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

DCIS

Tumor 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 source

Solid 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 TRIAL

Lancet 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!!