P R E S E N T S

LANDMARK TRIALS : BREAST CANCER

We acknowledge the contribution of our entire Department

- Team Apollo, Kolkata
Thanks to our Teachers and Friends for their inputs:

Dr Rajiv Sarin
Dr Tabassum Wadasadawala
Dr Rima Pathak
Dr Vineeta Goel
Dr Rohit Malde
Dr Ramesh Sarin
Dr Bhawna Sirohi
Dr Sapna Nangia
Dr Anil Goel
Dr Sayan Paul
Dr Dodul Mondal Contributors
Dr Nikhil Kalyani Dr Tanweer Shahid
Dr Kanhu Charan Patro Dr Arundhati De
Dr Sarthak Mohanty Dr Jibak Bhattacharya
Dr Abhishek Basu Dr Mukti Mukherjee
Dr Amitabh Ray Dr Tanmoy Ghosh
Dr Anish Banerjee Dr Rishav Raj
Dr Suryakanta Acharya
 INDEX
No Topic Author Year of Pub

1 Twenty five year follow-up of randomized trial comparing Radical Mastectomy, Total Mastectomy and Total Mastectomy followed by Fisher et al 2002
Irradiation – NSABP-B04
2 Twenty year follow-up of randomized trial comparing Total Mastectomy, Lumpectomy and Lumpectomy plus Irradiation for the Fisher et al 2002
treatment of invasive Breast Cancer – NSABP-B06
3 Lumpectomy and Radiation Therapy for the treatment of Intraductal Breast Cancer: Findings from NSABP B-17 Fisher et al 1998

4 Lumpectomy plus Tamoxifen with or without Irradiation in women age 70yrs of older with Early Breast Cancer: Long term follow-up Kevin et al 2013
of CALGB 9343
5 Sentinel lymph node resection compared with conventional axillary lymph node dissection in clinically node negative patients with Krag et al 2010
breast cancer: Overall survival findings from the NSABP B32 randomized phase 3 trial
6 Effect of Axillary dissection Vs No axillary dissection on 10yrs Overall Survival among women with Invasive breast cancer and Sentinel Giuliano et al 2011
node metastasis : The ACOSOG Z0011 (Alliance) RCT
7 Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981-22023 AMAROS): Ph 3 RCT Donker et al 2016
8 Regional Nodal Irradiation in Early Stage Breast Cancer - MA.20 Study Whelan T. J et al 2015
9 Effect of RT after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: Meta-Analysis of EBCTCG 2014
individual patient data for 8135 women in 22 RCT
10 Adjuvant Cyclophosphamide, Methotrexate, Fluorouracil in Node +ve Breast Cancer: The results of 20yrs Follow-up Bonadonna G et al 1995
11 Randomized Trial of Dose-Dense Vs Conventionally Scheduled & Sequential Vs Concurrent Combination Chemotherapy as Adjuvant Citron et al 2003
Treatment of Node +ve Primary Breast Cancer: 1 st Report
12 Neoadjuvant Vs Adjuvant Systemic Treatment in Breast Cancer: A Meta-Analysis Mauri D et al 2005
13 Intensive Dose-dense compared with High-dose Adjuvant chemotherapy for High-Risk operable Breast Cancer: SWOG/ Intergroup Moore et al 2007
Study 9623
14 Treatment of lymph-node negative, oestrogen-receptor +ve breast cancer: long-term findings from NSABP (B-14 & B-20) randomised Fisher et al 2004
clinical trials
No Topic Author Year of Pub

15 Aromatase inhibitors Vs Tamoxifen in early Breast Cancer: Patient-level Meta-analysis of the EBCTCG 2015
randomized trials
16 Tamoxifen in T/t of intraductal Breast cancer: NSABP B-24 RCT 1999
17 Tamoxifen for prevention of Breast cancer: Report of the NSABP P-1 Study(1998) Current Status of the NSABP P-1 Study after 7 Fisher et al 2005
years F.U (2005)
18 Trastuzumab Plus Adjuvant Chemotherapy for HER2 +ve Breast Cancer: Planned Joint Analysis of Overall Survival From NSABP B-31 Perez et al 2014
and NCCTG N9831
19 11yrs’ follow-up of Trastuzumab after adjuvant Chemotherapy in HER2-positive breast cancer: Cameron D et al 2017
Final Analysis of HERA trial
20 Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer: Long term results of CLEOPATRA trial Swain et al 2015

21 Use of Molecular Tools to Identify Patients With Indolent Breast Cancers With Ultralow Risk Over 2 Decades Esserman et al 2017
22 Adjuvant Pertuzumab & Trastuzumab in Early HER2+ve Breast Cancer : APHINITY Trial Minckwitz et al 2017
23 Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Ca Sparano et al 2018
24 Denosumab compared with Zoledronic Acid for treatment of Bone Metastases in patients with Stopeck et al 2010
Advanced Breast Cancer
25 Axillary Treatment in Conservative Management of Operable Breast Ca: Dissection or Radiotherapy? Results of a RCT With 15 years Louis-Sylvestre et 2004
Follow-Up al
26 SLN resection compared with conventional ALND in clinically node -ve patients with Breast ca: OS findings from the NSABP B-32 Krag et al 2010
trial
27 Internal mammary and medial supraclavicular lymph node chain irradiation in stage I-III breast Poortmans et al 2020
cancer (EORTC 22922/10925): 15yrs result of a randomized phase 3 trial
28 Regional Nodal Irradiation in Early stage Breast Cancer Whelan et al 2015
29 DBCG-IMN: A population based cohort study on the effect of IMN irradiation in Early Node positive Breast Cancer Thorsen et al 2016
30 BCT with or without Radiotherapy in DCIS: 10yr results of EORTC 10853 Randomized Phase III Bijker N et al 2006
Trial
31 Effect of Tamoxifen and RT in locally excised DCIS : long-term results from UK/ANZ DCIS trial Cuzick et al 2011
32 Long term outcomes of Invasive Ipsilateral Breast Tumor recurrences after Lumpectomy in NSABP B17 & B24 RCTs for DCIS Wapnir et al 2011
No Topic Author Year of Pub

33 Post-operative radiotherapy for DCIS of the breast (Review) - Cochrane Database of Systematic Reviews Goodwin et al 2013

34 Effect of Radiotherapy after Breast Conserving Surgery for DCIS : 20yrs Follow-up in the Warnberg et al 2014
Randomized SweDCIS Trial
35 RTOG 9804 : A Prospective Randomized Phase Trial for Good-Risk DCIS Comparing Radiotherapy McCormick et al 2015
with Observation
36 Long term results of a randomized trial comparing Breast conserving therapy with Mastectomy : EORTC 10801 Trial Van Dongen et al 2000
37 20yr Follow-up of a Randomized Trial comparing Total Mastectomy, Lumpectomy & Lumpectomy Plus Irradiation for the treatment Fisher et al 2002
of Invasive Breast Cancer
38 20-year F.U Of A Randomized Study Comparing BCS With Radical Mastectomy For Early Breast cancer Veronesi et al 2002
39 Effect of RT after BCS on 10-yr recurrence and 15-yr breast cancer death: Meta-analysis of individual patient data for 10801 women EBCTCG 2011
in 17 randomized trials
40 Tamoxifen, Radiation therapy, or Both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with Fisher et al 2002
invasive Breast Cancer of 1cm or less : NSABP 21
41 Lumpectomy + Tamoxifen with/without Irradiation in women >/= 70 yrs with Early Breast Cancer K S Huges et al 2013
42 PRIME II: Breast Conserving Surgery with or without irradiation in women aged 65yrs or older Kunkler et al 2015
with early breast cancer
43 Postoperative Radiotherapy in High Risk premenopausal women with Breast Cancer who receive Adjuvant Chemotherapy Overgaard et al 1997
44 Postop RT in high-risk postmenopausal breast cancer patients given adjuvant Tamoxifen: Danish Breast Cancer Cooperative Group Overgaard et al 1999
DBCG 82c randomised trial
45 Locoregional failure 10yrs after Mastectomy and Adj Chemotherapy with or without Tamoxifen Recht et al 1999
without Irradiation: Experience of ECOG
46 Locoregional Radiotherapy in Patients With High-Risk Breast Cancer Receiving Adjuvant Chemotherapy: 20-Yr Results of the British Ragaz et al 2005
Columbia Randomized Trial
47 RCT of Dose-Dense Vs Conventionally Scheduled & Sequential Vs Concurrent Combination Chemotherapy as Post-op Adjuvant T/t Citron et al 2003
of Node +ve Breast Cancer : CALGB 9741
48 Effect of Radiotherapy after Mastectomy and axillary surgery on 10yr recurrence and 20yr EBCTCG 2014
Breast Cancer mortality : meta-analysis of individual patient data for 8135 women in 22
randomized trials
No Topic Author Year of Pub

49 Postmastectomy RT Improves Local-Regional Control & Survival for Selected Pts with LABC treated with NACT & MRM Huang et al 2004

50 Sequencing of CT and RT in Early-Stage Breast Cancer: Updated results of a Prospective RCT Bellon et al 2005
51 Predictors of Locoregional Recurrence After NACT : Results From Combined Analysis of NSABP B-18 and B-27 Mamounas et al 2012

52 Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node negative Breast Cancer T J Whelan et al 2002
Long term results of Hypofractionated Radiation Therapy for Breast Cancer : ONTARIO Trial, Canada 2010
53 Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: Long Yarnold et al 2005
term results of a randomized trial
54 Effect of radiotherapy fraction size on tumor control in patients with early stage breast cancer after local tumor excision: long Owen et al 2006
term results of a randomized trial
55 The UK START Trial A of radiotherapy hypofractionation for treatment of EBC: a randomized trial START group 2008
56 The UK START Trial B of radiotherapy hypofractionation for treatment of EBC: a randomized trial START group 2008
57 First results of Randomised UK FAST Trial of Hypo# RT for Early Breast Ca(CRUKE/04/015) Yarnold et al 2011
10-Year Results of FAST: A RCT of 5 # Whole-Breast RT for Early Breast Ca Brunt et al 2020
58 Hypofractionated breast radiotherapy for 1 week Vs 3 weeks (FAST-Forward): 5-yr efficacy and A M Brunt 2020
late normal tissue effects results J S Haviland
59 Planning with IMRT and Tomotherapy to modulate dose across breast to reflect recurrence risk E M Donovan et al 2011
(IMPORT HIGH Trial)
60 Partial-breast radiotherapy after BCS for patients with early breast cancer (UK IMPORT LOW trial): 5-yr results from a multicentre, Coles et al 2017
phase 3, non-inferiority RCT
61 Whole Breast irradiation with or without a boost for patients treated with breast conserving Bartelink et al 2014
surgery for early breast cancer : 20yr follow-up of a randomized phase 3 trial
62 Intraoperative irradiation of early breast cancer (ELIOT): Long term recurrence and survival outcomes from a single centre, R Orecchia 2021
randomized, phase 3 equivalence trial U Veronesi
63 APBI compared with whole breast irradiation for Early Breast Cancer: Long term results of the randomized phase 3 APBI-IMRT- Meattini et al 2020
Florence trial
 NSABP-B04
Fisher et al
NEJM 2002

AIM: Less extensive Surgery with or without RT is as effective as Halsted radical

mastectomy
• 1971 and 1974.
• N=1765
• None received systemic
therapy . Clinically +ve
Clinical –ve Nodes: Nodes:
Randomized to Randomized
Halsted radical
to Radical
mastectomy and AD
mastectomy
Vs Total
mastectomy Vs Total
without AD with mastectomy
regional RT. and regional
RT.
Results: Conclusion:
• No significant diff. in DFS, Relapse
Free Survival, distant DFS, or OS
• No advantage of Radical
between –ve or +ve nodes. mastectomy over less extensive Sx
TEAM APOLLO, KOLKATA ES-v1-BREAST001
 NSABP-B06
Fisher et al
NEJM 2002

Is Lumpectomy with or without RT is as effective as total mastectomy for t/t of

• 1976 and 1984. invasive breast Ca?
• N=1765 Procedure Recurrence in No significant diff. in:
Ipsilateral
• Node +ve pt’s received Breast • DFS
Chemotherapy • Distant DFS
Total Lumpectomy 14.3 % • OS
Mastectomy STAGE I/II + RT
N=1851, pt’s RT was associated with
Lumpectom randomized Tumor < 4
y
Lumpectomy 39.2 % decrease in deaths due
to 3 arms cm. only to breast cancer.
Lumpectomy
+ RT
• Increase in contralateral breast cancer was not observed in this study due to RT.
• Many recurrence happens after 5 years of initial surgery. Hence, long term Follow up questionable.

Lumpectomy followed by breast RT is appropriate t/t for women with breast

CONCLUSION cancer, provided that the margins of resected specimens are free of tumor and
an acceptable cosmetic result can be obtained.
TEAM APOLLO, KOLKATA ES-v1-BREAST002
 NSABP-B17
Fisher et al
NEJM 1998

Is Lumpectomy followed by RT an appropriate t/t for pt”s with

Lumpectomy DCIS ?? Lumpectomy Lumpectomy f/b
R alone RT
• 1985 to 1990. N= 405
E
• N=818 R Lumpectomy S
• FU of 8 years f/b RT U
N= 413 L
RT Dose: 50 T
Gy S

• OS : Equivalent between the 2 arms of the study.

• 94% for pt’s treated with Sx alone and 95% for pt’s treated with Sx f/b RT (p = 0.84).
Use of RT following Lumpectomy led to a reduced rate of
both subsequent invasive and noninvasive ipsilateral
CONCLUSION
breast tumors in women with localized DCIS detected on
mammography.
TEAM APOLLO, KOLKATA ES-v1-BREAST003
 CALGB 9343
Kevin et al
JCO 2013

To determine if there is a benefit to adjuvant RT after BCS and

Tamoxifen in women age > 70 years with early-stage breast cancer
TREATED PATIENTS TAM + RT TAM only

• 1994-1999
BCS +Tamoxifen R Total Patients 317 319
N= 405 E Recurrences 23 42
• N= 636 pt’s S Ipsilateral Breast Recurrence alone 2 20
• BCS, Stage 1 R BCS +Tamoxifen + U
• ER +ve Axillary recurrences alone 0 5
RT L
• > 70 years N= 413 T Distal recurrences alone 17 10
RT Dose: 50 S All cause deaths 166 168
Gy Breast cancer specific deaths 13 8
o Improvement in Locoregional control with addition of RT.
o Addition of RT didn’t improve OS, distant DFS, or breast
CONCLUSION preservation.
o Tamoxifen is a reasonable option for women age > 70
years with ER+ve early stage breast cancer.
TEAM APOLLO, KOLKATA ES-v1-BREAST004
 NSABP-32
Krag et al, Phase
III
Lancet 2010
Aim: Does SLN resection in pts with breast cancer achieves same survival & regional control as
ALND, But with fewer side-effects ?
• 1999-2004 SLN : By Blue dye + Radioactive Type of Failure Group 1 Group 2
• 80 centres in tracer Local Recurrence 54 (2.7 %) 49 (2.4%)
USA/Canada SLN +ALND
End Point: Regional node Recur. 8 (0.4%) 14 (0.7%)
• N=5611 (Group 1) N = 2807
OS
• Age (≤49 , ≥50 Distant Metastasis 55(2.8%) 64(3.2%)
yrs), R
SLN –ve pts: Opposite Breast 56(2.8%) 44(2.2%)
• “T” size (≤2·0 cm, SLN alone Mean FU Second non-breast Ca 89(4.5%) 109(5.4%)
2·1–4·0 cm, ≥4·1
(ALND if SLN is +ve) 95.6 months
cm) Dead, no e/o disease 53 (2.7%) 56 (2.8%)
• Lumpectomy / (Group 2)
Mastectomy N = 2804 Total 1st event 315 336
CONCLUSION
In summary, NSABP B-32 results suggests that when the SLN is
negative,
SLN surgery alone with no further ALND is an appropriate, safe,
and effective therapy for patients with breast cancer.
TEAM APOLLO, KOLKATA ES-v1-BREAST005
 ACOSOG Z 0011
Giuliano et al,
Non-Inf, Phase III
JAMA 2011, 2017

Results of (ACOSOG Z0011) trial was 1st reported in 2005 with a median FU of 6.3
yrs.
Longer FU was needed because the majority of the patients had ER +ve that may
Aim:
recur To determine if 10 yr OS of pt”s with SLN metastases , treated with BCT and
later.
SLND alone without ALND is non-inferior to that of women treated with Axillary
dissection.
Trial Design and t/t:
• Before randomization: Underwent SLND and stratified according to age (<50
and >50 yrs), ER status, and Tumor size (<1cm,>1cm & < 2cm,or > 2cm).
• Randomized to ALND or no further axillary specific intervention. No third-field
nodal RT.
• ALND was defined as an anatomical level I and II dissection including at least 10
nodes.
Primary endpoints: • N= 891 pt’s.
•• All
OS women were to receive whole-breast opposing tangential-field RT. protocol.
• Planned for 1900 pts.
• DFS and • RT given in 89.6% of pt’s
• Locoregional who underwent SND
control. alone and 88.9% of pt’s in
Secondary : DFS the AND group.
TEAM APOLLO, KOLKATA ES-v1-BREAST006
 ACOSOG Z 0011
Giuliano et al,
Non-Inf, Phase III
JAMA 2011, 2017

b There are several limitations or criticisms:

1. Underpowered (891 accrued instead of 1900)

2. Low axillary failure rate as low risk patients with low axillary burden

3. No stratification according to the size of SLN

4. Not applicable in the setting of RT with non tangential fields (PBI, prone, IORT) and
mastectomy patients not needing PMRT.

5. Too many patients lost to follow up (19%)

6. RT details lacking in 71% and no RTQA protocol followed.

7. Issues with the radiation field design (high tangents and third field was used though it
was to be avoided)

8. Majority had ER+ tumors: late recurrences may develop on longer FU

TEAM APOLLO, KOLKATA ES-v1-BREAST006
 NEJM, 2015
Regional Nodal Irradiation in Early Stage Breast Cancer Whelan T. J et al.
MA.20 Study Randomized Controlled Trial

BCS + SLND/AD Compared survival outcome between whole breast irradiation with or without regional nodal irradiation
Node Positive
n=961 End Points
T ≥ 5cm N0
T≥2cm N0 but <10 node removed +/- Adjuvant Chemotherapy
Whole Breast RT Overall Survival
+1 High Risk Feature +/- Anti – HER-2 therapy
Disease Free Survival
(Gr3/ER-ve/LVSI+ve)
Stratification +/- Hormone Toxicity
R 50Gy/ 25Fr/ 5 weeks
EXCLUDED According to Risk group Therapy
T4 & cN2-3, M1 disease n=1832 Whole Breast + RNI From the time of Randomization
Serious Pulmonary/Cardiac (SCF/IMN/Axilla) ITT
comorbidities n=961

Survival and Toxicity Outcome – No difference in Baseline Characteristics, Median Follow-up – 9.5yrs
Patient Characteristics *LR DFS – isolated locoregional recurrence
*dDFS – distant Disease free survival No OS advantage with RNI
99% T1/T2 Significantly more in
85% pN1 Disease RNI Arm
75% ER positive ER-ve subgroup showed OS advantage Significant improvement of DFS, isolated Locoregional control &
with RNI distant DFS with RNI
Outcome WBI WBI+RNI HR p-value Adverse Events
10yr OS 81.8% 82.8% 0.91 0.38 Dermatitis RNI significantly increased Lymphedema and acute pneumonitis
Pneumonitis (1.2% vs 0.2%) but not cardiac morbidity & mortality
10yr DFS 77% 82% 0.76 0.01 Lymphedema (8.4% vs 4.5%)
Telangiectasia
10yr LR DFS* 92.2% 95.2% 0.59 0.009 Sub-cut Fibrosis Study was underpowered for subset analysis and did not adjust
10yr dDFS* 82.4% 86.3% 0.76 0.03 p-value for multiple comparison

CONCLUSION: Regional Nodal Irradiation with Whole Breast RT reduces breast cancer recurrence but doesn’t improve OS
TEAM APOLLO, KOLKATA ES-v1-BREAST0008
 Lancet 2014
Effect of RT after mastectomy and axillary surgery on 10-year recurrence and 20-year
EBCTCG
breast cancer mortality: Meta-Analysis of individual patient data for 8135 women in 22 RCT Meta Analysis

Aim: To assess the effect of RT in pts with 1 – 3 positive L.N, after mastectomy & axillary
dissection.
Methods Arm A ALND (at least level II) & if RT given, included chest wall, SCF +/- Axilla +/- IMC
Mastectomy RT to N -3786 LRR- 1st (%) Log rank 2p<0.0001
1964 – 1986 + Ax Sx CW + RNI
22 trials • pN0 –> 700 pt
N - 8135 Mastectomy • pN +ve –> 3131 pt
+ Ax Sx No RT
o pN 1 – 3 –> 1314 pt 1133 pts rcvd
Arm B o pN >/= 4 –> 1772 pt systemic T/t
Findings Med F.U. 9.4 yrs

RT vs No RT: INTERPRETATION
• pN0: No significant difference
• pN1-3 (with or without After Mastectomy & Axillary dissection, pN+ve (1–3 L.N.)
systemic T/t) and pN >/= 4: • RT reduced both recurrence and breast cancer
RT significantly reduced mortality even when systemic therapy was given.
 Locoregional recurrence • For today’s women, who are at lower risk of recurrence, absolute
(LRR) gains might be smaller but proportional gains might be larger
 Overall recurrence (OR) because of more effective RT
 Breast Cancer Mortality ES-v1-BREAST0009
TEAM APOLLO, KOLKATA
 NEJM 1995
Adjuvant Cyclophosphamide, Methotrexate, Fluorouracil In Bonadonna G. et al
Node +ve Breast Cancer: The Results Of 20 Years Follow-up RCT
Adjuvant chemotherapy (CMF) after radical mastectomy for Node +ve breast cancer to assess whether it would improve t/t outcome compared with surgery alone.

AIM
N=386(June,1973- September,1975)
Radical Mastectomy
RESULTS
N=179 Median Follow Up -19.4 Years

INCLUSION CRITERIA :
 Radical mastectomy for R
U/L breast cancer RFS OS
Radical Mastectomy f/b 12 Monthly Cycles Of CMF
 N+ disease(>1 node)
 Age <75 years

N=207
No postop RT or Adj. Endocrine therapy administered.

• RFS influenced by Extent of nodal involvement >3+ve nodes) and Treatment group (Chemotherapy or No
chemotherapy).

• Total survival influenced by:-

 Extent of nodal involvement (RR >3 +ve nodes, P= 0.001)
 Type of treatment (RR with adjuvant chemotherapy, P= 0.03)
 Benefit from adjuvant chemotherapy was evident in all subgroups of patients except postmenopausal women.

CONCLUSION:
Adjuvant CMF chemotherapy improves both RFS and OS in node +ve breast cancer.
TEAM APOLLO, KOLKATA ES-v1-BREAST010
 Randomized Trial of Dose-Dense Vs Conventionally Scheduled & JCO, 2003, Citron et al,
Prospective RCT, USA
Sequential Vs Concurrent Combination Chemotherapy as Adjuvant Intergroup
Treatment of Node +ve Primary Breast Cancer: 1st Report Trial C9741/ CALGB 9741
Aim: To determine whether dose density of cytotoxic agents improves survival & to compare toxicities using 2x2 factorial design.
T0-3 N1-2 M0 Breast Ca
n= 2005 Median age= 50 yrs
DFS by DFS by
Segmental mastectomy + axillary dissection/ MRM density sequence
R < 84 days after Sx

A-->T-->C AC-->T
RESULTS
 Dose-dense regimens (II & IV) improved DFS
(RR=0.74; p=0.010), and OS (RR=0.69; p=0.013).

 Sequential (I+II) arms had similar DFS/OS but less

toxicities compared to concurrent (III+IV) regimens.
q 3 wks q 2wks+G-CSF
q 3 wks  Less severe neutropenia in dose-dense arms.
A- Doxorubicin 60 mg/m 2 q 2wks+G-CSF
C- Cyclophosphamide 600 mg/m2 T- Paclitaxel 175 mg/m2 CONCLUSION: Dose density improves clinical outcomes.
TEAM APOLLO, KOLKATA ES-v1-BREAST0011
 Neoadjuvant Vs Adjuvant Systemic Treatment Journal of National Cancer Institute
Mauri D et al, 2005
in Breast Cancer: A Meta-Analysis Meta-analysis

Compared survival & locoregional control between Neoadjuvant and Adjuvant systemic treatment
N = 1972
9 RCTs, 3861 Pts Neoadjuvant Therapy End Points Heterogeneity
Comparing NeoAdj Vs Adj (CT or HT)
Same regimen (Pre and postop)
(Chemo or Endocrine) Considerable heterogeneity existed in
Irrespective of additional Sx/RT Death (Any Cause) design, mode of treatment and response
Disease Progression rates
Loco-regional control/rec Large variability in treatment regimens
Escalation Dose studies Adjuvant Therapy Systemic recurrence across the studies
Concurrent RT & HT studies (Chemo or Endocrine)
EXCLUDED N = 1974

RESULTS
Relative Risk 95% CI p-value
No difference in OS, Disease Progression and Distant
Death 1.00 0.90-1.12 ns Recurrence
Disease 0.99 0.97-1.07 ns
Progression Increased risk of loco-regional recurrence with
Distant 0.94 0.83-1.06 ns Neoadjuvant therapy
Recurrence
Difference was higher when radiotherapy was
Locoregional 1.22 1.04-1.43 0.015
recurrences adopted without adding any surgery

22% increased risk of loco-regional Driven largely by trials in which only RT Pathologic response rates were low regardless of
recurrence with Neoadjuvant therapy was adopted without surgery (after CR) regimen used

CONCLUSION: Demonstrated equivalence of Neoadjuvant and Adjuvant Systemic therapy – Surgery must not be omitted
TEAM APOLLO, KOLKATA ES-v1-BREAST0012
 Lancet, 2004, USA
Treatment of lymph-node negative, oestrogen-receptor +ve breast cancer: Fisher et al, Long FU
long-term findings from NSABP (B-14 & B-20) randomised clinical trials of prospective RCTs

Ca Breast post-op RESULTS & INTERPRETATION

HPE- Negative axillary nodes  With 15 yrs follow-up of NSABP B-14, RFS & OS improved
Oestrogen receptor +ve (≥10 fmol/mg cytosol protein) with Tamoxifen compared to placebo (HR for OS =0.8,
95% CI=0.71-0.91, p=0.0008).

 With 12 yrs follow-up of NSABP B-20, CMF-T improved

NSABP B-14 NSABP B-20 RFS & OS compared to Tamoxifen alone (HR for RFS=
0·52, 95% CI=0·39–0·68, p<0·0001).
R R
 CMF-T compared to placebo, led to 65% absolute
Adjuvant Placebo Adjuvant Adjuvant reduction in treatment failure in all age groups.
Tamoxifen CMF-T Tamoxifen
n=1439 n=1453 (Cyclophosphamide Only  Due to higher tumor ER concentration in older women,
+Methotrexate
+5-Fluorouracil they more likely to benefit from Tamoxifen, but younger
Initial results f/b Tamoxifen) patients tend to benefit more from chemotherapy.
Tamoxifen n=789 n=788
better  However, the notion that use of tamoxifen or
Initial results
chemotherapy should be based only on age is too
CMF-T better
restrictive.
15 yrs folllow up 12 yrs folllow up
TEAM APOLLO, KOLKATA ES-v1-BREAST0014
 Aromatase inhibitors Vs Tamoxifen in early Lancet Oncology
EBCTCG , 2015
Breast Cancer: Patient-level Meta-analysis of Meta-analysis
the randomized trials
Clarify relative benefits of AI and Tamoxifen and the effect of different scheduling during 5yrs of Endocrine Therapy
Intention to Treat Analysis
RCTs with different scheduling comparison Primary End Points Secondary End Points
N = 35718 Comp A 5y x AI Vs 5y x Tam

9 RCTs Comp B 5y x AI Vs 2-3y x Tam f/b AI to 5y Recurrence Second primary cancer

Individual Patient Datasets Comp C 5y x T Vs 2-3y x Tam f/b AI to 5y Mortality Bone fracture
Early Breast Cancer Death without Recurrence
Comp D 5y x AI Vs 2y x AI f/b Tam to 5y
Post Menopausal All-cause mortality Pre-specified subgroup Analysis
ER +Ve Comp E 5yr x T Vs 2y x AI f/b Tam to 5y

RESULTS
Comparisons Mortality Recurrence Rate and RR All recurrences were substantially reduced by AI compared
10yrs RR
with Tamoxifen (Any AI) – mostly when treatments differed
Comp A 0.85-0.89 Favoured AI significantly during 0-4yrs and non significantly thereafter and started with AI
Comp B 0.89 (NS) Favoured AI significantly during 0-1yrs, not when both group received AI
Breast cancer and All- cause mortality were significantly
Comp C 0.82-0.84 Favoured AI significantly during 2-4yrs
reduced with AI for all periods
Comp D - No apparent gain from continuing AI rather than switching to Tam (CI Wide)
Comp E - Recurrence reduction 0-1yrs, when treatment differed* Significantly lower incidence of uterine cancer with AI (0.4%
*Reassuring for women who cannot tolerate AI
vs 1.2%)

Fairly consistent pattern of recurrence reduction during periods when one group was on AI and other Significantly increased bone fracture with AI (5yrs Risk 8.2%
on Tamoxifen – switching (AI to T) does not mean loss of benefit (recurrence reduction) vs 5.5%)

CONCLUSION: AI significantly reduces mortality and recurrences compared to Tamoxifen in Postmenopausal women
TEAM APOLLO, KOLKATA ES-v1-BREAST0015
 Lancet 1999
NSABP B 24
Tamoxifen in T/t of intraductal Breast cancer: NSABP B-24 RCT RCT

Aim: To assess the benefit of Tamoxifen in pts with DCIS, in addition to lumpectomy and
RT.
Methods Arm A (N – 902) Objectives:

Lumpectomy
1991 – 1994 RT (50 Gy / 25 f) Placebo • Annual event rates
DCIS (LCIS) with Life • Cumulative probability of
expectancy >10 yrs
R
• invasive or non-invasive
(N-1804)
RT (50 Gy / 25 f) Tamoxifen*
• ipsilateral and contralateral tumour
Arm B (N – 902) over 5 years.

Findings Tamoxifen significantly reduced

 breast- cancer events at 5 years (8·2 vs 13·4%,
Med F.U. 74 m p=0·0009).
 cumulative incidence of
• all invasive breast-cancer events 4·1% at 5 years:
• 2·1% in the ipsilateral breast,
• 1·8% in the contralateral breast,
• 0·2% at regional or distant sites.
INTERPRETATION

Lumpectomy + Radiation therapy + Tamoxifen => effective in prevention of invasive cancer.

TEAM APOLLO, KOLKATA ES-v1-BREAST0016
 Tamoxifen for prevention of Breast cancer: Report of the NSABP P-1 Study(1998) Fisher et al
J Natl Cancer Inst
Current Status of the NSABP P-1 Study after 7 years F.U (2005) RCT

AIM: To assess whether Tamoxifen has a role RESULTS:

in Breast cancer prevention.
June,1992 – September,1997
N=13388
R
Placebo (N=6707) Tamoxifen (20 mg/day) (N=6681)
• Tamoxifen causes 62% reduction in ER +ve ca.
*The trial was unblinded in 1998 because of +ve results
• Cumulative rate of invasive endometrial ca
ELIGIBILITY CRITERIA:
 Age> =60 years. more with tamoxifen, P<.001.
 Age 35 -- 59 years with 5-year predicted risk for
• PE statistically significantly greater with
breast ca at least 1.66%.
 H/O of LCIS or atypical hyperplasia. Tamoxifen .
 Mammogram -ve for breast ca within 180 days
• DVT more with tamoxifen but difference not
before randomization.
 No HRT/OCPs/ androgens within 3 months of Comparison of RR(with 95% CI) of statistically significant.
benefits and undesirable effects of
randomization. •
 No H/O DVT or PE. Tamoxifen from initial and updated Cataract statistically significantly elevated
results of NSABP P-1. with Tamoxifen.
CONCLUSION:
• The net benefit achieved with Tamoxifen varies according to age, race, and level of Breast ca risk.
• Tamoxifen remains the only proven chemopreventive treatment for breast cancer risk reduction.
TEAM APOLLO, KOLKATA ES-v1-BREAST0017
 Trastuzumab Plus Adjuvant Chemotherapy for HER2 +ve Breast Cancer: Planned Joint Perez et al
Analysis of Overall Survival From NSABP B-31 and NCCTG N9831 JCO, 2014

NCCTG N9831 NSABP B-31

Control arm (N=971) Study arm (N= 973) Control arm (N= 1,047) Study arm (N = 1,055)
DOX + CYC f/b DOX +CYC f/b PAC80 + TRAS DOX + CYC f/b PAC80 or PAC175 DOX + CYC f/b PAC80 +TRAS or PAC175 + TRAS
PAC80
*After release of 1st interim joint analysis results in 2005, patients in control arms with acceptable LVEF were allowed to take trastuzumab but they were
evaluated with their initial assigned t/t arm.

RESULTS: (Median F.U 8.4 years)

ELIGIBILITY CRITERIA: •
 Age >=18 years. Addition of Trastuzumab to chemotherapy gives 37%
relative improvement in OS , P < .001. OS
 Primary, operable, histologically confirmed
• 10-year OS increased from 75.2% to 84%.
node +ve (both trials) or high-risk node -ve
invasive (N9831 only) .
• DFS improvement 40% , P < .001.
DFS
 Strongly HER2 +ve tumor.
• 10-year DFS increased from 62.2% to 73.7%.
 Adequate LVEF & no LVH, CHF,MI or
• All patient subgroups benefited from addition of Trastuzumab, irrespective of Age,
Cardiomyopathy.
Tumor size, Hormone status, Extent of Surgery.

CONCLUSION:
Adding Trastuzumab to Paclitaxel after Doxorubicin + Cyclophosphamide in early-stage HER2 +ve breast cancer
gives both improved survival and reduced recurrence.
TEAM APOLLO, KOLKATA ES-v1-BREAST0018
 11yrs’ follow-up of Trastuzumab after Lancet Oncology
Cameron D et al, 2017
adjuvant Chemotherapy in HER2-positive Phase III RCT
breast cancer: Final Analysis of HERA trial
Comparing two durations (1yr and 2yrs) of Trastuzumab Therapy Results
2001 - 2005 N = 5102 Observation Primary End Point DFS Groups – Well Balanced

Locally assessed HER2 +Ve ITT Analysis

Secondary End Points 52% Patients of
LVEF ≥ 55% Observation Arm –
Completed Adjuvant CT ±RT R Trastuzumab x 1yr FU
OS Selectively Crossed Over
pN0 with pT>1cm 12mo Landmark Analysis Site of first Relapse to Trastuzumab after
Adjuvant HT – for Receptor +Ve Analysis by Receptor Status release of interim
Trastuzumab x 2yr Cardiac Safety analysis (2005)

RESULTS – Median FU - 11Years

DFS 10yrs Absolute HR* OS 12yrs Absolute Selective Crossover was associated with reduction of risk for
DFS Benefit* OS Benefit*
DFS events (HR 0.79, CI 0.64-0.98) – Likely to provide an
Observation 63% Observation 73% underestimate of the long term efficacy of trastuzumab
1yr Trastuzumab 69% 6.8% 0.76 1yr Trastuzumab 79% 6.5%
Clinical Benefit of Trastuzumab – noted for both Hormone
2yrs Trastuzumab 69% 6.0% 0.77 2yrs Trastuzumab 80% 6.6%
Receptor positive and negative subgroups
*Compared to Observation
primary Cardiac End Point (Class III/IV NYHA
toxicity) - No difference between 1yr or 2yrs More recurrences and deaths in hormone receptor negative
No evidence of long term benefit of patients – Receptor status remains an independent predictor
2yrs compared to 1 yr of Trastuzumab
Secondary Cardiac End Point (Class I/II NYHA with
significant LVEF drop) was more with 2yrs of Cardiac Toxicity - No new safety concerns have emerged with
HR (DFS) – 1.02, 95% CI 0.89-1.17 long-term FU
Trastuzumab

CONCLUSION: 1yr of Trastuzumab is an important and curative part of standard of care in HER2 positive Breast Cancer
TEAM APOLLO, KOLKATA ES-v1-BREAST0019
 NEJM, 2015, USA
Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Swain et al, Double-
Cancer: Long term results of CLEOPATRA trial blind, Ph III RCT

• Metastatic/ Locally recurrent unresectable HER2+ve RESULTS

• LVEF ≥ 50% • Interim analysis:
• PS= ECOG 0-1 2012 PFS significantly longer with Pertuzumab (HR=0.62)
• Adjuvant/ Neo-adjuvant Trastuzumab allowed 2013  OS significantly better with Pertuzumab (HR=0.66)
• 2013 Cardiac safety profiles similar for 2 arms
Not received other anticancer therapy (except single line
hormone) for mets
• On final analysis, Median OS better for Pertuzumab (56.5
mths vs 40.8 mths, HR=0.68; P<0.001 ).
R
• Pertuzumab improved median PFS by 6.3 mths (HR=0.68).
Study arm Control arm
(n=402) (n=406) • Pertuzumab extended median response duration by 7.7
Pertuzumab Placebo mths.
+Trastuzumab + Docetaxel +Trastuzumab + Docetaxel
48 patients of control arm • Most adverse events occurred during docetaxel
crossed over to study arm administration, but long-term cardiac safety maintained.
after interim analysis, but
included in control arm for CONCLUSION
ITT analysis 1st line therapy with pertuzumab significantly improved OS in
HER2+ve metastatic breast cancer, as compared to placebo
49.5 months folllow up 50.6 months folllow up when added to trastuzumab and docetaxel.
TEAM APOLLO, KOLKATA ES-v1-BREAST0020
 JAMA 2017
Use of Molecular Tools to Identify Patients With
Esserman et al
Indolent Breast Cancers With Ultralow Risk Over Univ. of California
2 Decades
Can a molecular multigene classifier be used to demonstrate the long-term indolent behaviour of
some primary breast cancers, thereby reassuring patients and avoiding over treatment?
Trial validated the MammaPrint 70-gene expression RESULTS
score to predict indolent behaviour of tumour from
the Stockholm tamoxifen (STO-3) trial.
• MammaPrint was based on microarray
gene expression analysis of RNA
extracted.
• 70-gene signature: Classified as ultralow,
low but not ultralow, or high risk.

Inclusion: Conclusion
• Postmenopausal women • MammaPrint 70 can classify indolent tumor
• Node -ve breast cancers treated with behaviour & if integrated into screening can prevent
mastectomy or lumpectomy. over t/t .
• RT enrolled in the STO-3 trial, 1976 - 90. • It enables excellent outcomes with less toxic effects.
TEAM APOLLO, KOLKATA ES-v1-BREAST021
 Adjuvant Pertuzumab & Trastuzumab in NEJM 2017
APHINITY
Minckwitz et al
Trial Early HER2+ve Breast Cancer RCT

Aim: Whether Pertuzumab, in addition to Trastuzumab, improves outcomes

in HER2 +ve Early Breast cancer pt in Adjuvant setting
Nov, 2011 – Aug, 2013
43 Countries, 549 centres
Objectives: RESULTS
N+ve or high-risk N –ve, Primary End Point:
HER2+ve, operable Ca Br Pertuzumab vs Placebo
Invasive DFS
Adjuvant systemic T/t: (Assuming 91.8% with • Disease recurrence: 7.1% vs 8.7% (p=0.045)
Std Chemo pertuzumab and 89.2% with • 3 yr invasive DFS: 94.1% vs 93.2%
+ placebo) • N+ve: 92.0% vs 90.2% (p=0.02)
1 yr Trastuzumab • N –ve: 97.5% vs 98.4% (p=0.64)
+ 2nd -ary end points: • Toxicities:
OS, DFS, Relapse-free • Gr 3 Diarrhea: 9.8% vs3.7%
Pertuzumab Placebo interval, Distant relapse-free • Cardiac events – infrequent in both arms
N-2400 N-2405 interval, Safety, HR-QoL
CONCLUSION
Pertuzumab, in addition to Chemo and Trastuzumab, significantly
improved
invasive-DFS in pts with HER2+ve, operable breast cancer.
TEAM APOLLO, KOLKATA ES-v1-BREAST0022
 Sparano et al
Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Ca NEJM, 2018

OBJECTIVE:
• Whether chemotherapy is beneficial for women with a mid-range recurrence score of 11 - 25.
• To confirm that low RS of 0 - 10 is associated with low rate of distant recurrence if treated with endocrine therapy alone.
PRIMARY END POINT: N=10273 RS = Recurrence Score
ELIGIBILITY CRITERIA: (2006-2010)
• Invasive DFS
 Age: 18 - 75 years
 ER/PR : +ve SECONDARY END POINTS :
 HER2–negative • Freedom from recurrence at a distant N=1629 N=3458 N=3449 N=1737
 Axillary node : -ve or locoregional site RS ≤10 RS =11–25 RS =11–25 RS ≥26
• OS Endocrine alone Endocrine alone Chemo-Endocrine Chemo-Endocrine

RESULTS: (Median F.U for patients with RS 11-25 was 90 months for invasive DFS and 96 months for OS)
 Endocrine therapy Noninferior to chemoendocrine therapy for invasive DFS (P=0.26).

 At 9 years, similar rates of invasive DFS (83.3% vs. 84.3%), freedom from disease recurrence at
a distant site (94.5% vs. 95.0%) or at a distant or locoregional site (93.9% vs. 93.8%).

 Chemotherapy benefit for invasive DFS varied with the combination of recurrence score and age (P=0.004), with some benefit of
chemotherapy in women of <=50 years of age with RS of 16 - 25.

CONCLUSION:
85% women of EBC with age >50 years and RS of <=25, as well as women of age <=50 years with a RS of <=15
identified by 21-gene assay can be spared adjuvant chemotherapy.
TEAM APOLLO, KOLKATA ES-v1-BREAST0023
 Denosumab compared with Zoledronic Acid JCO
Stopeck et al, 2010
for treatment of Bone Metastases in patients Double Blinded RCT
with Advanced Breast Cancer
Comparison of Denosumab Vs Zoledronic Acid for preventing Skeletal-Related Events (SRE) in Bone Mets
≥18yrs n=1020 End Points (ITT)
MBC (at least one bone metastasis)
Serum Ca2+ 8-11.5mg/dl Denosumab 120mg SC + IV Placebo Primary EP – First on study SRE
ECOG PS 0-2 (Non-inferiority)
EXCLUDED R 4 WEEKLY +/- CT / HT
Secondary EP – First on study SRE
CrCl <30ml/min (Superiority) & Time to SRE
h/o Prior bisphosphonate therapy Zoledronate 4mg IV + SC Placebo
Non-healed dental/oral sx
n=1026 Dose Adjustment when needed Safety End Points – Adverse Events

SRE – Pathological Fracture, Bone Surgery or Radiotherapy, Cord Compression

With Denosumab Denosumab is superior to ZA for preventing SRE due to greater

Median time to 1st SRE – Not reached inhibition of osteoclast induced bone resorption
(ZA – 26.4mo)
Therapeutic option for patients with CRF or renal insufficiency,
18% Delayed time to first SRE
receiving nephrotoxic chemotherapy
p <0.001 Noninferiority
p = 0.01 Superiority
ZA is associated with 3 times more chance of Flu like syndrome
23% Reduced Risk of Multiple SREs while Denosumab is associated with more hypocalcemia (non
SAFETY ZA DEN p
p = 0.001 fatal)
Renal Toxicity 8.5% 4.9% 0.001
22% reduction in Skeletal Morbidity Rate ONJ 1.4% 2.0% 0.39 No difference in OS or Disease Progression

CONCLUSION: Monthly Denosumab is superior to Zoledronate for preventing SREs with less renal toxicity
TEAM APOLLO, KOLKATA ES-v1-BREAST0024
 JCO, 2004, France
Axillary Treatment in Conservative Management of Operable Breast Ca: Louis-Sylvestre et al,
Dissection or Radiotherapy? Results of a RCT With 15 years Follow-Up RCT

Axillary dissection, though was standard for invasive breast Ca, led to arm edema, necessitating exploring alternative options.

• RESULTS
T< 3 cm, cN0M0
• Age< 70 yrs Isolated axillary
• All patients: WLE + Breast RT recurrence

• n= 658, between 1982 & 1987

OS

• Initial results at 5 yrs showed increased OS in axillary

dissection group (P = 0.009).
Arm A Arm B • At 10 and 15 yrs, however, OS was identical in both groups
(n=326) (n=332) (73.8% v 75.5% at 15 years).
Axillary dissection Axillary Radiotherapy
• Axillary nodal recurrences were less frequent in the
axillary dissection group at 15 years (1% v 3%; P = 0.04).
21% patients of Arm A were cN0 but pN+. CONCLUSION
So more Arm A patients received adjuvant chemo based on  In cN0 early breast Ca, long-term survival does not differ
known +ve nodes, which may have caused better earlier after axillary RT and axillary dissection.
survival after axillary dissection.  However, axillary dissection had better axillary control.
TEAM APOLLO, KOLKATA ES-v1-BREAST0025
 SLN resection compared with conventional ALND in clinically node -ve patients with Krag et al , 2010
Lancet Oncol
Breast ca: OS findings from the NSABP B-32 trial RCT

OBJECTIVE:
• Whether SLND in clinically node –ve breast cancer achieves same survival and regional control as ALND, but with fewer
side-effects.
Group 1
STRATIFICATION VARIABLES PRIMARY END POINTS:
SLND + ALND
• Age (≤49 years ; ≥50 years). N=5611 • survival,
• Clinical tumour size (≤2·0 cm ; 2·1–4·0 cm; ≥4·1 cm). (1999-2004) • regional control,
Group 2
• Surgical plan (lumpectomy; mastectomy) . SLND f/b ALND if SLNs +ve • morbidity.

• RESULTS: (Mean F.U 95·6 months .

All outcome data reported for SLN -ve patients. )
• 309 deaths reported : 140 in group 1 and 169 in group 2.
DFS OS
• 8-year Kaplan-Meier estimates for OS 91·8% in group 1 and 90·3% in group 2.

• 8-year Kaplan-Meier estimates for DFS 82·4% in group 1 and 81·5% in group 2.

CONCLUSION:
• OS, DFS and regional control equivalent between two groups.
• For clinically node –ve , SLN –ve breast ca patients SLND alone with no further ALND is appropriate, safe, and
effective therapy.
TEAM APOLLO, KOLKATA ES-v1-BREAST0026
 LANCET, 2020,
RCT Ph III,
Poortmans et
To investigate the impact on OS of elective internal mammaryaland
medial supraclavicular (IM-MS) radiation: 15 year analysis of EORTC
• 1996-2004
• 46 centres
22922/10925 Trial
• 13 countries
• N=4004 pt’s Mastectomy or BCS and axillary
o Age < 75 staging
IM-MS RT: Endpoint: OS DFS
yrs
o Stage I–III 50 Gy/25 fr. o Primary:
N = 2002 OS
o Axillary R o Seconda Median FU: 15·7
node No RT ry : DFS, IM-MS
years No RT
involved N = 2002 Metastasi
o Central or s Free
OS 73.1 % 70.9 %
medial Conclusion Survival, Any Breast Ca Rec. 24.5 % 27.1 %
• tumour.
Significant reduction of Breast cancer mortality & any breast Breast Ca Mortality 16% 19.8 %
cancer recurrence by Internal Mammary-Medial
DFS 60.8% 59.9%
Supraclavicular nodal RT.
• No improvement in overall survival. Mets free Survival 70 % 68.2 %
TEAM APOLLO, KOLKATA ES-v1-BREAST027
 NEJM, 2015,
RCT Ph III,
Whelan et al
To see if addition of regional nodal irradiation to whole-breast
• 2000-2007
• N=1832 pt’s irradiation improves outcomes.
o Age < 75
yrs
o Node +ve
o High risk BCS + SLND +/- ALND and
node adjuvant
Whole Chemo
Breast RT OS DFS
negative + RNI: (Internal- Endpoint:
(T>5cm, or mammary +SCLN o Primary:
if >2cm + Axillary) OS
with R o Seconda Median FU: 9.5
inadequate Whole Breast RT ry : DFS, Years
WBI + WBI
p-value
ALND, N = 916 (Locoregi RNI only
Grade III, onal & OS 82.8% 81.8% NS
LVI+ve, ER – Metastati
ve.) Conclusion c) DFS 82% 77% 0.01
•o RNI
T4 & N2, N3 the rate of breast-cancer recurrence.
reduces Locoregional–DFS 95.2% 92.2% 0.009
excluded.
• Addition of RNI to Whole Breast RT did not Metastasis free 86.3% 82.4%
0.03
improve OS. Survival

TEAM APOLLO, KOLKATA ES-v1-BREAST028

 JCO, 2016
Non-
Randomize
Thorsen et al
To see if addition of IMN-RT in early node +ve breast ca, (I) Improves OS (II) Prevents distant
recurrence (III) Decreases mortality .
• Cohort study Only the Right sided Breast Ca treated by IMN-RT
• 2003-2007 Surgery : Mastectomy /
• N= 3089 Breast Lumpectomy
/ Chest wall
Endpoint:
• Early Breast + SCF RT+ IMN:
o Primary:
(Rt. Sided: IMN RT)
Ca N=1485 OS
Breast / Chest wall
• 1 or more + SCF o Seconda
metastatic RT ry :
(Left sided: No Metastati
axillary L.n IMN RT) c dis. & IMN RT
• Age<70 years N= 1586 Breast 75.9 No IMN RT
Conclusion Cancer 72.2

death) OS
• OS improved with IMN-RT Breast Ca
IMN RT
• Risk of metastatic dis. decreased with IMN-RT No IMN RT Mortality
• Risk of breast ca death decreased with IMN-RT
TEAM APOLLO, KOLKATA ES-v1-BREAST029
 BCT with or without Radiotherapy in DCIS: JCO
Bijker N et al, 2006
10yr results of EORTC 10853 Randomized Phase III RCT – 10yrs Update
Phase III Trial
Role of Radiotherapy after Local Excision of Ductal Carcinoma in situ (DCIS)
Confirmed DCIS n=507 End Points (ITT)
Complete Local Excision (LE) Radiotherapy
Up to 5cm diameter Local Recurrence (LR) -
No evidence of Invasion/Paget’s ds 50Gy/25Fr, Whole Breast Free Interval
Margin Status Defines as -
R No Boost/ Tamoxifen
Free >1mm Identification of Risk
or No residual on re-excision No Treatment Factors predicting LR
Close ≤1mm n=503

Median Follow up – 10.5yrs

47% reduction in risk of LR with RT (HR 0.53) Multivariate Analysis

10 yr LR Free Rate Significantly increased LR risk with –

LE + RT – 85%
LE – 74% Young Age ≤ 40yrs
Symptomatic Detection
10 yr Invasive LR Free Rate
LE + RT – 92% Intermediate or Poorly Differentiate DCIS Radiotherapy reduces risk of local recurrence
LE – 87% Cribriform or solid growth Pattern by 47% at 10yrs

10yr Metastasis free Survival and OS Doubtful margins Effect of Radiotherapy was homogenous
Similar in both arms (96% & 95%) Treatment by Local excision alone across all subgroups

CONCLUSION: Radiotherapy reduces local recurrence after local excision of DCIS across all subgroups
TEAM APOLLO, KOLKATA ES-v1-BREAST0030
 Cuzick et al ,2011
Effect of Tamoxifen and RT in locally excised DCIS : long-term results from UK/ANZ DCIS trial Lancet Oncol

PRIMARY END POINTS:

• Invasive I/L new breast events for Radiotherapy comparison.
• Any new breast event, including C/L disease and DCIS, for Tamoxifen. Cumulative Incidence

N=1694 *RT : 50Gy/25#/5wks

(1990-1998) **Tamoxifen : 20mg/Day

RT + Tamoxifen RT alone Tamoxifen alone No adjuvant t/t

INCLUSION CRITERIA: EXCLUSION CRITERIA:

• Lesion completely • LCIS.
excised, Margins – free. • Atypical ductal hyperplasia without DCIS.
• Paget’s disease of nipple.
• Uncertain pathological margins .
• Reduced life expectancy.

RESULTS: (Median F.U 12.7 years) Annual Hazard rate

RT Tamoxifen
Favours Tamoxifen Favours No Tamoxifen
New breast events (p<0·0001) (p=0·002)
I/L invasive disease p<0·0001 No effect(p=0·8) CONCLUSION:
I/L DCIS (p<0·0001 (p=0·03)
• Adjuvant RT is beneficial in DCIS patients.
• Tamoxifen is beneficial in reducing local and C/L new breast
C/L tumours No effect(p=0·6). (p=0·005) events for DCIS after complete local excision
TEAM APOLLO, KOLKATA ES-v1-BREAST0031
 NSABP B-17 & B-24
Trial
Wapnir et al, Ph III
JNCI 2011

Ipsilateral breast tumor recurrence (IBTR) is common after

lumpectomy for DCIS.
•ToNSABP
evaluate
B-17 IBTR and its impact
Lumpectomy only on survival in 2 NSABP Results:trials for DCIS.
• 1985 - 1990 Vs 15 Year cumulative incidence of I-IBTR
• N=813 Lumpectomy + RT Lumpectomy Lumpectomy + RT RT + Placebo RT + TAM
Endpoint: I-IBTR, DCIS-IBTR, C/L breast 19.4 % 8.9 % 10% 8.5 %
Ca, OS & Breast cancer–specific survival 15 Year cumulative incidence of contralateral I-IBTR
& OS.
Post Lumpectomy: 10.3 % 10.2 % 10.8 % 7.3 8%
• NSABP B-24
RT + Placebo 15 Year cumulative incidence of Breast cancer death
• 1991 – 1994
Vs 3.1 % 4.7 % 2.7 % 2.3 %
• N=1799 RT + Tamoxifen
RT and Tamoxifen reduces Invasive Ipsilateral Breast Tumor
Conclusion
Recurrence.

Long-term prognosis excellent after BCS for DCIS.

TEAM APOLLO, KOLKATA ES-v1-BREAST0032
 Post-operative radiotherapy for DCIS of the breast (Review) Cochrane Library, 2013,
Australia, Goodwin et al,
- Cochrane Database of Systematic Reviews Meta-analysis
Aim: To summarise data from RCTs testing effect of RT after BCS for treatment of DCIS.
Search criteria RESULTS
• RCTs
• BCS with vs without RT
• 1st diagnosis of DCIS
• Pure DCIS (no invasive disesae)
• All women, no age limit

Post-operative radiotherapy versus surgery alone, outcome: All ipsilateral recurrence

Included RCTs • Statistically significant benefit from addition of RT on all
ipsilateral breast events (HR 0.49; 95% CI 0.41 to 0.58, P <
1) EORTC 2006 (n= 1010):- Local excision with vs without RT; 0.00001), ipsilateral invasive recurrence (HR 0.50; p=0.001) and
1986-1996; Median FU=10.5 yrs ipsilateral DCIS recurrence (HR 0.61; P = 0.03).
2) NSABP 2001 (n= 818):- Lumpectomy with vs without RT;
1985-1990; Median FU=10.7 yrs • All subgroups analysed benefited from addition of RT.
3) SweDCIS 2008(n= 1067):- Segmental resection with vs
without RT; 1987-1999; Mean FU= 8.4 yrs
• No significant long-term toxicity from radiotherapy was found.
4) UKCCCR 2003 :- Tamoxifen & RT: 2/2 factorial design;
1030 women randomized to with vs without RT; 1990-1998; CONCLUSION
Median FU= 4.4 yrs This review confirms the benefit of adding RT to BCS for all DCIS.
TEAM APOLLO, KOLKATA ES-v1-BREAST0033
 SweDCIS Trial
Warnberg et al
JCO 2014
Purpose: RT lowers the risk of ipsilateral breast events (IBEs) after BCS for
DCIS by almost 50% at 10 to 15 years. 20 years of F.U data of SweDCIS trial is
presented here. • Absolute risk
• 1987-1999 BCS only reduction in
• N= 1067 pt’s N= 534 RT:12.0%.
• Screening R • Relative risk
reduction: 37.5%.
detected BCS + RT • Breast cancer–
• Age: 50 to 69 yr N= 533 specific death and OS
Primary end point: not influenced.
• Ipsilateral • Younger women
experienced
breast events
IBEs better in RT arm relatively higher risk
(IBEs) : DCIS OR
of invasive IBE and
Invasive lower effect of RT.
Secondary: CONCLUSION
• Contralateral Ca o Use of adjuvant RT is supported by 20-year
risk
• Breast cancer– follow-up.
specific death o Modest protection against invasive recurrences
(BCSD)
• APOLLO, KOLKATA and a possible increase in contralateral cancers.
TEAM OS ES-v1-BREAST034
 RTOG 9804 : A Prospective Randomized Phase JCO
McCormick et al, 2015
Trial for Good-Risk DCIS Comparing Phase III RCT
Radiotherapy with Observation
To address the question of RT benefit in a good-risk DCIS Patient after BCS
Unicentric End Points (ITT)
n=314 Radiotherapy
Low to Intermediate Grade
± Tamoxifen Primary EP : Local Failure (LF)
< 2.5cm
Minimal Margin - 3mm
50-50.4Gy/25-28Fr, Whole Breast*
Excluded Stratification R No Boost
Secondary EP
OS
Age < 26yrs
If already started on Hormone Observation Contralateral Breast Failure (CBF)
Therapy ± Tamoxifen Distant Failure (DF)
n=322
*Few patients received hypofractionated RT
Median Follow up – 7.17 yrs (Study closed early for not meeting targeted accrual)

Local Failure The study successfully identified a subset of

RT No RT P value Ipsilateral LF for women with good-risk DCIS
all eligible
5yrs 0.4% 3.5% patients
0.001 Local Failure rate is very low with Observation
7yrs 0.9% 6.7%
in good-risk DCIS, but it increases with time
HR 0.11 (95% CI 0.03-0.47)
However, Addition of RT is always beneficial
42.1% invasive recurrence in Observation Arm and will reduce the risk further
Low Mastectomy Rates (1.5% Vs 2.8%)
Excellent OS and DFS (No difference) The Study had significantly reduced statistical
Similar CBF in both arms power due to early closure

CONCLUSION: RT provides significant benefit in reducing in-breast recurrence in women who opt to receive it
TEAM APOLLO, KOLKATA ES-v1-BREAST0035
 EORTC 10801
Long-Term Results of a Randomized Trial Comparing Breast-Conserving Van Dongen et
Therapy With Mastectomy: European Organization for Research and al
Treatment of Cancer 10801 Trial JNCI, 2000
Purpose: To compare long-term efficacy of BCT with Mastectomy in stage I & II
Breast cancer. This article presents follow up data of 13.4 years.
Lumpectomy 
• 1980–1986 EBRT End point:
•
R
N = 868 pt”s (N = 448) 1. Survival
• Stage I – II IDC; 2. Time to Loco-regional recurrences
• 80% “T” size: 2.1 – 5 cm Mastectomy
(N = 420) 3. Time to Distant metastasis

RESULTS CONCLUSION
o Median follow up 13.4 years 1. BCT & mastectomy
o No difference in OS between two groups
demonstrate similar
(65% vs 66%, P=0.11)
o No difference in Distant metastasis-free rate survival rates in tumors
(61% vs 66%, P=0.24) up to 5 cm.
o Rate of LRR at 10 yrs significantly, 2. The long FU shows that the
higher in BCT. (20% vs 12%, P=0.01) number of LRR in both t/t
arms remains small.
TEAM APOLLO, KOLKATA ES-v1-BREAST036
 20 yr Follow-up of a Randomized Trial comparing Total Mastectomy, Lumpectomy NEJM, 2002, USA
Fisher et al,
& Lumpectomy Plus Irradiation for the treatment of Invasive Breast Cancer Phase III RCT

• Stage I/II Invasive Breast Ca RESULTS

• cT≤ 4cm, cN0/N+
• 1976 - 1984
• N= 1851 (primary analysis)
LR OS
R

Total Lumpectomy Lumpectomy • Lumpectomy + RT reduced local recurrence compared to

Mastectomy f/b RT
Levels II, III
lumpectomy alone (20 yr cumulative incidence 39.2% vs 14.3%,
Levels I-III axillary Whole breast p<0.001) among those with tumor free margins.
axillary dissection RT 50 Gy
dissection No boost, no • No significant differences among 3 groups with respect to DFS,
axillary RT OS, or DM-free survival.
o Previous analyses showed no significant differences in
survival among 3 arms but significant reduction in local
• RT caused marginally significant decrease in deaths due to
recurrence in lumpectomy + RT arm. breast ca, but it increased deaths from other causes.
o N+ patients had 5-FU based chemo.
CONCLUSION
Lumpectomy f/b RT continues to be appropriate therapy for breast
20 yrs Follow-up ca, provided –ve margins & acceptable cosmetic results obtained.
TEAM APOLLO, KOLKATA ES-v1-BREAST0037
 MILAN I 20-year F.U Of A Randomized Study Comparing BCS With Radical Mastectomy Veronesi et al
Study NEJM,2002
For Early Breast cancer
AIM: To compare the efficacy of Radical RESULTS: (Median F.U 20 years).
• Overall rate of local recurrences low In radical mastectomy
(Halsted) mastectomy with that of BCS.
arm and is not significantly affected by patient’s age and
baseline size of tumor.
1973 – 1980
N=701
R • Recurrences rate relatively high among women with >3
Crude Cumulative Incidence of
Radical Mastectomy ) BCS + Adj. RT (50 Gy + Boost Local Recurrences after
axillary nodes.
Mastectomy and Recurrences
of 10Gy) in Same Breast after BCS • In BCS arm, average event rate almost 4 times higher than
(N=349) (N=352) in mastectomy arm and varies with age with highest
*After 1976, patients in both arms with +ve axillary
incidence in age<=45 years .
nodes also received adj. Chemo (CMF) X 12 cycles, q = 1
month • No statistically significant diff in 20-year crude cumulative
incidence of C/L ca breast , distant mets or other primary
cancers between two arms
ELIGIBILITY CRITERIA:
• Max. Tumor diameter <=2 cm (cT1) • Overall rate of C/L Breast ca (0.66/100 woman-years of
• No palpable axillary nodes (cN0). observation) in mastectomy arm almost same with rate of
Survival after Radical
• Age < 70 years Mastectomy or BCS according Recurrent tumors in the same breast in BCS arm (0.63/100
• No previous H/O cancer. to Size of Primary Ca woman-years of observation).

CONCLUSION:
BCS is the treatment of choice for relatively small breast ca as it’s Long-term survival rate is same as radical mastectomy.
TEAM APOLLO, KOLKATA ES-v1-BREAST0038
 Effect of RT after BCS on 10-yr recurrence and 15-yr breast cancer death: Lancet, 2011,
UK, EBCTCG,
Meta-analysis of individual patient data for 10801 women in 17 randomised trials Meta-analysis

Search criteria RESULTS

• RCTs before Yr 2000
• RT vs no RT after BCS
• Invasive Breast Ca
• Axillary nodal status known-
pN0/pN+
• Individual patient data analysis

• RT reduced 10-yr any 1st recurrence (locoregional/distant) risk

from 35% to 19·3% (absolute reduction 15·7%, 95% CI 13·7–17·7,
Included trials
2p<0·00001) and reduced the 15-yr breast ca death risk from
Category No. of trials n 25·2% to 21·4% (absolute reduction 3·8%, 1·6–6·0, 2p=0·00005).
Lumpectomy, original trials 6 4398
• Reduction of recurrence risk in pN0 cases varied according to
Sector resection/quadrantectomy 4 2399 age, grade, ER status, tamoxifen use, and extent of surgery.

Lumpectomy in low-risk women 7 4004 • About 1 breast ca death was avoided by year 15 for every 4
recurrences avoided by year 10.

CONCLUSION
RT after BCS halves the rate of disease recurrence and reduces the breast cancer death rate by about 1/6 th.
TEAM APOLLO, KOLKATA ES-v1-BREAST0039
 NSABP 21
Fisher et al
JCO 2002

If t/t with TAM & Breast RT is more effective than either modality alone in
preventing IBTR & in reducing both systemic and C/L Breast ca (CBC).

Tam only
• N= 1009 pt’s N= 336
• Post
Lumpectomy RT + PLACEBO
N= 336 %
RT RT TAMOXIFEN
End Points: RT + Tam + + 5 Years
• Ipsilateral Rec. N= 337 Placebo TAM
• Distant Rec. 5 Years 5 Years
• Contralateral
breast Ca CONCLUSION
Use of RT with or without Tamoxifen after BCS with tumors of < 1
cm should be considered as cumulative incidence of IBTR through 8
years was 16.5% with TAM, 9.3% with RT + Placebo, and 2.8% with
TEAM APOLLO, KOLKATA
RT + Tamoxifen. ES-v1-BREAST040
 JCO, 2013
Lumpectomy + Tamoxifen with/without Irradiation NEJM, 2004
K. S Huges et al Long term F.U K. S Huges et al
in women >/= 70 yrs with Early Breast Cancer RCT RCT

Aim: whether lumpectomy + Tamoxifen is as effective as lumpectomy + RT + Tamoxifen

Methods Findings

Jul, 1994 – Feb, 1999 Primary end points: No significant differences b/w arms except for loco-regional recurrence
70 yrs or older women • Time to loco-regional
Breast Ca 2004 (@5 yrs) 2013 (@10 yrs)
recurrence,
T1N0M0, ER +ve • Frequency of Tam + RT Tam P value Tam + RT Tam P value
(N-636) mastectomy for LRR 1% 4% <0.001 2% 10 % <0.001
Post Lumpectomy recurrence,
• Breast-cancer–specific OS 87 % 86 % P = 0.94 67 % 66 % P=0.64
R survival,
Long-term follow-up confirmed: TAM +RT
• Time to distant
Tam • Improve locoregional recurrence free survival
Tam metastasis
+ RT • But not any advantage in OS, distant DFS or breast preservation.
• overall survival.
RT : [45 Gy/25 fr f/b Secondary end points: Depending on the value placed on local recurrence,
boost 14Gy/7 fr] • Cosmetic result
=> Tamoxifen remains a reasonable option for this
Tam : 20 mg/d for 5 yrs • Adverse effects
cohort.
INTERPRETATION
, elderly (>/=70 yrs), Early Breast Ca, ER+ve: Lumpectomy + Tamoxifen (No RT) => Reasonable T/t
option
TEAM APOLLO, KOLKATA ES-v1-BREAST0041
 PRIME II: Breast Conserving Surgery with or without Lancet
Kunkler et al, 2015
irradiation in women aged 65yrs or older with early Phase III RCT
breast cancer
To assess the effect of omission of whole breast RT in older women at lower risk
≥ 65yrs n=658 End Points (ITT)
Post BCS Radiotherapy + HT
pT-T2 (up to 3cm) N0 cM0 Primary EP : Ipsilateral Breast Tumor
ER+ve, On Hormone Therapy 40-50Gy/15-25Fr 10-15Gy Boost Recurrence (IBTR)
Excluded
Stratification R
Secondary EP
h/o previous in-situ Carcinoma Regional or Contralateral Breast Failure (CBF)
Current/Prev Malignancy No RT (HT only) OS and DFS
Gr3 with LVSI n=668

RESULTS

IBTR Local Radiotherapy is associated with 3.1% absolute Risk

RT No RT P value Multivariate Analysis reduction of local recurrence at 5yrs
5yrs (Median FU) 1.3% 4.1% 0.002
Prediction for Local Recurrence –

HR 5.19 (95% CI 1.99-13.52) 0.007

Clinician and patients need to decide whether 2.9% absolute
Absolute RR 2.9%( 3.1% Adjusted) Omission of Radiotherapy (HR 4.87) benefit justifies addition of RT in low risk old population
(5yrs) 95% CI 1.8-3.6 Poor ER status*
Grade 3 Tumors*
5yr OS – 93.9% (both groups) Patient should be assessed individually based on Tumor
Similar Regional Recurrence, Distant Mets, *Borderline Significance
characteristics, Comorbidity and Patient’s choice after discussion
CBF and New Cancer Rate on risk and benefits

CONCLUSION: Radiotherapy reduces risk of local recurrence in older low risk breast cancer patients
TEAM APOLLO, KOLKATA ES-v1-BREAST0042
 NEJM, 1997
Overgaard et al
Randomized Trial

PURPOSE: Whether Irradiation after Mastectomy prolongs Survival in High Risk

Premenopausal Woman EBRT Dose: either 50 Gy/ 25 fr or 48 Gy/ 22 fr;
N = 1708 Chemotherapy +
Target Volume: Chest Wall + Nodal irradiation
Irradiation
N = 852; 8 cycles of CMF + EBRT
•
•
Premenopausal woman
Post mastectomy R Chemotherapy alone
End point:
1. Locoregional recurrence
2. Disease free Survival
• Pathological Stage II or III N = 856; 9 cycles of CMF 3. Overall Survival

RESULTS

Median Follow up: 114 months CMF + RT CMF Alone P-value

10 Yrs DFS 48% 34% < 0.001
10 Yrs OS 54% 45% < 0.001
LRR or DM 9% 32% < 0.001

Multivariate analysis found that irradiation after mastectomy

significantly improved DFS & OS, irrespective of
• Tumor size
• The number of positive nodes
• The histopathological grade

CONCLUSION: The addition of postoperative irradiation to mastectomy & adjuvant

chemotherapy reduces LRR & prolongs survival in high-risk Premenopausal Breast Cancer.
TEAM APOLLO, KOLKATA ES-v1-BREAST0043
 Postop RT in high-risk postmenopausal breast cancer patients given adjuvant Tamoxifen: Danish Overgaard et al
Lancet,1999
Breast Cancer Cooperative Group DBCG 82c randomised trial RCT

AIM: To assess whether postop RT is necessary in high-risk postmenopausal women after total mastectomy + ALND and adj. Tamoxifen, for
locoregional tumour control, DFS and OS.
ENDPOINTS: 1st site of recurrence (locoregional/distant or both),DFS.OS RESULTS: (Median F.U 123 months).
1982 – 1990 • Locoregional recurrence : 52 (8%) of RT + tamoxifen
N=1460 group vs. 242 (35%) of Tamoxifen only group
R (p<0·001).
RT** + Tamoxifen* Tamoxifen* alone

(N=686) (N=689) • DFS : 36% in RT + Tamoxifen group vs. 24% Tamoxifen

alone group (p<0·001).
*Tamoxifen 30mg daily for 1 year
**RT to chest wall + regional LNs
ELIGIBILITY CRITERIA: • OS higher in RT group (385 vs 434 deaths; survival 45
• Age < 70 years vs 36% at 10 years, p=0·03).
• Node +ve,
• T> 5 cm
• Invasion to skin or pectoral fascia
 Postmenopausal status : >=5 years of amenorrhoea or women with
hysterectomy and age over 55 years.

CONCLUSION:
Postop RT is necessary in high-risk postmenopausal ca breast treated with adj Tamoxifen to secure both sufficient
locoregional control and maximum long-term survival.
TEAM APOLLO, KOLKATA ES-v1-BREAST0044
 Locoregional failure 10yrs after Mastectomy and Adj JCO
Recht et al, 1999
Chemotherapy with or without Tamoxifen without Data from 4 RCTs conducted by ECOG
Irradiation: Experience of ECOG
To assess the Pattern of Locoregional Failure in post Mastectomy patients without Adjuvant radiotherapy
pN+ve End Points
Post Radical Mastectomy/ MRM Trial (n)
Pre/Post Menopausal Locoregional Failure (LRF)
Each Trial Compared different
ER +ve / -ve E5177 (553)
Chemotherapy combinations
E6177 (223) Distant Failure (DF)
Excluded (Mostly CMF based) with No RT
E4181 (802) Isolated LRF without DF
cT4 different duration of therapy
E5181 (533) LRF with Simultaneous DF
SCF/IMN +ve, Fixed Axilla LN with or without Tamoxifen
Metastatic Disease 1978 - 1987 LRF ± DF

Median FU 12.1 years

Pattern of Failure Prognostic factors for LRF ± DF Locoregional Failure is a substantial problem for node positive
5yr 10yrs
cases after post mastectomy despite the use of CT ± HT
Univariate Analysis
Isolated LRF 10.1% 12.6% Increasing Tumor Size Tumor Size, No of Positive Axillary nodes, No of nodes examined
LRF with Simultaneous DF 6.3% 8.0% No of Positive Axillary Nodes and ER Negative status are poor prognostic factors predicting LRF
12.9% for 1-3 Vs 28.7% ≥ 4 node +ve at 10yrs
LRF with or without DF 16.4% 20.7%
ER Negative Status
DF only 24.5% 32.3%
Multivariate Analysis Significant Limitations of the Study –
Median time to LRF – 2.6yrs Increased no of involved nodes Other pathological risk factors were not evaluated
Similar patterns of Recurrence across Decreased no of nodes examined Older chemotherapy combinations were used
four trials ER negative Status (for LRF ± DF) Low power of the study for subgroup Analysis

CONCLUSION: LRF after mastectomy is a substantial clinical problem despite the use of chemotherapy ± Tamoxifen
TEAM APOLLO, KOLKATA ES-v1-BREAST0045
 Locoregional Radiotherapy in Patients With High-Risk Breast Cancer Receiving JNCI, 2005,
Canada
Adjuvant Chemotherapy: 20-Yr Results of the British Columbia Randomized Trial Ragaz et al
Aim: To determine whether reduction in LRR & systemic recurrence with adjuvant RT translated into improvement in survival.
• Invasive Breast Ca RESULTS
• Pre-menopausal women
• Post MRM Systemic
• pN+ Breast Ca
OS
• 1979 - 1986 free survival
• N= 318

R End points CT only vs CT+RT RR (95% CI) p value

Adjuvant
Isolated LRR free survival 74% vs 90% 0.36 (0.18-0.71) 0.002
Adjuvant
Chemotherapy Chemotherapy Systemic relapse free 31% vs 48% 0.66 (0.49-0.88) 0.004
survival
only + RT (sandwitched)
CMF regime q3 RT: 37.5 Gy/ 16# to Chest Breast Ca free survival 30% vs 48% 0.63 (0.47-0.83) 0.001
weeks x 9 cycles wall + RNI including b/l
IMN Breast Ca specific survival 38% vs 53% 0.67 (0.49-0.9) 0.008
Overall survival 37% vs 47% 0.73 (0.55-0.98) 0.03
15 yr results:- RT significantly reduced Breast Ca recurrence &
mortality but survival not improved. CONCLUSION
CT + RT leads to better survival outcomes than CT alone in high risk
20 yrs Follow-up Breast Ca after MRM, with acceptable long term cardiotoxicity.
TEAM APOLLO, KOLKATA ES-v1-BREAST0046
 CALGB RCT of Dose-Dense Vs Conventionally Scheduled & Sequential Vs Concurrent
JCO, 2003
Citron et al
9741 Combination Chemotherapy as Post-op Adjuvant T/t of N +ve Breast Cancer RCT

Methods Findings

1997 – 1999, N - 2005 A: Doxorubicin @ 60 mg/m2

histologically involved axillary Post Op C: Cyclophosphamide @ 600 mg/m2
Dose-dense treatment improved
L.N (T0 - T3, N1-2, M0) T: Paclitaxel @ 175 mg/m2 over 3 • DFS (risk ratio [RR] = 0.74; P= 0.010)
hrs
Adj Conv Dose Dense • OS (RR = 0.69; P = 0.013)
Chemo (3 wkly) (2 wkly) + GCSF
Concurrent vs Sequential chemo:
Seq Ax4 -> Tx4 -> Ax4 -> Tx4 -> No difference in either DFS or OS
Cx4 Cx4
Dose-density effect remained statistically
significant even after adjusting for
Conc ACx4 -> Tx4 ACx4 -> Tx4 • number of positive nodes,
• tumor size,
• menopausal status,
• tumor ER status

Primary End Point: Disease-free survival Severe neutropenia was less frequent in dose-
Secondary End Point: Overall Survival dense regimens arm.

CONCLUSION

1. Dose density improves clinical outcomes significantly 2. Sequential chemo is as effective as concurrent chemo.

TEAM APOLLO, KOLKATA ES-v1-BREAST0047

 EBCTCG
LANCET,
2014
Purpose: Benefit of RT in 1 to 3 +ve lymph nodes is uncertain. To
assess the effect of RT in these women after mastectomy and
axillary
Mastectomy + dissection. Any 1 recurrence Breast Ca Mortality
• 1964–1986 LR recurrence st

R
AD  RT
• N = 8135 Mastectomy + No RT
• 22 Trials AD No RT
RT
RT
Any 1 Recurrence
st

No RT

RT

Breast cancer Mortality RT better RT worse CONCLUSION

After mastectomy & Axillary
dissection, RT reduces both
recurrence and breast cancer
RT better RT worse mortality in 1 to 3 +ve nodes
TEAM APOLLO, KOLKATA ES-v1-BREAST048
 Postmastectomy RT Improves Local-Regional Control & Survival for JCO, 2004
Huang et al
Selected Pts with LABC treated with NACT & MRM Retrospective Analysis

Purpose : To evaluate the efficacy of radiation in patients treated with NACT and mastectomy
542 pts t/t on 6 prospective trials Multivariate Analyses:
Retrospective with NACT, Mastectomy, & RT. • Loco-Regional Recurrence => Hazard Ratio for lack of RT 4.7
(95% CI, 2.7 to 8.1; P < 0.0001)
Co to

analysis of
mp

outcome 134 pts ,in same trials • Cause Specific Survival => Hazard Ratio for lack of RT 2.0
are

but without RT. (95% CI, 1.4 to 2.9; P <0.0001)

d

Cause Specific Survival

LRR improved with RT LRR improved with LRR improved with RT in
improved with RT in
11% vs 22% (p=0.001) RT also in ypCR pt
3% vs 33% (p=0.06) • cT3 or cT4 • cT4
• Stage >/= IIB ds * • Stage >/= IIIB ds, *
• L.N +ve: > /= 4 • L.N +ve: > /= 4
• pT > 2 cm,
P < 0.002 for all comparisons)
* AJCC 1988 (P < 0.007 for all comparisons)
* AJCC 1988

CONCLUSION

Radiation (post NACT & post MRM) found to benefit both local control & survival for pts, presenting
with cT3, Stage III/ IV (ipsilat SCLN)ds, >/= 4 L.N +ve, regardless of response to NACT.
TEAM APOLLO, KOLKATA ES-v1-BREAST0049
 Sequencing of CT and RT in Early-Stage Breast Cancer: JCO
Bellon et al, 2005
Updated results of a Prospective RCT RCT

To determine the influence of sequence of RT and CT after BCS [Initial Result published in 1996]
Post BCS n=122 End Points Cyclophosphamide
T1-2 CT First RT Doxorubicin
Initially only Node Positive Locoregional Failure Methotrexate
No patient was to receive Tamoxifen 6 drug regime (CAMFP) x 4cycles (q -21days)* Survival Analysis 5-FU
Protocol Amendment
R 45Gy/25Fr/5wk f/b 16-18Gy Boost* Prednisolone
Leucovorin
Node Negative with ER-ve Contralateral Br Ca
Node Negative with LVSI RT First CT
Tamoxifen x 5yrs for ER +ve PM Pts n=122
Second Malignancy 35% received regional RT

Median FU 135mo
CT-first to RT-first HR P-value

OS 0.83 0.41 KM Survival Curves

No significant difference in rates of
f/f Distance Mets 0.92 0.70
freedom from (f/f) any event
Events at 10yrs CT-F RT-F
Any Event 46% 51%
Rate of Distant Mets 35% 36% Limitations
First site of Recurrence CT-F RT-F
Local 11% 10%
Small Patient number
Positive / Unknown Margins were included
Distal / Regional 25% 33% Event Free Survival Overall Survival
Only 35% received Tamoxifen

CONCLUSION: Delaying Radiotherapy to give 12 weeks of chemotherapy does not compromise outcome
TEAM APOLLO, KOLKATA ES-v1-BREAST0050
 Predictors of Locoregional Recurrence After Neoadjuvant Chemotherapy: Results Mamounas et al
JCO, 2012
From Combined Analysis of NSABP B-18 and B-27
Risk Prediction Nomograms to Predict LRR After NACT

• Adj. RT only for Lumpectomy patients.

• Patients age>50 years received Tamoxifen after chemo (10 mg,
BD, 5 years), regardless of receptor status.

RESULTS:
• Significant reduction in 10-year cumulative incidence of LRR with addition of Neoadj. Docetaxel (8.5%; P = .02 vs. .AC-alone arm of B-27)
and a nearly significant reduction with Adj. Docetaxel (9.5%; P= .08 v AC-alone arm of B-27)

• LRR incidence 12.6% among 1,947 patients treated with mastectomy and 10.3% among 1,100 patients treated with lumpectomy + XRT.

• Local recurrences 71% of 10-year LRRs in mastectomy patients and for 79% of 10-year LRRs in patients receiving lumpectomy plus breast
XRT.

CONCLUSION:
• For Patients treated with NACT, Age, cT characteristics before NACT and pN status/tumor response after NACT can be used
to predict risk for LRR and to optimize use of adjuvant RT.
TEAM APOLLO, KOLKATA ES-v1-BREAST0051
 1st Randomized trial to compare
2002conventional fractionation with
hypofractionation in Breast cancer
with long-term results.
• N=1234
• T1,T2, N0 ONTARIO
2010
• Post BCS TRIAL
• Clear margins CANADA
Conventional Fractionation
EBRT Cosmetic outcome and local control:
(50 Gy in 25 Fractions in 5 Initial results
LRC 5
R Acceleratedweeks)
Hypofractionation Arms Baseline 3 year 5 year
Yrs
EBRT
(42.5 Gy in 16 Fractions in 3
wk) Stan 83%(604) 77%(498) 79%(423) 97.2%
Survival dard
Hypofractionated
Local Recurrence

Hypo 84%(616) 77%(518) 78%(448) 96.8%

Standard Regimen
fr. CONCLUSION
Standard Regimen • Hypofractionated RT is non-inferior in
Hypofractionated
Regimen
term of Risk of Recurrence, Cosmesis and
Late toxicity at 10 years.
• No difference in OS.
TEAM APOLLO, KOLKATA ES-v1-BREAST052
 Yarnold et al
R & O 2005
RCT, Ph III

Purpose: To test the effects of Radiation fraction > 2.0 Gy on late normal tissue
responses in breast after BCT for early breast cancer.
• N= 1410 pt’s 50 Gy/25 fr Any change in Breast appearance by Breast Induration
• 1986-1998 N= 470 Fractionation schedule (n=1202) by Fractionation Schedule (n=806)
• Stage I to III 42.9 Gy/13 fr
• Max. of 1 +ve N= 466
node
• Post BCS 39 Gy/13
• < 75 Years fr
N= 474
End Points:
• Primary: Late change in Breast
appearance.
• Secondary: Ipsilateral relapse /: 3.6 Gy (95% CI 1.8–5.4) /: 3.1 Gy (95% CI 1.8–
4.4)
CONCLUSION / 3 Gy for late normal tissue changes in breast
- Modulation of fraction size is superior to modulation of fraction number .
- This is a way forward towards Hypofractionated RT in Early Breast Ca.
TEAM APOLLO, KOLKATA ES-v1-BREAST053
 Owen et al
Lancet 2006
RCT
To see if fewer, larger fractions (Hypofractionation) is as safe and as effective as
standard (conventional) regimens
• N= 1410 pt’s
Median FU: 9·7
• 1986-1998 50 Gy/25 fr
years
• Stage I to III N= 470
• Max. of 1 +ve
node 42.9 Gy/13 fr

Probability of Local
• Post BCS N= 466 39 Gy Arm
• < 75 Years • Recurrence-free survival curves for the
39 Gy/13
End Points: fr fractionation schedules diverge only after 5
• Primary: Late N= 474 years of follow-up.

relapse
• Probability of local recurrence between the 42·9 Gy and 39
change in Breast Gy groups differed significantly.
appearance.
• Secondary:
Ipsilateral relapse CONCLUSION
• Breast cancer tissue is equally sensitive to fraction size as dose-limiting
healthy tissues.
• RT schedules can be simplified by delivery of fewer, larger fractions without
compromising effectiveness or safety, and possibly improving both.
TEAM APOLLO, KOLKATA ES-v1-BREAST054
 UK START Trial
A
RCT, Ph III
2008
All the patients were treated over 5
Locoregional Normal Tissue Effect
weeks Fractionation
Conventional Relapse
EBRT 39 Gy
(50 Gy in 25 Fractions in 5
weeks)
Hypofractionation EBRT
(41.6 Gy in 13 Fractions in 5
R weeks)
Hypofractionation EBRT
(39 Gy in 13 Fractions in 5 Favors 41.6 Gy and 39 Gy Favors 50 Gy

•
weeks)
Study Period = 1999 to 2002; Locoregional Relapse (5 Moderate or marked normal
tissue effects:
yrs) • Significantly less in 39
• Completely excised Invasive o 3·6% in 50 Gy
Breast Ca, Stage pT1–3a N0–1 Gy.
o 3·5% in 41·6 Gy • Did not differ between
M0 41.6 Gy arm & 50 Gy
Primary Endpoint:
• Breast
o 5·2%cancer & the dose-limiting
in 39 Gy*** normal
arm.
1.Loco-regional relapse tissues respond similarly to change in RT
2.Normal Tissue effects fraction size.
3.QOL • 41·6 Gy in 13 fr, is similar to 50 Gy in 25 fr. in
terms of LRC and late normal tissue effects
TEAM APOLLO, KOLKATA ES-v1-BREAST055
Page 2 of 2
 UK START Trial
B
RCT, Ph III
2008
• Study Period: 1999 to 2001 Methods Results Med F.U 6 yrs
• N= 2215 pt’s. Locoregional Relapse (at 5 yrs)
• Completely excised Invasive o Arm 50 Gy: 3·3%
Breast Ca, Stage pT1–3a N0–1 M0
o Arm 40 Gy: 2·2%
Conventional
Absolute difference of –0·7% (95% CI –1·7% to 0·9%)
Fractionation RT
=> the absolute difference in local-regional relapse could
(50 Gy/25 fr in 5 wks)
be up to 1·7% better and at most 1% worse after 40 Gy
N=1105
R than after 50 Gy.
Photographic & Patient self-assessments indicated
Hypofractionation RT => lower rates of late adverse effects after 40 Gy than after 50 Gy.
(40 Gy/ 15 fr in 3 wks)
N=1110 Conclusio
Radiation schedule of 40 Gy in 15 fr seems to
Primary Endpoint: n: offer
1. Loco-regional relapse rates of local-regional relapse & late adverse
2. Normal Tissue effects
effects at least as favourable as the std
3. QOL
schedule (50 Gy in 25 fr.)
TEAM APOLLO, KOLKATA ES-v1-BREAST056
Page 2 of 2
 First results of Randomised UK FAST Trial of Hypo# 10-Year Results of FAST: A RCT of 5 # Whole-
RT for Early Breast Ca(CRUKE/04/015) Breast RT for Early Breast Ca
Yarnold et al, Radiother Oncol, 2011 Brunt et al,JCO,2020

PRIMARY END POINT RESULTS: Median F.U 9.9 years

Change in photographic breast appearance at 2 and 5 years
SECONDARY END POINTS
Physician assessments of Normal Tissue effects(NTE) and Local tumor control. Breast Induration Breast Shrinkage
INCLUSION CRITERIA:
• Age>50 years,
• Invasive ca
• BCS • FAST trial was not powered for formal statistical
• pT<3.0 cm comparison of local tumor control.
• Complete microscopic resection of • Deaths from other causes were most frequent
tumour consequential event.
• -ve axillary node # Schedule I/L Breast event(%) 5 years 10 years
EXCLUSION CRITERIA :
All Patients 1.2 0.7 1.3
• Mastectomy
• Lymphatic RT 50Gy 1.0 0.7 0.7
• Tumour bed boost dose 30 Gy 1.3 1.0 1.4
• Neoadj. or Adj. cytotoxic therapy 28.5 Gy 1.3 0.4 1.7

CONCLUSION:
For patients with low risk , early stage Breast cancer , 28Gy/5#/Once weekly RT might be an appropriate alternative to conventional
fractionation both from point of Breast appearance and Normal tissue effects.
TEAM APOLLO, KOLKATA ES-v1-BREAST0057
 Hypofractionated breast radiotherapy for 1 week Vs 3 Lancet 2020
Adrian M Brunt, Joanne S Haviland
weeks (FAST-Forward): 5-yr efficacy and late normal Multicentre Phase 3 RCT
tissue effects results
To identify a 5 fraction/ 1 week schedule that is non-inferior to standard 15-fraction regimen
≥ 18yrs 40Gy/ 15Fr/ 3 Wks End Points
Post BCS or MRM (ALND/SLNB) n=1368
pT1-3, pN0-1 Boost (BCS) Ipsilateral Breast Tumor Relapse
Concurrent Trastuzumab/ HT FU
Chest wall recurrence (IDC/DCIS)
R 27Gy/ 5Fr/ 1 Wk 10-16Gy, 2Gy/Fr
Excluded n=1370
Lowest Risk Patients * Nodal Radiotherapy Late Normal tissue effects
(Protocol Amendment) 26Gy/ 5Fr/ 1 Wk was not allowed Photographic sub-study (BCS) & PRO
n=1372
Median FU 71.5 month, Compliance to allocated treatment 99%

40Gy/15Fr 27Gy/5Fr 26Gy/5Fr Demonstrated non-inferiority of either regimen to

IBTR – HR (Vs 40Gy/15Fr) 0.86 0.67 40Gy/15Fr for IBTR at 5yrs
5Yr IBTR (2.1%) 1.7% 1.4%
Similar Normal tissue effect noted for 26Gy and 40Gy at
Regional Relapse (1%) 0.8% 0.7% 5yrs of follow-up
Normal Tissue Effect* 5yrs
9.9% 15.4% 11.9% Estimated α/β value for tumor control – 3.7Gy assuming
p – 0.0003 p – 0.17
no effect of time
OR (Vs 40Gy/15Fr) 1.55 1.12
p<0.0001 p - 0.20
PRO & Photographic Sub-study - 27Gy had significantly 5Fr regimen is convenient and substantially less
higher risk of changes compared to 40Gy or 26Gy expensive for patients and health service
* Most Common – Breast Shrinkage

CONCLUSION: 26Gy/5Fr/1wk is non-inferior to 40Gy/15Fr in terms of tumor control and normal tissue effect
TEAM APOLLO, KOLKATA ES-v1-BREAST0058
 Planning with IMRT and Tomotherapy to modulate dose IJROBP 2011
E. M. Donovan et al
across breast to reflect recurrence risk (IMPORT HIGH Preparatory study to multicentric RCT
Trial)
To establish planning solutions for a concomitant three-level radiation dose distribution to breast for IMPORT High Trial
Hypothesis: Adjusting the fraction Evaluation
size would be more effective strategy
of dose-intensity modulation than
Multicentre
Dosimetric comparison of the
adjusting fraction number for Boost three plans
Tomo/ LINAC Plan

2mm gold seeds inserted in Tumor * Control arm used PTV - Whole Breast and Tumor Bed
Photon/ Electron Coverage
cavity during lumpectomy
boost
9 CT Data sets OARs: Ipsilateral and Contralateral
SCF/Axilla treated when required Lungs, Heart, Contralateral Breast

RESULTS
Control Group Test Groups

Photon Plan fulfilled minimum constraints for PTV- PTV-WB and PTV-TB Dose constraints were fulfilled
WB and PTV-TB for all plans with some variation between Forward &
Inverse IMRT Plans
8/9 Electron boost plan failed to cover PTV-TB The test approach and the planning
(Median dose was comparable) Contralateral lung volume >2.5Gy was increased with solutions has been subject of several
inverse IMRT and Tomotherapy plan, did not exceed
Lung and heart constraint were met for all photon constraints studies and is tested in prospective
only plans randomized trial
IMRT methods delivered a greater whole body dose
than standard breast tangents

CONCLUSION: Demonstrated a set of widely applicable solutions for the delivery of a concomitant 3 level dose distribution
TEAM APOLLO, KOLKATA ES-v1-BREAST0059
 Partial-breast radiotherapy after BCS for patients with early breast cancer (UK Lancet, 2017,
UK
IMPORT LOW trial): 5-yr results from a multicentre, phase 3, non-inferiority RCT Coles et al
Hypothesis: Partial-breast RT improves balance of beneficial vs adverse effects compared to whole-breast RT in early Ca
breast.
• ≥50 yrs age; Post BCS; Margins ≥ 2 mm RESULTS & INTERPRETATION
• Unifocal Invasive ductal AdenoCa; pT1–2, pN0-1 (Median FU: 72.2 months)
• 2007- 2010; n= 2018 Local relapse 5 yr cumulative Hazard ratio p value for
incidence % (95% CI) non-
R (95% CI) inferiority

Control group 1·1% (0·5–2·3) 1

Control group Reduced-dose Partial-breast Reduced-dose 0·2% (0·02–1·2) 0·33 (0·09–1·20) 0.003
n= 674 group group
Partial breast 0·5% (0·2–1·4) 0·65 (0·23–1·84) 0.016
n= 673 n= 669
40Gy/ 15# 36Gy/ 15# to whole 40Gy/ 15# to partial
whole-breast RT breast, 40Gy/ 15# breast only • Reduced-dose /partial breast RT produced non-inferior LR
to partial breast compared to standard whole breast RT.

Technique:- Field-in-field IMRT delivered using standard tangential • Photographic/patient/clinical assessments recorded
beams; simply reduced in length for partial-breast group. equivalent or fewer late adverse effects with experimental
groups.
• 1° endpoint:- LR (80% power to exclude a 2·5% increase [non-
inferiority margin] at 5 yrs for each experimental group)
•
• This simple radiotherapy technique is implementable in
Non-inferiority was shown if the upper limit of the two-sided
95% CI for the HR of local relapse was < 2·03) radiotherapy centres worldwide.
TEAM APOLLO, KOLKATA ES-v1-BREAST0060
 Bartelink et
al
Netherland
Lancet
To see the effect of a Radiation boost of 16 Gy on OS, Local control, and Fibrosis inOncology PhII
stage I and
III, 2014
Breast ca who underwent BCS compared ith no boost. (Boost Versus No Boost)
50 Gy/25 fr.
• N= 5318 pt’s followed
• 1989-1996 by No Boost
• Stage I to II Boost
OS
Recurrence
• Post BCS N= 2661
• Median FU: 17.2 Local No Boost
50 Gy/25 fr.
Recurrence
Yrs (No Boost) No diff. in OS Boost more in
N= 2657 No Boost arm
End Points:
• Primary: OS
• Secondary: LC, Cosmesis & Fibrosis
CONCLUSION
• RT boost after whole-breast RT has no effect on Overall Survival.
• Improves local control, with the largest absolute benefit in young patients.
• Increases the risk of moderate to severe fibrosis.
• Boost can be avoided in most patients older than 60 years.
TEAM APOLLO, KOLKATA ES-v1-BREAST061
 Phase III RCT
Milan, Italy
Lancet
Oncology
April 2021
Compares (ELIOT) Electron Intraoperative RT (APBI) With Whole
Breast RT in early stage Breast cancer in terms of Recurrence and
Trial Design:
• 48–75 years. Whole Breast survival. ELIOT WBI P value
• Unicentric RT 0f 50 Gy in IBTR 11% 2% 0.001
25 fractions f/b • 2000=2007 at 12.4
Tumor • N= 1305 pt’s. Yrs
• USG diameter Boost of 10 Gy • Median FU: 12.4 Yr
< 25 mm N=654 ELIOT 5 YR 4.2% 0.5 %
• Clinically -ve R Surgery & IBTR
axillary Intraoperative 10 YR 8.1 % 1.1 %
nodes. Electron RT of IBTR
• Suitable for 21 Gy Single fr. 15 YR 12.6% 2.4 %
BCS to Tumor Bed IBTR
Primary endpoints: N=651
OS 5 YR 10 YR 15 YR
• Ipsilateral Breast
Conclusion IBTR 96.8 90.7 83.4
Tumor • Long-term results confirmed higher rate of IBTR in the ELIOT
Recurrence. than in the WBI group, without any differences in OS. WBI 96.8 92.7 82.4
Seconadry : OS • ELIOT to be offered in selected pt’s at low-risk of IBTR.
TEAM APOLLO, KOLKATA ES-v1-BREAST062
 We acknowledge the contribution of our entire Department
- Radiation Oncology, Apollo Hospital, Kolkata

Prof (Dr) Subir Gangopadhyay Dr Biplab Sarkar

Dr Arundhati Chakraborty Dr Arundhati De
Prof (Dr) Litan Naha Biswas Dr Animesh Saha
Dr Subrata Saha Dr Jibak Bhattacharya
Dr Suchanda Goswami Dr Mukti Mukherjee
Dr Suparna Ghosh Roy Dr Tanmoy Ghosh
Dr Santanu Acharya Dr Rishav Raj
Dr Prasenjit Chatterjee Dr Riddhijyoti Talukder
Dr Tanmoy Mukhopadhyay Dr Asesh Samanta
Dr Akhter Jawade Dr Gunturu Indira
Dr Tanweer Shahid Dr Chandrasekhar Rao P
Dr Shila Mitra Dr Soumyadip Mitra
Dr Sayan Paul Dr Aditi Mishra

THANK YOU