2. Stages Included in early breast cancer
And LABC
• EARLY --i.e. T1 – T3, N0 – N1 disease Stage 1a to stage IIb
• LABC – Any N2 , Any T4 Stage IIIA and IIIB
6. Types of MRM
• Patey1: Pectoralis major muscle is preserved and Pectoralis
minor removed.
• Auchincloss2: Pectoralis minor is retraced but not divided.
• Scanlon3: Pectoralis minor is divided but not removed.
1. Patey DH, Dyson WH. Br J Cancer 1948
2. Madden JL. Surg Gynecol Obstet 1965
3. Scanlon EF, Caprini JA. Cancer, 1975
13. Evidence behind PMRT
• Danish DBCG 82TM protocols were designed to assess the
impact of PMRT in premenopausal1 (82b, n = 1708) and
post-menopausal2 (82c, n = 1480) females respectively.
- Systemic therapy in 82b was 8 cycles of CMF, and in 82c was
+ Tamoxifen for 1 year + CMF.
- Both studies documented significant reductions in DFS and
OS with the addition of RT at 10 years:
82b 82c
RT No RT RT No RT
DFS 48% 34% 36% 24%
OS 54% 45% 45% 36%
1. Overgaard et al. NEJM 1997
2. Overgaard et al. Lancet 1999
14. EBCTCG 2014 Meta-analysis
• The finding comes from an IPD analysis of 8135 patients with an average follow up
of 11 years.
• Included 22 trials in patients with EBC where patients underwent MRM +
locoregional RT.
Lancet 2014
15. • For 700 women with axillary dissection and no positive
nodes, radiotherapy had no significant effect on locoregional
recurrence, overall recurrence or Breast cancer mortality.
• For 1314 women with axillary dissection and one to three
positive nodes, RT reduced locoregional recurrence (2p<
0.00001), overall recurrence (p = 0.00006), and breast cancer
mortality (p = 0.01).
• For 1772 women with axillary dissection and four or more
positive nodes RT reduced locoregional recurrence (2p <
0.00001), overall recurrence (2p = 0.0003) and breast cancer
mortality (2p = 0.04).
EBCTCG Meta-analysis: PMRT
17. pN1
1314
pN2
1772
LRR: 20.3% vs 3.8% Any Rec: 45.7% v 34.2%
CSS: Mortality
50.2% vs 42.3%
LRR: 32.1% vs 13.0% Any Rec: 75.1% vs 66.3%
CSS: Mortality
80% vs 70.7%
18.
19. ASCO/ASTRO/SSO Guideline update
• Intended for Early Breast Cancer, i.e. patient with T1-2 tumors
and pN1 (1-3 positive axillary nodes) undergoing Mastectomy.
• Unanimous agreement that available evidence shows that PMRT
reduces the risks of locoregional failure (LRF), any
recurrence, and breast cancer mortality for patients with
T1-2 breast cancer with one to three positive axillary nodes
(Recommendation 1).
• Subset of patients in whom toxicity may compete with the benefits:
• Patient characteristics
• Low tumor burden (T size, 1 node macro/micro metastasis).
• Tumor biology
Recht et al. JCO 2016
20. • For patients with positive SLNB but no furtherALND,
decision to be individualized.
(Recommendation 2)
• For patients achieving complete response with Neoadjuvant
systemic therapy (NAST), can consider omitting PMRT as a
part of research protocols but not in routine practice.
(Recommendation 3)
• If PMRT is given, regional nodal irradiation (RNI) should be
added for all patients with node positive disease.
• Subset of patients where benefits are not significant enough to
warrant RNI not yet identified; further research needed.
(Recommendation 4)
ASCO/ASTRO/SSO Guideline update for PMRT
21. Cambridge score (C-PMRT index)
3 2 1
Nodes/LVI > 4 1 - 3 LVI
T size T3 or T4 3 - 5cm 2 – 2.9 cm
Margins
Deep margin <1mm
Pectoral muscle invasion
- -
Grade - - 3
A patient with any category score of 3 is classified as High (H);
Score > 3: Intermediate (I); < 3: Low (L).
• Developed at Cambridge University Hospital in 1999 as a
tool to assist decision making for PMRT.
• All patients in H and I groups to receive PMRT.
22.
23. IN PRESYSTEMIC THERAPY PATIENTS
• Loco-regional RT is an independent prognostic factor both for LRRFS & OS
• Indications for PMRT should be based on prechemotherapy clinical stage
• Response to NACT alone cannot be used to guide indications for PMRT outside of
clinical trial
• No clear sub group identified in whom PMRT can be safely omitted
• EBCTCG MA: NACT vs ACT long term outcome reported higher 15-yr local
recurrences rate (21.4% vs 15.9%) without impact on survival
• Strategies to mitigate the increased local recurrence after breast-conserving
therapy in tumours downsized by NACT should be considered—eg, careful
tumour localisation, detailed pathological assessment, and appropriate
radiotherapy.
• Ongoing trials will throw light on the possible de-escalation of both Sx and RT in
post NACT setting
32. Rationale & Issues
• Studies have suggested that addition of RNI improves locoregional
control (but not OS)1. This benefit is especially prominent in patients
with heavy nodal burdens.
• However the addition thereof increases the complexity of RT, in
addition to exposing OARs to higher doses.
• However, improvement in RT delivery techniques coupled with the
clear survival benefit in node positive patients undergoing PMRT
suggested that a formal analysis was due.
• LowerAxilla receives 50-80% dose with standard tangents; level 3,
SCF and IMN?
1. Veronesi et al. Ann Oncol 2008
33. NCIC-MA.20 (2015)
A trial of regional nodal irradiation in early breast cancer.
• N = 1832, 916 randomized to each arm.
• Median follow up: 62 months
• Patients were well-matched in terms of baseline characteristics.
• Amedian of 12 axillary nodes were removed.
• 85% of patients had 1-3 positive nodes, 10% were node
negative, and 5% had > 4 positive nodes.
- Overall 90% node +ve
Whelan et al. NEJM 2015
34. • Isolated locoregional DFS: The addition of RNI to WBI was
associated with a decrease in isolated locoregional recurrence
(LRR) from 48 in the WBI arm to 29 in the WBI+RNI arm.
• The local-only recurrence rates were similar between the 2 groups,
while there was a marked reduction in regional recurrences, with 21
in the WBI arm versus only 4 in the WBI+RNI arm.
• An improvement in isolated locoregional DFS from 94.5% to
96.8%, HR = 0.59, (p = .02)
• DFS: Improvement in 5-year DFS from 84.0% to 89.7%
favouring the WBI+RNI arm, with a HR of 0.68 (p .003)
• Distant DFS at 5 years was 92.4% for WBI+RNI and 87.0% for
WBI alone ( p=.002)
• Overall Survival: with 5-year OS of 92.3% versus 90.7% for
WBI alone (HR=.76, p=.07).
NCIC MA 20
35. EORTC 22922/10925: Internal Mammary and Medial
Supraclavicular Irradiation in Breast Cancer
• 4004 patients randomized to receive whole breast RT/PMRT +
Regional nodal irradiation.
• Primary end point: OS
• Secondary end points: DFS, DDFS & death from CAbreast
• 85% patients Stage I/II
• Median follow up: 10.9 years
• OS trended better with RNI (p = 0.06), DFS was better (0.04);
breast cancer death was significantly lower (NNT 39).
• The 15-years results also showed a significant reduction in
breast cancer mortality & breast cancer recurrence (but not OS)
Poortmans et al. NEJM 2015; updt. 2018
36.
37.
38.
39. Pathologic rates of IMN involvement
Huang et al. Breast Cancer Res Treat 2008
40. • 1991-1997, 1407, median FU 11.3 years
• Primary endpoint: 10 year OS, expecting
10% difference in OS with IMNI (50% vs.
40%)
• Pre specified sub group analysis for tumor
location, Ax nodal status and adjuvant
therapy
• SCF+Apex at fixed depth of 3 cm with PAB
• Prescribed dose was 45 Gy in 18 fractions
but one centre used 26 Gy in 6 fractions
over 15 days
• IMNRT group was treated with P-E
combination: 4-6 MV or cobalt at 3 cm
depth, 6 x 14 cm to cover upper five spaces
41. French trial (condt…)
▫ No difference in late effects
▫ Cardiac evaluation not done
systematically
▫ Criticisms
▫ Too optimistic to get 10% gain in
OS
▫ Control arm had much better
survival than assumed
▫ Target volume: excessive cardiac
exposure because it included
upper 5 spaces for all patients
42. • 1996-2004, 4004, median FU 15.7
years
• Primary endpoint: 10 year OS,
expecting 4% difference in OS with RNI
(79% vs. 75%)
• Stratified by tumor location, size, Ax
nodal status and type of breast & Ax
surgery
• RNI comprised of medial SCF+IMN
• Prescribed dose was 50 Gy in 25
fractions
• RNI group was treated with P-E
combination: 4-10 MV photons 26 Gy
and 12-14 MeV electrons 24 Gy
Covered upper 3-5 spaces depending
upon tumor location
• Strict QA procedures followed and
published
43. NNT to avoid one
relapse and death was
30 & 39.
▫ No difference in late
effects (lung, heart,
second cancers)
▫ Cause of death was
similar in both arms
▫ Criticisms
▫ Negative trial with
respect to
primary endpoint ▫
Cardiac evaluation not
done
systematically ▫ Does
not test effect of IMNI
alone
44.
45.
46. • Positive axillary lymph nodes with central and medial lesions
• Stage III disease
• Positive sentinel lymph nodes in IM chain
• SLN +ve in axilla with drainage to IM on lymphoscintigraphy
Perez & Brady's Principles and Practice of Radiation Oncology, 7th ed
Indications of RT to IMN
47. Indications of RT to Axilla
• Node positive with extensive extra capsular extension
• Sentinel lymph node positive with no dissection
• Inadequate axillary dissection
• High risk with no dissection
Perez & Brady's Principles and Practice of Radiation Oncology, 7th ed
48. • Absolute
- cN2/3 disease
- pN2 or pN3 disease (> 4 positive lymph nodes after
axillary dissection
• Relative:
- 1-3 positive lymph nodes with high risk features
- Positive sentinel lymph node with no axillary dissection
Perez & Brady's Principles and Practice of Radiation Oncology, 7th ed
Indications of RT to SCF
59. Adjuvant Radiation Therapy After
Mastectomy- Post-Mastectomy RT
• Randomized clinical trials have shown that a DFS and OS advantage is conferred by the
irradiation of chest wall and regional lymph nodes in patients with positive ALNs after
mastectomy and ALN dissection.
• In these trials, the ipsilateral chest wall and the ipsilateral locoregional lymph nodes were
irradiated.
• The results of meta-analyses show that RT after mastectomy and axillary node dissection
reduced both recurrence and breast cancer mortality in the patients with 1 to 3 positive
lymph nodes even when systemic therapy was administered.
• According to the NCCN Panel, post-mastectomy radiation to the chest wall is
recommended
• Data from the EORTC 22922/10925 trial support the inclusion of RNI in patients
undergoing postmastectomy radiation. The trial assessed the independent effects of
including RNI versus no RNI when treating the chest wall after mastectomy. Based on the
benefits demonstrated in this trial, the NCCN Panel recommends comprehensive RNI to
include any undissected axilla at risk
60. Post-Mastectomy RT for Node-Negative
Disease:
• In patients with negative nodes, tumor less than or equal to 5 cm, and clear margins (≥1 mm),
post-mastectomy RT is typically not recommended.
• However, the panel has noted that it may be considered in subsets of these patients with high-
risk features- including central/medial tumors, T3 tumors, or tumors greater than or equal to 2
cm with fewer than 10 axillary nodes removed and at least one of the following: grade 3, ER-
negative, or LVI, should be considered for PMRT with RNI to include any undissected axilla at risk.
• Features in node-negative tumors that predict a high rate of local recurrence include primary
tumors greater than 5 cm or positive pathologic margins.
• In patients with positive pathologic margin, if re-resection to negative margins is not possible, the
panel recommends strongly considering chest wall irradiation with the addition of comprehensive
RNI including any portion of the axilla at risk.
• Chest wall irradiation should be considered with addition of comprehensive RNI, including any
portion of the axilla at risk in those with tumors greater than 5 cm.
• In patients with tumors less than or equal to 5 cm and negative margins but less than or equal to
1 mm, chest wall irradiation should be considered with consideration of comprehensive RNI
including any portion of the undissected axilla at risk only in those with high-risk features.
61. Considerations for RT in Patients Receiving
Preoperative Systemic Therapy
• The panel recommends that decisions related to administration of adjuvant RT for patients
receiving preoperative systemic chemotherapy should be made based on maximal stage (ie,
clinical/anatomic stage, tumor characteristics) at diagnosis (before preoperative systemic therapy)
and pathologic stage at definitive surgery (after preoperative systemic therapy).
• Data from numerous studies in patients with stage III disease suggest that postoperative RT
improves local control even for patients who have a pathologic complete response (pCR) to
neoadjuvant chemotherapy.
62. RT After Preoperative Therapy and
Mastectomy:
• Those who have clinically positive nodes at diagnosis that respond to
preoperative systemic therapy and become node-negative should be
strongly considered to receive RT to the chest wall and comprehensive RNI
with inclusion of any portion of the undissected axilla at risk based
• For those with positive nodes (ypN1+) after preoperative systemic therapy,
axillary dissection is the standard treatment arm of the ongoing Alliance
11202 trial; however, if RT is indicated it should include chest wall along
with comprehensive RNI with inclusion of any portion of the undissected
axilla at risk.
• Those who have node-negative disease at diagnosis and after preoperative
systemic therapy and whose axilla was assessed by SLNB or axillary node
dissection may forego RT.
