Terapie loco- regionali. Antonella Ferro UO Oncologia Medica Trento

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1 Terapie loco- regionali Antonella Ferro UO Oncologia Medica Trento

2 Outline Loco- regional recurrences: How to avoid them? Margins:what is an adeguate margin? How to manage them? Axilla: are its days numbered? Radiotherapy Updated PBI Updated PMRT

3 Rate of local recurrence (LRR) For pts treated in the 1970 s, the 5- ys LRR 10% Currently, the 5- ys rate is about 4% Improved mammographic evaluaqon Improved pathologic evaluaqon Most importantly, adjuvant systemic (chemo, endocrine and target therapy) Bouganim N, BCRT 2013 Age, tumor size, and estrogen receptor status were significantly associated with IBTR Younger Nodal status and ER and PR status were significantly associated with olrr. More nodes ER poor Path T size ER poor PR poor IBTR LRR

4 Outcomes aver IBTR and LRR LRR: an increased risk to develope distant disease and death 50% LLR accompagnied by distant MTS 5ys OS aver LRR 45-80% 5ys DDFS aner an IBRT: 67% (N0) and 51% (N+) 5ys DDFS aner nodal and chest wall recurrences: 29% (N0) and 19% (N+) AVer IBTR AVer LRR N0 N1

5 How to reduce the IBTR? What relaqonship between margin width and IBTR? What is the appropriate margin for breast conserving therapy? A posiqve margin, defined as ink on invasive cancer or DCIS, is associated with at least a 2- fold increase in local recurrence The increase in LR is not nullified by: An RT boost Systemic therapy Meta- analysis Houssami N et al; Ann Surg Oncol 2014 Consensus Statement Moran MS et al: Ann Surg Oncol 2014 SSO/ASTRO/ASCO guidelines; JCO 2014; 32: Favoreble biology NegaQve margins (no tumor on ink) opqmize local control (SSO- ASTRO guideline) Wider margin widths do not significantly improve local control even in unfavorable biologic subtypes What the impact on re- excision?

6 Marrow M Asco 2017

7 Chavez- MacGregor M SABCS P In 2014 there were approximately 113,894 BCS naqonwide. A decrease in the re- excision rate of 3.7% corresponds to 4,214 fewer unnecessary procedures just in one year. The comorbidity and the cost associated with this reducqon has profound implicaqons for paqents and for the health care system

8 Is this conclusion sqll correct? The final meta- analysis included 55,302 pazents from a total of 38 studies treated between 1968 and % T1 tumors; 72% node- negaqve disease Median follow up was 7.2 years. Minimum follow- up: 50 months Explicit pathologic definiqons of margin status Local recurrence reported in relaqon to margin status. For this meta- analysis, the authors used 3 different stazszcal models. Model 1: used dichotomous margin categories (neg vs close/posizve). All pts with at or equal margin width were compared with those who had wider margins 0 mm vs > 0 mm 1 mm vs > 1 mm 2 mm vs > 2 mm 5 mm vs > 5 mm Model 2: examined the impact of margin width range as opposed to a set margin width Model 3: neg vs close vs posiqve divided margin distance by cut points of 1 mm, 2 mm, and 5 mm Not included in previous metanalysis

9 Model 1: NegaQve vs close and posiqve margins Odd RaZos for LR for negazve vs. close/posizve margins > 0 mm: 0.46 ( ) > 1 mm: 0.43 ( ) > 2 mm: 0.49 ( ) > 5 mm: 0.53 ( ) ORs very similar: unable to say what s the opzmal margin Crude rates of LR with neg margins similar regardless of margin cut- point 3.8%>0mm; 3.5%>1 mm; 3.3%>2mm; 3.2%>5mm Model 2: Model 3: Range 0-2 mm: 7.2%; OR:0.56 ( , p<0.001) Range 2-5 mm: 3.6%; OR:0.44 ( , p<0.001) > 5 mm: 3.2%; OR:0.32 ( , p<0.001) NegaQve vs close vs posiqve margins MVA: the only significant predicqve variable was margin status across al definiqons (0,1,2,5 mm) Similar findings in previous meta- analysis MVA: margin width only significant variable (larger margin, lower recurrence) Odd RaZos for LR for negazve vs. close vs posizve margins Close vs neg: 1.58 ( ) Pos vs Neg: 2.49 ( ) 2 vs 1 mm: 0.50 ( ) 5 vs 2 mm: 0.40 ( ) 1 mm: 8%; 13% and 14% 2 mm: 3.6%; 5.5% and 9.5%) 5 mm: 2.9%; 4.1% and 12.8%. When modelling as negaqve, close or posiqve margins, reduced rates seen with negaqve margins with lowest rates at 2 and 5 mm MVA: confirmed margin status and width as factors associated with LRR

10 Should we change the exisqng recommendaqons? LimitaQons of meta- analysis preclude definiqve conclusion regarding appropriate margins Data suggest having a margin width beyond no tumor on ink may further reduce LRR Consistent with DCIS analysis: 2 mm Changing in praczce??? Should we achieve a 1- to 2- mm margin as compared to a no tumor on ink? PotenQal local control benefits vs morbidity, Qme, and cost? Which pts with «no tumor on ink» need more surgery? It may not only be related to the margin status itself, but to the volume of disease near the margin but these meta- analyses were not designed to look at that point

11 Managment of IBTR aver BCT 5 yrs IBTR rate: 4-10% Salvage mastectomy is sqll considered the treatment of first choice 5 ys 2 LR: 10-30%; OS: 80% Is re- lumpectomy alone appropriate? Vila J, J Surg Oncol 2014; 110:62 Ishitobi M; AnZcancer Res 2017; 37:5293 Morrow M SABCS ES 07_1 Not the standard of care High rates of addiqonal LR IndicaZon in: Low risk disease, long DFI

12 SABCS 2017; P Salvage lumpectomy following IBTR, while associated in MVA with higher second LR rate than SM, is not associated with inferior OS With survival >95% at 14 years in the SL cohort, salvage lumpectomy with or without re- radiazon, in a selected populaqon (unifocal T), represents an acceptable treatment opqon for paqents in order to delay Zme to mastectomy and keep the original breast without reducing BC survival. Both opqons should be discussed prior to any surgical decision.

13 Managment of IBTR aver BCT BCS + PBrl Studies Addional study with longer follow up is needed Low rates of 2 IBRT with acceptable toxicity May represent new alternaqve to salvage mastectomy

14 Managment of LRR Is reoperaqve SNB feasible and accurate? Does it provide useful informaqon? An SN can be idenqfied in the majority of pts who had iniqal SNB (81%) and in about half of those with ALND Chance of SN idenqficaqon is related to number of nodes removed, but not breast procedure (BCS or mastectomy) False negaqve rate not well defined, parqcularly aver mastectomy Aberrant drainage common Aberrant drainage pathways Technique of reoperaqve SN biopsy Combined radioacqve colloid + blue dye Intradermal and subareolar injecqon ( extra- axillary SN uncommon) Maaskant- Braat A; Breast Cancer Reas Treat 2013; 138:13 Morrow M SABCS ES 07_1 Technically feasible Impact on therapy varies with circumstances if iniqal therapy, type of LR Outcome likely to be determined by biology of LR, not surgical staging of nodes

15 Managment of LRR aver mastectomy Sites of LRR aner Mastectomy without PMRT Chest wall: 57% Supraclavicular nodes 23% Axilla 12% Parasternal/subclavicular (IMN) <1% LRR aver PMRT Meta- analysis: 34 studies 1 arm studies: 1438 pts 2- arm studies: 627 pts 5 random; 3 not random In the 2- arm studies CR 60.2% with RT + HT 38.1% with RT alone (OR 2.64, P<.0001). In 1- arm studies, RT + HT alained a CR of 63.4% 779 pazents had been previously irradiated A CR of 66.6% (event rate 0.64, 95% CI ) with HT + reirradiazon Hyperthermia and RadiaZon Therapy in Locoregional Recurrent Breast Cancers: A SystemaZc Review and Meta- analysis Dala NR et al;int J Radiat Oncol Biol Phys 2016 Apr 1;94(5):

16 What data for systemic Therapy aver LRR? Final analysis of CALOR confirms benefit of chemo for pts with resected ER- neg ILRR Long- term data do not support chemo in ER+ IBRT pts receiving ET Adjuvant therapy for ILRR should be informed by recurrent disease biology and not the pazent s primary tumor Aebi S Lancet Oncol 2014 Feb; 15 (2): ; Wapnir ASCO 2017

17 Managment of SC LRR Isolated SC recurrence rare Combined local and systemic treatment Pedersen A; Breast Cancer res Treat 2011; 125:815

18 Managment of Axillary LRR Isolated axillary recurrence AVer negaqve SNB: < 0.6% AVer posiqve SNB: 1.1% Axillary LRR aner SNB may be due to FN rate of SNB and be prognosqcally different than recurrence aner ALND Pepels M; Breast Cancer Res treat 2011; 125: 301 Bulte J; Breast Cancer Res treat 2013; 140: 143 Ø ALND appropriate approach Ø RT as indicated by findings of ALND, iniqal therapy

19 Managment of Controlateral LN recurrence ü Controlateral axillary drainage is rare with an untreated axilla but much more common aver prior ALND or SN biopsy ü Limited literature precludes definiqve recommendaqons, but good outcomes seen with surgery for selected cases

20 CriQcal decision- making in axilla surgery Nodal status/burden less relevant Biology decides systemic therapy SNB is the standard of care in cn0 NSABP B 32: Krag et al; Lancet 2010; Julian et al ASCO 2013 ALND has never shown a survival gain in ABC and EBC NSABP B04 NEJM 2002 (25 ys follow up) IBCSG 23: GalimberZ V Lancet Oncol 2013 Z0011: Giuliano, JAMA 2011 (6,5 ys follow up); Ann Surg 2016 (9.3 ys follow up) RT = ALND in SLB + EBC But lower lymphoedema rates Amaros: Donker, Lancet Oncol 2014

21 T< 2 cm 69% G 1and 2: 71% ER + 90% PR 75% Phase 3, mulqcenter, randomized, noninferiority trial that compared DFS in breast cancer paqents with one or more micrometastases ( 2 mm) in the SN who were randomized: Primary endpoint: idfs Secondary endpoint: OS, incidence of reappearance of tumor in undissected axilla

22 Outcomes at median follow- up of 9.8 years Subgroup analyses for tumor size, ER, PR, G and type of surgery (mastectomy or breast- conserving) did not idenqfy any paqent subgroup for which AD offered a DFS advantage No AD is now standard treatment in early breast cancer when the senznel node is only minimally involved These findings Z0011 trial (follow up 10 years) in pts with moderate disease burden in the axilla (1-2 SN+) undergoing BCS Non- AD is acceptable treatment in pazents scheduled for mastectomy with SN micrometastases

23 Arm morbidity is the most common late effect following axillary surgery Lymphedema 21% Shoulder impairement 4-28% Risk of arm morbidity higher aner ALND vs SN ü The study included 1,302 women aged 40 or younger who had undergone SLNB (55%), ALND (41%), or neither. ü Surveys: baseline ( 4 ms aner diagnosis), every 6 ms for 3 ys, then annually ü Incidence of paqent- reported arm swelling or decreased range of moqon 1 year post- diagnosis: ü 13% of women reported arm swelling ü 11 % of pts who underwent BCT ü 14% of pts who underwent any mastectomy ü 33% of pts reported decreased ROM ü 32% on BCT ü 34% on mastectomy

24 These finding highlight opportunizes for pre- operazve counseling, early referral to physical therapy and idenzficazon of resources for ongoing support for those at increased risk

25 This update addresses key quesqon (KQ) 1 from the original guideline APBI has been tested in a limited number of trials with more than 1000 pts over the past 10 years. In properly selected breast cancer pazents, APBI has provided outcomes similar to WBI. In light of new literature, the suitability criteria for APBI have now been updated Which pazents may be considered for APBI outside of a clinical trial? Correa CR SABCS 2017 ES01-1

26 Which paqents may be considered for intraoperaqve parqal breast irradiaqon (PBI)? In 2 clinical trials the risk of IBTR was higher with IORT Electron beam IORT (as ELIOT) should be restricted to women with invasive cancer considered suitable for PBI on the results of a MVA with median Fup of 5.8 years Low- energy x- ray IORT (as TARGIT) for PBI should be used within the context of a prospecqve registry or clinical trial it should be restricted to women with invasive cancer considered suitable for PBI Meta- Analysis of Local Recurrence of Invasive Breast Cancer aner Electron IntraoperaZve Radiotherapy Jay K. Harness, MD1, Kalatu Davies, PhD2, ChrisQna Via, MPH2, Elizabeth Brooks, PhD2, April Zambelli- Weiner, PhD2, Chirag Shah, MD3, Frank Vicini, MD4 Results: A total of 13 independent publicazons were idenqfied for abstracqon. The analysis demonstrated a pooled monthly local recurrence rate of 0.02% per person- month (95% CI: %) for the studies with < 5 years of follow- up, 0.03% per person- month ( %) for studies with 5 years of follow- up, and 0.02% per person- month ( %) overall. Based on this model, the predicted 5- year recurrence rate is 2.7%, with a 95% confidence interval of 1.9% - 3.7%. Conclusions: According to the published literature, the rate of breast cancer local recurrence aver electron IORT was 0.02% per person- month; with an adjusted 5- year recurrence rate of 2.7%. These findings support the recent guidelines from the American Society for RadiaQon Oncology (ASTRO) supporqng the use of electron IORT in low- risk paqents. Jay K. Harness SABCS 2017 P

27 Is PMRT indicated in pazents with T1-2 tumors with one to three posizve axillary lymph nodes who undergo ALND? PMRT reduces the risks of LRF, any recurrence, and breast cancer mortality for paqents with T1-2 BC with 1-3 posiqve axillary nodes. However, some subsets are likely to have a low risk of LRF Factors associated with smaller likely benefit from PMRT PaZent characteriszcs - age > years - limited life expectancy (older age or comorbidiqes) - coexisqng condiqons that might increase the risk of complicazons Pathologic findings (lower tumor burden) T1 tumor size No lymphovascular invasion Presence of only a single posizve node and/or small size of nodal metastases substanqal response to NAST Biologic characteriszcs - - low tumor grade strong hormonal sensizvity Recht A SABCS 2017ES01-2 The decision to use PMRT should be made in a mulzdisciplinary fashion

28 SABCS 2017 P We failed to idenqfy a higher- risk pn0-1mi group that benefited from PMRT, based on the number of RR factors (f- PMRT)

29 Is PMRT indicated in pazents with T1-2 tumors and a posizve SNB who do not undergo complezon ALND? For paqents with clinical T1-2N0, SNB is now generally performed at the Qme of mastectomy, with omission of ALND if the nodes are negaqve. Some clinicians omit axillary dissecqon with one or two SN in pts treated with mastectomy extrapolaqon from randomized trials of paqents treated exclusively or predominantly with BCS +WBI or BCS + axillary RT. In these paqents (1-2 SN+) : PMRT only if there is already sufficient informaqon to jusqfy its use without needing to know that addiqonal axillary nodes are involved «Would I recommend PMRT for this pt if she had undergone simultaneous ALND and there were no addiqonal nodal metastases in the nonsenqnel nodes?» If the answer is «no», then ALND should be performed This discussion should ideally be had prior to surgery MulQdisciplinary effort

30 PotenQal of radiaqon therapy to convert a tumor into an in situ vaccine FormenZ S SABCS2017 PL01_1