01 introduction to the transition to 3d hdr brachytherapy · 2018. 9. 27. · 3d mri based hdr...

IAEA

Special procedures:3D image guided brachytherapy of prostate cancer and gynaecological

cancers other than cervix

IAEA

Aims

To assure understanding of different prostate brachytherapy and gynaecological cancer (other than cervix) techniques. To position brachytherapy in the spectrum of different modalities used for treatment.

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Specific Learning Objectives

• To outline the historic perspectives of prostate and gynaecological brachytherapy

• To understand the limitations of conventional techniques• To understand application techniques, basics of dose prescription

schedules and optimization principles• To list the major technological developments that enable high impact of

prostate and gynaecological brachytherapy• To outline the role of brachytherapy as monotherapy or boost following

external beam radiotherapy in prostate and gynaecological cancer• To understand the principles of permanent prostate brachytherapy• To understand the principles of temporary prostate brachytherapy• To give an overview of prostate cancer brachytherapy clinical results

and compare them to results of other modalities• To describe clinical results of 3D image guided gynaecological

brachytherapy.

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Special Procedures• Prostate Cancer

• Overview• Techniques• Clinical evidence and trials

• Endometrium Cancer- Definitive Radiotherapy (Intact uterus)

• Tumour localization• Techniques• Target, imaging and treatment planning• Clinical evidence

- Pre-operative Radiotherapy• Clinical results• Pros and Cons

- Post-operative Radiotherapy• Target definition• Techniques• Treatment Planning

• Vaginal Cancer• Strategy and Imaging• Techniques• Treatment Planning• Clinical evidence

Prostate cancer

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TRUS guided insertion, followed by US, CT or MRI planning (refer to prostate BT presentation)

Prostate cancer brachytherapy is covered in more detail in a separate presentation. Depending on the departmental protocol, prostate cancer brachytherapy workflowconsists of a similar sequence of steps, including the creation of the plan of insertion,ultrasound guided insertion and unltrasound or other imaging method-based treatment planning.

First reports in prostate brachytherapy date back to the beginning of previous century,when intraurethral placement of radium sources was used. However, this techniqueresulted in high central urethral doses and low peripheral target doses, reflected in high morbidity and poor cure rates.

Historic perspectivesc/)CD

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Hugh Hampton Young1902 Radical perineal prostatectomy 1920’s: Prostate brachytherapy (alternating radium applications: rectal, intraurethral...)

Further developments

Barringer: pioneering permanent interstitial BT

Young: open transperineal approach

Barringer: open transvesical approach

Flocks: implantation of gold seeds

Whitmore & Carlton: open retropubic approach

Young HH. WB Saunders; 1926. p. 644-671Aronowitz JN. IJROBP54 (2002) 712-718

Hugh Hampton Young, famous for his work on radical perineal prostatectomy, performeda large number of prostate brachytherapy procedures, in particular in a palliative setting,applying the radium alternately into the rectum, intraurethrally and in the presacralregion.

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Fall of historic techniques

Decades of stagnation

All of these historic techniques resulted in suboptimal cure rates and high complication rates, resulting in the fall of brachytherapy use and decades of stagnation of this treatment modality.

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MODERN TECHNIQUES

Key points

1983, Holm: Introduction of TRUS

Advances of TRUS techniques

Sectional & functional imaging

Improved implantation techniques

New isotopes

Computerized treatment planning

Afterloading technology

Improved radioprotection measures

In the 1980s, introduction of the transrectal ultrasound and advances in other sectionaland functional imaging modalities, improved implantation techniques, implementationof new isotopes, computerized treatment planning systems, afterloading technology andimproved radioprotection led to renewed interest in brachytherapy and its establishmentin the field of prostate cancer as one of the most important treatment modalities.

There are two principal basic strategies regarding the use of prostate brachytherapy: as the single modality (in low risk disease) or in combination with external beam radiotherapy (intermediate and high risk disease).

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MODERN TECHNIQUES

Brachytherapy duration & dose rate

Permanent, Very Low Dose Rate (VLDR)

Temporary, High Dose Rate (HDR)

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According to the duration of treatment and dose rate, brachytherapy is divided into permanent and temporary implants.

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In permanent implants, radioactive seeds are inserted into the prostate under transrectal ultrasound guidance where they remain permanently.

Temporary - HDR BrachytherapyExample of EBRT + BT Boost schedule (Institute of Oncology Ljubljana)

Intermediate & High risk pts

External beam pelvic irradiation: 50 Gy in 2 Gy per fx

3D MRI based HDR Brachytherapy boost

’Schedules will vary across institutions! Study specific relevant literature for details on imaging approaches and dose prescription!

In high dose rate brachytherapy, interstitial applicator channels are inserted into theprostate under the ultrasound guidance, taking the pre-implant disease extent into account. Treatment planning can be carried out during the procedure as real time planning or after the procedure, based on the post-insertion images (ultrasound, CT or MRI). On the example on the slide, a specific departmental approach to prostate brachytherapy is presented, using the pre-implant MRI to evaluate the disease extent (note extracapsularextension in the right posterolateral region), followed by ultrasound and cystoscopy guided insertion. Post-insertion, pelvic MRI is performed and used for computerized treatment planning. By optimization of the dwell times and positions of the Iridium stepping source, a highly conformal dose distribution, respecting the normal tissue dose constraints and achieving adequate target coverage is achieved. Note the optimal implantation geometry, including the insertion of needles in the region of extraprostatic extension. Good implant is a prerequisite for successful treatment plan optimization. Following irradiation, the implant is removed and the patient discharged after a short period of observation. Schedules will vary across institutions! Study specific relevant literature for details on imaging approaches and dose prescription!

Future perspectives of image guided prostate brachytherapy include the use of functional MRI techniques to increase the dose to the dominant intraprostatic lesions, spare the organs at risk in re-irradiation of recurrent cases or even perform partial prostate treatments in well selected patients.

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Clinical results - biochemical controlIVIultiinstitutional analysis: 2693 pts

Zelefsky MJ, et al. IJROBP 67 (2007) 327-333, copyright Elsevier, reproduced with permission

Some of the clinical results of permanent and temporary brachytherapy are presented on the following slides. With an adequate D90, results were significantly better than with a D90 below 130 Gy in the multi-institutional analysis of 2693 patients.

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Excellent biochemical controls are reported for low and intermediate risk cancer, comparable to surgical treatment. Even in high risk disease, encouraging biochemical control and cause specific survival rates are obtained.

Journal of Clinical Oncology REPORT

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Randomized Trial Comparing Iridium Implant Plus External-Beam Radiation Therapy With External-Beam Radiation Therapy Alone in Node-Negative Locally Advanced Cancer of the ProstateJittka R. Sathya, Ian R. Davis, Jim A. Julian, Qing Guo, Dean Daya, Ian S. Dayes, Himu R. Lukka, and Mark Levine

Randomized comparisons between external beam radiotherapy and brachytherapy of prostate cancer have shown improved biochemical control rates for brachytherapy plus EBRT compared to EBRT alone. It has to be emphasized, however, that the majority of such published studies had some inherent limitations, such as application of an inadequate dose by external beam radiotherapy. See for example Sathya JR, et al. J Clin Oncol 23 (2005) 1192-1199.

The problem of dose!EBRT 66 Gy a 2Gy

BT + EBRT: 35 + 40 Gy

Randomized comparisons between external beam radiotherapy and brachytherapy ofprostate cancer have shown improved biochemical control rates for brachytherapy plus EBRT compared to EBRT alone. It has to be emphasized, however, that the majority of such published studies had some inherent limitations, such as application of aninadequate dose by external beam radiotherapy.

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On this slide, the results of another randomized comparison between EBRT and EBRT + BT demonstrated superiority of the combined modality arm.

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Systematic review

Comparison of three radiotherapy modalities on biochemical control and overall survival for the treatment of prostate cancer: A systematic review

Bradley R. Pietersa'-, Djuna Z. de Back3, Caro C.E. Koning'5, Aeilko H. Zwindermanb1 Department of Radiation Oncology. Academic Medical Center. University of Amsterdam. Tire Netherlandsb Department of Ginicui Epidemiology and Biostatistics. Academic Medical Center. University 0/Amsterdam. The Netherlands

Overall survival PSA failure free survival

Pieters BR, etal. Radiother Oncol 93 (2009) 168-173, copyright Elsevier, reproduced with permission

A recently published systematic review confirmed these findings.

In a recently published large report, retrospectively reviewing a large number of studies, favourable results of brachytherapy when compared to other modalities have been confirmed.

PSA progression free survival after brachytherapy compared favourably to EBRT andsurgery in low risk disease and was superior to other modalities in intermediate and highrisk disease.

Intermediate risk resultsPr

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Grimm P, etal. BJU Int. 109 Suppl 1 (2012) 22-29

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EBRT & Seeds□ Hypo EBRT U Seeds Alone ZS Surgery

□ EBRT Q CRYO ■ HIFU□ HDR0 EBRT, Seeds*

ADT□ Protons


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Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology ( NCCN Guidelines ® ) for Prostate V.3.2016 © 2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN Guidelines®, and all other NCCN Content are trademarks owned by National Comprehensive Cancer Network. Inc.

Prostate brachytherapy plays an important role and represents an excellent treatmentoption for prostate cancer patients. Patients should optimally be actively included in the decision making process, together with the radiation oncologist and urologist.

NCCN.org

IAEA NCCN Guidelines®NationalComprehensive NCCN Guidelines Version 3.2016 Cancer Network*

NCCN Guidelines IndexProstate Table of ContentsProstate Cancer

RISK GROUP EXPECTEDPATIENT

INITIAL THERAPY ADJUVANT THERAPY

[See• Monitoring I (PROS-6)

Prostatectomy

See RadiationTherapy

(EROJSrS)

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology ( NCCN Guidelines ® ) for Prostate V.3.2016 © 2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN Guidelines®, and all other NCCN Content are trademarks owned by National Comprehensive Cancer Network, Inc.

NCCN.org

IAEA NCCN GuidelinesNCCN Guidelines Version 3.2016 Prostate Cancer

NCCN Guidelines IndexProstate Table of Contents

Discussion

RISK GROUP

High:8• T3a or• Gleason

score 8-10 or•PSA >20 ng/mL

INITIAL THERAPY

EBRTh + ADT' (2-3 y) (category 1) orEBRT* + brachytherapy ± ADT1 (2-3 y) orEBRT*1 + ADT1 (2-3 y) + docetaxeP or .RP1 + PLND------------------------------------

ADJUVANT THERAPY

. See Monitoring (PROS-61

Very High:• T3b-T4• Primary

Gleason pattern 5 or

• >4 cores with Gleason score 8-10

EBRTh + ADT1 (2-3 y) (category 1) orEBRTh + brachytherapy ± ADT1 (2-3 y)or -------------------------EBRT*1 + ADT1 (2-3 y)+ docetaxeP orRP1 + PLND (in select patients: with no fixation)

See Monitoring(PROS-61

See Monitoring r(PRP_Sr$J

Adverse features:'EBRThorObservation1*

Lymph node metastasis: ADT1 (category 1) ± EBRT*1 (category 2B) orObservation1* (category 2B)

Adverse features:'EBRTh orObservation1*

Undetectable_PSA

I See•Monitoring

I (PROS-6)

See Radical

Regional:AnyT,N1,M0-

Metastatic:Any T, ___Any N, M1

ADT1 in select patients'!

EBRTh + ADT1 (2-3 y) (category 1)1 orADT1

See Monitoring(PROS-6)

ADT'(category 1) ± EBRTh (category 2B) orObservation1* (category 2B)

Detectable_PSA

- ADT1 __ See Monitoring(PROS-6)

Adapted with permission from the NCCN Clinical Practice Guidelines in Oncology ( NCCN Guidelines ® ) for Prostate V.3.2016 © 2016 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guidelines® and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and complete version of the NCCN Guidelines, go to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN Guidelines®, and all other NCCN Content are trademarks owned by National Comprehensive Cancer Network, Inc.

NCCN.org

Team work and adherence to protocols and published recommendations are required for optimal results.

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Sum

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•Historic techniques suboptimal

•Decades of stagnation of prostate BT (poor results of historic

techniques)

•Renewed impact of prostate BT with technological developments

•Temporary vs. Permanent prostate implants

•Implantation techniques

•Clinical results of BT in intermediate and high risk are superior

•The role of prostate BT is increasing

•Importance of appropriate training, following recommendations

and team work!

This slides summarizes the main points of the presentation on principles of prostate cancer brachytherapy.

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Courtesy of Primoz PetrieCourtesy of Primoz Petrie

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Endometrial cancer

Definitive & postoperative irradiaton and treatment of recurrence

On the left hand side of this slide, an example of 3D image based definitive endometrial brachytherapy is presented: Plastic Simon Heyman capsules and a vaginal ring have been inserted under paracervical anaesthesia, followed by MR imaging with the applicator in place. The steps of applicator reconstructiuon, contouring, dose optimization and treatment were carried out as specified on the previous slides, with specific adaptations related to this tumour site.On the right hand side, a recurrent endometrial cancer above the vaginal stump was treated with MRI guided adaptive brachytherapy with vaginal cylinder and interstitial needles, following the principal steps of the workflow as described for the cervix cancer.

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Principles: Definitive radiotherapye/>CD

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•If surgery is not possible or is medically contraindicated

•If the tumour is inoperable due to local extension

•Brachytherapy alone or following pelvic EBRT (depending on stage)

•Recurrences

•Whole uterus + upper third of vagina

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Definitive radiotherapy plays an important role if surgery is not possible or is medicallycontraindicated or if the tumour is inoperable due to local extension. Brachytherapy alone can be used or it can be combined with pelvic EBRT (depending on stage).Endometrial cancer recurrence is often amenable to definitive radiotherapy.

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Pre-treatment workupD

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Prin

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• Dilatation, fractional c., uterine length• Clinical examination, documentation of findings• Hysteroscopy,■ Transvagina!! Transabdominal ultrasound

- Assess the tumour:» Diffuse Endometrial thickening » Mixed echogeneity » Irregularity» Not clearly defined margins

- DD: endometrial hyperplasia, polyp- Assess the uterine topography- 3D sonography + power Doppler angiography

» Vascularization index (VI), 3D power Doppler, Resistive index » Need validation in large trials

Pre-treatment workup of a candidate for definitive endometrial cancer treatment includesDilatation, fractional c., uterine lengthClinical examination, documentation of findings Hysteroscopy,Transvaginal / Transabdominal ultrasound

Assess the tumour:Diffuse Endometrial thickening Mixed echogeneity IrregularityNot clearly defined margins

DD: endometrial hyperplasia, polyp Assess the uterine topography 3D sonography + power Doppler angiography

Vascularization index (VI), 3D power Doppler, Resistive index Need validation in large trials

Computed tomographyAssess the tumour / nodes:

^attenuation in uterine cavityMass / diffuse thickening

Irregular endometrial-myometrial interface: myometrial invasionAssess the uterine topography Less accurate than MRIBest reserved for nodal evaluation / distant metastases

Magnetic Resonance ImagingGold standard for local / locoregional evaluation:

Superior to US / CT Staging accuracy 85-93%Dynamic contrast enhanced MRI Diffusion weighted MR

Assess the uterine topography

PET CTStaging (regional, distant metastases)

Pre-treatment workupD

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Prin

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• Computed tomography- Assess the tumour / nodes:

» / attenuation in uterine cavity » Mass / diffuse thickening» Irregular endometrial-myometrial interface: myometrial invasion

— Assess the uterine topography- Less accurate than MRI- Best reserved for nodal evaluation/distant metastases

• Magnetic Resonance Imaging- Gold standard for local / locoregional evaluation:

>•> Superior to US/CT » Staging accuracy 95-93%» Dynamic contrast enhanced MRI » Diffusion weighted MR

- Assess the uterine topography

• PETCT- Staging (regional, distant metastases)

Pre-treatment workup of a candidate for definitive endometrial cancer treatment includes Dilatation, fractional c., uterine length Clinical examination, documentation of findings Hysteroscopy,Transvaginal / Transabdominal ultrasound

Assess the tumour:Diffuse Endometrial thickeningMixed echogeneityIrregularityNot clearly defined margins

DD: endometrial hyperplasia, polypAssess the uterine topography3D sonography + power Doppler angiography

Vascularization index (VI), 3D power Doppler, Resistive index Need validation in large trials

Computed tomographyAssess the tumour / nodes:

attenuation in uterine cavityMass / diffuse thickening

Irregular endometrial-myometrial interface: myometrial invasionAssess the uterine topography Less accurate than MRIBest reserved for nodal evaluation / distant metastases

Magnetic Resonance ImagingGold standard for local / locoregional evaluation:

Superior to US / CT Staging accuracy 85-93%Dynamic contrast enhanced MRI Diffusion weighted MR

Assess the uterine topography

PET CTStaging (regional, distant metastases)

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Brachytherapy techniques

The principles of brachytherapy workflow are presented in a separate presentation.

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Brachytherapy techniques

Individualized methods

Norman Simon (modified Heyman) technique

Pernot Umbrella technique

Standard methods

Two- or three-channel aplicators

One-channel applicators

The brachytherapy techniques in definitive endometrial cancer treatment can be divided into individualized and standard methods.

Individualized methods 1c/>CD

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Norman Simon (modified Hey man) technique

•Thin flexible tubes•Capsules of different sizes at the top (4/6/8 mm diameter) •Adaptation to individual patho-anatomy by individual packing

Norman Simon technique includes intrauterine placement of a variable number (depending on the uterine cavity size) of applicator capsules.

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Two- or three-channel applicators (Y - applicators)

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•2 rigid applicators with curved ends for uterine horns

•3rd applicator for mid-point of uterine fundus

•fixation of applicators to each other

•fixation by vaginal gauze packing

•appropriate for small or medium sized uterus

•appropriate for superficial tumour extension

•Appropriate for uterus with small AP dimensions Courtesy of Primoz Petrie

In a two or three channel (Y) applicator, 2 rigid applicators with curved ends for uterine horns are used. 3rd applicator may be used for mid-point of the uterine fundus. Applicators are fixed to each other. Applicator immobilization/fixation is achieved by vaginal gauze packing. The applicator is appropriate for small or medium sized uterus with small AP dimensions and for superficial tumour extension.

One channel applicators can be used for small uterus with superficial tumour. They are composed of one curved metallic tube (varying curvature) and a flange-indicating the length of uterine cavity. Fixation against cervix can be achieved by the by vaginal cylinder. The applicator is appropriate for small uterus with superficial tumour.

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Target specification and D prescription can be performed by 2D methods, such as prescription to My point or A line. In the conventional 2D approach, the organs at risk dose is typically assessed and reported by the use of rectal and bladder ICRU points.

Imaging and treatment planning

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3D methods, delineation of volumes

CT:- tumour poorly visible -> incorporate findings of hysteroscopy,

ultrasound, or MRI- uterus visible- discrimination of pelvic organs

MRI:- tumour and uterus visible- higher accuracy of the discrimination of pelvic organs

Information from hysteroscopy, clinical findings

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In 3D image guided brachytherapy of endometrial cancer, post-insertion sectional imaging is used to delineate the target volume and organs at risk, followed by applicator reconstruction and 3D dose optimization. On CT, the tumour is poorly visible delineation can be often done according to findings of hysteroscopy, ultrasound, or MRI. The uterus and the organs at risk are usually adequately visible. MRI is superior-the tumour and uterus are visible and it has higher accuracy for discrimination of pelvic organs. Information from hysteroscopy and clinical findings needs to be taken into account during contouring.


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CTV - traditional concepts• macroscopic tumour (GTV) and microscopic extension into

uterine wall /adjacent structures

• Stage I (tumour limited to uterine corpus)

> CTV = corpus + adjacent part of cervix

• Stage II (tumour infiltrating cervix)

> CTV = corpus + cervix + vaginal vault

• Higher stages (tumour extending beyond uterus)

>CTV = corpus + adjacent structures

• Complete diameter of the uterine wall is taken as thickness of CTV• Including endometrium, different layers of the myometrium and serosa

Following the traditional concepts of CTV delineation, the GTV and CTV are contoured assummarized on this slide, depending on the tumour stage.

In a study by Weitmann et al., the results of the 3D treatment planning methods were reported, showing excellent clinical results, in spite of incomplete coverage (as per traditional concepts).

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CTV - traditional concepts Should be revised?• macroscopic tumour (GTV) and microscopic extension into

uterine wall /adjacent structures

• Stage I (tumour limited to uterine corpus)

> CTV = corpus + adjacent part of cervix

• Stage II (tumour infiltrating cervix)

> CTV = corpus + cervix + vaginal vault

• Higher stages (tumour extending beyond uterus)

>CTV = corpus + adjacent structures

• Complete diameter of the uterine wal! is taken as thickness of CTV• Including endometrium, different layers of the myometrium and serosa

Following the traditional concepts of CTV delineation, the GTV and CTV are contoured assummarized on this slide, depending on the tumour stage.

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adapted GEC ESTRO recommendations?cocd

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Weitmann HD, et al. IJROBP 62 (2005) 469-478Petrie P et al. In: Viswanathan AN, ed. Gynecologic Radiation Therapy. Springer Verlag, 2011

Adaptation of GEC ESTRO contouring recommendations, applicable to cervix cancer, has been proposed to be used for other gynaecological malignancies, including endometrial cancer.

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Dose

Biologically equivalent doses!

2D techniques (GEC ESTRO Handbook of Brachytherapy)

BT alone:•70 - 80 Gy for the uterus (outer contour)•45 - 55 Gy (upper third of vagina)

Risk of pelvic nodal disease •30-45 Gy EBRT •35 to 50 Gy BT to the corpus

3D techniques

Similar strategies as in cervix cancer BT!BT alone or EBRT + BTDifferent planning aim dose levels for different CTVs:

•LR CTV: 45 -50 Gy•IRCTV: 60-65 Gy•HR CTV: 80-90 Gy•GTV: High dose

Dose prescription considerations should be based on the individual patient situation. The dose ranges given on this slide should not be regarded as recommendation!

Dose prescription considerations should be based on the individual patient situation. The dose ranges given on this slide should not be regarded as recommendations!

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All stages:

60-85 % local control rates

50-85 % disease specific survival

Depending on stage & grade

Overall survival:

Stage I: 86%

Stage II: 65%

Stage III: 45%

Stage IV: 15%

Stage I: DFS at 5 years :

100% for low risk pts

70% for high risk pts

Encouraging clinical results are obtained with definitive endometrial radiotherapy,making this approach a viable option for patients with uterine cancer, especially in thecase of surgical contraindications.

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ResultsD

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Author N° pts Stage Treatment

Survival % Recurr. % Compile. %

Churn [11] 37 I to II B DSS 68 - Gr2-3 8

Knocke [40] 280 I to III A-B DSS 77 25 Gr3 5

Kupelian [44] 152 I to IV A-B DSS I II86III IV 49

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14

Gr3 5

Landgren [46] 124 l-ll A-B-C OS 68 22 Gr3 7

Lehoczy [50] 171 I A DSS 74 23 Gr3 0

Pernot [63] 139 I to III A-B OS 55 17 15

Rouanet [70] 119 l-ll B DSS 65 24 Gr3 8

Varia [79] 73 l-ll A-B OS 43 40 Gr3 10


Def

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• Individualized and standardized applicators• Selection of applicator based on measurements

> uterus, tumour• Limitations by uterine (CTV) and tumour (GTV) size

for standardized applicators• 2D vs. 3D concept• Target volume concept: adaptation of concepts and

terms from cervix cancer IAGBT• Improvement of coverage by additional sectional

image based treatment planning

The main messages regarding definitive endometrial cancer radiotherapy are summarized on this slide.

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Preoperative RT Stage I: Clinical Results

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Salazar eta/., 1978 93 82Chung etal., 1981 94 88Bedwinek et al., 1984 90,8 71Baram etal., 1985 - 72,4Delmore et al., 1987 97,2 84-91Grigsby etal., 1991 95,7 8486-92 (DFS)

The preoperative approach to radiotherapy in endometrial cancer has been utilized in the past with the rationale of downstaging and improving the rates of complete surgical removal of the tumour. Encouraging results were obtained in the historical series for early stage tumours.

A study, published in 1990, compared the preoperative brachytherapy, followed by surgery, with surgery alone and showed comparable disease free survival with improved disease free survival in the subgroup with poorly differentiated tumours.

Preoperative RT Stage I: Clinical Results

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z105 patients

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RANDOMISATION55 patients BT+S

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\Z5y DFS 80% 5y DFS 70%

Residual disease 50,9% Residual disease 70%

Local failure 3,6% Local failure 12,6%

Wiegensberg IJ. Cancer 53 (1984) 242-247

In another study, 105 patients were randomised between preoperative BT and preoperative EBRT. Results in the preoperative BT group were superior.

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Early Stage Endometrial Cancer: Pre- or Post-operative RT?

Pros• Reduced risk of tumour

cells spread during surgery

• Reduction of viable tumour cells before surgery

Cons• Loss of pathologic

prognostic information• Over-treatment of low risk

patients

G0G16: endometrial cancer stage I, Grade 1-3 2 arms: preoperative RT and postoperative RTClosed due to poor accrual

Controversies remain regarding the preoperative radiotherapy in endometrial cancer andthis approach is currently not considered standard. The theoretical pros and cons of thepreoperative approach are summarized on this slide. A GOG16 study, comparing thepreoperative and postoperative RT was closed due to poor accrual.

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CTV dimensions

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Published schedules (length of CTV)

Without EBRT:

□ 7 Gy x 3 1/2 Nout et al, Lancet 2010□ 5.5 Gy x4 5 cm Onsrud et al, IJROBP 2001□ 5.5 Gy x 5 4 cm Atahan et al, Int J Gyn Can 2008□ 6 Gy x 6 2 cm Ng et al, Gynecol Oncol 2000□ 2.5 Gy x 6 2/3 Sorbe et al, IJROBP 2005

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As far as the CTV composition for postoperative endometrial (vaginal vault) BT isconcerned, it is generally agreed that the CTV should include the vaginal cuff mucosa, the scar and the adjacent vaginal mucosa.But the dimensions of this CTV are a matter of controversy. Several CTV lengths arereported in the literature.

CTV dimensions

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EBRT + BT

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BT

2/3 vag

BT

1/3 vagVagina G1 27% G1 12% G1 45% G1 4%

G2 18% G2 0% G2 5% G2 0%G3 10% G3 0% G3 2% G3 0%G4 1% G4 0% G4 0% G4 0%

Rectum G1 3% G1 0% G1 1% G1 0%G2 7% G2 0.5% G2 0.5% G2 0.5%

Bladder G1 9% G1 2% G1 8% G1 2%G2 4% G2 0% G2 0.5% G2 0%

Bowel G1 5% G1 0.5% G1 1% G1 0.5%G2 3% G2 0% G2 0% G2 0%

GEC ESTRO Handbook.W

Predilection region for recurrence: vault

GEC ESTRO Handbook of brachytherapy

According to the published experience, the probability of intestinal, urinary and vaginal morbidity increases with increasing length of vagina treated.This effect was most pronounced for Grade 1 and 2 vaginal complications, while G3-4 morbidity is extremely rare in any case.By including only the upper third of vagina into the CTV, we can expect significantly lower G1 and 2 vaginal complication rates.Taking into account, in addition, the fact that the main predilection region for cancer recurrence is located at the vaginal vault, it could be recommended that only the proximal third of vagina is to be included into the CTV in majority of cases.

CTV dimensions

hopcc<D

CD

Thickness & prescription depth

CD-£CD

LUCD>•+Z3<D

W

-•Vaginal wall: 2-8 mm

-• Majority of cases:adequate CTV coverage sparing organs at risk

*-• Some cases:overtreatment?undertreatment?

-• Varying vaginal wall

-• Varying scar thickness

-•Vicinity of organs at risk

Approaches that can be used for specification of prescription depth:A standard prescription depth is chosen, for example, at 5 mm from the applicator surface.This standard prescription depth is based on our knowledge from anatomy that thethickness of vaginal wall varies usually from 2-8 mm.Indeed, in majority of cases, a prescription depth of 5 mm will adequately cover the CTV without excessive irradiation of the adjacent organs at risk.However, we clearly have to assume that some patients will be overtreated, while some may be undertreated.An alternative approach to specification of prescription depth is taking into account the considerable patient-patient variation of the scar thickness (up to 10 mm), the vaginal wall thickness and the vicinity of organs at risk.When implementing an individually adapted image based approach to BT, these factors need to be taken into account.

Courtesy of Primoz Petrie

IAEA

Surgical I histopathological reports

Clinical findings

Individualized prescription depth

Imaging (endoluminal US)

*•*

Before choosing the appropriate prescription depth, it is recommended to perform careful clinical examination, including bimanual palpation to try and identify patients with excessive scar thickness.In addition, when possible, endoluminal ultrasound can be performed.Another important information that always has to be taken into account is the surgical and histopathological report.

Prescription depthIAEA

Standard vs. Individually determinedOnsrud et al. 2001:

*• 96 pts: prescription @ 5mm•I 121 pts: individualized prescription @

3/4/5 mm• Prescribed D: 5.5 Gy x 4

Reference point>________________________a

r Standard (5 mm) 1| Individualized

Vaginal surface 42 GyI J[ 29 Gy ]

Bladder base_______________ J 18 Gy ( 14 Gy

Rectum_______________ 22 Gy ( 17 Gy ]

Onsrud M, Int J Radiat Oncol Biol Phys 49 (2001) 749-55

Onsrud et al. published a comparison between the standard and individualized specification of prescription depth. When the vaginal mucosa is less than 5 mm the patients will be overtreated by prescribing to 5 mm depth.

In the early period, the investigators performed treatment by using standard dose prescription at 5 mm depth from the applicator surface.The late G1 and G2 morbidity rates in this period were 34% for vagina, 10% for the bladder and 5% for the rectum.After implementing an individualized approach to determination of prescription depth, the late morbidity rates for vagina and bladder decreased significantly.There was also a non-significant decrease in complication rate for rectum.It is important to note, that there was no G3-4 morbidity and no difference in recurrence rates between the two patient groups.Individual determination of the prescription depth is encouraged.

3D individualized approach

• 3D image guided treatment planning

> Post-insertion imaging (CT, MRI)> Determination of prescription depth> Delineation of the target volume and organs at risk> Optimization based on target volumes and organs at

risk> DVH analysis> Recording and reporting

The 3D individualized approach follows the workflow according to the basic steps as presented in the specific presentation.

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Application techniquePo

stop

erat

ive

Endo

met

rial c

ance

r RT:

App

licat

ion

Applicator:

Size according to vaginal dimensionsClose contact to mucosaStandard vs. individualized approaches

As far as the application technique is concerned, the applicator size should be selected according to the vaginal dimensions to assure close contact to mucosa. Standard and individualized application techniques are available.

In the historical Manchester system, endovaginal brachytherapy was specified by applying a certain amount of radium for a certain time. The treatment was described in terms of mgh of Radium.

EXAMPLE:226Ra: 5 x 10 mg Duration: 49hTotal mgh: 2450

APPLIED DOSE:5000 rat 1cm depth, 7 cm length

Application technique

Historical vaginal cylinders (II)

Modern vaginal cylinders were adapted first for the use with Caesium sources...

...and later for Iridium sources.Nowadays, standard one channel cylindrical applicators are commercially available and are widely used.By adaptation of one channel applicators, applicators with multiple channels can be fabricated to allow for differential loading and conformal tailoring of the dose distribution.

The individualization of application technique is represented by the French (InstitutGustave Roussy) approach, using individualized customized moulds. The principles of this technique have been presented in more extent during the talk on intracavitary cervix cancer applications.In some special situations, an alternative application technique may be utilized, such asinsertion of a pair of ovoids or a ring into the vaginal vault.

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A S 'y

Courtesy of PrimorPetric------' Courtesy of Primoz Petrie

o Adapt standard technique ------------ ► Individualize treatment

Details on the treatment planning approaches are beyond the scope of this presentation.

Prescribed doseCD

QLCD

CCO.CC

cc

Small et al, IJROBP 2005 {ABS Survey):without EBRT

7 Gy x3 (21 Gy) 42.1 %5 Gy x 6 (30 Gy) 8.1 %5 Gy x 5 (25 Gy) 7%5 Gy x4 (20 Gy) 3.5 %

with EBRT5 Gy x 3 (15 Gy) 43.3 %4 Gy x 3 (12 Gy) 8 %5Gyx2 (10 Gy) 5.4 %5 Gy x 4 (20 Gy) 3.8 %

LU Other published schedules

2CD

CO

without EBRT6 Gy x 3 5.5 Gy x 45.5 Gy x 5 16.2 Gy x 2 6Gyx62.5 Gy x6

Alektiar et al, IJROBP 2005 Chong and Hoskin, Brachyth 2008 Atahan et al, Int J Gyn Can 2008 Petereit et al. Int J Gyn Can 1999 Ng et al, Gynecol Oncol 2000 Sorbe et al, IJROBP 2005

Schedule with EBRT2 Gy x 6 Fayed et al, IJROBP 2007

Take the LQ model into account when comparing different schedules

In a survey of dose prescription practices within the ABS, a considerable variability wasfound with a wide range of doses applied.When comparing different dose fractionation techniques, the biological equivalent doses should be calculated.

IAEA

5 mm

Impact of dose specification depth

Dose specification depth

Published depth specifications - Without EBRT

☆-—■5

30 mm4.6 Gy

7 Gy

7 Gy x 3 5.5 Gy x4 5.5 Gy x 5 16.2 Gy x2 6 Gy x 6 5 Gy x 3

5 mm 5 mm 5 mm 0 mm 0 mm 0 mm

Nout et al, Lancet 2010 Chong and Hoskin, Brachyth 2008 Atahan et al, Int J Gyn Can 2008 Petereit et al. Int J Gyn Can 1999 Ng et al, Gynecol Oncol 2000 Small et al, IJROBP 2005

Surface

7 Gy Jf >

10.5 Gy

Dose prescription practice has to be described in terms of dose and prescription depth specification. Same dose, prescribed at different depths, results in a considerably different doses applied, due to the rapid brachytherapy dose fall off.

Post

oper

ativ

e En

dom

etria

l can

cer R

T: S

umm

ary

SUMMARY

CTV:- Length of vagina to be treated- Prescription depth:

• Standard (5 mm)• Individualized

Applicator:- According to vaginal dimensions- Close contact with mucosa

• Standard,• Modified standard,• Individualized

Treatment planning- Standard library plans, no optimization- Individualized adjustment of dose distribution- Dose schedules: Radiobiology; D gradient!

Main issues regarding postoperative brachytherapy in endometrial cancer are summarized on this slide.

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Vaginal cancerConcepts and terms from cervix cancer, specifically

adapted for vaginal cancer

Adequte implant geometry is a precondition for adequate dose optimisation!

On this slide, several examples of the use 3D image guided adaptive brachytherapy for cervix cancer are given. High risk clinical target volume is delineated in blue in all patients. Highly conformal dose distributions were possible to achieve due to good application geometry, resulting from optimal pre-insertion planning of the application geometry. Adequate implant geometry is a precondition for adequate dose optimization!In cases of vaginal cancer, the same principal steps of image guided brachytherapy as for cervix cancer (outlined in previous slides) were applied.

RCQ5

03.C&

JO

0303

Vaginal Cancer IGABT

Introduction

Primary vaginal cancer: « 2% of gynae malignancies

Definitive RT +/ Chemotherapy: modality of choice

- Stage 0-1 may be amenable to surgery or mono-BT

- Locally advanced tumours: Therapeutic challenge!

• combined EBRT + BT

• Local failure rates remain high with conventional BT

• New BT approaches required

Similarities with cervix cancer

- Image guided adaptive brachytherapy (IGABT)

• D to shrinking target & adaptation to individual topography

• Escalation of target D while sparing the normal tissues

Primary vaginal cancer is a rare tumour, accounting for « 2% of gynae malignancies. Definitive RT +/ Chemotherapy is the modality of choice. Stage 0-I may be amenable to surgery or mono-BT. Locally advanced tumours remain a therapeutic challenge! Local failure rates remain high with conventional BT and new BT approaches are required. There are similarities of vaginal cancer with cervix cancer, where image guided brachytherapy has been applied with success.

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Vag

inal

can

cer

IGA

BT:

Initi

al e

valu

atio

n

Treatment strategy will depend on tumour size, topography, location and overall medical condition & age of patient

In vaginal cancer, the treatment strategy will depend on tumour size, topography, location and overall medical condition and age of the patient.

Imaging at diagnosis

Hricak H, et al. ACRIN/GOG Radiology. 245 (2007) 491-8 Dimopoulos et al. MRI Recomm. Radother Oncol 103(2012) 113-122

•Contrast enhanced CT

•MRI

•PET CT

•Ultrasound

Institute of Oncology LjubljanaVaginal contrast (gel)!

Adequate diagnostic imaging is a prerequisite for thorough understanding of the pathoanatomy and for optimized treatment.

IAEA


Hricak et al. Radiology 2007 (Cervix cancer)

' Date m parentneses are un-ji-s over Erie readersf Campartsais batman MR imaging and Cl were perfumed tor the patients common to the MR imaging and CTanalisis sets. Data in parentheses are 95% coifrderrce Intervals (CJs|-1 The left and right sides ot the parametrium were treated as clusters within the same subject

Hricak H, et al. ACRIN/GOG Radiology. 245 (2007) 491-8Table and figures reproduced with permission courtesy RSNA

Area Under Curve for Tumour visualization

0.8

1.0

0.6

0.4

0.2

0.0

| Tumor visualization 0 58(0 52-{t63i 0 77 IO 67-0 85) 0 20 IO 12. 0 27) • 001 |Parametnal invasion’ 0.62 (O-W-0,68) 0-65(0.54-0.75) 007(0,001.0,15) -047

0.615 0,4

0.2

0,0

flUC Values for Retrospective Interpretation of CT and MR Imaging Studies

__________Mean AUC'__________ Difference in AlICParamele CT MP Imaging between Studies' PValue

1-Specificity 1 -Specificity

MRI

AUC 672 MRUAUC 659 MRI2AUC 759 MR aAUC 749 MR 4

AUC CT1517AUC 624 CT2AUC 539 CT3AUC CT4629

MRI is superior to CT for tumour visualization and parametrial invasion assessment.

Vag

inal

can

cer

IGA

BT:

Initi

al e

valu

atio

n

MRI is superior to CT for tumour visualization and parametrial invasion assessment.


IGABT doesn’t imply that we should rely only on imaging

Eye and finger remain the most important imaging modality in Vaginal cancer

However, it should be emphasized that image guidance in brachytherapy doesn't imply that we should rely only on imaging. Clinical examination remains the most important modality in evaluation of disease extent in vaginal cancer.

An example of an overall treatment schedule is presented. The overall treatmentschedules vary across institutions or even across patients in a particular institution. This schematic example is not intended as a recommendation for treatment schedule.In this schedule, 45 Gy of pelvic external beam radiotherapy, given in 25 daily fractions of 1.8 Gy, accompanied by weekly applications of cisplatin (40 mg/m2) were followed by two image guided brachytherapy applications in weeks 6 and 7, keeping the overalltreatment time below 50 days.

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Intracavitary techniques: Tumour < 5 - 8mm

coCD

CD

CD

l-CCQ§CD

CDO"c6C&

XD

Applicator compatibility with IGABT

As far as BT application techniques are concerned, the intracavitary approach should be adequate for the majority of tumours thinner than 5-8 mm.

AEAIntracavitary techniques: Tumour < 5 - 8mm

Optimization of intracavitary applications

Even in the simple intracavitary technique, a significant amount of dose optimization can be achieved by asymmetrical loading of the applicator channels in multi-channel applicators, according to the target volume topography.

Vag

inal

can

cer I

GA

BT:

App

licat

ion

tech

niqu

es

The uncertainties in applicator position translate into uncertainties in the delivered dose.These uncertainties refer to the translational and rotational movements of theapplicator.

co

,Cr

Intracavitary techniques: Tumour < 5 - 8mm

Uncertainties in applicator position How to reduce them?

I i Uncertainties in position

T1 Degrees of freedom for loading

The uncertainties in applicator position translate into uncertainties in the delivered dose.These uncertainties refer to the translational and rotational movements of theapplicator.Insertion of the uterine tandem and fixation needles, in addition to externalimmobilization of the applicator to the patient, result in reduction of the motion related uncertainties.

In cases of more advanced disease with tumour thickness exceeding 8 mm in the paravaginal / parametrial tissue and in cases of unfavourable topography of organs at risk and anatomical limitations for intracavitary insertions, an interstitial component is indicated.

Vag

inal

can

cer I

GA

BT:

App

licat

ion

tech

niqu

es

An important challenge when applying interstitial techniques in vaginal BT is the issue of the needle path length, which is related to uncertainties of the needle positioning accuracy.

Deej. Of Brachytherapy, IO Lfi^ljai

Insertion

tesy of Primoz Petrie

Courtesy of Primoz Petrie

Planning MRIBT findings

Clinical

Initial findings.> MR!

EBRT

Clinical

GEC ESTRO Recommendations l-IV (Radiother Oncol 2005-2012)

Guidance of needle insertion (aiming to achieve optimal implant geometry) can beaccomplished bay an off-line or on-line approach. On this slide an example of off-lineimage guided insertion of the needles in cervix cancer BT is presented. Pre-insertion MRIand clinical examination are used to determine the optimal needle positions.

Intracavitary I Interstitial techniquesV

agin

al c

ance

r IG

AB

T: A

pplic

atio

n te

chni

ques Real time on-line image guidance (ultrasound)

Stock 1997:7 patients, 12 procedures Syed-Neblett template

Weitmann 2006:23 patients (vaginal recurrences) Transvaginal or transperineal insertion

Stock et ah IJROBP 37 (1997) 819-825Weitmann HD, et al. Strahlenther Onkol 182 (2006) 86-95

For the real time guidance, ultrasound can be used, as on the example on the slide.

AEAIntracavitary I Interstitial techniques

on-line image guidance (MRI, CT)

Viswanathan AN (2006):Vaginal recurrence of endometrial cancer:MRI guidance

Lee LJ (2013):

68 Gynaecological tumours (11 cases vaginal): CT guidance

Viswanathan AN (2013):

25 Gynaecological tumours:MRI guidance

Maximized opportunity for tumour

targeting and normal tissue sparing

Viswanathan AN, et al. IJROBP 66 (2006) 91-99Lee LJ, et al. Brachytherapy 12 (2013) 303-310Viswanathan AN, et al. Brachytherapy 12 (2013) 240-247

When MRI or CT is used for "on-line” guidance, temporal interruptions of the insertion procedure are required to obtain images, followed by corrections of the implant.Several reports in the literature have demonstrated maximized opportunity for tumour targeting and normal tissue sparing with the use of CT or MRI guided interstitial techniques.

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Vicinity of organs at riskDose inhomogeneities, Loading patterns & Planning rules!

Adequte implant geometry is a precondition for adequate dose optimisation!

C of P' :r,o^ Petrel

Dose planning

Adequate implant geometry is a precondition for adequate dose optimization! 3D image guided brachytherapy techniques have the important advantage of meaningful treatment optimization/individualization when compared to the conventional 2D approach.

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There are several challenges when interpreting clinical results of vaginal cancer BT. Due to the rarity of disease, not many studies to base the recommendations on exist. When recommending treatment strategies, we need to rely on the mono-institutional retrospective reports and extrapolations from cervix cancer IGABT. ABS Consensus Guidelines for interstitial BT for Vaginal Cancer states that "3D treatment planning with CT and/or MRI is recommended” (Beriwal S, Demanes DJ, Erickson B, et al.Brachytherapy 2012)

AEAMono-institutional retrospective reports

Actuarial 5y survival by stage in % (n of patients)

Vag

inal

can

cer I

GA

BT:

Res

ults

Stage I Stage II Stage III Stage IV

Davis, Gyn Oncol 1991 82 (44) 53 (45) - -

Eddy, Am J Obstet Gynecol 1991 75 (25) IIA: 47 (17) MB: 35 (22)

40 (15) 25 (12)

MacNaught, Clin Radiol 1986 68 (14) 34 (22) 29 (18) 14(7)

Perez, IJROBP 1988 75 (50) IIA. 55 (49)IIB (35 (26)

45 (16) 38 (8)

Stock, Gyn Oncol 1995 67 (23) 53 (58) 0(9) 15 (10)

Tran, Gynecol Oncol 2007 92 (33) 68 (23) 44 (3) 13(9)

Frank, IJROBP 2005 (MDACC)* 85 (50) 78 (97) 58 (64) -

Long observed periods (i.e: *1970-2000), evolving techniques

Results of the mono-institutional reports on vaginal BT are summarized in the table on this slide.

Mono-institutional retrospective reports

co

co®ccQO

CD

CD.C&30

5 year local control rates by stage (%)

• I: 50-100• II : 50 to 85• III : 0 to 86• IV : 0 to 67

Why discrepancies?• Small series• Histological differences• Reports emerging over a long period of time:

• Improving imaging (MRI and/or PET-CT)• improving treatment techniques

This is a summary of the table on the previous slide. The discrepancies (ranges) of the reported results, are due to the size of the series, which are mainly small (rarity of tumour), histological heterogeneity and the fact that the reports are emerging over a long period of time, during which the imaging and application techniques haveimproved.

IAEAEvidence based treatment recommendations?

Emerging encouraging IGABT results

13 vaginal cancer patients

DVH parameters:• Mean D90 HR-CTV = 86 (+/-13) Gy• Mean D2cm3 bladder = 80 (+/-20) Gy• Mean D2cm3 urethra = 76 (+/-16) Gy• Mean D2cm3 rectum = 70 (+/-9) Gy• Mean D2cm3 sigmoid = 60 (+/-9) Gy

Treatment outcome:•1 local recurrence •2 distant metastases •Actuarial 3y-LC: 92%•Actuarial 3y-OS: 85%•1 rectovaginal fistula (stage 111)•1 vesicovaginal fistula (stage IVa)•1 periuerthral necrosis

Dimopoulos et al, IJROBP 32 (2012) 1880-1888, copyright Elsevier, reproduced with permission

In a recent report of Dimopoulos et al. on the use of 3D image guided BT, encouraging dosimetric and clinical results were obtained. Concepts, developed for cervix cancer IGABT are applicable to vaginal cancer with similar DVH and clinical outcome.

In a recent report of Dimopoulos et al. on the use of 3D image guided BT, encouraging dosimetric and clinical results were obtained. Concepts, developed for cervix cancer IGABT are applicable to vaginal cancer with similar DVH and clinical outcome.

Vaginal Cancer IGABT

Conclusions

• Individualisation of treatment, Initial evaluation

• Application techniques

• Contouring uncertainties

• Dose planning challenges

• Organs at risk in vicinity

• No prospective studies

• Infrastructural requirements

• Training, Team work

In conclusion, vaginal cancer BT achieves best results when the treatment isindividualized with special application techniques and 3D image guidance of insertionand planning. Several challenges and pitfalls of vaginal BT have been recognized and are listed on this slide. Adequate training and team work are the main strategies to overcome these challenges.

IAEA

Bibliography

• ALEKTIAR, K. M., VENKATRAMAN, E„ CHI, D. S„ BARAKAT, R. R„ Intravaginal brachytherapy alone for intermediate-risk endometrial cancer, Int. J. Radiat. Oncol. Biol. Phys. 62 (2005) 111-117.

• ARONOWITZ, J. N., Dawn of prostate brachytherapy: 1915-1930, Int. J. Radiat. Oncol. Biol. Phys. 54 (2002)712-718.

• ATAHAN, I. L., et al., Vaginal high dose rate brachytherapy alone in patients with intermediate- to highrisk stage I endometrial carcinoma after radical surgery, Int. J. Gynecol. Cancer 18 (2008) 1294-1299.

• BERIWAL, S., et al., American Brachytherapy Society consensus guidelines for interstitial brachytherapy for vaginal cancer, Brachytherapy 11 (2012) 68-75.

• CHONG, I., HOSKIN, P. J., Vaginal vault brachytherapy as sole postoperative treatment for low-risk endometrial cancer, Brachytherapy 7 (2008) 195-199.

• DAVIS, K. P„ STANHOPE, C. R„ GARTON, G. R„ ATKINSON, E. J., O'BRIEN, P. C., Invasive vaginal carcinoma: analysis of early-stage disease, Gynecol. Oncol. 42 (1991) 131-136.

• DEMANES, D. J., et al., The use and advantages of a multichannel vaginal cylinder in high-dose-rate brachytherapy, Int. J. Radiat. Oncol. Biol. Phys. 44 (1999)211-219.

• DIMOPOULOS, J. C., et al., The Vienna applicator for combined intracavitary and interstitial brachytherapy of cervical cancer: clinical feasibility and preliminary results, Int. J. Radiat. Oncol. Biol. Phys. 66 (2006) 83-90.

IAEA

Bibliography

• DIMOPOULOS, J., FIDAROVA, E., POTTER, R., Definitive radiotherapie und radiochemotherapie der vulva und vagina, Onkologe 15 (2009) 54-63.

• DIMOPOULOS, J. C., et al., Treatment of locally advanced vaginal cancer with radiochemotherapy and magnetic resonance image-guided adaptive brachytherapy: dose-volume parameters and first clinical results, Int. J. Radiat. Oncol. Biol. Phys. 82 (2012) 1880-1888.

• DIMOPOULOS, J. C., et al., Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (IV): Basic principles and parameters for MR imaging within the frame of image based adaptive cervix cancer brachytherapy, Radiother. Oncol. 103 (2012) 113-122.

• EDDY, G. L„ MARKS, R. D„ JR., MILLER, M. C„ 3RD, UNDERWOOD, P. B„ JR., Primary invasive vaginal carcinoma, Am. J. Obstet. Gynecol. 165 (1991) 292-296.

• FAYED, A., et al., Comparison of high-dose-rate and low-dose-rate brachytherapy in the treatment of endometrial carcinoma, Int. J. Radiat. Oncol. Biol. Phys. 67 (2007) 480-484.

• FRANK, S. J., JHINGRAN, A., LEVENBACK, C„ EIFEL, P. J., Definitive radiation therapy for squamous cell carcinoma of the vagina, Int. J. Radiat. Oncol. Biol. Phys. 62 (2005) 138-147.

• GALALAE, R. M., et al., Long-term outcome by risk factors using conformal high-dose-rate brachytherapy (HDR-BT) boost with or without neoadjuvant androgen suppression for localized prostate cancer, Int. J. Radiat. Oncol. Biol. Phys. 58 (2004) 1048-1055.

• GERBAULET, A., POTTER, R„ MAZERON, J. J., MEERTENS, H„ VAN LIMBERGEN, E„ The GEC ESTRO Handbook of Brachytherapy, ESTRO, Brussels (2002).

IAEA

Bibliography

• GRIMM, P., et al., Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group, BJU Int. 109 Suppl 1 (2012) 22-29.

• HAIE-MEDER, C., et al., Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group (I): Concepts and terms in 3D image based 3D treatment planning in cervix cancer brachytherapy with emphasis on MRI assessment of GTV and CTV, Radiother. Oncol. 74 (2005) 235-245.

• HELLEBUST, T. P., et al., Recommendations from Gynaecological (GYN) GEC-ESTRO Working Group: considerations and pitfalls in commissioning and applicator reconstruction in 3D image-based treatment planning of cervix cancer brachytherapy, Radiother. Oncol. 96 (2010) 153-160.

• HOSKIN, P. J., MOTOHASHI, K„ BOWNES, P„ BRYANT, L., OSTLER, P„ High dose rate brachytherapy in combination with external beam radiotherapy in the radical treatment of prostate cancer: initial results of a randomised phase three trial, Radiother. Oncol. 84 (2007) 114-120.

• HRICAK, H., et al., Early invasive cervical cancer: CT and MR imaging in preoperative evaluation - ACRIN/GOG comparative study of diagnostic performance and interobserver variability, Radiology 245 (2007)491-498.

• LEE, L. J., DAMATO, A. L., VISWANATHAN, A. N., Clinical outcomes of high-dose-rate interstitial gynecologic brachytherapy using real-time CT guidance, Brachytherapy 12 (2013) 303-310.

• MACNAUGHT, R., SYMONDS, R. P., HOLE, D., WATSON, E. R., Improved control of primary vaginal tumours by combined external-beam and interstitial radiotherapy, Clin. Radiol. 37 (1986) 29-32.

• MEREDITH, W. J. (Ed), Radium Dosage.The Manchester System, Livingstone, Edinburgh (1947).

IAEA

Bibliography

• NG, T. Y„ PERRIN, L. C„ NICKLIN, J. L., CHEUK, R„ CRANDON, A. J., Local recurrence in high-risk node-negative stage I endometrial carcinoma treated with postoperative vaginal vault brachytherapy, Gynecol. Oncol. 79 (2000) 490-494.

• NOUT, R. A., et al., Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial, Lancet 375 (2010) 816-823.

• ONSRUD, M., STRICKERT, T„ MARTHINSEN, A. B., Late reactions after postoperative high-dose-rate intravaginal brachytherapy for endometrial cancer: a comparison of standardized and individualized target volumes, Int. J. Radiat. Oncol. Biol. Phys. 49 (2001) 749-755.

• PEREZ, C. A., et al., Definitive irradiation in carcinoma of the vagina: long-term evaluation of results, Int J Radiat Oncol Biol Phys 15 (1988) 1283-1290.

• PETEREIT, D. G., TANNEHILL, S. P„ GROSEN, E. A., HARTENBACH, E. M„ SCHINK, J. C„ Outpatient vaginal cuff brachytherapy for endometrial cancer, Int. J. Gynecol. Cancer 9 (1999) 456-462.

• PIETERS, B. R„ DE BACK, D. Z„ KONING, C. C„ ZWINDERMAN, A. H„ Comparison of three radiotherapy modalities on biochemical control and overall survival for the treatment of prostate cancer: a systematic review, Radiother. Oncol. 93 (2009) 168-173.

• POTTER, R., et al., Recommendations from gynaecological (GYN) GEC ESTRO working group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy-3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology,Radiother. Oncol. 78 (2006) 67-77.

• SATHYA, J. R., et al., Randomized trial comparing iridium implant plus external-beam radiation therapy with external-beam radiation therapy alone in node-negative locally advanced cancer of the prostate, J. Clin. Oncol. 23 (2005) 1192-1199.

IAEA

Bibliography

• SAUSE, W. T., et al., Analysis of preoperative intracavitary cesium application versus postoperative external beam radiation in stage I endometrial carcinoma, Int J. Radiat. Oncol. Biol. Phys. 18 (1990) 1011-1017.

• SMALL, W., JR., ERICKSON, B., KWAKWA, F., American Brachytherapy Society survey regarding practice patterns of postoperative irradiation for endometrial cancer: current status of vaginal brachytherapy, Int. J. Radiat. Oncol. Biol. Phys. 63 (2005) 1502-1507.

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IAEA

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