1. What’s New in
Breast Cancer Radiotherapy?
Roger M. Macklis, M.D.
Cleveland Clinic Lerner College of Medicine
Cleveland Clinic Healthcare System

2. RM 9/05
What’s New in
Breast Cancer Radiotherapy?
Recent Meta-Analysis from
“Lancet”
Partial Breast Irradiation
Intensity Modulated
Radiation Therapy (IMRT)

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BREAST CANCER COMMANDS ATTENTION
“Few topics in medicine engender as much
emotional response as the treatment of primary
breast cancer.”
- Levene, Harris, Hellman
Cancer (1977)

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Early Investigations
Charles H. Moore, 1867
(surgeon to the Middlesex Hospital, London).
“ … Cancer of the breast requires the careful
extirpation of the entire organ; that the situation
in which this operation is most likely to be
incomplete is at the edge of the mamma near
the sternum …”

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Early Investigations
William Halsted, 1852-1922
(surgeon to the Johns Hopkins Hospital, Baltimore).
“ Most of us have heard our teacher in surgery admit
that they never cured a case of cancer of the breast …
Everyone knows how dreadful the end-results were
before cleaning out the axilla became recognized as
an essential part of the operation.”

6. RM 9/05
Early Investigations
Sir Geoffrey Keynes, 1920s
(St. Bartholomew Hospital, London).
Interstitial radium implants of tumor bed and
surrounding regions of the breast. “ … treatment
of choice for very advanced breast cancer.”

7. RM 9/05
Breast Cancer: Critical Benchmark Studies
NASBP (NEJM 2002: 347 1233-1241)
20 year F/U shows
lumpectomy + XRT 14% LRR
lumpectomy alone 39.2% LRR
Milan (Ann Oncol 2001 12: 997-1003)
Quadrantectomy + XRT 5.8% LRR
Quadrantectomy alone 23.5% LRR
New Meta-Analysis from Lancet 12/05

8. New Meta-Analysis Data on Breast Radiotherapy
strongly suggests that in addition to improving
local control, radiotherapy ALSO improves survival

9. Meta-Analysis of Breast Cancer XRT
Title: Effects of radiotherapy and of differences
in the extent of surgery for early breast cancer
on local recurrence and 15-year survival: an
overview of the randomised trials
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
Lancet 366:2087-2106 (2005)
Published Dec. 17, 2005

10. Meta-Analysis of Breast Cancer XRT
Meta-Analysis of 78 randomized controlled trials
beginning by 1995. These trials included approximately
42,000 women and roughly ¾ were involved in XRT vs
no XRT trials for either conservation therapy (intact
breast) or post-mastectomy therapy. Trials separated
into groups showing > or < 10% difference in LR.

11. Data from Lancet Meta-Analysis (N=42,000)
XRT No XRT
5 year local recurrence: 7% 26%
(conservation-intact breast)
Post-Mastectomy (LN+) 6% 23%
15 year breast cancer mortality 30.5% 35.9%
(intact breast)
15 year breast cancer mortality 54.7% 60.1%
(post-mastectomy LN+)
• Overall all-cause reduction in mortality approx 4.4%!
• Similar proportional reductions in all groups
• Major XRT-related toxicities included cardiac disease (RR 1.27)
lung ca (RR 1.78) and contralateral breast ca (RR 1.18)

12. Interpretation of Meta-Analysis Data:
“Differences in local treatment that substantially affect
local recurrence rates would, in the hypothetical absence
of any other causes of death, avoid about one breast
cancer death over the next 15 years for every four local
recurrences avoided, and should reduce 15-year overall
mortality.” Lancet 366:2087 (2005)
Will new treatment approaches further improve this
data set?

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CRITICAL QUESTIONS ON
PARTIAL BREAST IRRADIATION
Can less than the entire breast be treated?
If so, for which types of cases?
Which portion of the breast?
How big a margin?
External beam vs. brachytherapy?
What about overall cosmesis?
What about adjuvant systemic therapy?

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General Approaches to Partial Breast Radiotherapy
Interstitial implant brachytherapy
Intra-Operative Radiotherapy
External beam radiotherapy
MammoSite brachytherapy

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Interstitial Implant Breast Brachytherapy
1. Ochsner Clinic Team (King et al, 2000)
50 pts: Tis, T1, T2 up to 4 cm
Ө margins; ≤ 3 ⊕ LN
Target Tissue: tumor surgical bed plus
2-3 cm margin
Either LDR or HDR technique
Dose: 45 Gy LDR or 32 Gy (4 day BID) HDR
With median f/u 75 months, 1 breast and
3 LN recurrences seen
Cosmetic Outcomes: 75% good to excellent
(less than 85-90% for external beam)

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Interstitial Implant Breast Brachytherapy
2. William Beaumont Team (Vicini et al, 2003)
198 pts: Tis, T1, T2 ≤ 3 cm
Ө margins; age >40; Ө LN
Target similar to Ochsner group
Dose: LDR 50 Gy or LDR 3.4 Gy BID x 5 days
Cosmetic Outcome “good to excellent” 99%!!
Local recurrence rate 1% at 5 years
Basis for subsequent RTOG trial which
opened in 1997

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Intra-Operative Breast Irradiation
London study using Intrabeam device (Photo
Electron, now owned by Zeiss)
Spherical applicators of different sizes
50 kv orthovoltage beam producing 5 Gy at
1 cm from application surface
Clinical trial by Tobias et al. now underway;
each site chooses its own entrance criteria.
Other intra-op programs at MSK, etc.
CCF used for boost only. Veronesi (Milan)
just published results of 590 pts treated with
intra-op electron beam; 21 Gy single fraction.
3% breast fibrosis, 6/590 ipsilat. recurrence
after 2-year median f/u. [Ann. Surg 242:101
(2005)]

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External Beam Partial Breast Irradiation
William Beaumont group – developed
as non-invasive analog to implant
studies
3D conformal XRT
Target Tissue: tumor bed plus 2-3 cm
(breathing margin)
34-38.5 Gy BID over 5-7 days
RTOG 95-17 phase II protocol: 38.5 Gy
BID over 5-7 days
Excellent results led to current RTOG/
NSABP PBI trial

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MammoSite Balloon Brachytherapy
Catheter resembling Foley but with 2
channels: one for saline (expander) and
a second for radioactive source (Ir-192)
Placed directly in lumpectomy cavity
either at time of original lumpectomy or
in a second procedure (single scar)
Dose: 34 Gy BID in 5-7 days
With median F/U 29 months, local failure
rate 0% and cosmesis good-to-excellent
in 84%.
FDA clearance granted 2002
Said to be the most rapidly growing breast
cancer radiation procedure in the USA.

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MammoSite: Coming to a Clinic Near You!

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Current RTOG / NSABP Trial
Phase III randomized comparison of whole breast
vs. short-course partial breast XRT
Stage 0, I, or II with T<3cm
No more than 3 histologically positive nodes
Post-surgical CT evaluations of lumpectomy cavity
Defined ratios of partial-breast to whole-breast
volumes
Either interstitial catheters, Mammo Site, or 3D
conformal (NOT IMRT) radiotherapy
Twice daily for 10 fractions over 5-7 days
No data available yet

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BREAST IMRT

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Breast IMRT
Intensity Modulated Radiation Therapy (IMRT) refers to a
set of related processes involving both radiation treatment
planning and beam delivery. Unlike conventional radiation
treatments, which often strive to deliver uniform radiation
doses to large regions of tissue, IMRT allows small
beamlets to be used to change the shape and intensity
of the radiation field (sort of like a dot-matrix printer). This
allows the radiation team to focus the field more intensely
on tumor deposits and limit the dose to nearly normal
tissues.

24. RM 9/05
CCF Breast IMRT (T. Djemil, Ph.D.)
“Breast Forward IMRT Planning”
Start with routine tangential fields and then adjust each segment
of the plan to minimize hot spots
Number of segments related to hot spot location and intensity

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CCF Multislice Coplanar Breast IMRT
With Concurrent Boost to Tumor Bed
Usually 4-5 segments per field or 10 segments total

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BREAST IMRT
Basic Principles of Ochsner Approach
6 Field Treatment technique
3 Medial Fields + 3 Lateral Fields
Left Breast: 300, 315, 340, 110, 125, 150 Degrees
Right Breast: 200, 230, 250, 20, 45, 60 Degrees
No immobilization used
Same margins as 3D conformal technique used for
IMRT

27. BREAST IMRT
RM 9/05
Breast IMRT
6 Fld Technique
Note that very
peripheral deep
portion of breast
may be under-
treated but amount
of heart and lung
irradiated is very
small.

28. BREAST IMRT
RM 9/05

29. BREAST IMRT
RM 9/05
Breast IMRT
Boost to deep lesions

30. RM 9/05
Breast IMRT:
Why do we need it?
More conformal dose to breast
Lower doses to lungs and heart
Lower doses to contralateral breast
Field within a field (“concurrent boost”)
Inclusion of regional nodes

31. RM 9/05
Breast IMRT:
Why do we need it?
More conformal dose to breast
Lower doses to lungs and heart
Lower doses to contralateral breast
Field within a field (“concurrent boost”)
Inclusion of regional nodes
More Conformal Dose to Breast
The natural taper of the breast produces hot spots
of 3-20% unless customized wedge compensators
utilized.
IMRT can dramatically reduce these hot spots.

32. RM 9/05
Breast IMRT:
Why do we need it?
More conformal dose to breast
Lower doses to lungs and heart
Lower doses to contralateral breast
Field within a field (“concurrent boost”)
Inclusion of regional nodes
Lower Doses to Lungs and Heart
Dose is ordinarily fairly low even using routine
tangential fields.
Typical CCF case of left sided breast cancer shows
that total median dose to left lung and left ventricle
will be ≤ 500 cGy.
For cases of abnormal anatomy or serious pre-existing
organ damage, this improvement may be significant.
MSK treatment position is prone, so natural weight of
breasts pull target away from lung and heart tissue.

33. RM 9/05
Breast IMRT:
Why do we need it?
More conformal dose to breast
Lower doses to lungs and heart
Lower doses to contralateral breast
Field within a field (“concurrent boost”)
Inclusion of regional nodes
Lower Doses to Contralateral Breast
Dose to contralateral breast typically 2-5 Gy from
a routine course of tangent field XRT.
Recent data from Netherlands presented at ASCO
covered 999 cases of metachronous contralateral
breast ca. Use of XRT associated with 60%
increase in risk for patients <40!!

34. RM 9/05
Breast IMRT:
Why do we need it?
More conformal dose to breast
Lower doses to lungs and heart
Lower doses to contralateral breast
Field within a field (“concurrent
boost”)
Inclusion of regional nodes
Field Within a Field (“Concurrent Boost”)
Strategic use of dose inhomogeneity is one of
the strong arguments for IMRT at many body
sites.

35. RM 9/05
Breast IMRT:
Why do we need it?
More conformal dose to breast
Lower doses to lungs and heart
Lower doses to contralateral breast
Field within a field (“concurrent boost”)
Inclusion of regional nodes
Inclusion of Regional Nodes
Current investigational work ongoing for
inclusion of internal mammary nodes.
Significant dose to adjacent areas in many
cases.

36. Controversies Involving
RM 9/05
Partial Breast Irradiation
How much treatment margin necessary?
(remember Milan quadrantectomy trial yielded 23% LRR)
Which patients appropriate?
(young age is powerful risk factor for local recurrence; important limitation
of MammoSite device is that breast tissue must be greater than 3cm in
thickness where the device is placed and there must be at least 7-to-10
mm of distance between the MammoSite balloon and skin to prevent
skin injury and possible wound breakdown.)
Because local recurrence has minimal impact on survival, could we define
a patient group with a low enough risk that no XRT (i.e., hormone
therapy only) is necessary? (recent data for women >70 shows LRR 4%
without XRT and 1% with XRT)
Will the excellent 3-5 year results for each of these partial breast treatment
techniques hold up over time?
To what degree should we be driven by patient “consumerist” desires for
short-course treatment?

37. What’s New in
Breast Cancer Radiotherapy?
Roger M. Macklis, M.D.
Cleveland Clinic Lerner College of Medicine
Cleveland Clinic Healthcare System