Patient Selection for APBI. C. Polgár National Institute ofoncology, Budapest, Hungary

Transcription

1 Patient Selection for APBI C. Polgár National Institute ofoncology, Budapest, Hungary

2 Patient-, tumour- and treatment related factors affecting decision making in patient selection for APBI Patient age Histologic type Invasive lobulare carcinoma (ILC) Ductal carcinoma in situ (DCIS) Histologic grade Tumour size (pt) Surgical margin status Multifocality, multicentricity Extensive intraductal components (EIC) Hormone recptor status Lympho-vascular invasion (LVI) Surgical nodal staging pathologic axillary status (pn) Neoadjuvant chemotherapy

3 Why patient selection for APBI is so important? Lessons learned from the results of early APBI studies Institute Study period APBI technique Patient No. Median FUP (y) Crude LR% Annual LR% Christie Hospital* ELE Guy shospitali LDR BT 192 Ir Cookridge Hospital* EBI Guy shospitalii MDR BT 137 Cs UzsokiHospital MDR BT 60 Co University Florence LDR BT 192 Ir London Reg. Cancer Center HDR BT All pts * Phase III trial

4 Patient selection and results of early APBI studies Criteria Christie Hosp. Guy s Hosp. I. Cookridge Hosp. Guy s Hosp. II. Uzsoki Hosp. Univ. Florence London Reg. Ca. C. T-size 4 cm 5 cm 4.5 cm 4 cm 5 cm 5 cm 4.5 cm Margins 10% pos. 90% UK 56% pos. 7% UK 100% UK 43% pos. 100% UK 8% pos. 7% UK neg., 31% close EIC yes 41% yes yes yes yes 8% Nodes 100% pnx 44% N+ 41% N+ 44% N+ 4% N+ 80% pnx 38% N+ 15% N+ 5% pnx Age Any Any Any > 40 year Any Any Any LR rate 20% 37% 12% 18% 24% 6% 15% Annual LR 2.5% 6.2% 1.5% 2.9% 2% 1.4% 2.0% APBI with outdated techniques for unselected pts. Annual LR: %

5 Resultsof contemporaryapbi studies(medianfup 4 ys) Multicatheter brachytherapy series Institute Study period APBI Interstitial brachytherapy series technique Patient No. Median FUP (ys) Crude LR% Annual PROMIS LDR/HDR BT Oschner Clinic LDR/HDR BT W. Beaumont Hospital l LDR/HDR BT Örebro Medical Center PDR BT Budapest HDR BT RTOG LDR/HDR BT Tufts University HDR BT Harvard, Boston LDR BT Budapest Phase III HDR BT/ELE Ninewells Hospital LDR BT German-Austrian PDR/HDR BT University Navarra HDR BT Washington University HDR BT 202 > LR% All patients

6 Patient selection and results in contemporary APBI studies Criteria Beaumont Hospital Örebro Budapest Phase III German-Austrian Phase II T-size 3 cm 4.2 cm 2 cm 3 cm Margins 2 mm clear clear ( 2 mm; 1999-) 2 mm Unifocal EIC DCIS Nodes < 4 pos. (ECE neg.) < 4 pos. N0-N1mi (micromet.) N0-N1mi (micromet.) Age 40 y 40 y 40 y (2001-) > 35 y Actuarial LR rate 5% (12-year) 4% (7-year) 5.9% (10-year) 5% (8-year) Annual LR 0.42% 0.57% 0.59% 0.63% APBI for selected pts. Annual LR ~ 0.5%

7 Conclusions from early APBI series Majority of patients treated in early APBI studies were not acceptable candidates even for conventional breast-conserving treatment! High LR rates reflect inadequate patient selection, suboptimal QA and treatmenttechnique!

8

9 ASTRO consensus statement for APBI

10 IJROBP 2009;74:

11

12 Aim: To give recommendations on patient selection criteria for the use of APBI outside the context of prospective clinical trials based on available clinical evidence obtained from prospective APBI studies with a minimum median follow-up of 4 years. Methods & Materials: Systematic literature search using the keywords partial-breast irradiation and APBI + handsearching of relevant conference abstracts and book chapters(published by the end of July 2009) 340 articles were identified 191 original articles(excl. reviews, letters, case reports, editorials) 75 articles remained(excl. dosimetric/technical articles) 3 randomizedand 19 prospectivenon-randomizedstudieswitha FUP 4 yearswereidentified.

13 Results of APBI studies using suboptimal patient selection criteria with adequate( 4 years) follow-up APBI for unselected pts. Annual LR: %

14 Results of APBI studies using stringent patient selection criteria with 4 years FUP 14

15 Results of APBI studies using stringent patient selection criteria with 4 years FUP APBI for selected pts. Annual LR: % 15

16 Pts. can be treated outside of clinial trials Pts. can be treated in clinial trials Pts. should not be treated with APBI GEC-ESTRO recommendations on patient selection for accelarated partial breast irradiation. Characteristic Low-risk group - Intermediate-risk group - High-risk group Good candidates for APBI Possible candidates for APBI Contraindication for APBI Patient age >50 years >40-50 years 40 years Histology IDC, mucinous, tubular, IDC, ILC, mucinous, tubular, - medullary, and colloid cc. medullary, and colloid cc. ILC Not allowed Allowed - Associated LCIS Allowed Allowed - DCIS Not allowed Allowed - HG Any Any - Tumour size pt1-2 ( 30 mm) pt1-2 ( 30 mm) pt2 (>30 mm), pt3, pt4 Surgical margins Negative ( 2 mm) Negative, but close (<2 mm) Positive Multicentricity Unicentric Unicentric Multicentric Multifocality Unifocal Multifocal (limited within 2 cm Multifocal (>2 cm from the) of the index lesion) index lesion) EIC Not allowed Not allowed Present LVI Not allowed Not allowed Present ER, PR status Any Any - Nodal status pn0 (by SLNB or ALND*) pn1mi, pn1a (by ALND*) pnx; pn2a Neoadj. chemoth. Not allowed Not allowed If used Radiother Oncol 2010;94:

17

18

19 ASTRO Consensus versus GEC-ESTRO Recommendations Characteristic ASTRO suitable group GEC-ESTRO good candidate group Patient age 60 years > 50 years ER status positive any Tumour size 2 cm 3 cm

20 ABS Consensus Statement versus GEC-ESTRO Recommendations Characteristic ABS acceptable group GEC-ESTRO good candidate group Histology All invasive subtypes and DCIS ILC not allowed DCIS not allowed

21 ControversiesbetweenASTRO, ABS, and GEC-ESTRO recommendations Patient age cut-off(50 versus 60 years) ER status Tumour size cut-off(20 versus 30 mm) Histologictype Invasive lobulare carcinoma(ilc) Ductal carcinoma in situ (DCIS) Nodal status (pn0 versus pn1mic versus pn1a)

22 IJROBP 2011;80: % 5.0% 274 patients 50 GyPDR or 8x4 GyHDRBT 5-y actuarial LR rate: 2.3% 8-y actuarial LR rate: 5.0%

23 IJROBP 2011;80: Characteristic Age 50 years < 50 years Hormonal therapy No Yes 5-y LR %(n) p-value % (4/225) 7.5% (4/49) 15.1% (4/24) 1.0% (4/250) ER & PgRstatus, tumoursize, histologictype, pnstatus, HG, and HER-2 status had no significant impact on LR rate!

24 Budapest Phase III APBI study- 10-year actuarial results Median FUP: 10.2 years WBI APBI p-value LR 5.1% 5.9% 0.77 CLBC 6.4% 8.3% 0.56 RR 1.7% 2.4% 0.65 DM 11.5% 7.3% 0.61 DFS 84% 85% 0.97 OS 82% 80% 0.73 CSS 92% 94% 0.34 LTC % p WBI vs. PBI = WBI - 10-y LR: 5.1% (95% CI: %) 65 PBI - 10-y LR: 5.9% (95% CI: %) Time (months) Radiother Oncol 2013;108: Annual LR rate: APBI: 0.59% WBI: 0.51%

25 Budapest phase III trial Univariate analysis of prognostic factors for LR Menopausal status, ER & PgR status, tumour size,hg, NG and MAI had no significant impact on LR rate! Characteristic 10-y LR % (n) p-value Hazard Ratio Age > 40 years 40 years Systemic therapy* No Yes 4.8% (11/249) 22.2% (2/9) 10.1% (7/75) 3.6% (6/183) * Chemo and/or hormonal therapy

26 IJROBP 2011;100:

27 Crudelocal recurrencerateasa functionof patient age in prospective APBI studies Age (years) Budapest LR% (n) Germany/ Austria LR% (n) WBH LR% (n) Wisconsin LR% (n) RTOG LR% (n) Örebro LR% (n) All studies LR% (n) % (2 of 6) > % (1 of 39) 0% (0 of 3) 8.7% (4 of 46) 0% (0 of 1) 4.3% (1 of 23) 0% (0 of 8) 6.1% (4 of 66) 19% (4 of 21) 0% (0 of 1) 12.5 (2 of 16) 10.5% (2 of 19) 7.6% (16 of 211) > % (4 of 58) 1.2% (1 of 82) 8.7% (4 of 46) 2.2% (2 of 93) 4.2% (1 of 24) 0% (0 of 19) 3.7% (12 of 322) > % (3 of 70) 2.1% (3 of 143) 3.9% (5 of 129) 4.2% (5 of 120) 1.8% (1 of 54) 6.7 (1 of 15) 3.4% (18 of 531) All age 5.8% (10 of 173) 2.9% (8 of 274) 5.0% (10 of 199) 3.8% (11 of 286) 6.1% (6 of 99) 5.9% (3 of 51) 4.4% (48 of 1083) FUP 7.3 y 5.3 y 9.6 y 5 y 7 y 7.2 y - Results for patients 40 years and >40-50 years were reported together

28 Tumour size In most series tumour size did not affect local control significantly following BCS + RT. Holland data*: microscopic spread beyond primary tumour is similar in T1 and T2 tumours. However, at large volume (>160 cm 3 ) implants the larger implant volume (V100) and high-dose regions (V150 and V200) were correlated with a higher incidence of fat necrosis. Therefore, large tumours (>3 cm) might not be candidates for BT alone, because of high risk of late tissue toxicity caused by large volume implants. * Holland R et al.: Cancer 1985;56:

29 Invasive lobular carcinoma (ILC) The incidenceof EF is similarincaseof ILC and IDC!

30 German-Austrian Phase II trial Univariate analysis of prognostic factors for LR* Characteristic 5-y LR % p-value Histologic type ILC (n = 45) Allothers(n = 229) 2.4% 2.6% NS However, to date only few women having ILC have been treated with APBI in prospective studies. Therefore, at this time there is only limited evidence for the treatment of ILC outside the context of clinical trials. * Ott OJ et al. Int J Radiat Oncol Biol Phys 2010

31 N = 1131 Median FUP: 6.9 years

32 ER status, tumour size, histology, and nodal status had no significant impact on LR rate!

33 Cancer 2011;117: Inclusion criteria: -LIG group:low-intermed. gradedcis 2.5 cm; margins 3 mm -HG group:high-gradedcis 1 cm; margins 3 mm However, todateonlyfewwomenhavingdcis havebeentreatedwithapbi in prospective studies. Therefore, at this time there is only limited evidence for the treatmentof DCIS outsidethecontextof clinicaltrials.

34 However, todateonlyfewnode+ women have been treated with APBI in prospective studies. Therefore, at this time there is only limited evidenceforthetreatmentof node+ pts. outsidethecontextof clinicaltrials. IJROBP 2011

35 The significance of extensive intraductal component (EIC) Holland R et al.: J Clin Oncol 1990;8: Pts. with EIC are more likely to have residual tumour beyond 2 cm distance from the reference tumour than without EIC (33% vs. 2%)

36 Local recurrenceaccordingtoeic afterbcs

37 Local recurrence by Histological Grade - Van Limbergen: -5-y LR: -Grade I: 5% -Grade II: 10% - Grade III: 16% (p=0.12) -Polgár: -HG did not have significant effect on LR rate, BUT -Time to LR: - Grade I-II: 38 months (range: 28-50) - Grade III: 20 months (range: 10-34) Difficult to compare the results, because of the variety of grading systems and the difficulty in grading breast carcinomas.

38 Local recurrence by surgical margin status Author Margin + Margin FUP (y) LR% LR% Mansfield Smitt Spivack Anscher DiBiase Polgár Range ASTRO guidelines on margins: Negative margins = No tumour on ink!

39 Pts. can be treated outside of clinial trials Pts. can be treated in clinial trials Pts. should not be treated with APBI GEC-ESTRO recommendations on patient selection for accelarated partial breast irradiation. Characteristic Low-risk group - Intermediate-risk group - High-risk group Good candidates for APBI Possible candidates for APBI Contraindication for APBI Patient age >50 years >40-50 years 40 years Histology IDC, mucinous, tubular, IDC, ILC, mucinous, tubular, - medullary, and colloid cc. medullary, and colloid cc. ILC Not allowed Allowed - Associated LCIS Allowed Allowed - DCIS Not allowed Allowed - HG Any Any - Tumour size pt1-2 ( 30 mm) pt1-2 ( 30 mm) pt2 (>30 mm), pt3, pt4 Surgical margins Negative ( 2 mm) Negative, but close (<2 mm) Positive Multicentricity Unicentric Unicentric Multicentric Multifocality Unifocal Multifocal (limited within 2 cm Multifocal (>2 cm from the) of the index lesion) index lesion) EIC Not allowed Not allowed Present LVI Not allowed Not allowed Present ER, PR status Any Any - Nodal status pn0 (by SLNB or ALND*) pn1mi, pn1a (by ALND*) pnx; pn2a Neoadj. chemoth. Not allowed Not allowed If used Radiother Oncol 2010;94:

40 Budapest Phase III APBI trial Patient characteristics according to the ASTRO and GEC-ESTRO prognostic groups GEC-ESTRO prognostic group All pts. (n=258) ASTRO prognostic group All pts. (n=258) Good candidate: 181 (70%) Suitable: 98 (38%) Possible candidate: -Age y: -pn1mi: - Close margin: 56 (22%) 52 (20%) 9 (3.5%) 1 (0.5%) Cautionary: -Age y: -ER neg: -LVI: -Close margin: 96 (37%) 91 (35%) 26 (10%) 9 (3.5%) 1 (0.5%) Contraindication: -Age 40 y: -LVI: -pnx: 21 (8%) 9 (3.5%) 9 (3.5%) 5 (2%) Unsuitable: -Age < 50 y -pn1mi: -pnx: 64 (25%) 53 (20%) 9 (3.5%) 5 (2%)

41 Local control by GEC-ESTRO prognostic groups Local control by ASTRO prognostic groups LTC % p good vs. possible candidate = p good candidate vs.contraindicated = p possible candidate vs.contraindicated = LTC % p suitable vs. cautionary = p suitable vs. unsuitable = p cautionary vs. unsuitable = GEC-ESTRO-Good candidate - 10-year LR: 4.5% (9 of 181) GEC-ESTRO-Possible candidate - 10-year LR: 1.8% (1/56) GEC-ESTRO-Contraindicated - 10-year LR: 15.8% (3/21) ASTRO-Suitable - 10-year LR: 4.5% (4/98) ASTRO-Cautionary - 10-year LR: 5.6% (5/96) ASTRO-Unsuitable - 10-year LR: 6.7% (4/64) Time (months) Time (months)

42 APBI Direction of future clinical research Refinement of patient selection: years? Lobular cc.? DCIS? Close, but negative margins? 1-3 pos. lymph nodes? Selection of proper APBI technique: Brachytherapy? Multicatheter BT, MammoSite, Hybrid BT applicators Teletherapy? 3D-CRT, IMRT, IGRT Proton therapy? Standardisation of PTV definition: Selection of appropriate CTV to GTV (cavity) margin? Selection of appropriate PTV to CTV margin? How to avoid interobserver variability?

43 Study Participants APBI technique Accrual goal Study period Budapest NI0, Budapest HDR BT TARGIT Accelerated partial breast irradiation 8 randomized studies London/Australia multicentric IORT -50 kv photons ELIOT Milan IORT electrons GEC-ESTRO European multicentric HDR/PDR BT RAPID Canadian multicentric 3D-CRT NSABP-B39/ RTOG-0413 USA multicentric HDR BT/3D-CRT/ MammoSite Italy Univ. Florence IMRT IMPORT-LOW MRC, UK multicentric IMRT ~ pts.

44 Patient selection Phase III trials Criterion Budapest GEC- ESTRO NSABP- RTOG ELIOT IMPORT- LOW RAPID TARGIT Age (years) > 40 from 2001 > > > 18 T-size(cm) < 3 Any (excl. T4) Unifocality Yes Yes Same quadrant Yes Yes Same quadrant Yes EIC Lobular ca DCIS LVI Grade 1-2 Any Any Any 1-2 Any Any Margin status 2 mm 2 mm Clear Clear 2 mm Clear Clear Nodal status pn0-1mi pn0-1mi pn0-1a (no ECE) pn0-1a pn0 pn0 pn0-1

45 Conclusions APBI for a selected group of early-stage breast cancer patients produces long-term results similar to those achieved with conventional WBI. Until mature Phase III data: conservative patient selection criteria according to the GEC-ESTRO recommendations should be considered for selecting candidates for APBI. Long-term results of ongoing Phase III trials guidelines for patient selection should be revised and might be extended.

46 Individual risk-adapted RT after BCS Very low-risk Low-risk Intermediaterisk High-risk RT No RT or APBI or WBI or WBI + boost APBI AWBI orwbi AWBI Characteristics 70 y, T1N0, > 50 y, T2 (> 3 cm), 50 y, ER+, T1-2 ( 3 cm) N0, margins 2mm, margins< 2mm, margins 2mm, margins 2 mm, LVI+, N+, EIC + EIC-, LVI- EIC-, LVI-, multifocal unifocal tumour tumour Frequency Max. 5% 25-30% 30-35% 30-35%

47 Investigational treatment Thank you for your kind attention! Pilot study Phase I-II Phase III Standard treatment option The present The past The future

48 Thank you for your kind attention!