Θεραπευτική αντιμετώπιση καρκίνου μαστού – Ακτινοθεραπεία Τεχνική & Πρόοδος

ΒΑΚΑΛΗΣ ΞΕΝΟΦΩΝΑΚΤΙΝΟΘΕΡΑΠΕΥΤΗΣ ΟΓΚΟΛΟΓΟΣ

ΙΑΤΡΙΚΟ ΚΕΝΤΡΟ ΑΘΗΝΩΝ&

401 ΣΤΡΑΤΙΩΤΙΚΟ ΝΟΣ. ΑΘΗΝΩΝ

ΕΛΛΗΝΙΚΗ ΣΧΟΛΗ ΜΑΣΤΟΛΟΓΙΑΣ: Β' ΚΥΚΛΟΣ ΣΠΟΥΔΩΝ - 4η ΣΕΙΡΑ ΑΘΗΜΑΤΩΝ, 16-17 ΣΕΠΤΕΜΒΡΙΟΥ 2011, ΑΙΓΛΗ ΖΑΠΠΕΙΟΥ

Historical Perspective

Interstitial Radium Brachytherapy for Breast Cancer, 1917

Radiotherapy for Breast Cancer, London Hospital, c. 1917

Prospective Randomized Trials of Lumpectomy +/- Radiotherapy

Trial Pt # TumorSize-cm

Surgery % Failure - RT

% Failure + RT

NSABP 1265 <4.0 WE 36 12

Milan 601 <2.5 Q 24 6

BCS node-neg

↓LR: 16% ↓DSM: 5%BCS node-pos

↓LR: 30% ↓DSM: 7%

Mastectomy node-pos

↓LR: 17% ↓DSM: 5.4%

Lancet 2005; 366: 2087

42 000 womenin 78 randomized trials

Lancet 2005; 366: 2087

Radiation Therapy for Early Stage Breast Cancer Following Lumpectomy

Rationale: Addition of whole breast irradiation following lumpectomy yields local control rates comparable to mastectomy

Treatment: Whole breast irradiation 45-50 Gy to the entire breast 60 Gy to the lumpectomy cavity + margin1.8 – 2 Gy fraction given 5 days/ week5 – 7 week total treatment duration

Whole Breast Irradiation

External Beam

Treats “whole breast”

Large volume of incidental tissues

Requires protracted (6—7 week) delivery

Breast Irradiation Technique

Image-based Conformal Radiation Therapy:

Left Breast

60 Gy

62 Gy

50 Gy45 Gy20 Gy

axial sagittal

Score 3 2 1

Nodes≥ 4 Nodes 1 – 3 Vascular Invasion

Tumor size > 50 mm or T4

Tumor size30 – 50 mm

Tumor size20 – 29 mm

Deep margin < 1 mm or pectoral muscle involvement

Tumor grade 3

Example of guidelines for PMRT

RT is recommended to patients scoring ≥ 3 (Cambridge, UK)

1,234 patients - T1 – T2, N 0 (80% T1)- ER positive - 71% - Median F/U: 69 months

Accelerated Whole Breast Irradiation:Reducing the burden of careCanadian Phase III Randomized Trial:

42.5 Gy – 16 fractions – 22 days vs.50 Gy – 25 fractions – 35 days

In-Breast Recurrence

(%)

Excellent/ good

Cosmesis (%)

Accelerated WBI

2.8 76.8

Standard WBI 3.2 77.4

Randomized Boost Trials

Accelerated Whole Breast Irradiation:A Phase II clinical trial of a 4 week course of RT for breast cancer using hypo fractionated IMRT with a concomitant boost.

4 week course – 20 treatments– 45 Gy whole breast dose– 56 Gy boost dose

Results:– 16 patients treated– Acute toxicity: Grade I 57%, Grade

II 43%

Regional Nodal RT Awaiting results of two large trials (France and EORTC)

Full SCLV Field

IM Nodal Radiation Technique

Adapted from Larry Marks, Duke

Cuzick et al: Recent Results Cancer Research 111:108-129, 1988

Overall survival: radical mastectomy + / - RT

First 10 years Next 25 years

Overall Survival

XRT better XRT worse

XRT better XRT worse

XRT better XRT worse

Cardiac MortalityBreast Ca Mortality

Cuzick JCO 12:452, 1994

The shape of the breast and the position of the heart in relation to the chest wall can vary enormously

Decrease cardiac Exposure to RT

Partial Breast Irradiation Decubitus or Prone positions Breath Hold Technique Respiratory gating technique Proton therapy

Patient’s Position

Campana et al 2005 DeWyngaert et al 2007

Prone and IMRTLateral Decubitus

Prone Breast RT

Figure 1a. Customized prone breast board with adjustable aperture and wedge for contralateral breast.Figure 1b. Ipsilateral breast and anterior chest wall hang in a dependent fashion away from the thorax while the ipsilateral arm is placed above the head

Goodman

Figure 6. Left breast irradiation using prone breast IMRT technique can spare left ventricle and coronary arteries.

Goodman

Transaxial

Sagittal

3-DCRT for left prone breast radiation:

Improved targeting and avoidance of lung

60 Gy

50 Gy

45 Gy

Lumpectomy

PTV

Intensity Modulated Radiotherapy (IMRT)

… + Image Guidance (IGRT)

Breast is a moving target !

Heart

Double Trouble !

Heart

Solution = Gated Radiotherapy

Varian RPM respiratory management system

Deep Inspiration Breath-Hold (DIBH)

Rosenzweig Int. J. Radiation Oncology Biol. Phys. 2000

Increase spatial separation between target and organs at risk

Cardiac Sparing

Heart V5 V10 V20

Proton 4.1 2.7 1.5

Photon/Electron

33.2 20.8 10.4

PWTF 19.7 12.0 9.5

V5 Volume receiving 5% of the dose

Elsewhere Failure (Outside Lumpectomy Region)

No XRT XRT Randomized Trials (BCT)

# Cases

Follow-up Interval (mos)

Crude % Crude % Ontario

837 43 15/421 3.5 4/416 0.9

Milan III

579 109 8/280 2.8 2/299 0.6

NSABP B06

1265 144 17/636 2.7 24/629 3.8

Uppsala-Orebro

381 33 3/194 1.5 1/187 0.5

Finland 152 80 4/72 5.5 4/80 5.0

The majority of cancer recurrences in the treated breast occur at the

lumpectomy site

Pattern of In-Breast Cancer Recurrences Following Breast

Conserving Therapy

Potential Benefits of Partial Breast Irradiation

Reduce time and inconvenience of BCT Improve documented underutilization of

breast conserving therapy (BCT)? Potentially reduce acute and chronic

toxicity Reduce burden of care for patients Eliminate scheduling problems with

systemic chemotherapy

Rationale for Partial Breast Irradiation (PBI)

10%-40% of those who are candidates for breast conservation therapy actually do not receive it.

Why?– Patient’s choice– Complex and prolonged treatment course

can be inconvenient for those with poor access to a radiation facility, the elderly and working women

– Physician bias

Techniques for PBI

Interstitial brachytherapy with HDR or LDR

Intracavitary brachytherapy with Mammosite

Intraoperative electron beam therapy

3D conformal radiation therapy Proton beam

Partial breast irradiation techniques

InterstitialBrachyther.

IntracavitaryBrachyther

Intraop.RT

3DConformal RT

Dose 34 Gy in 10 frIn 5 days

34Gy in 10 frIn 5 days

20-21Gy in single fraction

30 Gy in 5 fr. In 10 days

Target 1.5 cm margin around WLEcavity

1cm aroundWLE cavity

Visual by surgeon and radonc perop

2.5cm margin around WLEcavity

Pros Many dwell positions forIrreg. cavity

Ease of placement andplanning

Single doseSpares skin

Fits with standard RTmachines

Cons Operatordependent

High costFewer dwellpositions

RT before path knownSpecialised centres only

Larger fields(respiration) and more normal tissue

Three Established Methods For PBI

Multi CatheterMammosite®

3-D Conformal

Accelerated Partial Breast Irradiation

Treatments delivered twice daily (with treatments separated by six hours) for 10 treatments delivered in 5 treatment days.

Delivery of radiation limited to lumpectomy site with a margin of normal tissue.

Each treatment takes approximately 10 minutes to deliver.

Target definition

Accelerated Partial Breast Irradiation

Benefits:– Limited radiation exposure to normal

tissue– Treatments completed in one week

instead of six weeks

Accelerated Partial Breast Irradiation

Limitations:– May require additional surgical

procedure – Requires twice daily treatment– Newer modality with far fewer

patients treated and much shorter follow-up

– As of now, no direct comparison with standard radiation

Who is eligible for PBI?(Off study)

Tumors < 3 cm Negative margins (> 2mm) Node negative Invasive ductal carcinoma or DCIS Older women (>45 yrs)

Revised Consensus Statement for Accelerated Partial Breast Irradiation, 12/8/05

Interstitial brachytherapy

Catheters are placed intraoperatively or later; usually 2 planes

Typical doses with HDR = 30-36 Gy and LDR = 45-60 Gy

Treatment delivered over one week.

Breast Brachytherapy

Multi-Catheter Brachytherapy

Dose Distribution of MultiCatheter PBI

PTV

100% isodose

5 years post treatment

Breast Appearance Following Multi-catheter Brachytherapy

Patient Selection for Breast Brachytherapy

Patients older than 45 Tumors less than 2 cm. in size >2mm. Margins Preferably Infiltrating Ductal or loclized

low grade DCIS. No Lobular CA There must be at least 7mm. of tissue

between the catheter surface and the skin of the breast.

Advantages of Breast Brachytherapy vs. External Beam RT

6 weeks (30 fractions) Homogeneous dose Logistical problem for

patients Difficult for frail, elderly,

or chronically ill patients Interferes with schedule

of working women Some BCT candidates will

opt for mastectomy

5 days (10 fractions) Dose is higher to tissue

at greatest risk for sub-clinical malignant cells

Reduction in skin, cardiac and lung dose

Ideal for patients who live far from RT Center

Convenient May increase number

of women treated with BCT

Disadvantages of Breast Brachytherapy vs. External Beam RT

Noninvasive Can cover nodal regions Treats multi-centric

carcinoma Low complication rate Linear accelerators

widely available Most radiation

oncologists experienced

Invasive Not useful for treatment

of nodal basins May miss tumor foci in

other quadrants Low, but definite risk of

infection and/or fat necrosis

Requires special skills for performing; in placing catheters and dosimetry

MultiCatheter PBI: HDR/ LDR

Institution

Pt. No.

Median age

F/U mo.

T size (cm)

median

N+%

ER +%

Tam%

LR%

Exc/ good

Cosmesis%

Oschner 51 63 75 1.4 18 - - 2 -

Beaumont 199 65 65 1.1 12 - 57 1.2 99

Tufts-NEMC 32 63 33 1.3 9 79 61 3 88

VCU 44 62 42 1.2 18 - 66 0 80

Nat. Inst. Onc.

Budapest45 56 81 1.2 2 82 16 6.7 97

Guys Cs 137 49 58 75 2.5 46 - - 18 81

61 mo. 5% 89%61 y 1.4 cm17.5%Average:

Breast Brachytherapy

There has got to be a better way than all of those needles.

Mammosite device from Proxima Therapeutics may be the answer.

FDA approved the device in May 2002

Mammosite® Breast Brachytherapy Applicator

• Simplified brachytherapy method for PBI

• Dual lumen single catheter with expandable balloon at

end• Balloon expands to fill the

lumpectomy cavity• Radiation dose prescribed

to 1 cm beyond balloon surface

• Uses 192Ir (HDR) as the source

• FDA approval May 2002

MammoSite PBI

5th Int. Meeting ISIORT Madrid, June 2008

Volume Definition

PTV: GTV + 1.5 – 2.0 (clinical margin) + 0.5 (setup margin)

excluding skin and chest wall

Skin: 5 mm depth below skin surface

GTVPTVSkin

Difficulties with Mammosite

Balloon must conform to cavity shape without air gaps. Device explanted in ~ 10-15% of pts.

Ideal is to have 7 mm b/w balloon and skin to decrease risk of erythema.

Very dependent on surgical placement.

CT Planning for Mammosite Brachytherapy

Isodose Lines

50%

80%

100%

120%

140%

200%

Mammosite® balloon

3-Dimensional rendering of applicator surface and prescription dose cloud.

Prescription Dose

34 Gy 10 fractions

over 5 -7days

Day 2 on treatment

Day 2 on treatment

2 weeks post treatment

4 months after PBI

Breast Appearance after MammoSite®

3 years post treatment

MammoSite PBI

Institution Pt. No.

Median age

F/U mo.

T size (cm)

median

N+%

ER +%

Local relapse

%

Exc/ good

Cosmesis%

Initial Multi- Institutional 43 69 48 1.0 0 - 0 80

Rush Univ. 112 64 -88%

Tis-T-17 - 0 80

Tufts-NEMC/ VCU 28 62 19 1.1 0 100 0 86

St. Vincent Hospital 32 62 11 97% T-1 9 94 - 86

Average: 64 y 26 mo 1 cm 4% 0% 83%

Toxicities of Mammosite

Seroma formation: Risk is increased with open technique for placement. In Beaumont series, found 60% risk with open cavity vs. 30% in closed cavity; overall rate of 45%, with 10% symptomatic.

Fat necrosis: Risk may be slightly lower than with HDR and no difference with placement technique.

Conclusion

The MammoSite RTS is the most commonly used PBI technique

MammoSite is minimally invasive, offers acceptable cosmetic results, and induces mild side effects

The duration of treatment is only five days making it more convenient for patients

The MammoSite RTS has criteria which prevent some patients from eligibility– New devices such as SAVI, ClearPath, and

Contura are overcoming those limitations

5th Int. Meeting ISIORT Madrid, June 2008

… and Mammosite begat ….

SAVI

ClearPath™

Contura

PBI: 3D-CRT Target definition

PBI: 3D-CRT Beam Arrangement

3.85 Gy BID x 10 fractions

PBI: 3D-CRT Isodose Distribution

axialsagittal coronal

3850 3752 3655 3557 3460

3-DCRT PBI

Institution

Pt. No.

Median age

F/U mo.

T size (cm)

median

N+%

ER +%

Local relapse

%

Beaumont 92 62 23 - 2 - 0

NYU 78 67.5 28 0.9 0 100 0

MGH 61 6212

(min) 0.9 0 - 0

RTOG 0319

42 61 - 0.85 - - -

Summary: 273 63 21 0.9 < 1 0

Accelerated Partial Breast Irradiation:Summary

Accelerated partial breast irradiation allows patients to complete a course of treatment in one week as opposed to the standard six weeks.

Treatment limited to part of the breast may be associated with less morbidity of treatment and better cosmetic outcome.

Hopefully, the randomized, prospective NSABP trial will answer the question of equivalence of partial and standard breast irradiation.

NSABP B-39/RTOG 0413 TrialPhase III

Stage 0, I-II breast cancer treated by lumpectomy

Randomization

WBI• 50-50.4 Gy (1.8-2.0 Gy)

Fractions to the whole breast followed by boost to 60 -66.6 Gy

PBI• 34 Gy in 3.4 Gy fxs bid

Mammosite® or Multicatheter brachytherapy

OR• 38.5 Gy in 3.85 Gy fxs bid

3D-CRT

Endpoints

Primary: in-breast tumor recurrence

Secondary:– Distant disease-free survival– Overall survival– QOL: Cosmesis, fatigue, symptoms,

burden of care

5th Int. Meeting ISIORT Madrid, June 2008

Zeiss Intrabeam®

-50 kV x-ray source at the end of a 15 cm long, 3.5 mm diameter tube.

-Spherical applicators with diameters of 15-50 mm in steps of 5 mm

-Dose rate of about 2 Gy/min at 1 cm in water

Spherical applicators 1.5 to 5cm diameter in 0.5cm steps

Uniform surface dose-rate

The pliable breast tissue is wrapped around the applicator. Subcutaneous stitches aid conformation, while ensuring that the skin is at least 1cm from the

applicator surface.

Intraoperative Radiation Therapy (IORT) for PBI

TARGIT trial is comparing whole breast irradiation to IORT delivering a single dose of 20 Gy. Primary accrual is in Europe.

Using the Intrabeam Photon Radiosurgery System, 50 kV x-rays.

Trial has enrolled 900 patients with target of 2200 patients.

Trials of partial breast RT

Trial Target accrual RT Technique Duration of RT

NSABP B-39 9000 Multisource Ir-192

5 days

TARGIT 3000 IntraoperativeXrays

1 day

ELIOT 2000 Intraoperativeelectrons

1 day

IMPORT Low 2000 External beamIMRT

3 weeks

GEC-ESTRO 1170 Multisource Ir-192HDR/PDR

2.5-4 days

What about IMRT?

Γιατί χρειαζόμαστε την IMRT ;

• Βελτιστοποίηση της ομοιογένειας της δόσης καλύτερη κατανομή της δόσης ενδεχομένως συνοδεύεται από μικρότερη οξεία και χρόνια τοξικότητα (δέρμα, μαζικό παρέγχυμα)

• Μείωση των τμημάτων του πνεύμονα, της καρδιάς (σε όγκους αριστερού μαστού) και του ετερόπλευρου μαστού που λαμβάνουν υψηλές δόσεις.

• Σε εξειδικευμένες περιπτώσεις: Μερική ακτινοβόληση μαστού Ακτινοβόληση έσω μαστικών λεμφαδένων Ταυτόχρονο boost

Δεν πρέπει να περιμένουμε βελτίωση στον τοπικό έλεγχο, αφού είναι ήδη πολύ υψηλός.

CANADA n= 331 3D-CRT με σφηνοειδή φίλτρα vs. IMRT 50 Gy/ 25 fr ± boost 8x2 Gy Πρωτογενές καταληκτικό σημείο: Οξεία τοξικότητα δέρματος κατά τη διάρκεια της θεραπείας και 1-6 εβδομάδες μετά

Καταληκτικό Σημείο IMRT % 3D-CRT p-value

Τοξικότητα δέρματος Grade 2 & 3 27.1 36.7 0.06

Υγρά απολέπιση, ολόκληρος ο μαστός 31.3 47.8 0.002

Υγρά απολέπιση, υπομαστική πτυχή 26.5 43.5 0.001

Πόνος Grade 2 – 4 23.5 25.5 0.68

JCO 2008; 26: 2085

Intensity Modulated Radiation Therapy (IMRT)

Dose distribution to breast with standard tangential fields

Dose distribution to breast using IMRT

Intensity Modulated Radiation Therapy (IMRT)

DVH – Coronary artery region

Other Clinical Scenarios

Inoperable presentations Bulky, non-resectable recurrent cancer IMRT plans have sometimes looked

significantly better than 3D conformal, on a CASE BY CASE basis

5th Int. Meeting ISIORT Madrid, June 2008

Proton/Photon Comparison

Photon

Proton

Photon

Proton

5th Int. Meeting ISIORT Madrid, June 2008

Conclusions from Proton Therapy Study

- Protons spare non target breast tissue - reduction of 40%-45% vs. mixed modality

- Protons also spare contralateral lung & heart

- May permit retreat for pts with ipsilateral recurrence outside original field.

- Dose escalation?- Effect of neutrons in passively scattered

proton beams (Hall et. al.), but not in IMPT

5th Int. Meeting ISIORT Madrid, June 2008

DVH for non-target breast tissue

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100

Dose(%)

Vol

ume(

%) Proton

IMRT

XRT

IMRT Protons Photons

El Ghamry et. Al. IJROBP 2002

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