Transcript INTRAOPERATIVE RADIATION THERAPY (IORT) for EARLY …

INTRAOPERATIVE RADIATION THERAPY
(IORT)
for EARLY-STAGE BREAST CANCER
Dr. Maria C.E. Jacobs
Director, Radiation Oncology
Mercy Medical Center
Baltimore, Maryland
EARLY-STAGE BREAST:
Local Breast Treatment
• BCT consisting of conservative surgery (CS)
with lumpectomy/partial mastectomy and RT
• Mastectomy +/- immediate reconstruction
BREAST CONSERVATION THERAPY:
Treatment Objectives
• Optimize local control
• Minimize acute and long-term complications
• Maintain optimal cosmesis
Breast Conservation Therapy (BCT) is a standard
of care supported by years of data.
• BCT refers to breast-conserving surgery (BCS) + radiotherapy.
• 27+ years of data support BCT as a standard of care.
• Six modern, prospective randomized trials found no significant
differences when comparing BCT to mastectomy.
– Clinical trials compared local recurrence, distant metastasis,
and long-term survival.
RANDOMIZED TRIALS COMPARING
MASTECTOMY vs. BCT
• NCI (Milan)
• NCI (USA)
• NSABP B-06
• EORTC
• NCI (France)
• Danish Group
Prospective Randomized Trials comparing
Mastectomy (M) vs. BCT
Trial
No. of Pts
%Local Recurrence
%Survival
F/U Interval
BCT
M
BCT
M
(YR)
NASBP
1219
12
8
63
59
15
MILAN
701
7
4
65
65
18
NCI
237
16
6
77
75
10
EORTC
868
20
12
65
66
10
IGR
179
9
14
73
65
15
DBCG
904
5
6
79
82
6
Summary of Randomized Trials:
BCT vs. Mastectomy
• Continuous follow-up demonstrates NO significant differences
between BCT and mastectomy in:
- loco-regional control
- distant metastases
- overall survival
• No disadvantage in the use of BCT for patients with
positive axillary lymph nodes
• No significant differences in the rate of second malignancies
or contralateral breast cancer
Critical Elements in the Selection
of Patients for BCT
• History and Physical Exam:
- Age should not be a contraindication for BCT
- Comorbid conditions should be considered prior
to BCT
- Locally-advanced disease
• Radiological Evaluation:
- Multicentricity
- Extent of calcifications
Critical Elements in the Selection
of Patients for BCT
• Pathologic Evaluation:
- Positive axillary lymph nodes are NOT
a contraindication for BCT
- NEGATIVE margins of resection
• Needs and Expectations:
- Self-esteem/Sexuality
- Sense of disease control
- Functionality
- Overall quality of life
Contraindications for BCT
• Absolute:
- More than two primaries in separate quadrants
- Diffuse and pleomorphic calcifications
- History of previous RT to the breast
- Pregnancy in the first and second trimesters.
Surgery can be performed in third trimester and
RT can be deferred until after delivery
- Persistent positive margins of resection after
“reasonable” surgical attempts
Contraindications for BCT
• Relative:
- History of collagen vascular disease. Scleroderma and
active systemic lupus are ABSOLUTE contraindications
- Large tumor in small breast
- Large and pendulous breast preventing daily
reproducibility and dose homogeneity
Non-Mitigating Factors in the Selection
of Patients for BCT (factors not affecting acceptability)
• Family history of breast cancer is NOT
a contraindication for BCT
• BRCA 1 and 2 mutations are NOT a contraindication
for BCT
• High risk for systemic relapse is NOT a
contraindication for BCT. It is a determinant
for adjuvant systemic management
• BCT can be offered to patients with
positive axillary lymph nodes
Radiation Therapy for
Early-Stage Breast Cancer (post-lumpectomy)
• Whole Breast Irradiation for 4500-5000 centiGray
in 25-28 daily fractions of 180-200 centiGray/fraction
• Tangential fields, 6-18 MV photon beam
• “Boost” for 1500-2000 centiGray in 8-10 fractions
using an electron beam or “mini-tangential fields
depending on tumor bed depth
Standard Breast Irradiation:
Side Effects and Long-Term Complications
• Acute
- Skin: discoloration, dry and moist desquamation
- Fatigue
- Anemia is rare
• Long-Term
- Arm and breast edema
- Myositis
- Pneumonitis
Under-Utilization of BCT
240,000 Breast Cancer Cases in 20071
~180,000 Eligible for Breast Conservation Therapy (BCT)2
a
~72,153
40%
BCT
Mastectomy
Lumpectomy
No Radiation
Receive BCT
Lumpectomy + WBRT or APBI
Eligible for lumpectomy
but receive mastectomy
Receive BCS w/o Radiation
~34,273
19%
~73,957
41%
108,2303
No Radiation
Source: 12007 Cancer Facts & Figures American Cancer Society
2U.S. Department of Health and Human Services, Office on Women’s Health
3SEER Data 2000-2004 Incidence Rates, NCI
Women Eligible for
Breast Conservation Therapy
41% mastectomies1
Reasons cited:2
19% lumpectomy w/o radiation.1
- Time commitment
- Inconvenience
- Fear of radiation
- Treating physician bias
Reasons cited:3
- Limited radiotherapy resources
- Treatment-related morbidity
- Loss of income due to prolonged
treatment duration with radiation
46% with DCIS have lumpectomy alone.4
Causative factors associated with under-treatment include
issues with transportation, insurance coverage, employment
and physical limitations.5
1Cancer
Trends Progress Report - 2005 Update, National Cancer Institute, NIH, DHHS, Bethesda, MD, December 2005, http://progressreport.cancer.gov.
ME. Breast Cancer Res. 2005;7:106-109. 3Vinh-Hung et al. J Nat Cancer Inst. 2004:96:115-121. 4Baxter et al. J Natl Cancer Inst. 2004;96:443-448.
5Jeruss et al. Ann Surg Oncol. 2006;13:967-976.
2Keisch
Is it Safe to Omit Radiation Therapy
After BCS?
• Several randomized trials have been conducted to
determine if radiation therapy (RT) can be omitted
after breast-conserving surgery.
• No subset of patients has been identified that can
conclusively be treated with surgery alone.
1 Baxter
et al. J Natl Cancer Inst. 2004;96:443-448.
et al. N Engl J Med. 2004;350:1430-1441.
3 Houghton et al. Lancet. 2003;362:95-102.
4 Julien et al. Lancet. 2000;355:528-533.
5 Fisher et al. N Engl J Med. 1993;328:1581-1586.
2 Burstein
Is Excision Alone Adequate
in Any Subset of Patients
• According to previous clinical trials,
all subsets of patients benefit from RT
• Risk factors for local recurrence after lumpectomy
alone include tumor size, margins, grade, EIC and
receptor status
• A very selected group of patients may not require RT
• RT is still STANDARD following CS
CS vs. CS AND RT for Early-Stage Breast
Cancer: Impact of RT
Trial
NSABP
Ontario
Milan
Scottish
English
Uppsala-Orebro
% Local Recurrence
%Reduction (Recurrence)
CS CS+RT
36
12
35
11
24
6
25
6
35
13
24
9
CS vs. CS+RT
67
69
75
76
63
63
Prospective Trials comparing
CS vs. CS and RT
• These trials have variables including extent of the
surgical resection (wide excision vs. quadrantectomy)
and length of follow-up
• However, they all show a substantial reduction in the
local recurrence rate with the addition of radiotherapy
Is Excision Alone Adequate in
Any Subset of Patients
• According to previous clinical trials,
all subsets of patients benefit from RT
• Risk factors for local recurrence after
lumpectomy alone include tumor size,
margins, grade, EIC and receptor status
• A very selected group of patients
may not require RT
• RT is still STANDARD following CS
New/Alternative Treatment Approaches
• Is excision alone adequate therapy?
• Is the “boost” necessary?
• Is partial breast irradiation an acceptable
treatment modality?
• Is accelerated partial breast irradiation (APBI)
an acceptable option?
How Did the Concept of Accelerated Partial
Breast Irradiation Originate?
• Findings suggest that the major benefit of radiation
therapy is derived from radiation directed at the breast
tissue immediately surrounding the lumpectomy site.1
– The majority of local recurrences after breast-conserving therapy
occur at or near the tumor bed.1
• The incidence of “elsewhere” failures appears to be
unaffected by whole breast irradiation: 1-5% of patients
fail elsewhere regardless of radiation.1,2
– Whole breast irradiation may not be needed in
appropriately selected patients.2
1King
et al. Am J Surg. 2000;180:299-304.
2Arthur
et al. Brachytherapy. 2002;1:184-190.
“Elsewhere” Failures
• Incidence of failures outside of tumor bed in randomized trials
comparing lumpectomy with or without postoperative irradiation.1
Surgery Alone
Surgery Plus RT
Median f/u
(mo)
N
%
N
%
NSABP-B06
125
17 / 636
2.7
24/629
3.8
Milan
39
4 / 273
1.5
0/294
0
Ontario
43
15 / 421
3.5
4/416
1.0
116
-
-
27/974
2.8
Trial
The data suggest WBRT does not protect against new disease development
elsewhere in the breast.
1Baglan
et al. Int J Radiat Oncol Biol Phys. 2001;50:1003-1011.
Disease Extension Illustrated
Imamura
40-64
>64
100% ISO
75% ISO
Imamura1: Max 8.32 mm
Ohtake
≥50
100% ISO
75% ISO
Ohtake2: Max 7.7 mm
Red Line is MammoSite Radiation Prescription Depth at 100% Isodose: 1 cm.
Green line is 75% Isodose.
1Imamura
2Ohtake
et al. Breast Cancer Res Treat. 2000;62:177-184.
et al. Cancer. 1995;76:32-45.
Accelerated Fractionation Schedules:
Partial Breast Irradiation
• Brachytherapy
• External Beam Radiotherapy
• Intraoperative Radiotherapy
APBI Techniques
External Beam for APBI
CONTURA
MammoSite
Interstitial multi-catheter
SAVI
Breast Brachytherapy Scientific Rationale
Published data reports
low local recurrence
rates, ranging from
0.0 - 4.4 %,
in patients treated
with brachytherapy as
primary treatment.
Interstitial Brachytherapy –
Multi-Entry/Multi-Catheter
Arthur and Vicini, 2005
Published Data on Breast Brachytherapy as Primary
Treatment: > 5-year Median Follow-up
Institution
1
# Patients
Follow-Up
% Local
Recurrence
Ochsner Clinic1
New Orleans, Louisiana
51
75
2.0
William Beaumont Hospital2
199
72
1.1
National Institute Oncology3
128
66
4.7
Totals
378
70
2.4%
King et al. Am J Surg. 2000;180: 299-304.
Vicini et al. JNCI. 2003;95:1205-1210.
3 Polgar et al. Int J Radiat Oncol Biol Phys. 2007;69:694-702.
2
William Beaumont Hospital Trial:
Cosmetic Outcomes with APBI1
• Population: 199 consecutive patients with invasive early-stage (I–II)
breast carcinoma.
• Treatment: Hypofractionated APBI using interstitial brachytherapy
directed only at the region of the tumor bed.
Cosmetic Outcome
<6 months
2 years
>5 years
Excellent
10%
29%
33%
Good
85%
68%
66%
Fair
1%
2%
1%
Total (Good + Excellent)
95%
97%
99%
1Chen
et al. Cancer. 2006;106(5):991-999.
MammoSite Rationale
2002 IJROBP MammoSite
Dosimetry Publication:
• Presents dosimetric characteristics
of MammoSite
• Analysis by William Beaumont,
leader in breast brachytherapy
• Key findings comparing MammoSite to
multicatheter interstitial brachytherapy:
- Favorable volume coverage and reproducibility
MammoSite –
Single Entry/Single Catheter
Arthur and Vicini, 2005
Contura ApplicatorSingle Entry/Multi-Catheter
PTV for Contura
Balloon
MammoSite
SAVI Applicator –
Single Entry/Multi-Catheter
ABS and ASBS Patient Selection Criteria
Age
Diagnosis
ASBS
Recommendations2
(updated February 2007)
(updated December 2005)
≥ 50
Infiltrating ductal
carcinoma
Tumor Size
≤ 3 cm
Surgical
Margins
Negative microscopic
surgical margins of
excision
Nodal Status
1American
ABS
Recommendations1
≥ 45
Invasive ductal
carcinoma or DCIS
≤ 3 cm
Negative microscopic
surgical margins of
excision
NØ
Brachytherapy Society, Breast Brachytherapy Task Group, February 2007.
statement for accelerated partial breast irradiation. American Society of Breast Surgeons, 2005.
2Consensus
NØ
NSABP B-39 /RTOG 0413: Phase III Trial
ABS
Recommendations
(Updated February
2007)
ASBS
Recommendations
(Updated December
2005)
*NSABP B39 - RTOG
0413 Eligibility Criteria
Age
>50
>45
>18
Diagnosis
Infiltrating ductal
carcinoma
Invasive ductal
carcinoma or DCIS
Invasive
adenocarcinoma or
DCIS
Tumor size
<3cm
<3cm
<3cm
Surgical
margins
Nodal status
Negative
Negative
microscopic surgical microscopic surgical
margins of excision margins of excision
NØ
NØ
Negative microscopic
surgical margins of
excision by NSABP
definition
NØ; N1 (1-3 nodes)
*NSABP B-39 enrollment now closed to lower risk patients: DCIS patients ≥ 50 years AND Invasive Breast Cancer
patients ≥ 50 years who are node negative and hormone-receptor positive.
ACCELERATED PARTIAL BREAST
IRRATDIATON
•
Reduction of treatment time
from 6-7 weeks to 5 days
•
It decreases the target volume
(lumpectomy plus 1-2 cm margin
•
Increases dose per fraction:
340 cGy twice daily (BID) x 5 days= 3,400 cGy
•
Use highly conformal dose delivery
using CT based 3D-CRT
Lessons learned from APBI
Patient Appeal
Decreased Overall Treatment Time:
Radiotherapy: 1 week vs. 6-7 weeks
CS--chemotherapy (4-6 months)--RT(6-7weeks)
VS.
CS------- RT (1 week) ------- Chemotherapy
Less skin toxicity
Less systemic toxicity
INTRAOPERATIVE RADIATION THERAPY
(IORT): DEFINITION
Intraoperative Radiation Therapy (IORT)
is the delivery of a single high dose of radiation
to the target area/tumor bed at the time of surgery.
IORT
It is TRULY a multidisciplinary approach during
which the surgeon removes the tumor and the radiation
oncologist directs the radiation to the tumor bed,
with both physicians working together, hand in hand,
to spare surrounding normal tissues.
IORT
IORT is NOT a new approach to cancer management.
As the result of pioneering work by Dr. Abe in Kyoto, Japan,
IORT using linear accelerators has been used in the U.S.A.,
Europe and Japan for the treatment of malignancies in the
abdomen (sarcomas, rectum, gynecologic and
retroperitoneal tumors)
IORT: History
• 1909: Beck treated a patient with colon cancer using
low-energy X-rays
• Early 1970, Dr. Abe in University of Kyoto, Japan
• 1978, IORT pioneered in the U.S.A.:
- Howard University/N.C.I., Washington, D.C.
- Massachusetts General Hospital
Why IORT?
• Partial breast Irradiation experience promising excellent
local control and acceptability by patients
• Single fraction
• Treatment delivered in sterile environment,
reducing risk for infection
• AIMING RADIATION where RADIATION IS NEEDED
Intraoperative Radiation Devices
Device
Beam
Delivery
time
IntraBeam
photon 40/50 kV
20 min
Breast, skin,
gyn, brain
1.5 - 5-cm
Reusable
20 min
Breast, skin, gyn
1 - 5-cm
Single use
2 min
Breast, skin, gyn,
rectal, pancreas,
sarcoma,
pediatric
3 - 10 cm
Reusable
Axxent eBx photon 50kV
Mobetron
electron 4-12MeV
Ash, RB, et al, Oncology, 107 (2013)
Sites
Applicators
IORT Systems of kV versus MV Devices
Carl Zeiss INTRABEAM and Xoft Axxent eBx vs IntraOp Medical Mobetron
Carl Zeiss IORTArm
IntraBeam
stand with x-ray System
X-ray source
source
Control Workstation
Solid applicator and balloon
Applicator on the x-ray source
Solid applicator size available:
1.5, 2.0, 2.5, 3.0, 3.5, 4.0,
4.5, 5.0 cm in diameter, labeled by
A, B, C, D, E, F, G, and H for the part
number. Reusable 100 times.
Balloon size available: 3.0, 3.5, 4.0,
4.5, 5.0 cm in diameter. Single use.
Spatial distribution of X-ray beam
-1.5 mm
50 kV, 40
µA
0
+1.5 mm
7 6 5 4 3 2 1 Gy/min
IORT Procedure with Solid Applicator
Step 1: The lumpectomy, immediately following tumor removal.
Step 2: After the surgeon has removed the tumor, the radiation oncologist
positions the INTRABEAM applicator in the area of the breast where the
tumor was located.
Step 3: Low energy radiation is delivered locally to the targeted tissue in the
tumor bed, minimizing healthy tissue exposure to radiation.
Step 4: After 20-30 minutes of radiotherapy, the applicator is removed and the
surgeon then closes the incision.
Carl Zeiss IORT IntraBeam System in OR
Radiation from a mini-xray source of 50kV
Drape
Applicator
Lead
Shield
A solid applicator with X-ray
source ready to insert
Why the excitement for IORT?
TARGETED INTRAOPERATIVE
RADIOTHERAPY
vs.
WHOLE BREAST RADIOTHERAPY
TARGIT-A TRIAL
Lancet Vol. 376
July 10, 2010
PATIENT SELECTION for TARGIT
• Age: 45 or older suitable for wide local excision
• Unifocal invasive ductal carcinoma
(lobular was excluded)
• Tumor size < 3.5 cm
• Clinically N0
• ECOG performance 0-3
• No neoadjuvant chemotherapy
TREATMENT PARAMETERS
• Lumpectomy and Sentinel Lymph Node (SLN) Biopsy
• If negative SLN, sizing of the lumpectomy cavity
and placement of IORT device
• Ultrasound for measuring skin-to-device distance
• Placement of shield to protect heart and lung
• Dosimetry in preparation for treatment delivery
• Single dose of 20 Gray prescribed to the surface
of the applicator
TARGIT-A Trial with IORT
• Four year median follow-up
• Local recurrence
•0.95% WBI with EBRT
•1.2% IORT with IntraBeam
Vaidya et al in 2010
3,451 patients as of 2013
• Local recurrence compared with ELIOT trial
• 3 year median follow-up
• 2.3 % IORT with electrons
IORT FOR BREAST CANCER:
MERCY MEDICAL CENTER
September 7, 2012 - February 20, 2014,
67 patients
68 IORT delivered
(1 pt with bilateral breast cancer)
12 patients received additional
whole breast irradiation:
beginning of IORT program
Margins
multifocality
2 patients had mastectomy
(multiple involved margins)
COMPLICATIONS
• Intraoperative: None
• Post-operative:
erythema
infection
dehiscence
• COSMESIS: good to excellence
CONCLUSIONS
• Large body of publications supporting that PBI
in selected group of patients can optimize local
control while minimizing radiation toxicity.
• TARGIT-A trial showed comparable results to PBI.
• Further trials are in progress using IORT (TARGIT-US)
as a registry trial following breast conserving surgery.
Thank You!
Muchas gracias!!