lancet. 1992 May 23;339(8804):1245-8.)
    • Survival (89% vs. 87%) and DFS (97% vs. 93%) benefit for axillary dissection
  • 15-years, 2004 PMID 14701770 Full text — "Axillary treatment in conservative management of operable breast cancer: dissection or radiotherapy? Results of a randomized study with 15 years of follow-up." (Louis-Sylvestre C et al. J Clin Oncol. 2004 Jan 1;22(1):97-101.)
    • No difference in OS or DFS. 10-year OS 86% vs 83%; 15-year OS 75% vs 75%. 5-year DFS 83%; 10-year 72%; 15-year 64%. 5-year distant mets, 10-12%; 10-year DM 18-21%; 15-year DM 25%. Ipsilateral breast recurrence at 5-years 7%, at 10 years 12%, at 15 years 17%. Isolated axillary recurrence (without breast recurrence) 1% vs 3% at 15 years (p=0.04).
  • Summary: with longer followup, no difference. Data agree with results from B-04

Surgery vs. Observation

• International Breast Cancer Study Group Trial 10-93, 2006 (1993-2002) - PMID 16344321 — "Randomized Trial Comparing Axillary Clearance Versus No Axillary Clearance in Older Patients With Breast Cancer: First Results of International Breast Cancer Study Group Trial 10-93." IBCSG (Rudenstam CM). J Clin Oncol. 2006 Jan 20;24(3):337-44.
  • 473 pts. Women >= 60 yrs, clinically node negative, operable, eligible for tamoxifen. Randomized to primary surgery + axillary clearance vs surgery without axillary clearance. Both groups received tamoxifen. Primary end point was quality of life. Axillary staging was clinical; no sentinel lymph node biopsy was performed. RT was tangents, no axillary RT.
  • Median f/u 6.6 yrs. 42% had 2 cm or larger tumors. 20% of pts (of those dissected) had 1-3 LN, 8% had 4 or more LN. Largest difference in QOL was before first post-op visit. Differences disappeared by 6-12 months. At median f/u, similar DFS and OS. 2% axillary recurrence rate (same in both arms).
  • Avoiding axillary clearance leads to similar efficacy and better early QOL.

RT vs. Observation

• Maastrichtt, Netherlands; 2009 (1998-2005) -- "Impact of omission of completion axillary lymph node dissection (cALND) or axillary radiotherapy (ax RT) in breast cancer patients with micrometastases (pN1mi) or isolated tumor cells (pN0[i+]) in the sentinel lymph node (SN): Results from the MIRROR study." (Tjan-Heijnen, J Clin Oncol 27:18s, 2009 (suppl; abstr CRA506))
  • Retrospective. Subset analysis of MIRROR trial, SN biopsy without macrometastases. 835 patients with pN0(i-), 799 patients with pN0(i+), and 958 patients with N1(mi). Median F/U 4.7 years
  • Outcome: 5-year axillary recurrence pN0(i-) ~2%, pN0(i+) ~1.5%, pN1(mi) CLND or RT 1.2%, pN1(mi) SN only 6.2% (SS)
  • Conclusion: Omission of cALND or RT in patients with pN1(mi) resulted in significantly higher axillary recurrence rate

Predictors of regional failure

General

• MD Anderson; 2005 PMID 16169678 -- "Clinical investigation: regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy." (Strom EA, Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1508-13. Epub 2005 Sep 19.)
  • Retrospective. 1031 patients, mastectomy + Level I-II ALND, chemotherapy, no PMRT. Median F/U 9.7 years
  • Outcome: 10-year low axilla failure rate 3%, regardless of risk factors. 10-year high axilla/SCV failure rate 8% (5% as only site). Predictors for ICV/SCV failure >=4 LN+ (15%), >20% LN+ (14%), gross ECE (19%). Extent of axillary LND not predictive
  • Conclusion: Failure in Level I-II uncommon after MRM/chemo. Patients with specified risk factors should receive adjuvant RT to Level III/SCV

1-3N+

• Harvard; 2009 (1990-2004) PMID 19327896 -- "Chest wall radiotherapy: middle ground for treatment of patients with one to three positive lymph nodes after mastectomy." (Macdonald SM, Int J Radiat Oncol Biol Phys. 2009 Dec 1;75(5):1297-303. Epub 2009 Mar 26.)
  • Retrospective. 238 patients, mastectomy, pT1-T2N1
  • Outcome: 10-year LRR without PMRT 11% vs with PMRT 0% (SS); 10-year DFS 75% vs 93% (SS). Similar benefit in patients treated to chest wall alone, LRR 0%, DFS 96%, OS 95%
  • Conclusion: Adjuvant PMRT to chest wall alone provides excellent disease control for patients with breast cancer <5cm and 1-3 positive lymph nodes

• MD Anderson; 2009 (1980-2007) ASCO Abstract -- "Value of adjuvant radiation therapy in breast cancer patients with one to three positive lymph nodes undergoing a modified radical mastectomy and systemic therapy." (Dawood S, J Clin Oncol 27:15s, 2009 (suppl; abstr 507))
  • Retrospective. 4.240 patients, T1-2N0-1 (T1N0 19%, T2N0 26%, T1N1 23%, T2N1 19%), treated with mastectomy without RT or with lumpectomy with RT. All received systemic treatment. Median F/U 4.5 years
  • Outcome: 5-year distant mets DFS mastectomy-RT 81% vs. lumpectomy+RT 86% (SS). No difference in N0 patients. In N1 patients, mastectomy-RT significantly higher risk of DM compared with lumpectomy+RT (HR 1.6, SS)
  • Conclusion: Provocative evidence for benefit of RT

• British Columbia; 2009 (1989-1999) PMID 18676091 -- "Patients with t1 to t2 breast cancer with one to three positive nodes have higher local and regional recurrence risks compared with node-negative patients after breast-conserving surgery and whole-breast radiotherapy." (Truong PT, Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):357-64.)
  • Retrospective. 5,699 patients, BCT (partial mastectomy + ALND), pT1-T2 0-3N+ SM-. Chemo N0 41%, N+ 97%. Regional RT in 35% of 1-3N+. Median F/U 8.6 years
  • Outcome: 10-year LR N0 5.1% vs. 1-3N+ 5.8% (SS); RR 2.3% vs. 6.1% (SS), LRR 6.7% vs. 10.1% (SS). In 1-3N+, 10-year LRR age <50 14%, Grade III 20%, ER- 23%.
  • Pattern of regional failure: N0: axillary 1.0% vs supra/infraclav 0.7% vs. IM 0.1%; 1-3N+ axillary 3.2% vs. supra/infraclav 2.2% vs. IM 0.1%
  • Conclusion: Patients with 1-3N+, who are young, Grade III, or ER- have high LRR risk (15-20%) despite BCS, whole breast RT and systemic therapy

• SEER Analysis; 2008 PMID 18234447 -- "Radiation use and long-term survival in breast cancer patients with T1, T2 primary tumors and one to three positive axillary lymph nodes." (Buchholz TA, Int J Radiat Oncol Biol Phys. 2008 Jul 15;71(4):1022-7. Epub 2008 Jan 30.)
  • SEER database. Comparison of 12,693 BCS+RT vs. 18,902 mastectomy without RT patients, Stage II with 1-3N+. BCS+RT patients younger, more recent, T1, fewer involved LNS (all SS)
  • Outcome: 15-year CSS BCS+RT 80% vs. M alone 72% (SS). M alone associated with +19% risk of breast cancer death and 20% risk of overall death
  • Conclusion: RT independently associated with improved survival in patients with one to three positive lymph nodes

Number of excised LNs

• Quebec; 2006 (1972-97) - PMID 16542789 — "The impact of the number of excised axillary nodes and of the percentage of involved nodes on regional nodal failure in patients treated by breast-conserving surgery with or without regional irradiation." (Fortin A et al. Int J Radiat Oncol Biol Phys. 2006 May 1;65(1):33-39.) Median F/U 5 years
  • Retrospective. 1372 pts. T1-T2 node-positive, treated with breast conservation. Analysis of the 904 pts who did not receive RT to the axilla.
  • Outcome: Negative hormonal status and LF were the only factors associated with axillary failure. Trend for increased failures with extracapsular extension. Median # of nodes excised was 11 (interquartile range: 8-14).
    • Number of nodes removed: No difference in axillary control for pts with complete (>10 nodes removed) vs incomplete axillary dissection.
    • Percentage of positive nodes: Median was 25%. For pts with 1-3 positive nodes, the median percentage was 14%, versus 60% for pts with >3 positive nodes. Higher risk of axillary failure for pts with >40% involvement (if 1-3 nodes are positive) or >50% involvement (if >3 nodes are positive).
    • Effect of regional RT: axillary RT is associated with increased axillary control for pts with higher percentage of involved nodes but not for those pts with a low percentage of involved nodes. Regional control rate (includes axilla and SCLV) improved even in pts with low percentage of positive nodes.
  • Conclusion: irradiation of the axilla should be reserved for pts with >40% involved nodes if there are 1-3 positive nodes and >= 50% involved nodes if more than 3 nodes are positive. Recommend irradiation of SCLV and level III of axilla for all node-positive pts.

Extracapsular extension

• Graz, Austria; 2006 (1994-2003) PMID 17013571 -- "Postoperative irradiation in breast cancer patients with one to three positive axillary lymph nodes. Is there an impact of axillary extranodal tumor extension on locoregional and distant control?" (Stranzl H, Strahlenther Onkol. 2006 Oct;182(10):583-8.)
  • Retrospective. 274 patients with 1-3N+. Mean 11 LN dissected. ECE in 33%. All patients tangents, 9% of ECE patients SCV field. Median F/U 3.6 years
  • Outcome: Local failure 4.7%, regional failure 2.9%. LRF number too small for ECE analysis. However, ECE negative indicator for DM (HR 2.7, SS) and 5-year DFS (81% vs. 69%, SS)
  • Conclusion: LRC low regardless of ECE and tangent are sufficient, however, considerable risk for distant failure

• MD Anderson; 2005 PMID 16169678 -- "Clinical investigation: regional nodal failure patterns in breast cancer patients treated with mastectomy without radiotherapy." (Strom EA, Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1508-13. Epub 2005 Sep 19.)
  • Retrospective. 1031 patients, mastectomy + Level I-II ALND, chemotherapy, no PMRT. Median F/U 9.7 years
  • Outcome: 10-year low axilla failure rate 3%. 10-year high axilla/SCV failure rate 8% (5% as only site). Predictors for ICV/SCV failure >=4 LN+ (15%), >20% LN+ (14%), gross ECE (19%). Extent of axillary LND not predictive
  • Conclusion: Failure in Level I-II uncommon after MRM/chemo. Patients with specified risk factors (including gross ECE) should receive adjuvant RT to Level III/SCV

Review

• Tufts; 2008 PMID 18525310 -- "Management of the axilla after the finding of a positive sentinel lymph node: a proposal for an evidence-based risk-adapted algorithm." (Evans SB, Am J Clin Oncol. 2008 Jun;31(3):293-9.)
  • Management algorithm proposed for patients with positive SLN, using MSKCC axilla nomogram
  • Based on likelihood of further disease: <5% then standard tangents; if 5-10% then high tangents; if 10-20% then comprehensive axillary RT; if >20% then axillary lymph node dissection

• 2007 PMID 17395107 -- "Management of the axilla in women with breast cancer." (Benson JR, Lancet Oncol. 2007 Apr;8(4):331-48.)

Supraclavicular/Internal Mammary

• In patients with N1 disease (1-3 nodes positive)
  • Overall SCV failure without SCR RT may be 6-9%, but isolated SCV failure without concurrent DM is only 2-3%
  • Several factors appear to predict for >10-15% risk of overall SCV failure: LVI+, ECE+, 2-3 involved LNs (vs 1 involved), involved Level II/III LNs (vs Level I only), >20% LN+, age <50, Grade III, and ER- disease
  • Given that SCV recurrence salvage is challenging, it may be reasonable to offer SCV RT to these patients
  • Please also see general studies in N1 section below
• NCCN Guideline (v2.2010):
  • Negative axillary nodes: whole breast RT only
  • 1-3 positive axillary nodes: "strongly consider" RT to infraclavicular and supraclavicular region (category 2B). Consider internal mammary RT (category 3)
  • ≥ 4 positive axillary nodes: whole breast, infraclavicular/supraclavicular RT, consider internal mammary RT (category 3)

• Samsung Medical Center, Korea; 2010 (1994-2003) PMID 20231065 -- "Determining Which Patients Require Irradiation of the Supraclavicular Nodal Area After Surgery for N1 Breast Cancer." (Yu JI, Int J Radiat Oncol Biol Phys. 2010 Mar 13. [Epub ahead of print])
  • Retrospective. 448 pN1 breast cancer, mastectomy without RT (67%) or BCT without SCV RT. Median LN dissected 17. LVI+ 20%, ECE+ 5%, >20% LN+ in 22%. Systemic chemotherapy 99%. Median F/U 7.3 years
  • Outcome: LRR 14%. SCV recurrence 8.9%, but SCV recurrence without DM 2.7% (isolated SCV 1.8%, SCV + regional recurrence 0.7%, SCV + LR 0.2%).
  • Predictors for SCV recurrence: LVI+ (5-year SCV-RFS 83% vs 95%), ECE+ (55% vs 95%), 2-3 involved axillary LNs (86% vs 98%), involved Level II/III LN (75% vs 94%), >20% positive (82% vs 95%, p=0.051). If 2+ RFs, SCV-RFS 73% vs 97% (SS)
  • Conclusion: Prognostic factors associated with SCV recurrence in N1 patients were LVI+, ECE+, >1 LN+ and level II/III of involved LNs. Patients with 2+ risk factors might benefit from SCV RT

• University of Florence; 2010 PMID 19540052 -- "Outcome after conservative surgery and breast irradiation in 5,717 patients with breast cancer: implications for supraclavicular nodal irradiation." (Livi L, Int J Radiat Oncol Biol Phys. 2010 Mar 15;76(4):978-83. Epub 2009 Jun 18.)
  • Retrospective. 5171 patients, pT1-T4 BCA. Median number removed LNs 16. Per protocol, SCV not irradiated. WBRT 50/25, boost at discretion. Adjuvant chemo 27%, adjuvant TAM 52%. Patient stratified based on number of positive nodes: P1 negative, P2 1-3 LN+, P3 >3 LN+. Median F/U 6.8 years
  • Outcome: isolated SCV fossa recurrence (first site of recurrence and no DM within 8 months) P1 0.9% vs P2 2.1% vs P3 5.5% (SS); breast recurrence 4.9% vs 3.0% vs 2.7%; DM 6.1% vs 12.0% vs 27.2% (SS); OS 93% vs 87% vs 71% (SS)
  • Conclusion: Main problem for patients with multiple (+) LNs was distant metastases. Isolated SCV recurrence is infrequent despite no RT

• MDACC; 2009 (2006-2007) PMID 18676090 -- "Effects of variable placement of superior tangential/supraclavicular match line on dosimetric coverage of level III axilla/axillary apex in patients treated with breast and supraclavicular radiotherapy." (Garg AK, Int J Radiat Oncol Biol Phys. 2009 Feb 1;73(2):370-4.)
  • Mean volume of Level III/axillary apex covered by 90% isodose line / 45 Gy: 100% (match line caudal to clavicular head), 92% (intermediate), 68% (cranial).
  • Conclusion: "Placement of the superior tangential/supraclavicular match line caudal to the clavicular head results in statistically improved dosimetric coverage of the Level III axilla/axillary apex in breast cancer patients undergoing tangential/supraclavicular radiotherapy."

• MDACC; 2008 (2005) PMID 18164831 -- "Risk of subclinical micrometastatic disease in the supraclavicular nodal bed according to the anatomic distribution in patients with advanced breast cancer." (Reed VK, Int J Radiat Oncol Biol Phys. 2008 Jun 1;71(2):435-40.)
  • 33 pts with SCLV node recurrence with advanced or metastatic breast cancer. Plotted location of SCLV node by PET scan; compared to standard SCLV fields.
  • Conclusion: "in patients with locally advanced disease, increased coverage of the supraclavicular fossa medially and posteriorly may be warranted."

Randomized trials

• EORTC 22922/10925 (1996-2004)
  • Randomized. 4004 women, 46 institutions. BCT 76%, mastectomy 24%, Stage I-III with central/medial tumor location or lateral tumor with axillary involvement. Full axillary dissection or SNB followed by ALND if positive. pN0 44%; pN1 43%; pN2 10%. Standard RT (breast/chest wall, boost) as per institutional preference. RT randomized: Internal mammary and medial supraclavicular 50/25 vs. no RT. Boost in 85% of whole breast.
  • Quality assurance; 2007 PMID 17240136 -- "Quality assurance in breast cancer: EORTC experiences in the phase III trial on irradiation of the internal mammary nodes." (Musat E, Eur J Cancer. 2007 Mar;43(4):718-24.)
  • Toxicity; 2010 PMID 20100142 -- "Toxicity at three years with and without irradiation of the internal mammary and medial supraclavicular lymph node chain in stage I to III breast cancer (EORTC trial 22922/10925)" (Matzinger O, Acta Oncol. 2010;49(1):24-34.)
    • Toxicity: Any lung toxicity standard RT 1.3% vs IM-MS RT 4.3% (SS); cardiac toxicity 0.3% vs 0.4% (NS). No difference in performance status
    • Outcome: Well tolerated at 3 years
  • 10-years; 2015 PMID 26200978 -- "Internal Mammary and Medial Supraclavicular Irradiation in Breast Cancer." (Poortmans PM, N Engl J Med. 2015 Jul 23;373(4):317-327.) -- Median F/U 10.9 years
    • Outcome: 10 year OS RNI 82% vs control 80.7% (0.06); DFS 72.1% vs 69.1% (0.04); distant mets-free survival 78% vs 75% (0.02); breast cancer mortality 12.5% vs 14.4% (0.02)
    • Toxicity: pulmonary fibrosis 4.4% vs 1.7% (SS); cardiac disease 6.5% vs 5.6% (NS). No difference in other toxicity
    • Conclusion: Irradiation of regional nodes marginal effect on overall survival; DFS and distant mets-free survival improved, and breast cancer mortality reduced

• Intergroup / NCIC-CTG MA.20 (2000-2007) - Whole breast RT +/- regional nodal irradiation
  • Randomized. Multicenter (Canada-86%; US, Australia). 1832 patients, high risk node-negative (pT3, or pT2 and <10 LN removed and >= 1 of the following: grade 3, ER-, LVI+) or node-positive (pN1), treated with BCS and adjuvant chemo +/- endocrine therapy. All had level 1-2 axillary dissection. Randomized to whole breast RT (50 Gy / 25 fx +/- boost (33%) or whole breast RT + regional nodal irradiation (45 Gy / 25 fx) to internal mammary, SCLV, and axillary apex.
  • 2011 -- "NCIC-CTG MA.20: An intergroup trial of regional nodal irradiation in early breast cancer." (Whelan T, J Clin Oncol 29: 2011 (suppl; abstr LBA1003) -- Median F/U 62 mo
    • Mean age 53 yr. 85% had 1-3+ LN, 10% node-negative, ≥4 LN 5%. Adjuvant chemo 91%, endocrine therapy 71%.
    • WBI+RNI associated with improved isolated locoregional DFS: 5-yr 96.8% vs 94.5% (HR=0.59, SS), distant DFS: 92.4% vs 87.0% (HR=0.64, SS), DFS: 89.7% vs 84.0% (HR=0.68, SS), and OS: 92.3% vs 90.7% (HR=0.76, trend p=0.07).
    • Increased gr2 or greater pneumonitis: 1.3% vs 0.2% (SS) and lymphedema (7.3% vs 4.1%, SS).
    • Conclusion: additional RNI reduces the risk of locoregional and distant recurrence, and improves DFS with a trend in improved OS.
    • ASCO Lecture video (16 minutes).
  • 10 years; 2015 PMID 26200977 -- "Regional Nodal Irradiation in Early-Stage Breast Cancer." (Whelan TJ, N Engl J Med. 2015 Jul 23;373(4):307-316.) -- Median F/U 9.5 years
    • Outcome: 10-year OS RNI 82.8% vs WB 81.8% (NS); breast cancer survival 89.7% vs. 87.7% (NS); DFS 82% vs 77% (SS). Incidence of distant mets 13.4% vs 17.3% (0.02); isolated locoregional recurrence 4.5% vs 7.2% (0.02)
    • Toxicity: acute pneumonitis G2+ 1.2% vs 0.2% (SS); lymphedema 8.4% vs 4.5% (SS)
    • Conclusion: Addition of regional nodal irradiation does not improve overall survival but reduces rate of breast cancer recurrence

Internal mammary

See also: Internal mammary irradiation after mastectomy

Randomized trials

• Intergroup NCIC-CTG MA.20 - whole breast RT +/- regional nodal irradiation
  • Node-positive or high-risk node-negative
  • See details at #Supraclavicular

• French 2013 (1991-97) - Post-mastectomy RT + SCF +/- IMN RT
  • 1334 women with positive axillary LN or medial tumors (LN negative) were randomized to CW + SCF (50 Gy) +/- IMN irradiation (50 Gy to first 5 IC spaces at 3cm depth).
  • 2013 PMID 23664327 -- "Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after mastectomy." (Hennequin C, Int J Radiat Oncol Biol Phys. 2013 Aug 1;86(5):860-6.)
    • Median Followup of 8.6 years, 25% of patients node negative on LN evaluation (SLN or ALND).
    • No difference in DFS 53.2% (IMN irradiated) vs 49.9% (IMN not irradiated) (P=0.35) or OS 62.8% (IMN irradiated) vs 59.3% (IMN not irradiated) (P=0.8)
    • Powered for a 10% improvement in DFS or OS (3% DFS and OS were observed in the MA20 and EORTC 22922-10925)
    • Subset analysis revealed 5-10% detriment to OS in Node Negative women who received IMN radiation.

• Finland, 1995 (1989-91) - PMID 8532902 — "Tangential breast irradiation with or without internal mammary chain irradiation: results of a randomized trial." Kaija H et al. Radiother Oncol. 1995 Sep;36(3):172-6.
  • Randomized. 263/270 patients. Stage I-II treated with BCS. RT 2 field tangent technique, randomized to include the IMN in the tangent fields or not. RT dose: 50 Gy + 10 Gy boost (71 patients), 54 Gy no boost (44 patients), 50 Gy no boost (146). Median F/U 2.7 years
  • No difference in pneumonitis (18% vs. 14%). No difference in recurrence rates
  • Conclusion: No difference in toxicity. Follow-up too short to comment on recurrences

• NSABP B-04 (see details at Early breast/Axilla)
  • No difference in risk of distant metastasis in pts treated with total mastectomy only (no treatment to IM nodes) compared with total mastectomy + RT (treated IM nodes)

Prospective (non-randomized) studies

• DBCG-IMN (Danish) (2003-2007) - Cohort study.
  • Early stage, node-positive breast cancer. 3089 pts, 60% had pN1 (1-3 LN+). Pts with right-sided disease were assigned to IMN RT, 1st-4th intercostal space. Pts with left-sided, no IMN RT. All groups received RT to SCLV and axillary apex, 48 Gy in 24 fractions.
  • Patients did not receive taxane-based chemotherapy. Chemo was given in premenopausal pts (all), postmenopausal (only if ER-). ~53% received chemo, 47% endocrine therapy only.
  • Primary outcome, 2015 PMID 26598752 -- "DBCG-IMN: A Population-Based Cohort Study on the Effect of Internal Mammary Node Irradiation in Early Node-Positive Breast Cancer" (Thorsen LB, J Clin Oncol. 2016 Feb 1;34(4):314-20.)
    • Median f/u 8.9 yr. 8-yr OS 75.9% with IMN RT vs 72.2% without IMN RT (SS, HR = 0.82). Breast cancer mortality 20.9% vs 23.4% (SS). Distant recurrence 27.4% vs 29.7%. The effect of IMNI was more pronounced in patients at high risk of internal mammary node metastasis. Equal numbers in each group died of ischemic heart disease.
    • Conclusion: In this naturally allocated, population-based cohort study, IMNI increased overall survival in patients with early-stage node-positive breast cancer.
  • IM dose evaluation; 2014 PMID 24957557 -- "CT-planned internal mammary node radiotherapy in the DBCG-IMN study: benefit versus potentially harmful effects." (Thorsen LB, Acta Oncol. 2014 Aug;53(8):1027-34. doi: 10.3109/0284186X.2014.925579. Epub 2014 Jun 24.)
    • Methods: 10% selected randomly; IMN and OAR contoured in 68 scans, and dose recalculated
    • Outcome: IMN V90 = 73% right (planned coverage) vs 35% left (incidental covereage)
    • Organ at risk dose: Heart MHD right side 1.1 Gy vs left side 4.0 Gy. With re-planned IMN coverage on the left, MHD would have increased by average 4.8 Gy. Lung V20 right 31% vs left 26%. Number need to treat outweighed number needed to harm from ischemic heart disease perspective
    • Conclusion: The benefit of IMN outweigh costs in terms of ischemic heart disease (accepting 4.8 Gy MHD increase)

Non-randomized studies

• Centre Antoine-Lacassagne, Nice, France; 2013 (1975-2008) PMID 23891092 -- "Influence of internal mammary node irradiation on long-term outcome and contralateral breast cancer incidence in node-negative breast cancer patients." (Courdi A, Radiother Oncol. 2013 Jul 25. pii: S0167-8140(13)00307-1. doi: 10.1016/j.radonc.2013.06.028. [Epub ahead of print])
  • Retrospective. 1630 breast cancer patients, pN0, breast conservation surgery, ALND/SLN, treated with adjuvant RT. IMN-RT at discretion, more frequent in inner/central tumors.
  • Outcome: 10-year OS IMN+ 85% vs 86% IMN- (NS); however for inner/central tumors 10-year OS 92% vs 87% (SS). No difference in DFS
  • Toxicity: 20-year contralateral BCA developoment IMN+ 7.2% vs IMN- 5.3% (SS)
  • Conclusion: IMN RT in node-negative patients associated with improved OS for patient with inner/central tumors. Possibly increased risk in contralateral breast cancer

• Linz, Austria; 2009 (1984-1995) PMID 19806331 -- "Medial tumor localization in breast cancer--an unappreciated risk factor?" (Brautigam E, Strahlenther Onkol. 2009 Oct;185(10):663-8. Epub 2009 Oct 6.)
  • Retrospective. 1,100 T1-T2 invasive cancers, lateral quadrants 64%, central 9%, medial quadrants 27%. If N+ (26%) received chemotherapy. Median F/U 8.1 years
  • Outcome: 10-year OS medial tumors 71% vs lateral tumors 82% (SS), DSS 80% vs 89% (SS). No difference in DFS in N+, only N0. No difference in local control.
  • Conclusion: Medial tumor location lower OS but same local control. Likely unidentified internal mammary chain nodal metastases

• Milan; 2008 (1998-2006) PMID 18467318 -- "The value of radiotherapy on metastatic internal mammary nodes in breast cancer. Results on a large series." (Veronesi U, Ann Oncol. 2008 Sep;19(9):1553-60. Epub 2008 May 7.)
  • Retrospective. 663 patients, primarily inner quadrants, biopsy of IM nodes. If N+, RT given to IM node chain (1st-3rd intercostal spaces, anterior angled electons/photons or IMRT 50/25) and systemic treatment given.
  • Outcome: positive IM node 10%. 5-year OS 95%
  • Conclusion: Propose IM exploration should be part of staging

• Israel; 2003 PMID 12860949 -- "The role of irradiation of the internal mammary lymph nodes in high-risk stage II to IIIA breast cancer patients after high-dose chemotherapy: a prospective sequential nonrandomized study." (Stemmer SM, J Clin Oncol. 2003 Jul 15;21(14):2713-8.)
  • Phase II, non-randomized. 100 patients with high risk Stage II-III BCA, treated with adjuvant chemo -> high-dose chemo -> stem cell support, and loco-regional RT. 67 patients received IM RT with electrons, 33 patients did not due to machine unavailability in the middle of the protocol. Median F/U 6.4 years
  • Outcome: DFS IM RT 73% vs. no RT 52% (SS), OS 78% vs. 64% (p=0.08). No treatment-related mortality
  • Conclusion: In high risk, IM RT associated with improved DFS and borderline better OS
  • Comment: Prescription depth 1cm below sternum with 9-12MEV beam may not be sufficient

• Fox Chase / U. Pennsylvania; 2000 (1979-1994) PMID 10863056 — "Internal mammary node irradiation neither decreases distant metastases nor improves survival in stage I and II breast cancer." Fowble B et al. Int J Radiat Oncol Biol Phys. 2000 Jul 1;47(4):883-94.
  • Retrospective. 1383 pts, Stage I-II, treated with lumpectomy + ALND (>=10 nodes removed) + XRT. 114 pts had radiation to the IMN with deep tangents. The rest did not have IMN treated.
  • Median f/u 6 yrs. No difference in 5 or 10 yr IBTR, nodal recurrence, DM, OS, or CSS in the two groups.
  • No evidence of a benefit for IMN RT for stage I-II pts in this retrospective review.

Review

• Harvard; 2008 PMID 18711171 -- "Internal mammary nodes in breast cancer: diagnosis and implications for patient management -- a systematic review." (Chen RC, J Clin Oncol. 2008 Oct 20;26(30):4981-9. Epub 2008 Aug 18.)

RT Technique

• Please see the breast RT technique section