breast cancer - สมาคมรังสีรักษาและ ... · 2018-02-07 · breast...

Breast CancerREFRESHER COURSE

20 JAN 2018

KITWADEE S. ATHIGAKUNAGORNKING CHULALONGKORN MEMORIAL HOSPITAL

Saturday, January 20, 18

Staging

AJCC Cancer StagingManualEighth Edition

FOR PERSONAL U

SE ONLY


staged according to AJCC Breaststaged according to AJCC Breaststaged according the

classification of

Yes

invasive (infiltrating) carcinoma of the breast,

ductal carcinoma in situ of the breast

No Breast sarcomasSoft tissue sarcoma of the

trunk and extremities

No Phyllodes tumorSoft tissue sarcoma –

unusual histologies and sites

No lymphomas Hematologic malignancy


AJCC 8th

• Anatomic stage

• Clinical prognostic stage

• Pathological prognostic stage


48. Breast

AJCC Cancer Staging Manual, Eighth Edition © The American College of Surgeons (ACS), Chicago, Illinois. Content is available for user’s personal use.It cannot be sold, distributed, published, or incorporated into any software, product, or publication without a written license agreement with ACS. The content cannot be modified, changed, or updated without the express written permission of ACS. All Rights Reserved. Last updated 11-Dec-17 Page 78 of 96

When TNM is… And Grade is…

And HER2 Status is…

And ER Status is…

And PR Status is…

Then the Clinical

Prognostic Stage Group

is…

T0 N2 M0 T1* N2 M0 T2 N2 M0

T3 N1*** M0 T3 N2 M0

G1

Positive Positive

Positive IIA Negative IIIA

Negative Positive IIIA Negative IIIA

Negative Positive


Negative Positive IIIA Negative IIIB

G2

Positive Positive



Negative Positive


Negative Positive IIIA Negative IIIB

G3

Positive Positive

Positive IIB Negative IIIA


Negative Positive

Positive IIIA Negative IIIB

Negative Positive IIIB Negative IIIC

FOR PERSONAL U

SE ONLY

Clinical prognostic stage


updated T stage

• LCIS is removed as a pTis , is treated as a benign entity and is removed from TNM staging.

• T= maximum invasive tumor size

• Small microscopic satellite foci of tumor around : not added to the maximum tumor size

• the size of multiple tumors is not added


48. Breast


FIGURE 48.5. T4 is defined as a tumor of any size with direct extension to chest wall and/or to the skin (ulceration or skin nodules). (a) T4a is extension to the chest wall. Adherence/invasion to the pectoralis muscle is NOT extension to the chest wall and is not categorized as T4. (b) T4b, illustrated here as satellite skin nodules, is defined as edema (including peau d’orange) of the skin, or ulceration of the skin of the breast, or satellite skin nodules confined to the same breast. These do not meet the criteria for inflammatory carcinoma. (c) T4b illustrated here as edema (including peau d’orange) of the skin. (d) T4c is defined as both T4a and T4b. T4d (not illustrated) is inflammatory cancer (see text for definition).

Regional Lymph Nodes – Clinical (cN) The definitions for clinical and pathological node categorization are different. See Figure 48.6 for illustrations of the clinical categories for regional lymph nodes. Clinical categorization includes nodes detected by imaging studies (excluding lymphoscintigraphy) or by clinical examination and having characteristics highly suspicious for malignancy or a presumed histologic macrometastasis based on FNA biopsy, core needle biopsy, or sentinel node biopsy. Confirmation of clinically detected metastatic disease by fine needle aspiration or core needle biopsy is designated with an (f) suffix, for example, cN3a(f). Histologic confirmation in the absence of assignment of a pT (through surgical resection) is classified as cN, including excision of a node; for example, an axillary sentinel node biopsy with a macrometastasis is classified cN1a(sn) when primary tumor classification is clinical (cT). The method of confirmation of the nodal status should be designated as either clinical (cN), FNA/core biopsy (cN(f)), or sentinel node biopsy (cN(sn)). Imaging studies are not necessary to categorize the regional nodes as negative. The designation cN0, not cNX, should be used for an axilla that is negative solely by physical examination. Even when regional lymph nodes have been previously removed, if no disease is identified in the nodal basin by imaging or clinical examination, it should be categorized as cN0. For patients who are clinically node-positive, cN1 designates metastases to one or more movable ipsilateral Level I, II axillary lymph nodes. cN2a designates metastases to Level I, II axillary lymph nodes FOR P

ERSONAL USE O

NLY


48. Breast


T Category T Criteria T1c Tumor > 10 ŵŵ�ďƵƚ�ч 20 mm in greatest dimension T2 Tumor > ϮϬ�ŵŵ�ďƵƚ�ч 50 mm in greatest dimension T3 Tumor > 50 mm in greatest dimension T4 Tumor of any size with direct extension to the chest wall and/or to the skin

(ulceration or macroscopic nodules); invasion of the dermis alone does not qualify as T4

T4a Extension to the chest wall; invasion or adherence to pectoralis muscle in the absence of invasion of chest wall structures does not qualify as T4

T4b Ulceration and/or ipsilateral macroscopic satellite nodules and/or edema (including peau d’orange) of the skin that does not meet the criteria for inflammatory carcinoma

T4c Both T4a and T4b are present T4d Inflammatory carcinoma (see “Rules for Classification”) * Note: Lobular carcinoma in situ (LCIS) is a benign entity and is removed from TNM staging in the AJCC Cancer Staging Manual, 8th Edition.

Definition of Regional Lymph Nodes – Clinical (cN) cN Category cN Criteria cNX* Regional lymph nodes cannot be assessed (e.g., previously removed) cN0 No regional lymph node metastases (by imaging or clinical examination) cN1 Metastases to movable ipsilateral Level I, II axillary lymph node(s) cN1mi** Micrometastases (approximately 200 cells, larger than 0.2 mm, but none larger

than 2.0 mm) cN2 Metastases in ipsilateral Level I, II axillary lymph nodes that are clinically fixed or

matted; or in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases

cN2a Metastases in ipsilateral Level I, II axillary lymph nodes fixed to one another (matted) or to other structures

cN2b Metastases only in ipsilateral internal mammary nodes in the absence of axillary lymph node metastases

cN3 Metastases in ipsilateral infraclavicular (Level III axillary) lymph node(s) with or without Level I, II axillary lymph node involvement; or in ipsilateral internal mammary lymph node(s) with Level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without FOR PERSONAL U

SE ONLY

includes ribs, intercostal muscles, and serratus anterior muscle, but not the pectoral muscles


N

• Regional LNs

• ipsilateral axillary (I,II and interpectoral ( Rotter’s ), III)

• ipsilateral internal mammary

• ipsilateral supraclavicular ( lower cervical = M1)

• intramammary (considered axillary LNs)


resected margin DCIS invasive

SSO/ASTRO 2 mm BCS : no ink on tumor

ESMO 2015 no inkpreferred 2 mm

BCS : no ink on tumor

St.Gallen 2017 preferred 2 mm

BCS : no ink on tumor

St.Gallen 2017 preferred 2 mmafter neoAdj systemic

2 mm in multifocal residual disease/scattered remission

MRM : no ink on tumor or 1 mm.


Hypofractionation : concern

grade 3

age < 50

Hypofr actionated R adiation Ther apy for Breast Cancer

n engl j med 362;6 nejm.org february 11, 2010 517

tionated-radiation group (absolute difference, !10.9 percentage points, 95% CI, !19.1 to !2.8; test for interaction, P = 0.01).

MortalityThere were 248 deaths (126 in the control group and 122 in the hypofractionated-radiation group). The probability of survival over time was similar in the two groups (P = 0.79) (Fig. 1B). At 10 years, the probability of survival was 84.4% in the con-trol group as compared with 84.6% in the hypof-ractionated-radiation group (absolute difference, !0.2 percentage points; 95% CI, !4.3 to 4.0). In the control group of 612 patients, 82 deaths were related to cancer (13.4%), 9 were related to cardiac disease (1.5%), and 35 were due to other causes (5.7%). In the hypofractionated-radiation group of 622 patients, 82 deaths were related to cancer (13.2%), 12 were related to cardiac disease (1.9%), and 28 were due to other causes (4.5%). No significant differences were detected be-tween the groups (P = 0.56).

Toxic Effects of Radiation and Cosmetic Outcome

Table 1 shows the percentage of patients with toxic effects of irradiation of the skin and subcu-taneous tissue 5 and 10 years after randomiza-tion. Neither grade 4 skin ulceration nor soft-

tissue necrosis was observed. Although the incidence of late toxic effects of radiation did increase over the follow-up period, at 10 years, the proportion of women with grade 3 radiation-associated morbidity was 4% or less. At 10 years, there were no skin toxic effects in 70.5% of wom-en in the control group as compared with 66.8% of women in the hypofractionated-radiation group (absolute difference, 3.7 percentage points; 95% CI, !4.9 to 12.1). There were no toxic effects in subcutaneous tissue in 45.3% of women in the control group as compared with 48.1% of women in the hypofractionated-radiation group (abso-lute difference, !2.8 percentage points; 95% CI, !11.7 to 6.5).

Table 2 shows the cosmetic outcome at base-line, 5 years, and 10 years. Although the global cosmetic outcome worsened over time, no signifi-cant differences were observed between the groups at any time. At 10 years, 71.3% of women in the control group as compared with 69.8% of women in the hypofractionated-radiation group, had an excellent or good cosmetic outcome (absolute dif-ference, 1.5 percentage points; 95% CI, !6.9 to 9.8). The repeated-measures logistic-regression analysis suggested that the cosmetic outcome was affected by the time from randomization as well as by the patient’s age and tumor size, but there was no interaction with treatment (Table 3).

6 col33p9

1.00 2.00 5.00 10.00

Age!50 yr<50 yr

Tumor size!2 cm<2 cm

Estrogen-receptor statusPositiveNegativeEquivocal

Tumor gradeLowModerateHigh

Systemic therapyNoYes

1.02 (0.62–1.70)

0.86 (0.48–1.55)1.06 (0.58–1.97)

3.08 (1.22–7.76)0.57 (0.29–1.12)0.70 (0.31–1.58)

1.30 (0.22–7.81)1.32 (0.62–2.82)0.71 (0.41–1.23)

0.95 (0.55–1.64)0.99 (0.49–1.98)

0.25

0.77 (0.35–1.70)

0.67

0.90

0.36

0.01

0.65

AUTHOR:

FIGURE:

RETAKE:

4-C H/TLine Combo

Revised

1st2nd3rd

Whelan

2 of 2

ARTIST:

TYPE:

MRL

2-11-10JOB: 361xx ISSUE:

Figure 2. Hazard Ratios for Ipsilateral Recurrence of Breast Cancer in Subgroups of Patients.

The New England Journal of Medicine Downloaded from nejm.org on August 20, 2016. For personal use only. No other uses without permission.

Copyright © 2010 Massachusetts Medical Society. All rights reserved.


Articles

1092 www.thelancet.com/oncology Vol 14 October 2013

treatment groups enabled an unconfounded test of sensitivity to fraction size. The CIs around the α/β estimate for breast cancer become narrower as more data are collected, and the low value is supported by the evidence from the combined hypofractionation trials.14 The average estimate describes an underlying distribution of α/β that can be narrow or broad: its characterisation is a challenge for correlative research. The 10-year results of START-B confi rm that 40 Gy in 15 fractions over 3 weeks is at least as safe and eff ective as 50 Gy in 25 fractions over 5 weeks. Some normal tissue eff ects were less common after the 15 fraction regimen than the control schedule (breast shrinkage, telangiectasia, and breast oedema). Application of an α/β value of 3·5 Gy for breast shrinkage—as obtained from START-A—and assuming no eff ect of treatment time on late normal tissue eff ects, 40 Gy in 15 fractions corresponds to 45 Gy in 2 Gy equivalents. The 15 fraction regimen is less harmful to normal tissues, and there is no suggestion that it is less eff ective in treating the cancer.

The data from the START trials are consistent with the 10-year results of the Ontario trial, which reported that local tumour control and breast cosmesis were no worse with a regimen of 42·5 Gy in 16 fractions over 3·2 weeks compared with 50 Gy in 25 fractions over 5 weeks.5 The START pilot trial, Ontario trial, and START-A and START-B trials, considered together, present robust evidence that hypofractionation is a safe and eff ective approach to breast cancer radiotherapy (panel).15 The corollary is that the continued use of small (2 Gy) fractions spares the cancer as much as the normal tissues, thereby bringing no benefi t to patients. The unexpected survival benefi t with the 40 Gy schedule at 5 years in START-B still exists at 10 years. The proportion of patients who had distant metastases diff ered after the fi rst few years of follow-up, which translated into an overall survival benefi t (table 4). This eff ect did not occur in START-A and it occurs too early to be a result of better local control, in which case the survival benefi t would not be apparent until after 15 years. Similarly, it is unlikely to be caused by baseline diff erences in patient and treatment characteristics, which were well balanced between schedules, and unknown factors are unlikely to be imbalanced in randomised trials of this size. Following publication of the START trials’ 5-year results, most UK centres pragmatically adopted the 15 fraction schedule as standard of care, as recommended by NICE guidelines in 2009.11 The 15 fraction schedule was already in widespread use in the UK and elsewhere before the START trials, but had not been formally tested in a randomised controlled setting.

Controversy remains about generalising trial fi ndings to all patients satisfying the eligibility criteria of the START trials.12 To address this concern, we did unplanned subgroup meta-analyses of the START-A and START-B trials and the START pilot trial comparing all

Moderate or marked events (n/patients; %)

Estimated proportion of patients with event by 5 years (%; 95% CI)


Crude hazard ratio (95% CI)

p value*

Breast shrinkage†

50 Gy 256/1003 (25·5%) 15·8% (13·6–18·3) 31·2% (27·9–34·9) 1·00 ··

40 Gy 221/1006 (22·0%) 11·4% (9·5–13·6) 26·2% (23·1–29·6) 0·80 (0·67–0·96) 0·015

Breast induration (tumour bed)†

50 Gy 153/1003 (15·3%) 12·1% (10·2–14·4) 17·4% (14·9–20·3) 1·00 ··

40 Gy 129/1006 (12·8%) 9·6% (7·9–11·6) 14·3% (12·1–16·9) 0·81 (0·64–1·03) 0·084

Telangiectasia

50 Gy 52/1081 (4·8%) 3·8% (2·8–5·2) 5·8% (4·4–7·7) 1·00 ··

40 Gy 34/1094 (3·1%) 1·8% (1·1–2·8) 4·2% (2·9–5·9) 0·62 (0·40–0·96) 0·032

Breast oedema†

50 Gy 86/1003 (8·6%) 8·1% (6·6–10·1) 9·0% (7·3–11·0) 1·00 ··

40 Gy 49/1006 (4·9%) 4·7% (3·5–6·2) 5·1% (3·9–6·7) 0·55 (0·39–0·79) 0·001

Shoulder sti! ness‡

50 Gy 4/73 (5·5%) 2·9% (0·7–11·0) 8·2% (2·9–21·8) 1·00 ··

40 Gy 3/81 (3·7%) 3·1% (0·8–11·9) 3·1% (0·8–11·9) 0·76 (0·17–3·39) 0·71

Arm oedema‡

50 Gy 7/73 (9·6%) 6·0% (2·3–15·3) 13·5% (6·4–27·0) 1·00 ··

40 Gy 3/81 (3·7%) 2·8% (0·7–10·7) 4·7% (1·5–14·0) 0·42 (0·11–1·63) 0·21

Other

50 Gy 77/1082 (7·1%) 5·6% (4·3–7·2) 8·1% (6·5–10·2) 1·00 ··

40 Gy 53/1095 (4·8%) 3·3% (2·4–4·6) 6·4% (4·8–8·4) 0·65 (0·46–0·93) 0·018

*Assessed by Wald test compared with 50 Gy. †Only assessed in women who had breast-conserving surgery. ‡Restricted to women who received lymphatic radiotherapy (to axilla or supraclavicular fossa).

Table !: Physician-assessed normal tissue e! ects by fractionation schedule in START-B

Figure ": Meta-analysis of local-regional relapse comparing hypofractionated regimens versus 50 Gy in 25 fractionsIncludes 5861 patients from the START pilot trial, START-A, and START-B.

Age (years)<4040–4950–59!60Primary surgeryBreast conservation surgeryMastectomyAxillary nodes (pN)NegativePositiveTumour grade123Tumour bed boost radiotherapyNoYesAdjuvant chemotherapyNoYes

Number of events/patients

60/343 116/1046 154/2226 114/2246

409/5348 35/513

289/4318 149/1421

41/1213 108/2398 114/1272

199/2749 241/3071

303/4346 139/1480

Hazard ratio(95% CI)

0·79 (0·47–1·34)0·88 (0·60–1·28)1·03 (0·74–1·44)1·11 (0·75–1·63)

0·97 (0·80–1·19)0·91 (0·46–1·81)

1·10 (0·86–1·40)0·80 (0·57–1·11)

0·96 (0·51–1·82)1·07 (0·72–1·59)0·86 (0·59–1·25)

0·99 (0·74–1·32)0·99 (0·76–1·29)

1·09 (0·86–1·38)0·81 (0·57–1·14)

Favours fraction sizes >2·0 Gy Favours fraction size 2·0 Gy

0·4 0·6 0·8 1·0 1·2 1·4 1·6 1·8 2·0

Articles

1092 www.thelancet.com/oncology Vol 14 October 2013

treatment groups enabled an unconfounded test of sensitivity to fraction size. The CIs around the α/β estimate for breast cancer become narrower as more data are collected, and the low value is supported by the evidence from the combined hypofractionation trials.14 The average estimate describes an underlying distribution of α/β that can be narrow or broad: its characterisation is a challenge for correlative research. The 10-year results of START-B confi rm that 40 Gy in 15 fractions over 3 weeks is at least as safe and eff ective as 50 Gy in 25 fractions over 5 weeks. Some normal tissue eff ects were less common after the 15 fraction regimen than the control schedule (breast shrinkage, telangiectasia, and breast oedema). Application of an α/β value of 3·5 Gy for breast shrinkage—as obtained from START-A—and assuming no eff ect of treatment time on late normal tissue eff ects, 40 Gy in 15 fractions corresponds to 45 Gy in 2 Gy equivalents. The 15 fraction regimen is less harmful to normal tissues, and there is no suggestion that it is less eff ective in treating the cancer.

The data from the START trials are consistent with the 10-year results of the Ontario trial, which reported that local tumour control and breast cosmesis were no worse with a regimen of 42·5 Gy in 16 fractions over 3·2 weeks compared with 50 Gy in 25 fractions over 5 weeks.5 The START pilot trial, Ontario trial, and START-A and START-B trials, considered together, present robust evidence that hypofractionation is a safe and eff ective approach to breast cancer radiotherapy (panel).15 The corollary is that the continued use of small (2 Gy) fractions spares the cancer as much as the normal tissues, thereby bringing no benefi t to patients. The unexpected survival benefi t with the 40 Gy schedule at 5 years in START-B still exists at 10 years. The proportion of patients who had distant metastases diff ered after the fi rst few years of follow-up, which translated into an overall survival benefi t (table 4). This eff ect did not occur in START-A and it occurs too early to be a result of better local control, in which case the survival benefi t would not be apparent until after 15 years. Similarly, it is unlikely to be caused by baseline diff erences in patient and treatment characteristics, which were well balanced between schedules, and unknown factors are unlikely to be imbalanced in randomised trials of this size. Following publication of the START trials’ 5-year results, most UK centres pragmatically adopted the 15 fraction schedule as standard of care, as recommended by NICE guidelines in 2009.11 The 15 fraction schedule was already in widespread use in the UK and elsewhere before the START trials, but had not been formally tested in a randomised controlled setting.

Controversy remains about generalising trial fi ndings to all patients satisfying the eligibility criteria of the START trials.12 To address this concern, we did unplanned subgroup meta-analyses of the START-A and START-B trials and the START pilot trial comparing all

Moderate or marked events (n/patients; %)



Crude hazard ratio (95% CI)

p value*

Breast shrinkage†

50 Gy 256/1003 (25·5%) 15·8% (13·6–18·3) 31·2% (27·9–34·9) 1·00 ··

40 Gy 221/1006 (22·0%) 11·4% (9·5–13·6) 26·2% (23·1–29·6) 0·80 (0·67–0·96) 0·015

Breast induration (tumour bed)†

50 Gy 153/1003 (15·3%) 12·1% (10·2–14·4) 17·4% (14·9–20·3) 1·00 ··

40 Gy 129/1006 (12·8%) 9·6% (7·9–11·6) 14·3% (12·1–16·9) 0·81 (0·64–1·03) 0·084

Telangiectasia

50 Gy 52/1081 (4·8%) 3·8% (2·8–5·2) 5·8% (4·4–7·7) 1·00 ··

40 Gy 34/1094 (3·1%) 1·8% (1·1–2·8) 4·2% (2·9–5·9) 0·62 (0·40–0·96) 0·032

Breast oedema†

50 Gy 86/1003 (8·6%) 8·1% (6·6–10·1) 9·0% (7·3–11·0) 1·00 ··

40 Gy 49/1006 (4·9%) 4·7% (3·5–6·2) 5·1% (3·9–6·7) 0·55 (0·39–0·79) 0·001

Shoulder sti! ness‡

50 Gy 4/73 (5·5%) 2·9% (0·7–11·0) 8·2% (2·9–21·8) 1·00 ··

40 Gy 3/81 (3·7%) 3·1% (0·8–11·9) 3·1% (0·8–11·9) 0·76 (0·17–3·39) 0·71

Arm oedema‡

50 Gy 7/73 (9·6%) 6·0% (2·3–15·3) 13·5% (6·4–27·0) 1·00 ··

40 Gy 3/81 (3·7%) 2·8% (0·7–10·7) 4·7% (1·5–14·0) 0·42 (0·11–1·63) 0·21

Other

50 Gy 77/1082 (7·1%) 5·6% (4·3–7·2) 8·1% (6·5–10·2) 1·00 ··

40 Gy 53/1095 (4·8%) 3·3% (2·4–4·6) 6·4% (4·8–8·4) 0·65 (0·46–0·93) 0·018

*Assessed by Wald test compared with 50 Gy. †Only assessed in women who had breast-conserving surgery. ‡Restricted to women who received lymphatic radiotherapy (to axilla or supraclavicular fossa).

Table !: Physician-assessed normal tissue e! ects by fractionation schedule in START-B

Figure ": Meta-analysis of local-regional relapse comparing hypofractionated regimens versus 50 Gy in 25 fractionsIncludes 5861 patients from the START pilot trial, START-A, and START-B.

Age (years)<4040–4950–59!60Primary surgeryBreast conservation surgeryMastectomyAxillary nodes (pN)NegativePositiveTumour grade123Tumour bed boost radiotherapyNoYesAdjuvant chemotherapyNoYes

Number of events/patients

60/343 116/1046 154/2226 114/2246

409/5348 35/513

289/4318 149/1421

41/1213 108/2398 114/1272

199/2749 241/3071

303/4346 139/1480


0·79 (0·47–1·34)0·88 (0·60–1·28)1·03 (0·74–1·44)1·11 (0·75–1·63)

0·97 (0·80–1·19)0·91 (0·46–1·81)

1·10 (0·86–1·40)0·80 (0·57–1·11)

0·96 (0·51–1·82)1·07 (0·72–1·59)0·86 (0·59–1·25)

0·99 (0·74–1·32)0·99 (0·76–1·29)

1·09 (0·86–1·38)0·81 (0·57–1·14)

Favours fraction sizes >2·0 Gy Favours fraction size 2·0 Gy

0·4 0·6 0·8 1·0 1·2 1·4 1·6 1·8 2·0

the treatment effect was not significantly different irrespective of age/tumor grade

Lancet Oncol 2013; 14: 1086–94

START trial : 10 yr F/U


PMRTretrospective studies , small

prospective studies

low IBRT, low toxicity

DCIS retrospective studies

low IBRT, low toxicity

Hypofractionation : concern


HypoFx in PMRT

Trial NF/U (yrs) fractionation IBTR(%)

R British Columbia 318 20 37.5Gy/16Fx 18% ~Danish

R Pinitpatcharalert A, 215 3.2 50Gy/25Fx42.4Gy/16Fx

5-yr 87%86% (NS)

R Eldeeb H, 300 250Gy/25Fx45Gy/17Fx40Gy/15Fx

NS

R Ko DH, 133 5 40Gy/16Fx5 yr LRFS

97.6%

P2 Atif JK, 69 3 36.63/11Fx5 yr LRFS

89.2%IBRT 3%

Ko DH, J Med Imaging Radiat Oncol. 2015 Eldeeb H, Med Oncol. 2012 Pinitpatcharalert A, J Med Assoc Thai. 2011 Atif, J Clin Oncol. 2017


Trial N F/U (yrs) fractionation IBTR(%)

Ciervide 145 5 42/15 40.5/15 + SIB 7.5/15

4.1%( no invasive)

Hathout 440 4.4 42.7/16 + SeQ 10/4 3%(30% invasive)

Williamson 266 3.7650/25

42.4/1640/16 + 12.5 boost

6%7%

Lalani 1609 9.2 50/2542.4/16

LFS 86%89%

Radiother Oncol. 2010 Jun;95(3):317-20. doi: 10.1016/j.radonc.2010.03.021. Epub 2010 Apr 17.Int J Radiation Oncol Biol Phys, Vol. 90, No. 5, pp. 1017-1024, 2014

HypoFx in DCISretrospective studies


Hypofractionation

Haviland, Radiotherapy and Oncology 2017

concern : regional LNs radiation (14.7% of START trials)

arm/shoulder

pain

swelling in arm/hand

difficult in raising

arm

shoulder stiffness

patient assess

STARTASTARTB

no statistically significantno statistically significantno statistically significantno statistically significant

physicianassess

STARTASTARTB

no statistically significantno statistically significantno statistically significantno statistically significant

START-A 50 Gy41.6 Gy 39 Gy

START-B 50 Gy40 Gy

* interpreted as none/mild versus moderate/marked effects


hypofractionated schedules and the 50 Gy control groups for eitherSTART-A or START-B.

For physician-assessed moderate/marked arm oedema or shoul-der stiffness, cumulative incidence rates up to 5 and 10 years weregenerally similar between the test and control schedules in theSTART-pilot, START-A and START-B trials, with few events reportedin most categories (Table 3). There was a statistically significantincreased rate of physician-assessed shoulder stiffness in the42.9 Gy schedule compared with 50 Gy in START-pilot (HR 3.07,95%CI 1.62–5.83, p = 0.001) but no such effect for the hypofraction-ated schedules in START-A and START-B. There were no statisticallysignificant differences in physician-assessed moderate/markedarm oedema between the schedules for any of the trials. Therewas generally little increase in effects over time, with 5- and 10-year cumulative incidence rates for physician-assessed armoedema and shoulder stiffness broadly similar.

Using the patients in the START trials who only received breast/chest wall RT as a comparison group, there was no evidence of astatistical difference in hazard ratios for the hypofractionatedschedules compared with 50 Gy according to whether or not lym-

phatic RT was given (results for arm oedema and shoulder stiffnessare shown in Figs. 1 and 2 for patient and physician assessmentsrespectively).

Cross-sectional analyses

At 5 years following radiotherapy, the point prevalences ofmoderate/marked effects in the arm or shoulder reported bypatients and physicians were low overall, with very few eventsand no statistically significant differences between the hypofrac-tionated and control schedules for any of the trials (Tables 2 and3). This remained so for the physician assessments at 10 years(Table 3). The 5- and 10-year point prevalences were much lowerthan the estimates of cumulative incidence up to 5 and 10 yearsfor all of the effects.

Discussion

Our investigation of late normal tissue effects in the arm andshoulder for women treated with locoregional RT within the START

Table 2Patient-assessed moderate/marked normal tissue effects in the arm or shoulder following lymphatic radiotherapy in START-A andSTART-B.

Schedule Total moderate/

marked events

(n/total, %)

Estimated cumulative

incidence by 5years, % (95%CI)

Hazard ratio(95% CI)1

P-value2

Prevalenceof

moderate/marked

events at 5years,

n/total (%)

P-value3

Arm/shoulder painSTART-A

50 Gy41.6 Gy

39 Gy

30/95 (31.6)24/78 (30.8)23/77 (29.9)

32.3 (23.3-43.7)31.4 (22.1-43.6)30.8 (21.4-43.0)

11.03 (0.60-1.77)0.96 (0.56-1.66)

0.920.89

12/65 (18.5)5/58 (8.6)

7/58 (12.1)0.130.45

START-B50 Gy40 Gy

13/46 (28.3)15/52 (28.9)

29.7 (18.0-46.6)23.6 (14.1-37.9)

10.94 (0.44-2.00) 0.87

2/28 (7.1)4/35 (11.4) 0.68

Swelling in arm or handSTART-A

50 Gy41.6 Gy

39 Gy

15/95 (15.8)13/78 (16.7)13/77 (16.9)

14.2 (8.3-23.8)18.2 (11.0-29.3)16.1 (9.2-27.3)

11.01 (0.46-2.18)1.15 (0.54-2.47)

0.990.72

6/65 (9.2)1/58 (1.7)

6/58 (10.3)0.12>0.99

START-B50 Gy40 Gy

5/46 (10.9)3/51 (5.9)

9.5 (3.7-23.3)6.0 (2.0-17.4)

10.55 (0.13-2.36) 0.42

1/28 (3.6)0/36 (0) 0.44

Difficulty in raising armSTART-A

50 Gy41.6 Gy

39 Gy

17/95 (17.9)9/78 (11.5)

11/77 (14.3)

18.8 (11.9-29.0)9.5 (4.7-19.0)

15.4 (8.8-26.1)

10.63 (0.28-1.43)0.83 (0.39-1.80)

0.270.64

3/65 (4.6)2/58 (3.4)2/58 (3.4)

>0.99>0.99

START-B50 Gy40 Gy

8/46 (17.4)7/51 (13.7)

18.6 (9.2-35.4)10.1 (4.3-22.6)

10.64 (0.23-1.78) 0.40

3/28 (10.7)3/36 (8.3) >0.99

Shoulder stiffnessSTART-A

50 Gy41.6 Gy

39 Gy

25/96 (26.0)15/78 (19.2)10/77 (13.0)

27.5 (19.0-38.7)17.7 (10.6-28.5)14.0 (7.8-24.4)

10.75 (0.39-1.43)0.52 (0.25-1.11)

0.390.09

8/65 (12.3)4/58 (6.9)2/58 (3.4)

0.370.10

START-B50 Gy40 Gy

5/46 (10.9)7/52 (13.5)

12.0 (5.2-26.5)14.2 (7.0-27.6)

10.88 (0.26-2.97) 0.83

1/28 (3.6)2/36 (5.6)

>0.99

1Results adjusted for baseline; P-values represent comparison of each test schedule with 50 Gy; 2Wald test; 3Fisher’s exact test.

4 Hypofractionated lymphatic radiotherapy

Please cite this article in press as: Haviland JS et al. Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: Results from theUK START (Standardisation of Breast Radiotherapy) trials. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.033Downloaded for Anonymous User (n/a) at Chulalongkorn University from ClinicalKey.com by Elsevier on December 30, 2017.

For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.

Patient-assessed moderate/marked normal tissue effect

Haviland, Radiotherapy and Oncology 2017Saturday, January 20, 18

trials suggests that appropriately-dosed hypofractionated lym-phatic irradiation is comparable to the traditional normofraction-ated (2.0 Gy) schedule in terms of safety. Adverse event rateswere low overall, and point prevalences at 5 and 10 years weregenerally considerably lower than cumulative incidence rates,partly due to reversal of post-surgical effects reported early infollow-up. Although we have not carried out formal tests of inter-action due to small sample sizes in subgroups, comparing results ofrelative treatment effects between patients with and without lym-phatic RT in the START trials showed no evidence of differentialeffects of the hypofractionated schedules compared with the con-trol schedule of 50 Gy in 25 fractions, supporting our conclusions.This is an important point, since it suggests that arm oedema andshoulder stiffness are no more sensitive to fraction size thanbreast/chest wall toxicity endpoints. Thus, the higher hazard ratiosfor arm oedema and shoulder stiffness reported in the START-pilottrial after 13 fractions of 3.3 Gy compared with 50 Gy in 25 frac-tions are not surprising given that this test dose level is equivalentto prescribing 54 Gy in 2.0 Gy fractions, assuming an alpha/betaratio of 3 Gy.

A comparison of these results with published data is notstraightforward as various studies define and measure arm andshoulder normal tissue effects in distinct ways and at differenttime points. Evaluation method and time interval from treatmenthave an impact on arm oedema scores, as reported in a systematicreview of the evidence related to lymphedema in breast cancerpatients [13]. In the review, clinical diagnosis by physiciansresulted in 12.6% incidence of lymphoedema compared with self-reported swelling in 20.4%. In the EORTC 10981-22023 AMAROStrial testing radiotherapy versus surgery of the axilla after a posi-tive sentinel node biopsy, lymphoedema was reported less oftenwhen defined as an increase in arm circumference of !10% (6% rateat 5 years) compared with clinician evaluation based on presence

of ‘any’ signs of arm oedema (11% rate at 5 years) [14]. The system-atic review and the AMAROS trial both suggested that incidence ofarm oedema tended to increase in the first 1 or 2 years followingdiagnosis or surgery, and then to decrease [13,14]. It is reassuringthat the START data show no relative differences between theschedules, however it is likely that absolute rates of normal tissueeffects are now lower using modern target volume-based RT com-pared with the field-based RT used in the era of the START trials.

In the START trials radiotherapy-related adverse effects in thearm and shoulder were assessed using both patient and physicianassessments, each based on a 4-point scale. Although patientsreport higher absolute event rates than physicians, as previouslydescribed for breast adverse effects [15], the overall conclusionsfrom the comparison of schedules are consistent, strengtheningthe conclusions from this retrospective analysis that there is noevidence of a detrimental effect of the hypofractionated scheduleson arm and shoulder symptoms. The importance of the PROMS isre-enforced by data suggesting a correlation between functionalsymptoms, including shoulder stiffness and arm/shoulder pain,and quality of life indices in women treated with conservative sur-gery and radiotherapy for breast cancer [16]. In our study, the 5-and 10-year prevalence data from physician assessments showthat lymphoedema rates are relatively stable at these time points,suggesting the safety of hypofractionated lymphatic radiotherapyin the long-term.

Due to differences between the START-pilot, A and B trials, thepatient sample included in this retrospective analysis is heteroge-neous in terms of proposed risk factors for arm and shoulder tox-icity, i.e. axillary treatment, extent of surgery, adjuvant systemictherapy and radiotherapy technique. This variation does notimpact on the comparative analysis between normofractionatedand hypofractionated schedules however, as these variables arewell-balanced amongst randomised groups in each trial [2–4].

Table 3Physician-assessed moderate/marked normal tissue effects in the arm or shoulder following lymphatic radiotherapy in START-pilot, START-A and START-B.

Schedule Total moderate/

marked events

(n/total, %)


incidence by 5years, % (95%CI)


incidence by 10 years, %

(95%CI)


P-value1

Prevalence of moderate/

marked events at 5

years, n/total (%)

P-value2

Prevalence of moderate/

marked events at 10years, n/total

(%)

P-value2

Arm oedemaSTART-pilot

50 Gy42.9 Gy

39 Gy

8/102 (7.8)14/99 (14.1)

5/97 (5.2)

6.6 (3.0-14.1)13.9 (8.1-23.3)

3.6 (1.2-10.9)

8.2 (4.0-16.7)17.0 (10.4-27.3)

3.6 (1.2-10.9)

11.95 (0.82-4.66)0.63 (0.21-1.93)

0.130.42

0/57 (0)2/56 (3.6)2/63 (3.2)

0.24>0.99

1/36 (2.8)2/27 (7.4)1/33 (3.0)

0.570.19

START-A50 Gy

41.6 Gy39 Gy

15/117 (12.8)16/95 (16.8)

6/92 (6.5)

12.8 (7.6-12.2)11.9 (6.6-21.0)6.4 (14.1-34.7)

16.3 (9.9-26.2)22.5 (14.1-34.7)

8.2 (3.7-17.6)

11.31 (0.65-2.66)0.50 (0.20-1.30)

0.450.16

2/80 (2.5)3/63 (4.8)2/61 (3.3)

0.65>0.99

1/27 (3.7)2/32 (6.3)2/29 (6.9)

>0.99>0.99

START-B50 Gy40 Gy

7/73 (9.6)3/81 (3.7)

6.0 (2.3-15.3)2.8 (0.7-10.7)

13.5 (6.4-27.0)4.7 (1.5-14.0)

10.42 (0.11-1.63) 0.21

0/51 (0)2/57 (3.5) 0.50

0/27 (0)0/20 (0) -

Shoulder stiffnessSTART-pilot

50 Gy42.9 Gy

39 Gy

13/102 (12.8)34/99 (34.3)14/97 (14.4)

12.3 (7.2-20.7)33.4 (24.7-44.1)11.9 (6.8-20.6)

13.7 (8.2-22.6)36.6 (27.3-47.7)14.9 (8.9-24.5)

13.07 (1.62-5.83)1.09 (0.51-2.31)

0.0010.83

1/57 (1.8)1/56 (1.8)5/63 (7.9)

0.500.21

0/35 (0)2/27 (7.4)1/33 (3.0)

>0.990.48

START-A50 Gy

41.6 Gy39 Gy

14/117 (12.0)10/95 (10.5)

8/92 (8.7)

8.8 (4.7-16.4)7.1 (3.3-15.2)7.5 (3.4-16.0)

17.5 (10.2-29.1)14.8 (8.0-26.6)11.0 (5.6-21.0)

10.85 (0.38-1.91)0.74 (0.31-1.76)

0.690.49

1/80 (1.3)0/63 (0)0/61 (0)

>0.99>0.99

1/27 (3.7)0/32 (0)0/29 (0)

0.460.48

START-B50 Gy40 Gy

4/73 (5.5)3/81 (3.7)

2.9 (0.7-11.0)3.1 (0.8-11.9)

8.2 (2.9-21.8)3.1 (0.8-11.9)

10.76 (0.17-3.39) 0.72

1/51 (2.0)1/57 (1.8)

>0.99>0.99

1/27 (3.7)1/20 (5.0)

>0.99>0.99

P-values represent comparison of each test schedule with 50 Gy; 1Wald test; 2Fisher’s exact test.

J.S Haviland et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx 5

Please cite this article in press as: Haviland JS et al. Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: Results from theUK START (Standardisation of Breast Radiotherapy) trials. Radiother Oncol (2017), https://doi.org/10.1016/j.radonc.2017.10.033Downloaded for Anonymous User (n/a) at Chulalongkorn University from ClinicalKey.com by Elsevier on December 30, 2017.

For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.

Physician-assessed moderate/marked normal

tissue effect


APBI : updated guidelines

B. Electron beam IORT should be restricted to womenwithinvasive cancer considered “suitable” for PBI (Table 1)based on the results of a multivariate analysis withmedian follow-up of 5.8 years (MQE recommendationrated as “Strong,” 100% Agreement).

C. Low-energy x-ray IORT for PBI should be used withinthe context of a prospective registry or clinical trial, perASTRO Coverage with Evidence Development (CED)statement. When used, it should be restricted to womenwith invasive cancer considered “suitable” for partialbreast irradiation (Table 1) basedon the data at the timeofthis review (MQE, recommendation rated as “Weak”).

Clinical trials

Two large phase 3 trials, the Intraoperative radiother-apy with electrons (ELIOT) trial and the TARGIT trial,compared WBI with IORT PBI using either electron beam(ELIOT)21 or low-energy x-rays (Intrabeam device,TARGIT).22 Both trials reported increased risk of IBTRafter IORT. In ELIOT, the 5-year IBTR risk was 4.4%(35/651) after IORT versus 0.4% (4/654) after WBI.

ELIOT has a median of 5.8 years follow up (n =1305).However, ELIOT patients with invasive cancer fitting the“suitability” criteria had a very low rate of IBTR.23

Among these patients, the 5-year occurrence of IBTR wasapproximately 1.5%, pointing out the importance ofpatient selection.23

In TARGIT, the 5-year IBTR risk was 3.3% (23/3375)in the low-energy x-ray IORT arm compared to 1.3%(11/3375), (P = .042) in the WBI arm.22 The overallmedian follow up for TARGIT is 2.4 years (n = 3451). Thetask force acknowledges that the initial 1222 patients havea median follow up of five years, however notes thefive-year IBTR risk is based on the overall short follow upof the TARGIT trial, which limits precision of thefive-year risk estimates. Although there was no statisti-cally significant difference in IBTR risk for patients treatedwith IORT versus WBI in the TARGIT prepathologysubgroup (2.1% (10 of 2234) with IORT vs 1.1% (6 of2234) with WBI),22 the task force thought greater weightshould be placed on evaluation of the efficacy of IORT inthe prespecified primary analysis population that includedall patients. The task force also noted concerns from thechair of the TARGIT Data Monitoring Committee

Table 1 Comparison of patient groups in original and updated consensus statements

Patient group Risk factor Original Update

Suitability Age !60 y !50 yMargins Negative by at least 2 mm No changeT stage T1 Tis or T1DCIS Not allowed If all of the below:

• Screen-detected• Low to intermediate nuclear grade• Size "2.5 cm• Resected with margins negative at !3 mm

Cautionary Age 50-59 y • 40-49 y if all other criteria for "suitable" are met• !50 y if patient has at least 1 of the pathologic factorsbelow and does not have any "unsuitable" factorsPathologic factors:• Size 2.1-3.0 cm a

• T2• Close margins (b2 mm)• Limited/focal LVSI• ER(-)• Clinically unifocal with total size 2.1-3.0 cm b

• Invasive lobular histology• Pure DCIS "3 cm if criteria for "suitable" not fully met• EIC "3 cm

Margins Close (b2 mm) No changeDCIS "3 cm "3 cm and does not meet criteria for “suitable”

Unsuitable Age b50 years • b40 y• 40-49 y and do not meet the criteria for cautionary

Margins Positive No changeDCIS N3 cm No change

a The size of the invasive tumor component.b Microscopic multifocality allowed, provided the lesion is clinically unifocal (a single discrete lesion by physical examination and ultrasonography/

mammography) and the total lesion size (including foci of multifocality and intervening normal breast parenchyma) falls between 2.1 and 3.0 cm.

4 C. Correa et al Practical Radiation Oncology: Month 2016

Practical Radiation Oncology (2017) 7, 73-79Saturday, January 20, 18

NSABP B-39/RTOG 0413 – Page 2

Figure 1

NSABP B-39/RTOG 0413 Schema

Patients with Stage 0, I, or II Breast Cancer Resected by Lumpectomy Tumor Size d 3.0 cm

No More Than 3 Histologically Positive Nodes

STRATIFICATION

x Disease Stage (DCIS only; invasive and node negative; invasive with 1-3 positive nodes) x Menopausal Status (premenopausal, postmenopausal) x Hormone Receptor Status (ER-positive and/or PgR-positive; ER-negative and PgR-negative) x Intention to Receive Chemotherapy (yes or no)

RANDOMIZATION

GROUP 1*

Whole Breast Irradiation (WBI)

50 Gy (2.0 Gy/fraction) or 50.4 Gy (1.8 Gy/fraction)

to whole breast, followed by optional boost**

to 60.0 Gy – 66.6 Gy

GROUP 2*

Partial Breast Irradiation (PBI)***

34 Gy in 3.4 Gy fractions using multi-catheter brachytherapy

or

34 Gy in 3.4 Gy fractions using MammoSite® balloon catheter or

other intracavitary device†

or

38.5 Gy in 3.85 Gy fractions using 3D conformal external beam radiation

For all PBI techniques: RT given to tissue surrounding lumpectomy cavity only, BID

(with a fraction separation of at least 6 hours), for a total of 10 treatments given

on 5 days over a period of 5 to 10 days.

* See Section 15.0 for instructions regarding chemotherapy and hormonal therapy. Chemotherapy, if given, will be administered before WBI or following PBI. ** Brachytherapy boost is not allowed. (See Section 11.1.4.) *** The PBI technique utilized will be at the physician's discretion and will be based on technical considerations, radiation oncology facility technique credentialing (see Section 5.0), as well as patient preference. † Options for other single-entry intracavitary devices include these multi-lumen devices:

MammoSite® ML, Contura� MLB, and SAVI® (see Section 13.0).

03/30/06, 03/07/11


Figure 1




STRATIFICATION


RANDOMIZATION

GROUP 1*




to 60.0 Gy – 66.6 Gy

GROUP 2*



or



or







03/30/06, 03/07/11


Figure 1




STRATIFICATION


RANDOMIZATION

GROUP 1*




to 60.0 Gy – 66.6 Gy

GROUP 2*



or



or







03/30/06, 03/07/11

mean time 41.0 months, no significant toxicity-related issuesThe rates of fibrosis-cosmesis and fibrosis-deep connective tissue toxicities are: Grade 2 12%, Grade 3 3% and Grade 4/5 =0%

Abstract presentation from the 2011 ASCO Annual Meeting


http://meeting.ascopubs.org/cgi/external_ref?conf_id=102&access_num=4127&link_type=ASCO_MTG_URL&year=2011

http://meeting.ascopubs.org/cgi/external_ref?conf_id=102&access_num=4127&link_type=ASCO_MTG_URL&year=2011

Omit radiation• can be done in selected patients especially

elder patients with comorbidities , short life expectancy


ECOG 5194 Boston RTOG 9804

low to interm gr, <=2.5 cm.high gr ,1 cm or lessmargin >=3 mmtamoxifenno RTm F/U 12.3 yrs

low to interm gr<=2.5cmmargin >=1 mm.no RTm F/U 11 yrs

mammographically detected diseaselow or interm gr.<2.5 cm sizemargins ≥ 3 mmTamoxifenm F/U 7.17 years

DCIS

RT 50Gy

ObserveWong JS, Breast Cancer Res Treat. 2014 Beryl McCormick, JCO 20, 2015Solin LJ, J Clin Oncol. 2015


http://jco.ascopubs.org/search?author1=Beryl+McCormick&sortspec=date&submit=Submit

http://jco.ascopubs.org/search?author1=Beryl+McCormick&sortspec=date&submit=Submit

http://www.ncbi.nlm.nih.gov/pubmed/?term=Solin%20LJ%5BAuthor%5D&cauthor=true&cauthor_uid=26371148

http://www.ncbi.nlm.nih.gov/pubmed/?term=Solin%20LJ%5BAuthor%5D&cauthor=true&cauthor_uid=26371148

ipsilateral breast events

ECOGlow/intm gr.

ECOGlow/intm gr.

Bostonlow/intmBoston

low/intmRTOGRTOGipsilateral

breast events non-Inv Invasive non-Inv Invasive non-Inv Invasive

RT -- --0.9%0.9%

RT -- --50% 50%

OBS12 yr 14.4%12 yr 14.4% 8 yr 13%8 yr 13%

7 yr 6.7%(p<0.001)7 yr 6.7%(p<0.001)

OBS- 12 yr

7.5%68% 32% - -

DCIS after BCS can be considered omission of radiation in some groups of patients

JCO September 14, 2015


CALGB 9343

Canada ABCSG PRIME II

- age >70- T1N0- ER+

- age >50- T1-2N0- margin-- ER+

- mAge 66- <3cm- N0- gr.1-2- ER+

- age > 65- T <= 3 cm- N0- ER+- margin -

10 yr LRR 5 yr LRR 4.5 yr LRR 5 yr LRR

Sx + TamSx + Tam + RT

8%2% (SS)

7.7%0.6% (SS)

5.1%0.4% (SS)

4.1%1.3% (SS)

OS not significantPotter R, Int J Radiat Oncol Biol Phys. 2007 Jun 1;68(2):334-40. Epub 2007 Mar 23Hughes KS, ASCO 2010 ,Anthony W. Fyles,N Engl J Med 2004;351:963-70.

Invasive


Tumor bed boost


Defining what constitutes an adequate surgical margin inpatients with DCIS has been controversial. In a meta-analysisof !""# patients with DCIS treated with breast-conservingsurgery and postoperative RT, Dunne et al$! reported that a%-mm margin was superior to a margin of less than %.# mm.In the current analysis, the use of RT boost was significantlyassociated with decreased IBTR across the entire cohort but,on subset analysis, did not achieve significance in the posi-tive margin subgroup irrespective of positive margin defini-tion of ink on tumor or the SSO/ASTRO/ASCO definition ofmargins of less than %.# mm. Similar to other publishednegative studies of RT boost in DCIS, the lack of benefit witha boost in the subgroup with positive margins is likely relatedto the small sample size of this cohort, which representedless than !% of the entire cohort and thus was substantiallyunderpowered to detect a significant benefit. Thus, theresults in the positive-margin cohort should be interpretedwith caution.

The challenge in demonstrating a statistically significantbenefit for the RT boost in DCIS is understandable given theexcellent outcomes of DCIS with WBRT. To date, availabledata assessing the benefit of a boost in patients with DCISare limited to single-institution, registry, and multiple-center retrospective reviews; the existing published studiesare summarized in Table !.%$-%&,%'-&# Each study failing todemonstrate a significant benefit in the RT boost for DCIScan be rationalized by small cohort size (lack of statisticalpower), inadequate proportions of patients in the boost vsno-boost groups, limited follow-up, or a combination ofthese factors.

Limitations and StrengthsAlthough we wholly recognize that the retrospective natureof our study is a fundamental limitation, our collaborative ef-fort attempted to improve on the quality of existing pub-lished data by only including data sets from large, academicinstitutions that underwent quality reviews by at least % dif-ferent breast specialists (from contributing and receiving in-stitutions) to ensure its integrity. We believe that the use of in-dividual patient-level data from academic institutions withbreast cancer expertise (radiation oncology and pathology), the

review of each institutions’ data sets by assigned primary in-vestigators, and the secondary central data review have ulti-mately provided a more valuable data set than that of a simpleretrospective review or population-based data set, which havesignificant variability in contributions. Another limitation, theinherently nonrandomized selection of the boost vs no-boostgroups, was believed to be at risk for confounding by clinico-pathologic variables across institutions and physicians. To ad-dress this, the multivariable analytic regression model incor-porated all variables that were significant on univariateanalysis. Furthermore, although differences in delivery tech-niques are inevitable over time and across institutions and phy-sicians, our current knowledge of the risks and benefits ofbreast RT suggest that any such differences should only affecttoxicity (ie, fibrosis, telangiectasias) and not efficacy out-comes. Our protocol specified that patients included in the fi-nal analysis receive standardized doses and boost techniquesand thus receive uniform treatment with regard to the studyquestion concerning the benefit of an RT boost on IBTR. Pub-lished literature on the use of a boost$( (in similar median doseranges) in addition to individual radiation oncologists’ clini-cal experiences with the use of a boost have already estab-lished the additional risk for fibrosis when an RT boost is de-livered after WBRT.

Last, although the suboptimal reporting of clinical vari-ables such as ER status and tamoxifen use is inherent to ret-rospective data collection, the proportions of missing data inour database are consistent (or better) with those of population-based data sets such as the Surveillance, Epidemiology, andEnd Results (SEER) program." To handle missing data, we as-sumed that the choice of delivering the RT boost (vs no boost)did not heavily depend on the missing variables and there-fore chose the missing-indicator method,$' which is com-monly used for large data set analysis, particularly because can-cer registries such as SEER routinely include an unknowncategory. Notwithstanding these limitations, the present studyrepresents the largest series, to our knowledge, to assess DCISoutcomes with and without an RT boost and demonstrates thesignificant decrease in IBTR with the use of the RT boost forDCIS of a scale similar to that demonstrated with the RT boostfor invasive cancer.

Table 3. Studies Reporting Outcomes of DCIS by Receipt of Boost vs No Boost

Source

Total No. of Patients(Patients ReceivingBoost, %)

MedianFollow-up, y

Effect ofBoost on IBTR

Omlin et al,21 2006 a 316 (52.0) 6.0 Yes

Yerushalmi et al,22

200675 (25.0) 6.8 No

Jiveliouk et al,23 2009 107 (37.3) 4.0 No

Monteau et al,24 2009b 208 (71.0) 7.4 Yes

Wai et al,25 2011 482 (29.8) 9.3 No

Rakovitch et al,26 2013 1895 (29.6) 10.0 No

Meattini et al,27 2013 389 (48.8) 7.7 Yes

Wong et al,28 2012 220 (36.0) 3.8 Yes

Kim, et al29 2014 728 (31.9) 6.7 No

Cutuli et al,30 2016 819 (48.0) 7.5 No

Present study 4131 (64.4) 9.0 Yes

Abbreviations: DCIS, ductalcarcinoma in situ; IBTR, ipsilateralbreast tumor recurrence.a Included only patients with DCIS

younger than 45 years.b Cohort included patients with DCIS

with close and focally positivemargins.

Research Original Investigation Radiotherapy Boost for Ductal Carcinoma In Situ

1066 JAMA Oncology August 2017 Volume 3, Number 8 (Reprinted) jamaoncology.com

© 2017 American Medical Association. All rights reserved.

Downloaded From: by a Chulalongkorn University User on 01/14/2018

Tumor bed boost in DCIS

age <45

margin +


Tumor bed boost in DCIS

• retrospective analyis

• 10 academic institution

• 4131 patients

• mF/U 9 yrs

• median boost dose 14Gy

Moran ,JAMA Oncol. 2017


margin status, !."#; $"% CI, !.%$-!.&&; HR for positive mar-gin status, !.&'; $"% CI, !.#(-).#'; P = .)&).

DiscussionWhole-breast radiation therapy delivered after breast-conserving surgery for DCIS consistently results in a decreasein IBTR of approximately "!% and is supported by multiplephase % trials with long-term follow-up.(-" Although boostingthe tumor bed is a common practice, a paucity of data sup-ports its use in the setting of DCIS, and its rationale is extrapo-lated from invasive cancer trials. The largest trial among theseis the European Organization for Research and Treatment ofCancer (EORTC) (('') trial,)& which included ""*$ patients,"%)' of whom had negative margins defined by local patho-logic findings and who were randomized to a )*-Gy boost vsnonboost groups after WBRT. In the most recent (!-year fol-low-up report, the cumulative IBTR incidence was )(% with aboost vs )*.#% without a boost.)& Despite an absolute differ-ence of only #% at (! years, the EORTC (('') study high-lights the importance and clinical value that incrementallysmall decreases in IBTR provide for the patient: at )! years,mastectomy for recurrence was decreased by approximately#!% in patients who had received a boost (compared with thosewho did not). Most recently, a reanalysis of a subset ofpatients treated with long-term follow-up further elucidatedthat being younger and having high-grade invasive cancerwere the most important risk factors for recurrence in thistrial.)'

Given these benefits of the boost for invasive cancers, manyradiation oncologists similarly use the RT boost in the con-text of DCIS, with a belief in its potential to similarly providea small additional benefit in decreasing IBTR for DCIS and thusmitigate risks and emotional implications of recurrence andmastectomy after a DCIS diagnosis. In particular, given that ap-proximately "!% of DCIS recurrences are invasive in nature,

with the potential for regional and distant disease progres-sion, any incremental benefit in decreasing IBTR likely has thepotential to significantly affect individual patients. Thus, weare not entirely surprised that the benefits of the RT boost inDCIS appear to similarly parallel what has been demon-strated across all age groups and grades for invasive breast can-cers: the estimated absolute benefit of %.*% at )" years (HR,!.&!; $"% CI, !."#-!.$() for the use of a boost in DCIS is simi-lar in magnitude to the most current update of the EORTC trialdemonstrating an absolute benefit of #.#% at (! years (HR,!.*"; $"% CI, !."(-!.')) for a boost in invasive cancer.

Our study differs from the current existing (retrospec-tive) literature in that an a priori power estimation was con-ducted to estimate the total sample size and proportion of pa-tients required to detect the estimated difference in IBTRbetween the boost and no-boost groups. Our threshold of atleast %% was a conservative underestimation of the approxi-mately #% to "% benefit derived from the EORTC invasive-boost vs –no-boost trial& and was derived from the %% benefitanticipated for the ongoing BONBIS trial.)( With more than

Figure 1. Comparison of Ipsilateral Breast Tumor Recurrence (IBTR)by Treatment Group

00

10231878

11362052

12102123

6

277535

104 8

74166

12

0.3

Prob

abili

ty o

f IBT

R

Duration of Follow-up, y

0.2

0.1

2

8211600

5071034

No. at riskNo-boost groupBoost group

Log-rank P = .04

No-boost group

Boost group

Patients were stratified by those who received a radiotherapy boost (boostgroup) vs those who did not (no-boost group).

Table 2. Cox Proportional Hazards Regression Multivariable Analysisof Ipsilateral Breast Tumor Recurrence

Patient Characteristic HR (95% CI) P ValueAge, y

<50 1 [Reference] NA

!50 0.54 (0.41-0.71) <.01

DCIS grade

I 1 [Reference] NA

II or III 1.59 (1.02-2.46) .04

Unknown 1.56 (0.93-2.59) .09

Tumor size (continuous variable) 1.15 (1.02-1.29) .03

Margin status

Negative 1 [Reference] NA

Positivea 1.72 (0.97-3.05) .06

Unknown 1.65 (1.13-2.41) .01

Comedo necrosis

No 1 [Reference] NA

Yes 1.12 (0.78-1.62) .53

Unknown 0.51 (0.34-0.77) <.01

Estrogen receptor status

Negative 1 [Reference] NA

Positive 0.7 (0.39-1.25) .23

Unknown 0.85 (0.52-1.38) .51

Tamoxifen citrate use

No 1 [Reference] NA

Yes 0.56 (0.36-0.87) .01

Unknown 0.93 (0.53-1.63) .81

RT boost

No 1 [Reference] NA

Yes 0.68 (0.5-0.91) .01

Abbreviations: DCIS, ductal carcinoma in situ; HR, hazard ratio; NA, notapplicable; RT, radiotherapy.a Indicates the National Surgical Adjuvant Breast Project B-17 definition of ink on

tumor or 0-mm margin width. The log-rank ratio tested the interactionbetween age and boost (P = .46), which was not statistically significant.

Research Original Investigation Radiotherapy Boost for Ductal Carcinoma In Situ

1064 JAMA Oncology August 2017 Volume 3, Number 8 (Reprinted) jamaoncology.com




IBRT free survival RT boost No boost

5 yrs 97.1% 96.3%

10 yrs 94.1% 92.5%

15 yrs 91.6% 88% 3.6%


!""" patients in the final analysis, this cohort exceeded thesample size power estimation by #$% with a median fol-low-up longer than that of most existing published studies.With these considerations, this study demonstrates the an-ticipated small but statistically significant benefit in decreas-ing long-term IBTR with a boost for DCIS of a similar degreeexperienced with invasive cancers. The use of a boost was sig-nificantly associated with decreasing IBTR across the entire co-

hort. In addition, this benefit was independent of tamoxifenuse and was significant across all age groups, although the mag-nitude of the benefit appears to be greater in younger pa-tients (similar to the boost data with invasive cancer). Of re-assurance, the other variables significantly associated withIBTR on multivariable analysis (such as grade) are consistentwith established prognostic factors in DCIS that have been pre-viously described in the literature.%$,&"

Figure 2. Radiotherapy (RT) Boost by Patient Characteristic

00 6 104 8 12

0.3

Prob

abili

ty o

f IBT

R


0.2

0.1

2

No. at riskNo-boost group, – marginNo-boost group, + marginBoost group, – margin

919

22

1706

69

1018

31

1852

85

1086

31

1910

89

238

6

468

24

59

5

140

10

738

16

1458

59

448

10

923

41Boost group, + margin

Negative vs positive margin statusA

P = .93aP < .001a

No-boost group, – marginBoost group, – marginNo-boost group, + marginBoost group, + margin

00 6 104 8 12

0.3

Prob

abili

ty o

f IBT

R


0.2

0.1

2

No. at riskNo-boost group, margin !2 mmNo-boost group, margin <2 mmBoost group, margin !2 mm

798

143

1435

340

888

161

1537

400

954

163

1587

412

209

33

402

90

50

14

116

34

659

95

1232

285

406

52

792

172Boost group, margin <2 mm

Margins at least vs less than 2 mmB

P = .34a

P < .001a


00 6 104 8 12

0.3

Prob

abili

ty o

f IBT

R


0.2

0.1

2

No. at riskNo-boost group, !50 yNo-boost group, <50 yBoost group, !50 y

672

247

1195

511

744

274

1294

558

794

292

1331

579

155

81

338

130

41

18

103

37

526

212

1030

428

308

140

647

276Boost group, <50 y

Negative margins by ageC

P = .02a

P = .007a

No-boost group, !50 yBoost group, !50 yNo-boost group, <50 yBoost group, <50 y

Patients are compared between those who received an RT boost (boost group)vs those who did not (no-boost group), with additional stratification bycharacteristics. A, Negative (!) margin status indicates the National SurgicalAdjuvant Breast Project B-17 definition of no ink on tumor; positive (+) marginstatus, ink on tumor. B, Margins were stratified using the Society of SurgicalOncology/American Society of Radiation Oncology definition of at least 2.0 vsless than 2.0 mm. The benefit of the RT boost in decreasing ipsilateral breast

tumor recurrence (IBTR) is apparent in patients with margins of at least 2.0 mmbut is not significant in patients with margins of less than 2.0 mm. C, Patientswith negative margins were stratified by those younger than 50 years vs 50years or older. IBTR estimates are significantly lower with the delivery of an RTboost relative to no boost.a P value was calculated with control by confounders.

Radiotherapy Boost for Ductal Carcinoma In Situ Original Investigation Research

jamaoncology.com (Reprinted) JAMA Oncology August 2017 Volume 3, Number 8 1065




neg margin

+ margin





00 6 104 8 12

0.3

Prob

abili

ty o

f IBT

R


0.2

0.1

2


919

22

1706

69

1018

31

1852

85

1086

31

1910

89

238

6

468

24

59

5

140

10

738

16

1458

59

448

10

923



P = .93aP < .001a


00 6 104 8 12

0.3

Prob

abili

ty o

f IBT

R


0.2

0.1

2


798

143

1435

340

888

161

1537

400

954

163

1587

412

209

33

402

90

50

14

116

34

659

95

1232

285

406

52

792



P = .34a

P < .001a


00 6 104 8 12

0.3

Prob

abili

ty o

f IBT

R


0.2

0.1

2


672

247

1195

511

744

274

1294

558

794

292

1331

579

155

81

338

130

41

18

103

37

526

212

1030

428

308

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647



P = .02a

P = .007a









+ margin

neg margin





00 6 104 8 12

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Prob

abili

ty o

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R


0.2

0.1

2


919

22

1706

69

1018

31

1852

85

1086

31

1910

89

238

6

468

24

59

5

140

10

738

16

1458

59

448

10

923



P = .93aP < .001a


00 6 104 8 12

0.3

Prob

abili

ty o

f IBT

R


0.2

0.1

2


798

143

1435

340

888

161

1537

400

954

163

1587

412

209

33

402

90

50

14

116

34

659

95

1232

285

406

52

792



P = .34a

P < .001a


00 6 104 8 12

0.3

Prob

abili

ty o

f IBT

R


0.2

0.1

2


672

247

1195

511

744

274

1294

558

794

292

1331

579

155

81

338

130

41

18

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37

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1030

428

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140

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P = .02a

P = .007a










• RT boost for DCIS : a small but statistically significant benefit in decreasing long-term IBTR ~ invasive cancer (3-4%)

• the effect of the RT boost for DCIS in + margins remains inconclusive

• patients who have a life expectancy > 10-15 yrs : addition of RT boost should be considered



Ongoing trial• BONBIS trial : France

• TROG 0701

Randomization

Whole breast RT

Whole breast RT + boost 16 Gy

Randomization

WB 50Gy/25Fx

WB 50Gy/25Fx + B 16Gy/8Fx

WB 42.5Gy/16Fx

WB 42.5Gy/16Fx + B 10Gy/4Fx


Boost in invasive Lyon Budapest EORTC

F/U 3.3 yrs 5.3 yrs. 17.2

No. of Pts 1024 207 2657

Dose 50Gy/20Fx +Boost 10Gy/4Fx

50Gy/25Fx +Boost 12-16 Gy

50Gy/25Fx +Boost 16Gy8Fx

LRRBoost vs No Boost

3.6 % vs 4.5% p= 0.044

6.7% vs 15.5%p=0.049

9% vs 13%p<0.0001

Romestaing P et al. J Clin Oncol. 1997 Polgar et al,Strahlenther Onkol. 2002 Bartelink, Lancet Oncol 2015

4%


young age & presence of DCIS : prognostic of increased risk of IBTR

Copyright 2017 American Medical Association. All rights reserved.

negative impact on local control: young age and the presence ofan additional DCIS component adjacent to the primary tumor.

The negative impact of young age on local control couldbe reduced by the boost in radiation therapy dose. Bartelinket al!! showed that the relative improvement in local controlby the boost was similar for the different age groups; how-ever, the absolute risk reduction in local recurrence was thelargest in the younger patients. Younger patients were not athigher risk for adverse effects of the boost dose in terms of cos-metic outcome or fibrosis development, which remained in-dependent from age.!"

In our previous analysis,!# we showed that the grade of in-vasive cancer, together with boost and age, remained signifi-cant in the final multivariable analysis. With longer follow-up, the relative effect of invasive tumor grade decreased rapidlywithin the first $ years, losing its significance with longer fol-low-up, whereas the relative effect of presence of DCIS did notdiminish over time (Figure %), doubling the IBTR incidence at%# years. This factor has a constant relative effect on local con-trol over time, meaning that the absolute difference betweenthe cumulative incidence curves continues to widen, empha-sizing the importance of long-term follow-up.!&

All excisions were complete according to local patholo-gists, but resection margin width was analyzed from central re-view data. Neither the margin for the invasive tumor nor for the

Figure 3. Effect of the Radiotherapy Boost Dose on IBTR for the Different Subgroups

0 1.50 2.501.00 2.00

Hazard Ratio (16 Gy Boost vs No Boost)0.50

InteractionP Value

16 Gy BoostBetter

No BoostBetter

Age (grouped)27-50 0.51 (0.33-0.77) .3151+ 0.70 (0.43-1.14)

Positive nodesNo 0.56 (0.39-0.80) .56

.52

Yes 0.71 (0.35-1.44)Diameter, mm (grouped)

0-20 0.67 (0.46-0.98)

.19

21-50 0.53 (0.29-0.99)Oestrogen

Negative 0.43 (0.22-0.81)

.61

Positive 0.71 (0.45-1.11)Chemotherapy

No 0.56 (0.39-0.80)

.73

Yes 0.70 (0.34-1.44)Tamoxifen administration

No 0.60 (0.43-0.83)

.03

Yes 0.49 (0.17-1.43)Histologic grade

Low/intermediate 0.79 (0.54-1.16)

.015

High 0.36 (0.18-0.70)DCIS

No 1.13 (0.63-2.05)

.63

Yes 0.47 (0.31-0.69)Margin invasive tumor

Close/very close 0.52 (0.28-0.94)

.22

Free 0.61 (0.41-0.92)Margin DCIS

Close/very close 0.63 (0.33-1.20)Free 0.35 (0.18-0.68)

Group HR (95% CI)

DCIS indicates ductal carcinoma insitu; IBTR, ipsilateral breast tumorrecurrence.

Table 2. Multivariable Analysis for Ipsilateral Breast Tumor Recurrenceas First Event

Variable HR (95% CIs) P ValueTreatment

No Boost vs 16 Gy Boost 0.62 (0.41-0.92) .02Age

Per yeara <.001Positive nodes

No vs yes 0.82 (0.43-1.56) .55Systemic therapyb

No vs yes 0.76 (0.44-1.29) .31Diameter

Per mm 1.03 (1.00-1.06) .05Grade invasive tumor

Intermediate/low vs high 0.87 (0.52-1.46) .60DCIS

No vs yes 2.15 (1.36-3.38) .001Estrogen

Negative vs positive 1.11 (0.67-1.85) .67Progesterone

Negative vs positive 0.79 (0.48-1.29) .34

Abbreviations: DCIS, ductal carcinoma in situ; mm, millimeter.a See eFigure 5 in Supplement 2.b Systemic therapy indicates tamoxifen or chemotherapy.

Research Original Investigation Prognostic Factors for Local Control in Breast Cancer With Boost vs No Boost

46 JAMA Oncology January 2017 Volume 3, Number 1 (Reprinted) jamaoncology.com




20 yr cumulative IBTR

p value

<50 yrs 24 -> 15% 0.002

additional DCIS 22 -> 14% <0.001

<50 yrs + DCIS 31 -> 15% <0.001

high grade 15 yr IBTR 31 ->5%

0.01

Vrieling C, JAMA Oncol. 2017



CI, !."#-"."$; P = .%%!) were statistically significant predic-tors of IBTR (Table !). The histological grade of the invasivetumor did not significantly influence long-term local control.The association between age at randomization and IBTR wasnonlinear (eFigure & in Supplement '), but similar in both treat-ment arms. The risk of IBTR decreased from age "% to about(% from "&% ()(% CI, '(%-&!%) to !!% ()(% CI, $%-!(%)(Table !). As of the age of (%, the risk more or less stabilized.In tumors with and without additional DCIS, the cumulativeincidence of IBTR at '% years was !$% ()(% CI, !&-'') and )%()(% CI, #%-!'%), respectively (P < .%%!) (Table !).

A total of !'& patients had estrogen receptor (ER) and pro-gesterone receptor-negative, high-grade tumors. In this groupwere !# events. The !(-year cumulative incidence of IBTR in thispopulation was !#% ()(% CI, $%-'"%). The IBTR incidence re-lated to age showed the following trend: !(-year cumulative in-cidence of IBTR was "&% ()(% CI, )%-("%) in patients youngerthan &% years of age, !)% ()(% CI, '%-"'%) in patients aged &!to (%, compared with #% ()(% CI, %%-!'%) for patients olderthan (% years (P = .%&). The presence of additional DCIS did notinfluence local control in this population.

&#& patients had ER-positive, low-grade tumors. In thisgroup were &" events. The !(-year cumulative incidence of IBTRin this subgroup was !!% ()(% CI, $%-!&%). Age had a signifi-cant influence also in this population: patients younger than&% years had a !(-year IBTR incidence of "&% ()(% CI, !&%-&)%) compared with !%% ()(% CI, (%-!(%) for patients &%years or older (P < .%%!). The presence of DCIS in this popula-tion showed a trend in !(-year IBTR incidence: !&% ()(% CI,)%-!)%) for patients with additional DCIS vs *% ()(% CI, "%-!!%) for patients without (P = .%').

Effect of the Boost Treatment in High-Risk PatientsThe influence of the radiotherapy boost on the different sub-groups is shown in Figure ".

For patients younger than (% years, the !#-Gy boost dosereduced the '%-year cumulative incidence of IBTR from '&%()(% CI, !$%-"%%) to !(% ()(% CI, !%%-'%%) (HR, %.(!; )(%CI, %.""-%.**; P = .%%'). In patients with additional DCIS, theboost dose reduced the '%-year cumulative incidence of IBTRfrom ''% ()(% CI, !*%-'*%) to !&% ()(% CI, )%-!)%) (HR,%.&*; )(% CI, %."!-%.#); P < .%%!). In the population with bothrisks combined, the boost dose reduced the '%-year cumula-tive incidence of IBTR from "!% ()(% CI, ''%-")%) to !(% ()(%CI, $%-'!%) (HR, %."*; )(% CI, %.''-%.#'; P < .%%!). The in-fluence of the boost in the older patients with DCIS ((&( pa-tients with &( events) was not significant: a '%-year cumula-tive incidence of IBTR of !(% ()(% CI, )%-'!%) without vs !&%()(% CI, (%-'"%) with the boost (P = .!!).

Forthesubgroupofpatientswithhormonereceptor-negative,high-grade tumors, the !#-Gy boost dose reduced the !(-year cu-mulative incidence of IBTR from "!% ()(% CI, !&%-&&%) to (%()(% CI, %%-)%) (HR, %.'"; )(% CI, %.%*-%.*%; P = .%!).

For patients with ER-positive, low-grade tumors, the !#-Gyboost dose did not change the IBTR rate. Neither was this thecase for patients with ER positive, low-grade tumors and ad-ditional DCIS.

DiscussionThis long-term analysis of randomized BCT patients with a cen-tral pathology review showed that ' factors had a significant

Figure 2. Log HR Over Time

6

4

2

0

–20.5 1.0 2.0 5.0 20.0

Log

HR fo

r Pre

senc

e of

HIG

Time, y10.0

High invasive grade (HIG)A

6

4

2

0

–20.5 1.0 2.0 5.0 20.0

Log

HR fo

r Pre

senc

e of

DCI

STime, y

10.0

Ductal carcinoma in situ (DCIS)B

Log HR over time for (A) high invasive grade (P < .001) and (B) presence of DCIS (P = .41) with confidence intervals at 2 standard errors. The time axis has beengraduated according to the log scale.

Prognostic Factors for Local Control in Breast Cancer With Boost vs No Boost Original Investigation Research

jamaoncology.com (Reprinted) JAMA Oncology January 2017 Volume 3, Number 1 45



greater hazard of IBTR in first 5 yrs of F/U, but the effect declined in the course of time


High grade




CI, !."#-"."$; P = .%%!) were statistically significant predic-tors of IBTR (Table !). The histological grade of the invasivetumor did not significantly influence long-term local control.The association between age at randomization and IBTR wasnonlinear (eFigure & in Supplement '), but similar in both treat-ment arms. The risk of IBTR decreased from age "% to about(% from "&% ()(% CI, '(%-&!%) to !!% ()(% CI, $%-!(%)(Table !). As of the age of (%, the risk more or less stabilized.In tumors with and without additional DCIS, the cumulativeincidence of IBTR at '% years was !$% ()(% CI, !&-'') and )%()(% CI, #%-!'%), respectively (P < .%%!) (Table !).

A total of !'& patients had estrogen receptor (ER) and pro-gesterone receptor-negative, high-grade tumors. In this groupwere !# events. The !(-year cumulative incidence of IBTR in thispopulation was !#% ()(% CI, $%-'"%). The IBTR incidence re-lated to age showed the following trend: !(-year cumulative in-cidence of IBTR was "&% ()(% CI, )%-("%) in patients youngerthan &% years of age, !)% ()(% CI, '%-"'%) in patients aged &!to (%, compared with #% ()(% CI, %%-!'%) for patients olderthan (% years (P = .%&). The presence of additional DCIS did notinfluence local control in this population.

&#& patients had ER-positive, low-grade tumors. In thisgroup were &" events. The !(-year cumulative incidence of IBTRin this subgroup was !!% ()(% CI, $%-!&%). Age had a signifi-cant influence also in this population: patients younger than&% years had a !(-year IBTR incidence of "&% ()(% CI, !&%-&)%) compared with !%% ()(% CI, (%-!(%) for patients &%years or older (P < .%%!). The presence of DCIS in this popula-tion showed a trend in !(-year IBTR incidence: !&% ()(% CI,)%-!)%) for patients with additional DCIS vs *% ()(% CI, "%-!!%) for patients without (P = .%').

Effect of the Boost Treatment in High-Risk PatientsThe influence of the radiotherapy boost on the different sub-groups is shown in Figure ".

For patients younger than (% years, the !#-Gy boost dosereduced the '%-year cumulative incidence of IBTR from '&%()(% CI, !$%-"%%) to !(% ()(% CI, !%%-'%%) (HR, %.(!; )(%CI, %.""-%.**; P = .%%'). In patients with additional DCIS, theboost dose reduced the '%-year cumulative incidence of IBTRfrom ''% ()(% CI, !*%-'*%) to !&% ()(% CI, )%-!)%) (HR,%.&*; )(% CI, %."!-%.#); P < .%%!). In the population with bothrisks combined, the boost dose reduced the '%-year cumula-tive incidence of IBTR from "!% ()(% CI, ''%-")%) to !(% ()(%CI, $%-'!%) (HR, %."*; )(% CI, %.''-%.#'; P < .%%!). The in-fluence of the boost in the older patients with DCIS ((&( pa-tients with &( events) was not significant: a '%-year cumula-tive incidence of IBTR of !(% ()(% CI, )%-'!%) without vs !&%()(% CI, (%-'"%) with the boost (P = .!!).

Forthesubgroupofpatientswithhormonereceptor-negative,high-grade tumors, the !#-Gy boost dose reduced the !(-year cu-mulative incidence of IBTR from "!% ()(% CI, !&%-&&%) to (%()(% CI, %%-)%) (HR, %.'"; )(% CI, %.%*-%.*%; P = .%!).

For patients with ER-positive, low-grade tumors, the !#-Gyboost dose did not change the IBTR rate. Neither was this thecase for patients with ER positive, low-grade tumors and ad-ditional DCIS.

DiscussionThis long-term analysis of randomized BCT patients with a cen-tral pathology review showed that ' factors had a significant

Figure 2. Log HR Over Time

6

4

2

0

–20.5 1.0 2.0 5.0 20.0

Log

HR fo

r Pre

senc

e of

HIG

Time, y10.0

High invasive grade (HIG)A

6

4

2

0

–20.5 1.0 2.0 5.0 20.0

Log

HR fo

r Pre

senc

e of

DCI

S

Time, y10.0

Ductal carcinoma in situ (DCIS)B

Log HR over time for (A) high invasive grade (P < .001) and (B) presence of DCIS (P = .41) with confidence intervals at 2 standard errors. The time axis has beengraduated according to the log scale.

Prognostic Factors for Local Control in Breast Cancer With Boost vs No Boost Original Investigation Research

jamaoncology.com (Reprinted) JAMA Oncology January 2017 Volume 3, Number 1 45



no change in hazard over time was observed


• young age and the presence DCIS increase the risk of IBTR

• pts with high-grade invasive tumors should be monitored closely, especially in the first 5 years

• pts with additional DCIS : need longer F/U to estimate absolute effects of boost



regional LNs

• 1-3 LNs

• volume of radiation

• IMN radiation


PMRT in 1-3 LNs

• no PMRT

• PMRT : which volume?


+ studies in PMRT in LN+

study Pts RT field mF/U(yr)

LRRRT vs no RT

DFS OS

Danish 82b

premen, T3-4,>1LN+,MRM,CMFLN removed ~7

CW, SCV,IFV,AX, and

IMN 50Gy/25Fx

9.5 9% vs 32%

48% vs

34%

54% vs

45%

Danish 82c

postmen, stageII,III, No

CMT, Tam

CW, SCV,IFV,AX, and

IMN 50Gy/25Fx

10.28% vs 35%

36% vs

24 %

45% vs

36%

British Columb

premen, >1LN+,MRM,CMFLN removed ~11

CW, SCV,AX, and IMN 37.5Gy/

16Fx

20 10% vs 28%

38%vs

25%

47%vs

37%

Overgaard M et al. Lancet. 1999Overgaard M et al. N Engl J Med. 1997 Ragaz J et al. J Natl Cancer Inst. 2005 All SSSaturday, January 20, 18

DiscussionThe results from the present subgroup analysis strongly

indicate that the benefit of postoperative radiotherapy isequally pronounced in patients with 1–3 nodes positiveand in patients with 4+ nodes. Thus, the present resultsmay compensate for the lack of more evidence in order torecommend radiotherapy in patients with 1–3 nodes posi-tive along with patients with 4+ nodes, where it is a stan-dard treatment. This has also been pointed out before,but apparently not with sufficient strength to influencethe consensus reports [7,18,19].

In addition to the data presented here, there is accumu-lating information from other subgroup analyses that sup-ports our results. Thus, the 20-year results of the BritishColombia study have shown that the impact of radiationtherapy for all survival outcomes in the subgroup with 1–3nodes involved was similar to the subgroup with 4+ nodes in-volved and had a magnitude of risk reduction, which forboth groups were of the same order as in the present sub-group analysis [20]. Further, in the 2005 EBCTCG overview[8] additional data are presented (Annex-figures 2d and2e) which indicate the same benefit of radiotherapy to

Time after treatment (years)0 5 10 15

Loco

-regi

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rrenc

e (%

)

0

20

40

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100

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p<0.001

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4%

Failure All RT 8 276 no RT 63 276RR 0.10 (0.05-0.22)

RT 276 197 173 136no RT 276 165 131 106

1-3 positive nodes


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4+ positive nodes

RT


Ove

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(%)

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no RTp=0.03

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48%

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RT 276 224 187 129no RT 276 220 164 154

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Ove

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ival

(%)

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4+ positive nodes

Fig. 1. Fifteen-year actuarial values and frequencies of LLR and survival as a function of number of positive lymph nodes and postmastectomyradiotherapy.

Table 2The Bottom line estimate

Parameter 1–3 pos. nodes 4+ pos. nodes

Endpoint: loco-regional recurrenceRelative risk reduction 87% 82%Absolute risk reduction 20% 24%Number of patients needed to treat to avoid an LRR 5 4

Endpoint: deathRelative risk reduction 17% 11%Absolute risk reduction 9% 10%Number of patients needed to treat to avoid a death 11 10

Relative and absolute risk reduction and number of patients needed to treat to achieve benefit of postmastectomy radiotherapy as afunction of number of positive lymph nodes. Estimates are calculated for the benefit of avoiding an isolated first loco-regional recurrence ordeath.

250 DBCG 82 b&c postmastectomy radiotherapy

DiscussionThe results from the present subgroup analysis strongly

indicate that the benefit of postoperative radiotherapy isequally pronounced in patients with 1–3 nodes positiveand in patients with 4+ nodes. Thus, the present resultsmay compensate for the lack of more evidence in order torecommend radiotherapy in patients with 1–3 nodes posi-tive along with patients with 4+ nodes, where it is a stan-dard treatment. This has also been pointed out before,but apparently not with sufficient strength to influencethe consensus reports [7,18,19].

In addition to the data presented here, there is accumu-lating information from other subgroup analyses that sup-ports our results. Thus, the 20-year results of the BritishColombia study have shown that the impact of radiationtherapy for all survival outcomes in the subgroup with 1–3nodes involved was similar to the subgroup with 4+ nodes in-volved and had a magnitude of risk reduction, which forboth groups were of the same order as in the present sub-group analysis [20]. Further, in the 2005 EBCTCG overview[8] additional data are presented (Annex-figures 2d and2e) which indicate the same benefit of radiotherapy to


Loco

-regi

onal

recu

rrenc

e (%

)

0

20

40

60

80

100

RT

no RT

p<0.001

27%

4%


RT 276 197 173 136no RT 276 165 131 106

1-3 positive nodes


Loco

-regi

onal

recu

rrenc

e (%

)

0

20

40

60

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100

no RT

p<0.001

51%

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RT 287 101 64 51no RT 313 72 35 23

4+ positive nodes

RT


Ove

rall

surv

ival

(%)

0

20

40

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RT

no RTp=0.03

57%

48%


RT 276 224 187 129no RT 276 220 164 154

1-3 positive nodes


Ove

rall

surv

ival

(%)

0

20

40

60

80

100

RT

no RT

p=0.03

21%

12%


RT 287 132 83 59no RT 313 125 65 37

4+ positive nodes

Fig. 1. Fifteen-year actuarial values and frequencies of LLR and survival as a function of number of positive lymph nodes and postmastectomyradiotherapy.

Table 2The Bottom line estimate

Parameter 1–3 pos. nodes 4+ pos. nodes

Endpoint: loco-regional recurrenceRelative risk reduction 87% 82%Absolute risk reduction 20% 24%Number of patients needed to treat to avoid an LRR 5 4

Endpoint: deathRelative risk reduction 17% 11%Absolute risk reduction 9% 10%Number of patients needed to treat to avoid a death 11 10

Relative and absolute risk reduction and number of patients needed to treat to achieve benefit of postmastectomy radiotherapy as afunction of number of positive lymph nodes. Estimates are calculated for the benefit of avoiding an isolated first loco-regional recurrence ordeath.

250 DBCG 82 b&c postmastectomy radiotherapy

RT reduced15-yr LRFR from 27% to 4% (p < 0.001), 15-yr survival benefit after RT was significantly improved (57% vs 48%, p = 0.03)

Overgaard et al, Radiother Oncol. 2007

Danish 82b+c : subgr LN >=8


EBCTCG meta-analysis • 8135 women from 22 trials

EBCTCG, Lancet 2014

Articles

2130 www.thelancet.com Vol 383 June 21, 2014

nodal status was known and who were classifi ed as having axillary dissection (however, for 45 women with node-positive disease, the number of nodes aff ected was not known); all of these women were in trials in which radiotherapy included the chest wall, the supraclavicular or axillary fossa (or both), and the internal mammary chain (appendix pp 10–12).

Of the 1594 women with node-negative disease, 700 (44%) had axillary dissection, 870 (55%) had axillary sampling, and for 24 (1%) the extent of axillary surgery was unknown. For the 700 women who had axillary dissection, only 1·4% of unirradiated women had a locoregional recurrence before a distant recurrence (appendix p 14), and radiotherapy had no signifi cant eff ect on locoregional recurrence (2p>0·1), overall recurrence (rate ratio [RR], irradiated vs not, 1·06, 95% CI 0·76–1·48, 2p>0·1), or breast cancer mortality (RR 1·18,

95% CI 0·89–1·55, 2p>0·1; fi gure 2A–C). Radiotherapy did, however, increase overall mortality (RR 1·23, 95% CI 1·02–1·49, 2p=0·03; appendix p 13). By contrast, for the 870 women with node-negative disease who had only axillary sampling, 16·3% of unirradiated women had a locoregional recurrence before any distant recurrence (appendix p 37), and radiotherapy reduced locoregional recurrence (2p<0·00001) and overall recurrence (RR 0·61, 95% CI 0·47–0·80, 2p=0·0003), but had no signifi cant eff ect either on breast cancer mortality (RR 0·97, 95% CI 0·77–1·22, 2p>0·1) or on overall mortality (RR 1·00, 95% CI 0·84–1·18, 2p>0·1; appendix p 36).

Of the 5821 women with node-positive disease, 3131 (54%) had axillary dissection, 2541 (44%) had axillary sampling, and for 149 (2%) the extent of axillary surgery was unknown. Radiotherapy reduced locoregional recurrence and overall recurrence both for women who

0

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RT34·2%

B Any first recurrence

Any first recurrence

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20-year gain 7·9% (SE 3·1)RR 0·80 (95% CI 0·67!0·95)log-rank 2p=0·01

No RT50·2%

RT42·3%

C Breast cancer mortality

Locoregional recurrence first Breast cancer mortality

0 5 10 15 200

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No RT75·1%RT66·3%

E1772 pN4+ women with Mast+AD

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F

1314 pN1–3 women with Mast+AD

Figure !: E! ect of radiotherapy (RT) after mastectomy and axillary dissection (Mast+AD) on 10-year risks of locoregional and overall recurrence and on 20-year risk of breast cancer mortality in 1314 women with one to three pathologically positive nodes (pN1–3) and in 1772 women with four or more pathologically positive nodes (pN4+)Analyses of locoregional recurrence fi rst ignore distant recurrences, see appendix pp 8–9 for details. See appendix pp 19, 28, for analyses of both locoregional and distant recurrences, and appendix pp 18, 27, for analyses of overall mortality. RR=rate ratio. NS=not signifi cant. Vertical lines indicate 1 SE above or below the 5, 10, 15, and 20 year percentages.

PMRT reduced LRR, overall recurrence, and breast cancer mortality (SS)86% received CMF or tamoxifen


ASCO-ASTRO-SSO

• Is PMRT indicated in T1-2 with 1-3 LN+ who undergo ALND?

• Is PMRT indicated in T1-2 with SNB+ who do not undergo completion ALND?

• Is PMRT indicated in clinical stage I or II who have received neoadjuvant systemic therapy?

• Should regional nodal irradiation (RNI) include the internal mammary (IMNs) and/or supraclavicular-axillary apical nodes when PMRT is used in patients with T1-2 with 1-3 LN+

A Recht , JCO 2016


ASCO-ASTRO-SSO

• Risk factors

• age

• limited life expectancy (old , comorbidities)

• Tumor size

• LVI

• biologic characteristic

some subsets of these patients are likely to have such

a low risk of LRF that the absolute benefit of PMRT is

outweighed by its potential toxicities

A Recht , JCO 2016


SUPREMO ( BIG 2-04)

-pT1-2, pN1, M0 -pT2, pN0 + grade III and/or LVI -Multifocal breast cancer if largest discrete tumour at least 2cm if N0 and grade III and/or LVI-Multiple small adjacent foci of IDC (overall maximum dimension >2cm.) and grade III and/or LVI

PMRT vs no PMRT

RT field : CW, SCV,IFV, IMN 50Gy/25Fx, 40-45Gy/15-20FxSaturday, January 20, 18

LN1-3 in BCS

EBCTCG, Lancet 2011

Articles

www.thelancet.com Vol 378 November 12, 2011 1709

(category A, 4398 women), four were of radiotherapy after sector resection or quadrantectomy (category B, 2399 women), and seven more recent trials were of radiotherapy after lumpectomy in low-risk women (category C, 4004 women). In most of the trials radiotherapy was to the conserved breast only (webappendix p 4). Median follow-up was 9·5 years at risk per woman and 25% of women were followed up for more than a decade. 3143 (29%) had died by the fi nal follow-up date of Sept 30, 2006.

The 10-year risk of any (locoregional or distant) fi rst recurrence was 19·3% in women allocated to radiotherapy and 35·0% in women allocated to breast-conserving surgery only, corresponding to an absolute risk reduction of 15·7% (95% CI 13·7–17·7, 2p<0·00001; fi gure 1). Nearly three-quarters of fi rst recurrences in the no radiotherapy group were locoregional (25% locoregional fi rst, 10% distant fi rst), compared with fewer than half of those in the radiotherapy group (8% locoregional fi rst, 12% distant fi rst; webappendix p 9). In addition to reducing recurrence substantially, radiotherapy also reduced breast cancer death by a moderate amount: the 15-year absolute risk reduction was 3·8% (95% CI 1·6–6·0, 2p=0·00005), suggesting on average about one breast cancer death avoided for every four recurrences avoided by radiotherapy.

Allocation to radiotherapy halved the average annual rate of any fi rst recurrence (rate ratio [RR] 0·52, 95% CI 0·48–0·56, fi gure 1). The proportional reduction was greatest in the fi rst year (0·31, 0·26–0·37), but was still substantial during years 5–9 (0·59, 0·50–0·70; web-appendix p 13). Beyond year 10 there was no evidence of any further eff ect on the fi rst recurrence rate, but information about recurrence in this period was incomplete so the number of events was small and the CI wide (fi gure 1). Radiotherapy reduced the annual breast cancer death rate by a sixth (RR 0·82, 0·75–0·90). The timing of breast cancer death diff ered from that of fi rst recurrence, with few events during the fi rst year

(fi gure 1), and there were substantial numbers of breast cancer deaths after year 10.

Mortality without recurrence from non-breast-cancer causes was slightly higher in women allocated to radio-therapy than in women allocated to breast-conserving

Figure !: E! ect of radiotherapy (RT) after breast-conserving surgery (BCS) on 10-year risk of any (locoregional or distant) fi rst recurrence and on 15-year risks of breast cancer death and death from any cause in 10 801 women (67% with pathologically node-negative disease) in 17 trialsFurther details are in webappendix p 5. RR=rate ratio. Rate ratios in this fi gure include all available years of follow-up.

Figure ": E! ect of radiotherapy (RT) after breast-conserving surgery (BCS) on 10-year risk of any (locoregional or distant) fi rst recurrence and on 15-year risk of breast cancer death in women with pathologically verifi ed nodal statusVertical lines indicate 1 SE above or below the 5, 10, and 15 year percentages. Further details are in webappendix pp 6–7. pN0=pathologically node-negative. pN+=pathologically node-positive. RR=rate ratio. Rate ratios in this fi gure include all available years of follow-up.

0 5 10 150

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eath

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Any death10-year gain 15·7% (SE 1·0)RR 0·52 (95% CI 0·48–0·56)Log-rank 2p<0·00001

15-year gain 3·8% (SE 1·1)RR 0·82 (95% CI 0·75–0·90)Log-rank 2p=0·00005


BCS35·0%

19·3%BCS+RT

BCS25·2%

BCS37·6%

21·4%BCS+RT

34·6%BCS+RT25·6%

7·8%

12·6%6·8%

14·2%

17·2%

24·6%

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Women with pN0 disease (n=7287)

Women with pN+ disease (n=1050)

0

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00

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)

10-year gain 15·4% (SE 1·1)RR 0·49 (95% CI 0·45–0·55)Log-rank 2p<0·00001

10-year gain 21·2% (SE 3·4)RR 0·53 (95% CI 0·44–0·64)Log-rank 2p<0·00001



BCS31·0%

15·6%BCS+RT

BCS20·5%17·2%BCS+RT

BCS63·7%

42·5%BCS+RT

BCS51·3%

42·8%BCS+RT

22·5%

10·6%

12·7%

5·5%10·9%

4·6%

42·6%

34·2%22·4%

19·8%

31·1%

53·7%

RT reduced 10-yr recurrence risk from 63·7% to 42·5% and15-year risk of breast cancer death from 51·3% to 42·8%


trial MA20 EORTC

m-age(yr) 54 54

surgery BCS 100% MRM 25%BCS 75%

pT T1 55%T2 45%

T1 60%T2 35%

pN N0 10%N1 85%

N0 45%N1 43%

tumor location N/A M/Cent

dose RT(Gy) Breast/RNI 50 Breast/CW/RNI 50

Whelan , N Engl J Med. 2015 Poortmans, N Engl J Med. 2015


trial MA20MA20 EORTCEORTC

F/U (yr) 9.59.5 10.910.9

Arm WBIWBI

+MS+IMN WBIWBI

+MS+IMN

local only recurrence LR-DFS

92.2%LR-DFS

95.2% (SS)

5.3 5.6

regional recurrence

LR-DFS92.2%

LR-DFS95.2% (SS)

4.2 2.7

distant mets 16.5 12.9 19.6 15.9

DFS 7782

(SS) 69.172.1(SS)

OS 81.882.8(NS) 80.7

82.3(NS)

Breast Camortality

12.310.3(NS) 14.4

12.5(SS)

any 1st recurrence 22.9% vs19.4% (SS)Saturday, January 20, 18

One Size fits all


Volume of RT• Is PMRT indicated in T1-2 with 1-3 LN+ who undergo ALND?

• Is PMRT indicated in T1-2 with SNB+ who do not undergo completion ALND?

• Is PMRT indicated in clinical stage I or II who have received neoadjuvant systemic therapy?

• Should regional nodal irradiation (RNI) include the internal mammary (IMNs) and/or supraclavicular-axillary apical nodes when PMRT is used in patients with T1-2 with 1-3 LN+

ASCO-ASTRO-SSO


Study FrenchFrench EORTCEORTC MA20MA20 DanishDanish

Pts 13321332 40044004 18321832 30893089

m F/U (yr)

8.68.6 10.910.9 9.59.5 8.98.9

RT fieldCW+SC/ICCW+SC/IC Breast/

CW(25%)Breast/

CW(25%)BreastBreast Breast/CW

+SC/ICBreast/CW

+SC/ICRT field-IMN +IMN -RNI SC/IC/

IMN-RNI SC/IC/

IMN-IMN +IMN

DFS 50% 53%NS

69% 72% (SS)

77% 82% (SS)

- -

distant DFS

- - 75% 78% 83% 87% 70% 73%

Breast CSS

- - 14% 12% (SS)

12% 10% 23% 21%

OS 59% 63% 81% 82% 91% 92% 72% 76%(SS)


consensus• both the IMN and supraclavicular-axillary

apical areas should generally be treated when PMRT is used for LN+

• some subgroups may limit benefit , RT can result in toxicities with lungs/heart ???

• full axilla RT : not radiated after ALND (low rate recur , lymphedema)

• full axilla RT in extensive bulky involvement

Abram Rechf,Cancer 1995A Recht , JCO 2016


RT after neoadjuvant systemic treatment


study NmF/U(yr) stage

10 yr LRR(%)10 yr LRR(%) 10 yr OS(%)10 yr OS(%)study N

mF/U(yr) stage

RT -RT RT -RT

MDACC 676 ~6II 30%III 70% 11 22

p0.00154 47

p0.06

McGuire 106 5II 30%III 70% 5

10p0.4 77.3

33.3p0.001

LeScodan 134 7.6II 63%III 37% 4 12 77.2 87.8

p0.15

KROG 151 5II 60%III 40% 1.9

6.5(NS) 93

90(NS)


ugene H. Huang, JCO 2003no radiation, P ! .063). Because a greater percentage ofpatients who did not receive radiation died of intercurrentdisease, we focused our analyses on CSS. The 10-year actu-arial rates of CSS were nearly identical in the two groups(58% for radiation v 55% for no radiation, P ! .85). Table 5presents the associations between radiation treatment andCSS for various subgroups. On univariate analysis, radia-tion improved CSS rates in patients with clinical stage IIIBto stage IV disease, clinical T4 tumors, or four or morepositive nodes (P ! .007 for all comparisons; Figs 3A to C).For these three subgroups, the benefit of radiation withrespect to OS was also highly significant (42% v 20%, 42% v20%, and 38% v 15%; P ! .0002 for all comparisons).

Multivariate Cox regression analysis of factors associ-ated with CSS for all 676 patients (Table 6) revealed that thehazard ratio for lack of radiation treatment was 2.0 (95% CI,1.4 to 2.9; P " .0001). Other factors found to be significantfor worse CSS included: clinical stage IIIB to stage IV dis-ease, residual pathological tumor involvement after chemo-therapy, four or more positive nodes, minimal or worse

clinical response to neoadjuvant chemotherapy, fewer than10 axillary nodes sampled, no tamoxifen, and estrogen re-ceptor–negative disease (P ! .03 for all comparisons). Onunivariate analyses of the entire study population, achieve-ment of a clinical complete response (79% v 54%, P " .001)or a pathological complete response (95% v 55%,P " .001) were associated with higher CSS. However,neither clinical nor pathological complete response toneoadjuvant chemotherapy was independently associ-ated with CSS in the multivariate model.

A separate analysis was completed (n ! 713), whichincluded the 37 patients who were treated with preoper-ative radiation. The results of this analysis continued toshow significant differences with the irradiated cohortand its subgroups having lower rates of LRR and higherrates of CSS.

Table 4. Multivariate Analysis of LRR

Factor Hazard Ratio 95% CI P

No radiation 4.68 2.70 to 8.13 " .0001" 20% sampled nodes positive 3.58 2.11 to 6.08 " .0001Stage " IIIB 2.38 1.42 to 4.02 .001No tamoxifen 2.19 1.19 to 4.06 .012Minimal or worse clinical response to neoadjuvant chemotherapy 1.88 1.10 to 3.23 .021Estrogen receptor–negative 1.69 1.04 to 2.76 .033

Abbreviation: LRR, local-regional recurrence.

Fig 2. Rate of local-regional recurrence (LRR) for patients who initially hadclinical stage III or IV advanced disease but subsequently achieved apathological complete response to neoadjuvant chemotherapy. RT, withradiation; No RT, without radiation.

Table 5. Ten-Year Actuarial Rates of CSS According to Clinicaland Pathological Disease Status

Factor

10-Year CSS Rate

PNo Radiation (%) Radiation (%)

Combined clinical stageI-II 73 71 .482IIIA 64 70 .742" IIIB 22 44 .002

Clinical T-stageT1 80 92 .550T2 56 66 .977T3 71 69 .878T4 24 45 .007

Clinical N-stageN0 65 62 .749N1 66 64 .818N2-3 27 49 .024

Pathological tumor size, cm0-2 64 69 .1682.1-5.0 49 53 .887" 5.1 25 37 .577

No. of positive nodes0 67 81 .2711-3 70 56 .179" 4 18 44 .005

Abbreviation: CSS, cause-specific survival.

Huang et al

4696 JOURNAL OF CLINICAL ONCOLOGY

Downloaded from jco.ascopubs.org on September 6, 2016. For personal use only. No other uses without permission.Copyright © 2004 American Society of Clinical Oncology. All rights reserved.

cIIIB

cT4

cN2-3

ypN2

MDACC


study NmF/U(yr) stage

10 yr LRR(%)10 yr LRR(%) 10 yr OS(%)10 yr OS(%)study N

mF/U(yr) stage

RT -RT RT -RT

MDACC 676 ~6II 30%III 70% 11 22

p0.00154 47

p0.06

McGuire 106 5II 30%III 70% 5

10p0.04 77.3

33.3p0.001

LeScodan 134 7.6II 63%III 37% 4 12 77.2 87.8

p0.15

KROG 151 5II 60%III 40% 1.9

6.5(NS) 93

90(NS)


LRR , DMFS, CSS, and OS rates differed significantly between irradiated and nonirradiated patients who presented with Stage III disease.

abdomen and pelvis had been negative for DM at the timeof diagnosis. After three cycles of neoadjuvant chemother-apy, the patient underwent a mastectomy and was found tohave a pCR. The patient then received adjuvant chemother-apy as planned but developed leptomeningeal metastaticdisease 3 months after surgery. It could not be retrospec-tively determined whether the development of DM discour-aged the use of postmastectomy radiation therapy. To ac-count for this potential source of bias, we recalculated theoutcome statistics excluding the data on this patient. Forpatients with clinical Stage III disease, the LRR rates did notchange, and the differences in DMFS, CSS, and OS re-mained significantly different.

DISCUSSION

A number of studies have indicated that patients whoachieve a pCR after neoadjuvant chemotherapy have anexcellent prognosis, with a significantly lower risk of de-veloping a distant metastases and a lower risk of dyingcompared with patients who have residual disease afterneoadjuvant chemotherapy. However, few published studieshave addressed how an achievement of pCR should affectlocal-regional treatment decisions. In this study, we showed

Table 2. Univariate analysis of factors associated with local-regional recurrence (LRR) after a pathologic complete response

(pCR) in patients with Stage III disease treated with mastectomy

CharacteristicNo. ofpatients

10-Year actuarialLRR rate p Value

Age 0.27!50 years 50 14.3!50 years 24 5.3

Clinical T stage 0.43T1 3 0T2 8 27T3 30 7T4 31 12

Clinical N stage 0.46N0 5 20N1 31 4.2N2 22 11.5N3 13 15.4

Menopausal status 0.55Premenopausal 44 13.9Postmenopausal 28 8.0

Histology 0.67Ductal 61 11.5Lobular 2 0

Estrogen receptor status 0.24Positive 12 0Negative 42 14.3

Progesterone receptorstatus

0.36

Positive 9 0Negative 37 12.5

Lymphovascularinvasion status

0.063

Yes 6 45No 68 8.5

Nuclear grade 0.232 13 03 54 13.0

No. of lymph nodesexamined

0.68

!10 18 6!10 55 11.1

Radiation therapy given 0.04Yes 62 7.2No 12 33.4

Fig. 2. Freedom from distant metastases (DM) in patients withclinical Stage III breast cancer treated with neoadjuvant chemo-therapy and mastectomy with or without radiation therapy ("XRTand #XRT, respectively).

Fig. 3. Overall survival in patients with Stage III breast cancertreated with neoadjuvant chemotherapy and mastectomy with orwithout radiation therapy ("XRT and #XRT, respectively).

1007Postmastectomy RT after pathologic complete response ! S. E. MCGUIRE et al.

SEAN E. MCGUIRE,Int. J. Radiation Oncology Biol. Phys., Vol. 68, 2007

pCR was defined as a negative invasive ca both in breast and LN


predictor of LRR

• data from NSABP B18 + 27

• NAC -> Surgery

• MRM patients did not get PMRT

Mamounas et al, J Clin Oncol 30.2012


clinical stage ypN+ypN-/no

breast pCR pCR

T1-2N0 11% 6% 7%

T3N0 14-53% 13% 0-8%

T1-2N1 15-27% 10% 0-9%

N2 or T3N1 or T4N0-1 16-40%16-40%16-40%

PMRT after neoadjuvant chemotherapy

no RT with other risk factorsyoung age, breast subtype

slide courtesy to Alice Ho,M.D.


PMRT after neoadjuvant systemic treatment

clinical stage III, cN2-3, ypN+(even in pCR)

PMRT

clinical stage II , cN1->ypN0PMRT if with 2-3 risk factors

(young age, grade3, TNBC,Her2+, ypT2-3)

clinicalN0 -> ypN0 no PMRT


• consider that radiotherapy following neoadjuvant chemotherapy should in general be directed to the extent of disease before therapy

1

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]

Tailoring therapies - improving the management of early breast cancer: St

GallenInternational Expert Consensus on the Primary Therapy of Early Breast

Cancer 2015.

A. S. Coates1, E. P. Winer2, A. Goldhirsch3, R. D. Gelber4, M. Gnant5, M. Piccart-Gebhart6, B.

Thürlimann7, H.-J. Senn8 and Panel members†

1International Breast Cancer Study Group and University of Sydney, Sydney, Australia

2Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston,

USA

3International Breast Cancer Study Group, Program of Breast Health (Senology), European Institute

of Oncology, Milan, Italy

4International Breast Cancer Study Group Statistical Center, Department of Biostatistics and

Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA

5Department of Surgery and Comprehensive Cancer Center, Medical University of Vienna, Vienna,

Austria

6Internal Medicine/Oncology, Institut Jules Bordet, Brussels, Belgium

7Breast Center, Kantonsspital St Gallen, St Gallen, Switzerland

8Tumor and Breast CenterZeTuP, St Gallen, Switzerland

†See Appendix 1

Key Message: "The 14th St. Gallen International Breast Cancer Conference (2015) reviewed substantial new evidence on locoregional and systemic therapies for early breast cancer."

Annals of Oncology Advance Access published May 4, 2015

by guest on September 6, 2016

http://annonc.oxfordjournals.org/D

ownloaded from

A. S. Coates,Annual Oncology 2015

PMRT after neoadjuvant systemic treatment


ongoing trials

RNI-BCS:breast +RNI-MRM:CW+RNI

no RNI-BCS: breast -MRM:no RT

CT1-3N1M0

Neoadj systemicTx

surgery SLNB/ALND

NRG9353 Alliance A11101

no ALNDbreast/CW +RNI

ALNDbreast/CW +RNI

pN0 pN+


Others

• phyllodes

• breast ca in pregnancy

• inflammatory breast


phyllodes tumor ( cystosarcoma)

• rare fibroepithelial tumors

• rapid growing presentation

DDx Benign Borderline Malignant

fibroademoma metaplastic carcinoma, primary breast sarcoma

metaplastic carcinoma, primary breast sarcoma


Histo features Benign Borderline Malignant

stromal cellularity mild moderate marked

stromal atypia mild moderate marked

mitosis(/10-HPF) <5 5-9 >+10

stromal overgrowth absent absent/focal present

tumor margin well-definedwell-defined/

focal infiltrative infiltrative

WHO classification 2012


phyllodes tumor treatment

• BCS/mastectomy

• rarely metastasize to the axillary LNs -> surgical axillary staging not necessary

• unless clinical LN+

• resected margin : at least 1 cm

• adjuvant radiation


characteristics between RT and non-RT groups are the major limi-tations of this study. Detailed histopathologic data includingresection margin status were unavailable. Moreover, grade and LNstatus were not reported in more than 50% of patients. In addition,SEER data does not provide data of local recurrence and distantmetastasis. Therefore, for more precise analyses on clinical benefitsof RT for MPTB, investigations for multiple endpoints arewarrantedwith more various clinico-pathologic factors.

5. Conclusion

In the analysis of SEER 18 data (1983e2013), MPTB patients withmore adverse prognostic factors were treated with postoperativeRT, and CSS was not statistically different from non-RT group,regardless of type of surgery (mastectomy or BCS).

Conflict of interest statement

None.

Funding source

This research did not receive any specific grant from fundingagencies in the public, commercial, or not-for-profit sectors.

Appendix A. Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.breast.2016.12.006.

References

[1] Kessinger A, Foley JF, Lemon HM, Miller DM. Metastatic cystosarcoma phyl-lodes: a case report and review of the literature. J Surg Oncol 1972;4:131e47.

[2] Parker S, Harries S. Phyllodes tumours. Postgrad Med J 2001;77:428e35.[3] Chaney AW, Pollack A, Mcneese MD, Zagars GK, Pisters PW, Pollock RE, et al.

Primary treatment of cystosarcoma phyllodes of the breast. Cancer 2000;89:1502e11.

[4] Salvadori B, Cusumano F, Del Bo R, Delledonne V, Grassi M, Rovini D, et al.Surgical treatment of phyllodes tumors of the breast. Cancer 1989;63:2532e6.

[5] Treves N, Sunderland DA. Cystosarcoma phyllodes of the breast: a malignantand a benign tumor. A clinicopathological study of seventy-seven cases.Cancer 1951;4:1286e332.

[6] Mitus J, Reinfuss M, Mitus JW, Jakubowicz J, Blecharz P, Wysocki WM, et al.Malignant phyllodes tumor of the breast: treatment and prognosis. Breast J2014;20:639e44.

[7] Reinfuss M, Mitu!s J, Duda K, Stelmach A, Ry!s J, Smolak K. The treatment andprognosis of patients with phyllodes tumor of the breast: an analysis of 170cases. Cancer 1996;77:910e6.

[8] Guillot E, Couturaud B, Reyal F, Curnier A, Ravinet J, Lae M, et al. Managementof phyllodes breast tumors. Breast J 2011;17:129e37.

[9] Ben Hassouna J, Damak T, Gamoudi A, Chargui R, Khomsi F, Mahjoub S, et al.Phyllodes tumors of the breast: a case series of 106 patients. Am J Surg2006;192:141e7.

[10] ChenWH, Cheng SP, Tzen CY, Yang TL, Jeng KS, Liu CL, et al. Surgical treatmentof phyllodes tumors of the breast: retrospective review of 172 cases. J SurgOncol 2005;91:185e94.

[11] Pandey M, Mathew A, Kattoor J, Abraham EK, Mathew BS, Rajan B, et al.Malignant phyllodes tumor. Breast J 2001;7:411e6.

[12] Macdonald OK, Lee CM, Tward JD, Chappel CD, Gaffney DK. Malignant phyl-lodes tumor of the female breast. Cancer 2006;107:2127e33.

[13] Pezner RD, Schultheiss TE, Paz IB. Malignant phyllodes tumor of the breast:local control rates with surgery alone. Int J Radiat Oncol Biol Phys 2008;71:710e3.

[14] Belkac!emi Y, Bousquet G, Marsiglia H, Ray-Coquard I, Magn!e N, Malard Y, et al.Phyllodes tumor of the breast. Int J Radiat Oncol Biol Phys 2008;70:492e500.

[15] Barth Jr RJ, Wells WA, Mitchell SE, Cole BF. A prospective, multi-institutionalstudy of adjuvant radiotherapy after resection of malignant phyllodes tumors.Ann Surg Oncol 2009;16:2288e94.

[16] Gnerlich JL, Williams RT, Yao K, Jaskowiak N, Kulkarni SA. Utilization of

Table 6Treatment outcomes of postoperative radiation therapy for borderline or malignant phyllodes tumors of the breast.

Study Patient source Patient no.(malignant/borderline)

TreatmentGroup (No.)

Resection margin RT dose Local control Survival

Macdonaldet al. [12],2006

SEER database(1983e2002)

821/0 BCS (1636)BCS ! RT (202)MS (1109)MS ! RT (254)

NA NA NA 10-year CSS(tumor <5 cm)(overall p < 0.01)-BCS 98%*-BCS ! RT 80%*-MS 88%*-MS ! RT 48%*

10-year CSS(tumor "5 cm)(overall p < 0.02)-BCS 96%*-BCS ! RT 100%*-MS 85%*-MS ! RT 60%*

Belkacemiet al. [14],2008

The Rare CancerNetwork

79/80 BCS (109)MS (50)RT (32)

Negative 43%Positive 15%NA 42%

37-60 Gy 10-year local control-Non-RT 59%-RT 86% (p # 0.02)

No effect on DFS or OS

Barthet al. [15],2013

A prospectivestudy

40/16 All BCS Negative 100% 50.4 Gy/28 Fx!10 Gy/5Fx

100% Mortality 7%

Zenget al. [19],2014

A meta-analysis of8 studies

2699/109 BCS (NA)BCS ! RT (NA)MS (NA)MS ! RT (NA)

Negative ~90% 45-70 Gy HR of RT-BCS 0.31 (0.10e0.72)-MS 0.68 (0.28e1.64)

No effect on DFS or OS

Mituset al. [6],2014

A singleinstitutional data

70/0 MS (34)BCS withRM " 1 cm (30)BCS ! RT withRM < 1 cm (6)

Negative 100% 50.4 Gy/28 Fx!10 Gy/5 Fx

100% 5-year DFS-MS 82.4%-BCS with RM " 1 cm 83.3%-BCS ! RT with RM < 1 cm 83.3%

Gnerlichet al. [16],2014

The NationalCancer Data Base

3120/0 BCS (1636)BCS ! RT (202)MS (1109)MS ! RT (254)

R0 87%%R1/R2 8%

NA HR of RT-BCS 0.43 (0.19e0.95)-MS 0.64 (0.19e2.21)

5-year OS (overall p < 0.001)-BCS 94%*-BCS ! RT 88%*(p # 0.064)-MS 77%*-MS ! RT 72%*(p # 0.064)

Abbreviations: RT, radiation therapy; SEER, the Surveillance, Epidemiology, and End Results; BCS, breast conserving surgery; MS, mastectomy; RM, resection margin; NA, notavailable; CSS, cancer-specific survival, DFS, disease-free survival; OS, overall survival; Fx, fractions; CI, confidence interval; HR, hazard ratio.*The values were read from the graphs.

Y.-J. Kim, K. Kim / The Breast 32 (2017) 26e32 31


study Pts T (cm.)grade(M/B)

RT dose Conclusion

Haberer 22 6.5 22/0 45-55 Uncertain

Soumarova 25 10 25/0 46-70 RT decrease LRR

Pandey 36 10.8 36/0 45-50RT decrease LRRimprove survival

Kim 42 4 13/29 NA uncertain

Belkacemi 159 4.6 79/80 37-60 RT decrease LRR

Gnerlich 3,210 4.2 3,210/0 NA RT decrease LRR

Badar 32 9.2 32/0 NA uncertain

Macdonald 618 NA 618/0 uncertain


Phyllodes Tumor

Clinical suspicion of phyllodes tumor:● Palpable mass● Rapid growth● Imaging with ultrasound suggestive of fibroadenoma except for size (greater than 2 cm) and/or history of rapid growth

Core needle biopsy1,2

1 Fine needle aspiration will not, and core biopsy may not, distinguish fibroadenoma from phyllodes tumor in most cases (tumor heterogenity may not allow for a definitive diagnosis as some phyllodes arise in a background of fibroadenoma )2 It is recommended that the review of the pathology material be performed by a pathologist who is experienced in phyllodes tumor3 If initially excised with negative margin, wide local excision not required4 Referral to a multidisciplinary sarcoma center for treatment recommendations is appropriate for malignant phyllodes tumor or one with stromal overgrowth5 For patients with malignant phyllodes tumor on pathology review, refer to Adult Soft - Tissue Sarcoma for Clinical Stage III algorithm6 There is no prospective randomized data supporting the use of radiation treatment (XRT) with phyllodes tumor. If the phyllodes tumor of the breast is benign or borderline histology, radiation therapy not routinely recommended after excision. If the tumor has malignant features (i.e., stromal overgrowth, cellular atypia, high number of mitoses) radiotherapy can be considered as follows: ● If mastectomy is performed and margins negative, do not recommend XRT ● If mastectomy was performed and margins were concerning/close, tumor involved the fascia or chest wall, or tumor was very large (greater than 5 centimeters), consider XRT to chest wall ● If partial mastectomy only is performed, consider adjuvant XRT to breast, especially if margins are less than 1 cm7 Excisional biopsy includes complete mass removal, but without the intent of obtaining widely negative surgical margins

INITIAL EVALUATION

Page 1 of 4

Fibroadenoma

● History and physical exam● Ultrasound● Mammogram for women greater than or equal to 30 years of age

Close clinical follow-up

Phyllodes tumor includes benign3,

borderline and malignant4,5

Wide excision3 without axillary staging

Invasive or in situ breast cancer See Breast cancer - Invasive or Noninvasive Algorithm

Fibroepithelial lesion or

indeterminate pathology2

Excisional biopsy7

Review final pathology

Review final pathology ● If benign or borderline, observe● If malignant, consider radiation therapy4,5,6

● If greater than 5 cm with stromal overgrowth, refer to Adult Soft – Tissue

Sarcoma for Clinical Stage III Algorithm

Fibroadenoma

Phyllodes, including benign, borderline and malignant

This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson, including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not intended to replace the independent medical or professional judgment of physicians or other health care providers . This algorithm should not be used to treat pregnant women.

Note: Consider Clinical Trials as treatment options for eligible patients.

TREATMENTPATIENT PRESENTATION

Observation

Department of Clinical Effectiveness V7Approved by Executive Committee of the Medical Staff 10/31/2017

- benign/ borderline : not routinely RT - malignant : RT

● If mastectomy and margins negative = NO RT● If mastectomy and margins closed , T involved the fascia or chest wall, or tumor > 5 cm.= RT● If partial mastectomy = RT


RT in phyllodes tumor

• controversy, lack of clear randomized studies

• adjuvant RT : no OS benefit

• adjuvant RT in malignant ( BCS, tumor > 5-10cm, close margin)

• not routinely in borderline

• dose 50-60 Gy


Breast CA in Pregnancy

1st trimester2nd trimester

3rd trimester

postpartum

Endocrine

RT

surgery (MRM/BCS)chemotherapy(neoadj/adj)

terminationsurgery(MRM)

Gwyn K, Oncology 2001;15:39-46.


Breast CA in Pregnancy

2nd trimester

3rd trimester

surgery: SLN (No blue dye, Yes sulfur colliod)

chemotherapy (fetal malformation 1-2%) - not AFTER 35 wk or 3 wk before delivery - Doxorubicin ,taxane wkly

Johnson PH,. J Clin Oncol 2005;23


inflammatory BC (IBC), T4d

• 1-6%

• clinical diagnosis that requires erythema and dermal edema (peau d’orange) of a third or more of the skin of the breast.

• blockage of dermal lymphatics by tumor emboli.

• a biopsy look at the presence of cancer in breast tissue and the dermal lymphatics (not required)

• DDx : cellulitis, mastitis


mastitis

usually : HR - , HER2+


Treatment

• neoadjuvant systemic (CMT/targeted therapy)

• surgery : MRM ( BCS not recommended)

• adjuvant radiation


RT in IBC

• dose

• fractionation


Is more better?

the data favor increased LRC using doses of 60–66 Gy.Woodward, Int J Radiat Oncol Biol Phys. 2014

study N Dose 5-yr LRC (%)

MDACC 125 60Gy (50Gy+boost10Gy)66Gy (1.5Gy bid)

91

Cleveland 104 45-66 Gy, bolus NS 83

Florida 61 42-60Gy, qd bolus 78

MSKCC 107 50Gy, qd bolus 87

Mayo 49 60-66Gy, qd bolus 81

Penn 19 46-50Gy,qod bolus 88

BCCA 148 42.4Gy (hypoFx), bolus NS 63


https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=25035202

https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=25035202

Hyperfractionationstudy N Dose mF/U

month

Local control

rate

DFS OS

Gurney 1998

19 69Gy/44Fx(1.5Gy BID)

37 58% 25.3 18

Liao 2000 57

60Gy/40Fx(1.5bid) 68

57.8 26 35Liao 2000 57

66Gy/44Fx(1.5bid)68

84.3 39 46

Bristol 2008 192

60Gy66Gy

20% OD80% bid

64

78888184

51

Gurney, Aust N Z J Med. 1998

SS

Bristol, Int. J. Radiation Oncology Biol. Phys., 2008Liao, Int. J. Radiation Oncology Biol. Phys., 2000


mastectomy and postmastectomy radiation had a 5-year OSrate of 51%—an encouraging result given that IBC wasonce considered a uniformly fatal disease (1). For such pa-tients, the achievement of LRC becomes a matter of greaterimportance than in those with chemo-refractory disease. In-deed, several previous studies have confirmed that, in pa-tients who respond to modern chemotherapy, there is an

association between achievement of durable LRC and sur-vival (8–10). Locoregional recurrence in patients with IBCis invariably associated with distant dissemination and deathfrom disease (11–13).

Over the last three decades we have refined the radiationtherapy of IBC at our institution in an attempt to improveLRC rate. Early in that period, we moved from a once-daily

Fig. 2. (Top) Locoregional control (LRC) as a function of response to neoadjuvant chemotherapy. (Bottom left) LRC inpatients who experienced at least a PR to chemotherapy as a function of radiation dose (n = 94 for dose 66 Gy, n = 59 for60 Gy). (Bottom right) LRC in patients who experienced less than a PR to chemotherapy as a function of radiation dose(n = 14 for dose 66 Gy, n = 16 for 60 Gy).

480 I. J. Radiation Oncology d Biology d Physics Volume 72, Number 2, 2008

Bristol, Int. J. Radiation Oncology Biol. Phys., Vol. 72, No. 2, pp. 474–484, 2008


Bristol, Int. J. Radiation Oncology Biol. Phys., Vol. 72, No. 2, pp. 474–484, 2008

fractionation schema to an accelerated hyperfractionated ap-proach (15, 19); later we escalated the total radiation dosefrom 60 Gy to 66 Gy (8). In our previous report updatingour experience with IBC, Liao et al. (8) reviewed the resultsof 115 patients with IBC and concluded that escalating thedose from 60 Gy to 66 Gy delivered by twice-daily fraction-

ation significantly improved the 5-year LRC rate (58% vs.84%, respectively; p = 0.04).

With a greater number of patients and more mature follow-up, we now confirm that treatment to a chest-wall cumulativedose of 66 Gy is of clinical value for patients with a poor re-sponse to chemotherapy, patients with close or positive

Fig. 3. (Top) Locoregional control (LRC) as a function of surgical margin status. (Bottom left) LRC in patients with neg-ative surgical margins as a function of radiation dose (n = 87 for dose 66 Gy, n = 46 for 60 Gy). (Bottom right) LRC inpatients with positive or unknown surgical margins as a function of radiation dose (n = 26 for dose 66 Gy, n = 33 for60 Gy).

Locoregional treatment of inflammatory breast cancer d I. J. BRISTOL et al. 481


SPECIAL ARTICLE

De-escalating and escalating treatments forearly-stage breast cancer: the St. Gallen InternationalExpert Consensus Conference on the Primary Therapyof Early Breast Cancer 2017

G. Curigliano1*,†, H. J. Burstein2†, E. P. Winer2, M. Gnant3, P. Dubsky3,4, S. Loibl5, M. Colleoni1,M. M. Regan6, M. Piccart-Gebhart7, H.-J. Senn8 & B. Thurlimann9, on behalf of the Panel Members of theSt. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017

1Breast Cancer Program, Istituto Europeo di Oncologia, Milano, Italy; 2Breast Oncology Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA;3Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria; 4Klinik St. Anna, Luzern, Switzerland; 5German BreastGroup, Neu-Isenburg, Germany; 6Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA;7Department of Medical Oncology, Institut Jules Bordet, UniversitO Libre de Bruxelles, Brussels, Belgium; 8Tumor and Breast Center ZeTuP, St. Gallen; 9Breast Center,Kantonsspital St. Gallen, St. Gallen, Switzerland

Panel Members of the St. Gallen International Expert Consensus on the Primary Therapy of Early BreastCancer 2017

F. Andre10, J. Baselga11, J. Bergh12, H. Bonnefoi13, S. Y. Brucker14, F. Cardoso15, L. Carey16, E. Ciruelos17,J. Cuzick18, C. Denkert19, A. Di Leo20, B. Ejlertsen21, P. Francis22, V. Galimberti1, J. Garber2, B. Gulluoglu23,P. Goodwin24, N. Harbeck25, D. F. Hayes26, C.-S. Huang27, J. Huober28, K. Hussein29, J. Jassem30, Z. Jiang31,P. Karlsson32, M. Morrow11, R. Orecchia1, K. C. Osborne33, O. Pagani34, A. H. Partridge2, K. Pritchard35,J. Ro36, E. J. T. Rutgers37, F. Sedlmayer38, V. Semiglazov39, Z. Shao40, I. Smith41, M. Toi42, A. Tutt43,G. Viale44,45, T. Watanabe46, T. J. Whelan47 & B. Xu48

10Institut de Cancerologie Gustave Roussy, Villejuif, France; 11Memorial Sloan Kettering Cancer Center, New York, USA; 12Karolinska Institute and University Hospital,Stockholm, Sweden; 13University of Bordeaux, Bordeaux, France; 14Universit!ats-Frauenklinik Tubingen, Tubingen, Germany; 15Champalimaud Cancer Centre, Lisbon,Portugal; 16Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, USA; 17Hospital Universitario 12 de Octubre, Madrid, Spain; 18Centrefor Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK; 19Institut fur Pathologie, ChariteUniversit!atsmedizin Berlin, Berlin, Germany; 20Azienda Usl Toscana Centro, Prato, Italy; 21Rigshospitalet, Copenhagen, Denmark; 22Peter McCallum Cancer Centre,Melbourne, Australia; 23Marmara University School of Medicine, Istanbul, Turkey; 24University of Toronto, Mount Sinai Hospital, Toronto, Canada; 25University ofMunich, Munchen, Germany; 26Comprehensive Cancer Center, University of Michigan, Ann-Arbor, USA; 27National Taiwan University Hospital, Taipei, Taiwan;28University of Ulm, Ulm, Germany; 29The National Cancer Institute, Cairo University, Cairo, Egypt; 30Medical University of Gdansk, Gdansk, Poland; 31HospitalAffiliated to Military Medical Science, Beijing, China; 32Institute of Clinical Sciences, Sahlgrenska Academy, Sahlgrensky University Hospital, Gothenburg, Sweden;33Baylor College of Medicine, Houston, USA; 34Institute of Oncology Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland; 35Sunnybrook OdetteCancer Center, University of Toronto, Toronto, Canada; 36National Cancer Center, Ilsandong-gu, Goyang-si, Gyeonggi-do, Korea; 37Netherlands Cancer Institute,Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; 38LKH Salzburg, Paracelsus Medical University Clinics, Salzburg, Austria; 39N.N. Petrov ResearchInstitute of Oncology, St. Petersburg, Russian Federation; 40Fudan University Cancer Hospital, Shanghai, China; 41The Royal Marsden, Sutton, Surrey, UK; 42GraduateSchool of Medicine Kyoto University, Sakyo-ku, Kyoto City, Japan; 43Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK; 44Universityof Milan, Milan; 45Istituto Europeo di Oncologia, Milan, Italy; 46Hamamatsu Oncology Center, Hamamatsu, Japan; 47McMaster University, Hamilton, Canada;48National Cancer Center, Chaoyang District, Beijing, China

*Correspondence to: Prof. Giuseppe Curigliano, Division of Early Drug Development for Innovative Therapies, Istituto Europeo di Oncologia, Via Ripamonti 435, 20141 Milano,Italy. Tel: !39-02-57-48-94-39; Fax: !39-02-94-37-92-24; E-mail: [email protected]†Both authors contributed equally as senior authors.

VC The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For Permissions, please email: [email protected].

Annals of Oncology 28: 1700–1712, 2017doi:10.1093/annonc/mdx308Published online 21 June 2017

Downloaded from https://academic.oup.com/annonc/article-abstract/28/8/1700/3877632by Chulalongkorn University - Faculty of Medicine useron 15 November 2017

Curigliano, Annals of Oncology 28: 1700–1712, 2017


Curigliano, Annals of Oncology 28: 1700–1712, 2017

RT De escalation Escalation

HypoFx Strong recommendation for ages >=50 and LN-

Consider standard RT for all others

PBIConsider for ASTRO/ESTRO low

risk group, with adjuvant endocrine

Consider whole breast irradiation for all others

BoostOmit boost in >=60 years, low grade, or favorable biological

profileConsider boost in other patients

PMRTConsider omitting in pT1–pT2,

pN1 (1–3), and favorable biological profile

PMRT in pT3 or LN+>=4

RNIConsider omitting RNI in N1 (1–3 LN+) in the absence of

adverse clinical factors

RNI in N1 cancers and adverse clinical features

<=40 yrs, low or ER- , G3, extensive LVI or LN+>3


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