Post on 23-Feb-2016
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INTRAOPERATIVE RADIATION THERAPY (IORT)for EARLY-STAGE BREAST CANCER
Dr. Maria C.E. JacobsDirector, Radiation OncologyMercy Medical CenterBaltimore, 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)
• NSABP B-06
• NCI (France)
• NCI (USA)
• EORTC
• 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 determinantfor 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 BCT240,000 Breast Cancer Cases in 20071
~180,000 Eligible for Breast Conservation Therapy (BCT)2
a
~72,15340%
~34,27319%
~73,95741%
Receive BCT Lumpectomy + WBRT or APBI
Receive BCS w/o Radiation
Eligible for lumpectomybut receive mastectomy
MastectomyBCT
LumpectomyNo Radiation 108,230
3
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
No Radiation
Women Eligible for Breast Conservation Therapy
19% lumpectomy w/o radiation.1
Reasons cited:3
- Limited radiotherapy resources
- Treatment-related morbidity - Loss of income due to
prolonged treatment duration with
radiation
1Cancer Trends Progress Report - 2005 Update, National Cancer Institute, NIH, DHHS, Bethesda, MD, December 2005, http://progressreport.cancer.gov. 2Keisch 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.
46% with DCIS have lumpectomy alone.4
Causative factors associated with under-treatment include issues with transportation, insurance coverage, employment and physical limitations.5
41% mastectomies1
Reasons cited:2
- Time commitment - Inconvenience - Fear of radiation - Treating physician bias
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;96:443-448.2 Burstein 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.
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 % Local Recurrence %Reduction (Recurrence)
CS CS+RT CS vs. CS+RT
NSABP 36 12 67Ontario 35 11 69Milan 24 6 75Scottish 25 6 76English 35 13 63Uppsala-Orebro 24 9 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.
• Incidence of failures outside of tumor bed in randomized trials comparing lumpectomy with or without postoperative irradiation.1
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.
Surgery Alone Surgery Plus RT
Trial 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
“Elsewhere” Failures
Disease Extension Illustrated
Red Line is MammoSite Radiation Prescription Depth at 100% Isodose: 1 cm. Green line is 75% Isodose.
Imamura40-64>64
100% ISO75% ISO
Imamura1: Max 8.32 mm Ohtake2: Max 7.7 mm
1Imamura et al. Breast Cancer Res Treat. 2000;62:177-184.2Ohtake et al. Cancer. 1995;76:32-45.
100% ISO
Ohtake
≥50
75% ISO
Accelerated Fractionation Schedules:Partial Breast Irradiation
• Brachytherapy• External Beam Radiotherapy• Intraoperative Radiotherapy
External Beam for APBI
Interstitial multi-catheter
MammoSite
APBI Techniques
CONTURA
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
1 King et al. Am J Surg. 2000;180: 299-304.2 Vicini et al. JNCI. 2003;95:1205-1210.3 Polgar et al. Int J Radiat Oncol Biol Phys. 2007;69:694-702.
Institution # 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%
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.
1Chen et al. Cancer. 2006;106(5):991-999.
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%
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 Applicator- Single Entry/Multi-Catheter
PTV for Contura
MammoSite
Balloon
SAVI Applicator – Single Entry/Multi-Catheter
ABS and ASBS Patient Selection Criteria
ABS Recommendations1
(updated February 2007)
ASBS Recommendations2
(updated December 2005)
Age
Diagnosis
Tumor Size
Surgical Margins
Nodal Status
1American Brachytherapy Society, Breast Brachytherapy Task Group, February 2007.2Consensus statement for accelerated partial breast irradiation. American Society of Breast Surgeons, 2005.
≥ 50 ≥ 45
Infiltrating ductal carcinoma
Invasive ductal carcinoma or DCIS
≤ 3 cm ≤ 3 cm
Negative microscopic surgical margins of
excision
Negative microscopic surgical margins of
excision
NØ NØ
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
DCISTumor size <3cm <3cm <3cm
Surgical margins
Negative microscopic surgical margins of excision
Negative microscopic surgical margins of excision
Negative microscopic surgical margins of excision by NSABP
definition
Nodal status NØ NØ 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.
NSABP B-39 /RTOG 0413: Phase III Trial
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 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
• 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
IORT: History
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 Sites Applicators
IntraBeam photon 40/50 kV 20 min Breast, skin, gyn, brain
1.5 - 5-cmReusable
Axxent eBx photon 50kV 20 min Breast, skin, gyn 1 - 5-cmSingle use
Mobetron electron 4-12MeV 2 min
Breast, skin, gyn, rectal, pancreas,
sarcoma, pediatric
3 - 10 cmReusable
Ash, RB, et al, Oncology, 107 (2013)
IORT Systems of kV versus MV Devices
Carl Zeiss INTRABEAM and Xoft Axxent eBx vs IntraOp Medical Mobetron
Control Workstation
Arm stand with x-ray source
X-ray sourceCarl Zeiss IORT IntraBeam System
Solid applicator size available:1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0 cm in diameter, labeled byA, 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.
Applicator on the x-ray sourceSolid applicator and balloon
Spatial distribution of X-ray beam
0
+1.5 mm
-1.5 mm
7 6 5 4 3 2 1 Gy/min
50 kV, 40 µA
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.
IORT Procedure with Solid Applicator
Carl Zeiss IORT IntraBeam System in OR
A solid applicator with X-ray source ready to insert
Radiation from a mini-x-ray source of 50kV
Drape
ApplicatorLead Shield
Why the excitement for IORT?
TARGETED INTRAOPERATIVE RADIOTHERAPY
vs.WHOLE BREAST RADIOTHERAPY
TARGIT-A TRIALLancet Vol. 376July 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
• Four year median follow-up
• Local recurrence•0.95% WBI with EBRT •1.2% IORT with IntraBeam
Vaidya et al in 20103,451 patients as of 2013
• Local recurrence compared with ELIOT trial• 3 year median follow-up• 2.3 % IORT with electrons
TARGIT-A Trial with IORT
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 programMargins
multifocality2 patients had mastectomy
(multiple involved margins)
COMPLICATIONS
• Intraoperative: None
• Post-operative: erythema
infectiondehiscence
• 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!!