Radiotherapy Manual...2017/05/15 · Radiotherapy Manual Confidential EuroNet-PHL-C2 final 4.0 2017-05-15 Page 6 of 32 as demonstrated on the staging PET-CT scans at the time of diagnosis

The information provided in this document is confidential and is not to be circulated to third parties.

Inter-group chairpersons

Prof. Dr. Dieter Körholz (Coordinating chairperson) Universitätsklinikum Giessen und Marburg GmbH; Standort Giessen - Abteilung für Pädiatrische Hämatologie und Onkologie Feulgenstr. 12, 35392 Giessen

Germany

Sponsor

Prof. Dr. W. Hamish Wallace Royal Hospital for Sick Children, Sciennes Road, Edinburgh EH9 1LF, Scotland, UK.

Prof. Dr. Judith Landman-Parker Service d’hématologie et d’oncologie pédiatrique Hôpital Trousseau AP-HP Paris, France

Justus-Liebig-University of Giessen Medizinische Fakultät Rudolf-Buchheim-Str. 23 35392 Giessen Germany

EudraCT number: 2012-004053-88

Date of Version: 2017-05-15

EuroNet-PHL-C2

EuroNet-Paediatric Hodgkin’s Lymphoma Group

Second International Inter-Group Study

for Classical Hodgkin’s Lymphoma in Children and Adolescents

Radiotherapy Manual

Radiotherapy Manual Confidential

EuroNet-PHL-C2 final 4.0 2017-05-15 Page 2 of 32

Table of Content

1. RADIOTHERAPY SUBCOMMITTEE OF EURO-NET-PHL ............................................ 4

2. INTRODUCTION ............................................................................................................ 5

3. DELINEATION OF TARGET VOLUMES AND ORGANS AT RISK ................................ 5

3.1. Patients in TL1 and TL-2 & TL-3 treated with COPDAC-28 ......................................... 5

3.2. Patients in TL-2 & TL-3 treated with DECOPDAC-21 .................................................. 6

3.3. Definition of target volumes ........................................................................................ 6

3.3.1. Gross tumour volume (GTV) ................................................................................... 6

3.3.2. Clinical target volume (CTV) for patients in TL1 patients and in patients in TL-2 and TL-3 treated with COPDAC-28 ......................................................................... 6

3.3.3. GTV and CTV for patients treated with DECOPDAC-21 .......................................... 7

3.3.4. Planning target volume (PTV) ................................................................................. 7

3.4. Involved site radiotherapy (ISRT) ................................................................................ 8

3.4.1. CTV-ISRT for patients in TL1 and patients in TL-2 & TL-3 treated with COPDAC ... 8

3.4.2. CTV-INRT for patients in TL-2 & TL-3 treated with DECOPDAC-21 ........................ 9

3.4.3. CTV for Boost volume in patients who were treated with COPDAC-28 .................... 9

3.4.4. CTV for E-lesions and disseminated organ involvement .......................................... 9

4. ORGANS AT RISK (OAR) (FIGURE 6 A AND 6 B) .......................................................10

4.1. OAR definition of the spinal cord, thyroid gland, liver and kidney ...............................10

4.2. OAR definition of the lung ..........................................................................................10

4.3. OAR definition of mammary glands/breast .................................................................10

4.4. OAR definition of the heart .........................................................................................10

4.5. Gonads ......................................................................................................................11

5. ORGANISATION OF RADIOTHERAPY TREATMENT..................................................11

6. TIMING OF RADIOTHERAPY .......................................................................................11

7. RADIOTHERAPY TREATMENT PLANNING AND DOSE PRESCRIPTION ..................11

8. RADIOTHERAPY DOSE ...............................................................................................12

8.1. Radiotherapy dose .....................................................................................................12

8.2. E-lesions and dissiminated organ involvement ..........................................................12

8.3. Lung irradiation ..........................................................................................................12

9. RADIOTHERAPY DELIVERY........................................................................................13

10. TECHNICAL REQUIREMENTS .................................................................................13

11. SIDE EFFECTS OF RADIOTHERAPY ......................................................................15

11.1. Acute side effects ...................................................................................................15

11.2. Long term side effects ............................................................................................15

12. QUALITY ASSESSMENT ..........................................................................................15

13. REFERENCES: .........................................................................................................17

14. TABLES .....................................................................................................................20



15. FIGURES ...................................................................................................................26

LIST OF ABBREVIATIONS: .................................................................................................32



1. RADIOTHERAPY SUBCOMMITTEE OF EURO-NET-PHL

Chairperson

Prof. Dr. Karin Dieckmann*

Department of Radiotherapy

Medical University Vienna

Waehringer Guertel 18-20

1090 Vienna, Austria

[email protected]

Group Members

Cristian Carrie

Dr. Line Claude*

Departement of radiation oncology

Centre Leon Berard

28 rue laennec

69373 LYON cedex 08, France

[email protected]

[email protected]

Dr. Eve Gallop-Evans*

Velindre Cancer Centre

Velindre Road

Whitchurch, Cardiff, CF14 2TL, UK

[email protected]

Bela Malinova

Department of radiotherapy and oncology

Faculty Hospital Motol

V Úvalu 84

150 06 Prague 5, Czech Republik

[email protected]

Kristina Nilsson

Överläkare Onkologkliniken Akademiska sjukhuset 751 85 Uppsala, Sweden [email protected]

Prof. Dr. Dirk Vordermark*

Tanja Pelz

Department of Radiotherapy

Martin-Luther-University Halle-Wittenberg

Dryanderstr 4-7

06110 Halle, Germany

[email protected]

[email protected]

Associated partner for evaluation of proton

Prof. Dr. Rita Engenhart-Cabilic

Prof Dr. Andrea Wittig

Department of Radiooncology,

mailto:[email protected]








University Hospital Gießen-Marburg Klinikstr. 33 35392 Gießen, Germany

[email protected]

[email protected]

* Members of the Quality control team

2. INTRODUCTION

Radiotherapy continues to play an important role in the treatment of Paediatric Hodgkin

Lymphoma particularly in patients with an inadequate response to chemotherapy [31].

Successive study generations have led to improvements in systemic therapy, allowing a

stepwise reduction in radiation doses and volumes without compromising cure rates [18]. The

HD 95 study was the first to demonstrate that radiotherapy could be omitted in patients with

early stages and an adequate response to chemotherapy [5, 23], and this was confirmed in

the GPOH-HD-2002 pilot study [19].

The introduction of functional imaging by PET-CT for staging and response assessment has

been tested in the EuroNet PHL-C1 study [16], and initial results are encouraging. In the PHL-

C2 study, the response adapted approach to treatment continues to evolve, and introduces

the concept of target definition based on functional imaging.

As in the C1 study, all patients will have an early response assessment PET (ERA-

qPETquantitative) performed after two cycles of chemotherapy. Patients with an inadequate

metabolic response will receive radiotherapy after completion of chemotherapy.

The principles of target volume definition in radiotherapy for Hodgkin lymphoma have been

based on initially involved sites, taking into account the post-chemotherapy volumes and

topography [10, 29]. However, terms and definitions vary across protocols; for example, the

term INRT [4,6,9] implies that only the involved lymph nodes are irradiated, but does not

specify the term “involved” with respect to time point and/or image modality. In practice, INRT

is hard to deliver except in very specific circumstances as it requires accurate assessment of

involved nodes prior to chemotherapy, ideally by contrast enhanced CT scans in the

radiotherapy treatment position, and the use of contrast-enhanced radiotherapy planning

scans [13,27]. As a result, international guidelines for the use of “involved site radiotherapy”

(ISRT) have been published [1, 2]. This allows for smaller fields, integrating modern imaging

for target delineation with 3D planning techniques and will form the basis for treatment in the

EuroNet-PHL-C2 protocol. Boost volumes will be based on INRT defined at the time of the

LRA-PET.

3. DELINEATION OF TARGET VOLUMES AND ORGANS AT RISK

3.1. Patients in TL1 and TL-2 & TL-3 treated with COPDAC-28

The target volume definition in patients in TL1 (treatment level) and in patients in TL-2 and TL-

3 treated in the COPDAC-28 arm will be based on initial nodal and extra-nodal involvement,




as demonstrated on the staging PET-CT scans at the time of diagnosis (Fig.1 and 2). The term

modified involved field radiotherapy (mIFRT) was used to describe this volume in EuroNet

PHL-C1, the HD-2002 pilot study, HD95 and HD90 [5, 18, 19, 23, 24]. In this study the use of

“involved site radiotherapy” (ISRT) will replace “modified involved field radiotherapy“(mIFRT)

as 3D target definition will be based on involved lymph nodes with an appropriate safety

margin. The resulting volume is not expected to differ significantly from the previously defined

modified involved field technique used in the C1 study. For patients in TL-2 and TL-3, an

additional late response assessment (LRA-qPET) will be performed after completion of

chemotherapy, to determine the need for a boost. Only residual lymph nodes > 10mm, which

are still positive on the LRA-qPET, will receive a 10Gy boost (Fig 4).

For patients in TL-2 & TL-3 treated with COPDAC-28, extranodal or E-lesions i.e. any

contiguous infiltration of a lymph node mass into extra-lymphatic structures or organs)

must receive radiotherapy as part of the nodal volume, even if the extranodal extension

is not ERA-qPET-positive.The target volume is detailed in Tab 3.

For patients in TL-3 treated with COPDAC-28, organ involvement ( i.e. stage IV) will only

require radiotherapy if positive on the ERA-qPET after the initial 2 cycles of chemotherapy.

The target volume is detailed in Tab 4.

3.2. Patients in TL-2 & TL-3 treated with DECOPDAC-21

The target volume definition for patients in TL-2 & TL-3 treated with DECOPDAC-21 will be

any LRA-qPET-positive lymph nodes > 10mm at the end of all planned chemotherapy (Tab.5).

If more than one LN is LRA-qPET-positive, they should be delineated as one target wherever

feasible, to avoid multiple small fields (patchwork irradiation) (see Fig. 3).

In TL-2 & TL-3 patients treated with DECOPDAC-21, E-lesions and organ involvement will only

require radiotherapy if these lesions are LRA-qPET-positive at the end of chemotherapy. The

target volume is detailed in Tab 6 and Tab 7.

3.3. Definition of target volumes

Target volumes are defined according to the ICRU 50/62 guidelines [14, 15].

3.3.1. Gross tumour volume (GTV)

The GTV includes all gross visible involved lymph nodes or sites. As radiotherapy follows

chemotherapy, the GTV can only be defined in cases with visible residual tumour at LRA-

qPET, i.e. LN >10mm. This provides the basis for target definition in the DECOPDAC-21 arm,

and boost target definition in the COPDAC-28 arm.

3.3.2. Clinical target volume (CTV) for patients in TL1 patients and in patients in TL-2



and TL-3 treated with COPDAC-28

The CTV is an anatomical-clinical concept, which accounts for subclinical disease and

microscopic involvement at the time of diagnosis. Anatomical borders have to be respected

and the CTV adapted to the post-chemotherapy topography. As far as possible, displaced

normal tissue (e.g. lung, oesophagus, heart) should be excluded, particularly beside the lateral

mediastinal borders and heart (Fig 2).

All adjacent involved lymph nodes should be encompassed in a single CTV, which should

include the cranio-caudal extent of all involved nodes at diagnosis (defined as initially PET-

positive LN > 10mm as well as any initially PET-negative LN > 20mm) plus 5 mm in all

directions. Fig 4)

3.3.3. GTV and CTV for patients treated with DECOPDAC-21

The GTV includes all LRA-qPET-positive lesions > 10mm. Even where only parts of the LN

are PET-positive the whole LN must be included in the GTV.

The CTV is the GTV plus 5 mm in all directions (Fig 3).

3.3.4. Planning target volume (PTV)

The PTV is a geometrical concept to compensate for systematic and random variations, which

may occur during radiotherapy treatment planning and delivery. The CTV to PTV margin

represents the sum of the internal margin (IM) and setup margin (SM). The IM will vary

according to the site and shape of the CTV and the SM will be defined within each institution’s

protocol. The PTV margin should usually be within a range of 5 to 10 mm.

In young children, to avoid asymmetric growth resulting from irradiation of part of the

epiphyseal plate or the vertebrae, the PTV should include the whole bony structure.



Flow Diagram for treatment in TL-2 and TL-3

3.4. Involved site radiotherapy (ISRT)

3.4.1. CTV-ISRT for patients in TL1 and patients in TL-2 & TL-3 treated with COPDAC

All patients in TL1, TL-2 & TL-3 treated with COPDAC-28 who have an inadequate response

to OEPA at ERA will receive ISRT. This is analogous to what was termed modified IFRT

(mIFRT) in EuroNet PHL-C1, the HD-2002 pilot study, HD95 and HD90. The CTV includes the

initial cranio /caudal extension of all involved lymph nodes at diagnosis plus 5 mm in all

directions (Fig 1). This volume is defined on the treatment planning scan and should take

account of the post-chemotherapy topography as well as the uncertainties of changes in

position. The lateral margins include the post-chemotherapy lymph nodes plus 5 mm in all

directions, where anatomically relevant. For mediastinal LN involvement, the CTV should not

extend beyond the lateral mediastinal border, to minimize normal lung irradiation (Fig 2).



3.4.2. CTV-INRT for patients in TL-2 & TL-3 treated with DECOPDAC-21

Patients in the DECOPDAC-21 arm will only require RT if the LRA-qPET is positive. The GTV

will be any LRA-qPET-positive nodes > 10mm. The GTV includes the entire lymph node,

rather than just the PET-positive areas. The CTV is the GTV plus 5 mm in all directions (Fig

3).

3.4.3. CTV for Boost volume in patients who were treated with COPDAC-28

For patients in the COPDAC-28 arm, the need for a boost will depend on the LRA-qPET. Any

LRA-qPET-positive residual lymph node >10mm will require a boost. The GTVboost

encompasses the morphological volume of the LRA-qPET-positive lymph node. The CTV is

the GTV plus 5 mm in all directions (Fig 4).

3.4.4. CTV for E-lesions and disseminated organ involvement

In patients treated with COPDAC-28:

E-lesions will require RT, even if these are no longer visible on the LRA-qPET or the

RT planning scan, while disseminated organ involvement will require RT only if ERA-

qPET positive

The CTVE-lesion and the CTVorgan are described in detail in Tab 3 and 4.

In patients treated with DECOPDAC-21:

E-lesions and disseminated organ involvement that are visible as LRA-qPET-positive

morphological residual abnormalities will require RT.

The CTVE-lesion and the CTVorgan are described in detail in Tab 6 and 7..

Pleural or pericardial effusions will never be irradiated.

Whole lung irradiation (unilateral or bilateral) may only be necessary in case of > 1 ERA-qPET-

positive lesions in patients treated with COPDAC-28 or >1 LRA-qPET-positive lesions in

patients treated with DECOPDAC-21. Single lesions in either lung will be treated by local

radiotherapy to the lesion only. The CTV for a single lung lesion is defined by the residual

volume at LRA (for both arms) plus 5 mm in all directions (Tab. 4 and 7). If there is > 1 PET-

positive lesion in one lung, the whole unilateral lung will be treated; the other lung does not

need to be irradiated. If there are 2 or more ERA-qPET-positive lesions in both lungs

(COPDAC-28 patients) or 2 or more LRA-qPET-positive lesions in both lungs (DECOPDAC-

21 patients), bilateral whole lung irradiation is required.

If there is extranodal extension into the lung, this will be irradiated in COPDAC-28 patients

requiring nodal radiotherapy, while in the DECOPDAC-21 arm only LRA-qPET-positive lesions

will be irradiated. The CTV for this E-lesion is defined by the residual volume at LRA (both

arms) plus 5 mm in all directions (Tab.3 and 6).



4. ORGANS AT RISK (OAR) (FIGURE 6 A AND 6 B)

Radio-sensitivity of normal tissues varies with age. Radiation effects are more significant in

young children than in older children or adults [12, 26]. Soft tissue, bones, thyroid gland, lung,

spinal cord, heart, large vessels, breasts, kidney, liver and gonads are regarded as organs at

risk [2, 3, 11, 20, 21, 22, 25, 26]. Relevant organs at risk must be delineated on the treatment

planning scan.

Bony structures within and adjacent to the PTV should be delineated in young children. Dose

constraints for whole kidneys (12Gy), whole lung (15Gy), whole liver (15Gy) testis (<1Gy) and

ovary (<5Gy) must be taken into account and the dose to normal structures should be kept as

low as reasonably achievable.

4.1. OAR definition of the spinal cord, thyroid gland, liver and kidney

Outer contour should be defined on soft tissue window settings. Each organ is delineated as

one OAR. The left and the right kidneys are regarded as separate OAR. Regarding the spinal

cord, delineation according to the bony limits of the spinal canal is recommended [17].

4.2. OAR definition of the lung

The outer contour should be contoured using the soft tissue window and lung window settings.

The lung contours are limited to the air-inflated lung parenchyma. The proximal bronchial tree

should be excluded, and small sized vessels (<1 cm or vessels beyond the hilar region) should

be included. Right and left lungs are regarded as separate OAR [17].

4.3. OAR definition of mammary glands/breast

Visible breast glandular tissue should be defined on CT [standard soft tissue window level (40)

and width (300)]. Anteriorly, the breast is limited by the skin and posteriorly by the fascia of the

pectoral muscle. The cranial, caudal, medial and lateral borders are highly variable and depend

on patient position, breast shape and size and clinical reference need to be taken into account

[30].

Pre-pubertal gland: visible ducts or area behind mammary papilla plus 1cm

4.4. OAR definition of the heart

The soft tissue whole heart and pericardium will be delineated as one structure using standard

soft tissue window [(40) width and (300) level]. For simplicity, the whole heart is delineated as

a round structure including the great vessels, but excluding the superior, inferior cavae where

feasible (figure 1.6 a.+b). Superiorly the heart starts just inferior to the left pulmonary artery

(figure 1.6 a). The pericardium is regarded as the outer contour since the coronary arteries run

within the fatty tissue within the pericardium [7].



4.5. Gonads

If possible, ovaries should be delineated in the case of iliac or inguinal radiation, even if

ovariopexy or cryopreservation is planned prior to radiotherapy.

TLD measurements must be performed for boys in the case of inguinal irradiation.

5. ORGANISATION OF RADIOTHERAPY TREATMENT

For study patients undergoing central review, the radiation treatment proposal will be provided

by the central GPOH-study office in Giessen/Halle or in Vienna (for Austria), or as agreed with

the study coordinators (France). Treatment centres will receive the radiotherapy proposal with

dose prescription and pictogram on which all involved lymph nodes and/or E-lesions/organs

are delineated.

6. TIMING OF RADIOTHERAPY

TL1 patients requiring radiotherapy should start two weeks after ERA-qPET; delays of more

than four weeks must be avoided.

TL-2 and TL-3 patients will be randomised to either COPDAC-28 or DECOPDAC-21

chemotherapy. The definitive radiotherapy proposal will be established at the end of

chemotherapy, after the LRA-qPET (for DECOPDAC-21) and after the ERA-qPET (for

COPDAC-28, except for boost definition which will depend on LRA-qPET).

For all patients radiotherapy planning and delivery can be started immediately after the LRA-

qPET has been performed and the radiotherapy proposal (COPDAC-28: boost yes or no;

DECOPDAC-21: RT yes or no) is confirmed by the respective central review panel and the

patient recovered from chemotherapy. Radiotherapy should be started ideally within two

weeks after LRA-qPET; delays of more than four weeks must be avoided.

In case of both supra- and infra-diaphragmatic tumour involvements, radiotherapy may be

performed sequentially depending on the radiation volume (small supra- and infra-

diaphragmatic volumes can be irradiated at the same time). If the volumes are treated

separately, the gap between the first and second series should be as short as possible but not

longer than one week.

7. RADIOTHERAPY TREATMENT PLANNING AND DOSE PRESCRIPTION

All images from the time of diagnosis, ERA-qPET and LRA-qPET will be required prior to target

definition. Co-registration of diagnostic scans (at presentation, ERA-qPET, LRA-qPET) with

the treatment planning scan is recommended where ever possible. The treatment planning CT

scan should be performed with adequate immobilisation devices and if feasible, intravenous

contrast for optimal outlining of target volume and OAR. The recommended slice thickness is

2-5 mm. In patients requiring mediastinal irradiation, treatment planning and delivery should

be performed with deep-inspiration-breath-hold, gating or tracking if possible. This will help to

reduce the IM and hence doses to the OAR (heart, breast, thyroid and lung).

In case of inguinal LN irradiation in boys gonad shielding has to be performed.

Conventional simulation and virtual simulation are both acceptable.



An opposed field technique remains the acceptable convention. Modern treatment techniques

such as IMRT or arc therapy, including VMAT are permitted in individual circumstances. This

is left to the discretion of the treating radiation oncologist. However, given the larger volume

receiving low dose irradiation, these techniques should be critically evaluated as they may be

associated with more long term adverse effects [26]. Dose volume histograms have to be

analyzed with respect to PTV coverage and dose constraints for OAR. Following the

ICRU52/60 recommendations, dose variations between +7% and -5% for the PTV are

acceptable [14,15]. Dose constraints for whole kidneys (12Gy), whole lung (12-15Gy), whole

liver (15Gy), testis (<1Gy) and ovary (<5Gy) must be respected if possible.

8. RADIOTHERAPY DOSE

8.1. Radiotherapy dose

For patients in TL1 and TL-2 & TL-3 receiving COPDAC-28, the standard radiotherapy dose

consists of 19.8 Gy in 11 fractions (1.8 Gy per fraction). If required, the boost dose is 10 Gy

in 5 fractions (2 Gy per fraction).

For patients in TL-2 & TL-3 receiving DECOPDAC-21 who have a positive LRA-qPET, the

prescribed dose is 28.8 Gy in 16 fractions (1.8 Gy per fraction).

8.2. E-lesions and dissiminated organ involvement

In all patients treated with COPDAC-28, E-lesions should be treated with 19.8 Gy in 11

fractions, or for disseminated involvement of organs the appropriate tolerance dose to the

OAR.

In patients treated with DECOPDAC-21 positive E-lesions at LRA-qPET require 28.8 Gy in 16

fractions 1.8 Gy per fraction or for disseminated involvement of organs the appropriate

tolerance doses of the OAR.

8.3. Lung irradiation

Patients randomised to COPDAC-28

with only one ERA-qPET-positive lesion in each or either lung: local radiotherapy with

14.4 Gy to the morphologic residual visible at LRA. If the lesion is still LRA-qPET

positive, give a 5.4 Gy boost

with 2 or more ERA-qPET-positive lesions

o in one lung only – unilateral whole lung irradiation 14.4 Gy; do not irradiate other

lung.

o in both lungs – bilateral whole lung irradiation 12 Gy to both lungs.

If one e.g left lung has a single ERA-qPET-positive lesion, give local radiotherapy to

lesion as detailed above i.e. 14.4 Gy +/- 5.4 Gy boost if still LRA-qPET positive.

And if in addition the other e.g. right lung has two or more ERA-qPET-positive lesions,

give whole lung irradiation 12 Gy to this lung.



Patients randomised to DECOPDAC-21

with only one LRA-qPET-positive lesion in either or each lung; local radiotherapy to

lesion with 19.8 Gy.

with 2 or more LRA-qPET-positive lesions

o in one lung only – unilateral whole lung irradiation 14.4 Gy; do not irradiate other

lung.

o in both lungs – bilateral whole lung irradiation 12 Gy to both lungs.

If one e.g. left lung has a single LRA-qPET-positive lesion, give local radiotherapy to

lesion with 19.8 Gy.

And if in addition the other e.g. right lung has two or more LRA-qPET-positive lesions,

give unilateral whole lung irradiation 12 Gy to this lung.

For whole lung irradiation the fraction size should not exceed 1.2 Gy.

All E-lesions should be treated at the same time as the ISRT/INRT fields.

8.4. Liver irradiation

Patients randomised to COPDAC-28

With only one ERA-qPET-positive lesion: which is LRA-pET negative

o Local radiotherapy with 14.4. Gy in 8 fractions

With only one ERA-qPET-positive lesion: which is LRA-pET positive

o Local radiotherapy with 19.8 Gy in 11 fractions

Patients randomized to DECOPDAC-21

With only one LRA-qPET positive lesion

o Local radiotherapy with 19.8 Gy in 11 fractions

For all patients with more than one ERA-qPET-positive lesion (COPDAC-28) or more than one

LRA-qPET positive lesion (DECOPDAC-21) please contact the study centre in Gießen or

Vienna for individual treatment recommendation.

9. RADIOTHERAPY DELIVERY

Radiotherapy should be given daily (five days per week). Rests must be kept to a minimum

and interruptions due to machine service or holidays should be avoided unless absolutely

necessary. Treatment verification should be assessed at the first treatment and then weekly

during treatment with the use of EPID or CBCT or ExacTrac. The dose for CBCT should be as

low as possible and the volume adapted according to the extent of the radiation field.

10. TECHNICAL REQUIREMENTS

Radiotherapy should be delivered with high energy photons. Alternatively, in selected cases

radiotherapy can be delivered with protons if this is accepted standard of care by the relevant

national regulatory authorities. The choice of treatment technique is left to the discretion of the

treating radiation oncologist.



For quality control purposes, indication of proton radiotherapy in an individual patient should

be discussed in advance with Prof. Dr. Engenhart-Cabillic or Prof Dr. Wittig.

The following equipment is required:

Computed tomography for treatment planning

3D Treatment Planning System integrating 3D sectional imaging, DVH

Linear accelerators with photon energies of 4 - 6 (- 10) MV, or cyclotron or synchrotron

for radiotherapy with protons

Multileaf collimators and/or conformal blocks for individual shielding, in case of proton

radiotherapy passive scattering or active scanning beams delivery with apertures

and/or compensators, as appropriate, to shape the fields laterally and distally

LINAC on-board verification system (EPIDs, CBCT, ExacTrac system) or equivalent

verification system for use in proton radiotherapy

Positioning equipment as mask systems and vacuum cushions.

Radiotherapy with protons:

If proton radiotherapy is used, target coverage should be equivalent compared to state-of-the-

art photon techniques. Technical facility-specific requirements to safely and reproducibly

deliver the prescribed radiation dose must be ensured.

Proton therapy may be delivered using passively scattered protons or scanning beam

technology (preferred). Selected proton energies must be high enough to adequately provide

target coverage. Range shifters may be used to make fine adjustment to the maximum proton

range. Both passive scattering and scanning beams may employ apertures and/or

compensators, as appropriate, to shape the fields laterally and distally.

The biological effectiveness of protons must be considered. Proton dose will be prescribed and

reported in Gy (relative biological effectiveness, RBE), where 1 Gy (RBE) = proton dose Gy x

RBE, RBE = 1.1. Apart from consideration of the RBE, the prescribed total absorbed dose as

well as fraction dose, number of fractions, timing of radiotherapy and total treatment time do

not differ from radiotherapy with photons. Protocol specific dose constraints to organs at risk

apply without modifications.

The radiation dose is prescribed using the protocol specific definitions for GTV, CTV and PTV

as described above (chapter 3.3) without modifications as compared to photon radiotherapy.

For technical reasons, a margin can be assigned depending on the penumbra specific to the

proton beam being used. Proton beam penumbra is a function of the proton energy and the

distance between aperture and patient’s anatomy. It may therefore vary from one clinical

situation to another and also vary depending on the facility-specific technical equipment.

Motion assessment must be done in all patients to determine if and which motion management

technique (i.e. breath hold, gating, active breathing control (ABC-device)) is required for robust

planning and beam delivery and to determine the appropriate type of CT (3D or 4D). The CT

field of view must be large enough to ensure that none of the patient’s anatomy along the path

of the treatment beams is cut off. A CT scanner unit calibrated for proton treatments with the

appropriate proton relative linear stopping power (RLSP) vs. HU conversion function must be

used. Positioning of patients allowing for accurate and reproducible position of the target



volume relative to the beam is of special importance and will be done using customized

immobilization devices. Verification of reproducible and accurate positioning of the target

volume as well as the patient´s anatomy is required frequently and is encouraged prior each

fraction. The imaging dose should be kept as low as reasonably achievable.

Single / multiple field optimization or intensity modulated proton therapy (IMPT) may be used.

Robust planning is necessary, distal range uncertainty should be evaluated for each beam.

11. SIDE EFFECTS OF RADIOTHERAPY

11.1. Acute side effects

Acute side effects including nausea, mucositis, erythema, hair loss, dry mouth, diarrhoea,

leucocytopenia, and thrombocyctopenia during radiotherapy with doses of less than 20 Gy are

rare and mostly temporary. The nature and severity of side effects will also depend on the site

irradiated, field size, and the chemotherapy received. Most acute side effects can be treated

symptomatically and are self-limiting.

11.2. Long term side effects

Radiosensitivity of normal tissues varies with age. Radiation effects are more pronounced in

young age (0-6 years) and pre-pubertal children compared to young adults, but most children

with Hodgkin lymphoma are over 6 years. Late effects reflect the location and field size and

dose of radiotherapy as well as the type of chemotherapy received, e.g. doxorubicin [12, 28].

Radiation-induced changes in organs and tissues may develop after long latency periods and

may not become clinically evident until puberty or adulthood. Secondary malignancies (e.g.

increased risk of breast and thyroid cancer) may increase after 20 to 30 years [2, 20], and

these, together with cardiac late effects, remain a major cause of mortality in long-term

survivors [21].

The collection on data of long-term side effects will continue in the RISK Study or in the relevant

different national data bases.

12. QUALITY ASSESSMENT

Quality control is an essential component of radiotherapy planning and treatment [1, 8]. In the

EuroNet-PHL-C2 Study, the data from all patients having radiotherapy will be reviewed and

analysed centrally in Halle, Vienna, Cardiff and Lyon. Therefore, CT 3-D treatment plans with

structure sets (defined GTV, CTV, PTV and OAR) and isodose distributions plus DVHs will be

transferred from the local radiotherapy centre directly onto the Hermes server in Sweden or is

sent on a CD to the central study centre in Giessen or Vienna (for Austria), where it will be

transferred to the central Server in Sweden, Portal images should also be submitted. This

process should occur as soon as radiotherapy is completed, but not longer than four weeks

after the end of radiotherapy. Data from all patients will be evaluated by the reference radio-

oncologists in Halle, Vienna, Cardiff and Lyon. All study centres of EuroNet-PHL will receive

feedback on the most important protocol deviations and recommendations to avoid these, via

six-monthly reports from the RT quality control teams. The responsibility for the reports lies



with Prof. Karin Dieckmann, Chairperson of the EuroNet-PHL-RT subcommittee. Based on 3D

or 4D CT data set uploaded to the Hermes server for patients receiving proton radiotherapy a

comparative spatial dose-distribution with photons will be retrospectively calculated including

DVHs by the radiotherapy reference centres of Vienna (Prof. Dr. Dieckmann) and Giessen

(Prof. Dr. Engenhart-Cabillic and Prof. Dr. Wittig).



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14. TABLES

Target definition COPDAC-28 and DECOPDAC-21

These tables give an overview of PET-CTs used for target definitions in the two study arms

according to stage of disease, treatment level and chemotherapy target definition is described

separately.

Table 1: Target Definition for lymph nodes / COPDAC-28 Arm

GTV CTV PTV

Initial staging PET/CT

Initially PET-positive LN >10mm plus initially PET-negative LN > 20mm primary cranio/caudal tumour extension plus 5 mm in all directions, respecting anatomical boundaries at the end of chemotherapy

CTV plus 5-10 mm

Table 2: Target Definition Boost COPDAC-28 Arm

GTV CTV PTV


ERA (PET/CT)

LRA (PET/CT)

qPET pos. enlarged LN >10mm

GTV plus 5mm CTV plus 5-10 mm

Table 3: Target Definition for E-lesion COPDAC-28 Arm

Target definition based on

GTV CTV PTV


Chest wall: primary tumour extension plus 5 mm Bone (E-Lesion) Long bones, pelvis or ribs: primary tumour extension plus 5 mm Vertebra: Whole vertebra

CTV plus 5 mm

LRA (PET/CT)

Lung (E-lesion) Morphological lung residual at LRA plus 5mm Liver (E-lesion) Morphological lung residual at LRA plus 5mm

CTV plus individual margin



Table 4: Target definition for organ involvement (i.e. stage IV) COPDAC-28 Arm


GTV CTV

PTV

ERA (PET/CT)

Bone (i.e. stage IV) Long bone - PET-positive areas at ERA plus 20-30mm (avoid irradiating epiphysis if possible) Ribs - PET-positive area at ERA plus 10-20mm Vertebra - PET-positive whole vertebra Pelvis – PET-positive at ERA plus 10-20mm

CTV plus 5 mm

LRA (PET/CT)

Lung (i.e. stage IV)* If only one ERA-qPET-positive lesion in each or either lung: Morphological lung residual at LRA plus 5mm Liver (i.e. stage IV)** If only one ERA-qPET-positive lesion: Morphological liver residual at LRA plus 5mm


*For >1 ERA-qPET positive lesion per lung. Whole lung irradiation of the involved lung,

** In the rare case of more than one liver lesion, please contact study centre for advice

Table 5: Target Definition for lymph nodes DECOPDAC-21 Arm


GTV CTV PTV

LRA-qPET PET pos LN > 10mm GTV+5 mm in all directions CTV + 5-10mm depending on site, CTV shape, motion

In case of partial lymph node PET positivity, the whole lymph node has to be included into the GTV. If

more than one lymph node in one region is positive, they have to be included into one target.



Table 6: Target Definition for LRA-PET-positive E-lesion DECOPDAC-21 Arm


GTV CTV PTV

Initial staging (PET/CT)

Chest wall: primary tumour extension plus 5 mm Bone (E-Lesion) Long bones, pelvis or ribs: primary tumour extension plus 5 mm Vertebra: Whole vertebra

CTV plus 5 mm

LRA (PET/CT)

Lung (E-lesion) Morphological lung residual at LRA plus 5mm Liver (E-lesion) Morphological lung residual at LRA plus 5mm


Table 7: Target Definition for LRA-PET-positive organ involvement (i.e. stage IV) DECOPDAC-21 Arm


GTV CTV PTV

Initial staging (PET/CT)

Chest wall: primary tumour extension plus 5 mm

CTV plus 5 mm

LRA-qPET

Lung (i.e. stage IV)* If only one LRA-qPET-positive lesion in each or either lung: Morphological lung residual at LRA plus 5mm Bone (i.e. stage IV) Long bone - PET-positive areas at LRA plus 20-30mm (avoid irradiating epiphysis if possible) Ribs - PET-positive area at LRA plus 10-20mm Vertebra - PET-positive whole vertebra Pelvis – PET-positive at LRA plus 10-20mm Liver (i.e. stage IV)** If only one LRA-qPET-positive lesion PET-positive lesion at LRA plus 5 mm

CTV plus individual margin CTV plus 5 mm CTV plus individual margin

*For >1 LRA-qPET positive lesion per lung. Whole lung irradiation of the involved lung

** In the rare case of more than one liver lesion, please contact study centre for advice



Table 8: Dose prescription in TL-1 and TL-2 or TL-3 treated with COPDAC-28

Patient cohort Treatment site and phase Dose prescription

TL-1 patients

ERA PET positive Treat all initially involved nodal sites. 19.8Gy in 11 fractions

TL-2,TL-3 - COPDAC patients

ERA PET positive

LRA-PET negative – no boost required

Treat all initially involved nodal and all extra-nodal sites.

19.8Gy in 11 fractions

ERA PET positive

LRA-PET positive node > 10mm - boost required

Phase 1:Treat all initially involved nodal and all extra-nodal sites.

Phase 1: 19.8Gy in 11 fractions

Phase 2:Treat only the LRA PET-positive involved node

Phase 2: 10Gy in 5 fractions

COPDAC patients - lung irradiation if required – to be treated at the same time as ISRT/INRT fields

1 ERA PET positive lesion in one or both lungs which is still visible at time of LRA PET but which is LRA PET negative.

Treat only the residual lesion visible at time of LRA in one or both lungs; if no residual, do not irradiate.

14.4Gy , SD 1.8Gy; 8 fractions

1 ERA PET positive lesion in one or both lungs which remains LRA PET positive

Treat only the LRA PET-positive lesion in one or both lungs.

19.8Gy ; SD 1.8 Gy; 11 fractions

> 1 ERA PET positive lesion in one lung even if no longer visible on LRA.

Unilateral whole lung irradiation. 14.4Gy; SD 1.2Gy; 12 fractions

>1 ERA PET positive lesion in both lungs even if no longer visible on LRA.

Bilateral whole lung irradiation. 12Gy; SD 1.2Gy; 10 fractions




One lung with a single ERA-qPET-positive lesion, Local radiotherapy to lesion if visible at LRA with 14.4Gy if LRA-PET negative , and a 5.4Gy boost if still LRA-qPET positive.

14,4Gy; SD 1.8Gy; 8 fractions

+/- Boost 5.4Gy; SD 1.8; 3 fractions

And

>1 LRA PET positive lesion in the other lung Treat the whole lung side with more than one LRA-PET-positive lesions with 12Gy(!) Note Do not give 15Gy

Whole lung irradiation of the other lung with 12Gy SD; 1.2Gy; 10 fractions

Liver (i.e. stage IV); if only one ERA-qPET-positive lesion: which is LRA-pET negative

Treat only the residual lesion visible at time of LRA in liver; if no residual, do not irradiate.

14.4Gy , SD 1.8Gy; 8 fractions

Liver (i.e. stage IV); if only one ERA-qPET-positive lesion: which is LRA-pET positive

Treat only the LRA PET-positive lesion in liver 19.8Gy ; SD 1.8Gy; 11 fractions



Table 9: Dose prescription in TL-2 or TL-3 treated with DECOPDAC-21


LRA PET positive node > 10mm or extra-nodal site Treat only the LRA PET positive involved node > 10mm or extra-nodal site

28.8Gy; SD 1.8Gy; 16 fractions

DECOPDAC patients - lung irradiation if required – to be treated at the same time as ISRT/INRT fields:

1 LRA PET positive lesion in 1 lung or both lungs Treat only the LRA PET-positive lesion in 1 lung or both lungs.

19.8Gy; SD 1.8Gy; 11 fractions

>1 LRA PET positive lesion in one lung

Unilateral whole lung irradiation 14.4Gy; SD 1.2Gy; 12 fractions

>1 LRA PET positive lesion in both lungs Bilateral whole lung irradiation 12Gy; SD 1.2Gy;10 fractions

1 LRA PET positive lesion in 1 lung Treat the single lesion in one lung locally with 19.8 Gy

Local RT in one lung with 19.8Gy; SD 1.8Gy; 11 fractions

And

>1 LRA PET positive lesion in the other lung Treat the whole lung side with more than one LRA-PET-positive lesions with 12Gy(!) Note Do not give 15Gy

Whole lung irradiation of the other lung with 12Gy; SD 1,2Gy;10 fractions

DECOPDAC patients - liver irradiation if required – to be treated at the same time as ISRT/INRT fields

If only one LRA-qPET-positive lesion PET-positive liver lesion

Treat the single lesion with 19.8 Gy 19,8,Gy; SD 1,8Gy; 11 fractions



15. FIGURES

Figure 1: CTV-ISRT in patients with COPDAC-28 (TL-1, TL-2 and TL-3)

Axial and coronal view initial PET/CT and treatment planning. The cranio/caudal target

definition is based on the tumour extension at time of diagnosis. The lateral borders include

the lymph node extension at time of diagnosis plus 5 mm respecting the anatomical boundaries

after chemotherapy.



Figure 2: Bulky disease in the mediastinum before and after chemotherapy with COPDAC-28

In the mediastinum the CTV is adapted to the mediastinal borders.



Figure 3: CTV-INRT in patients with DECOPDAC-21 (TL-2 and TL-3) Axial and coronal view initial PET/CT and LRA-qPET. Target definition is based on LRA-

qPET. The GTV includes the PET pos. LN >10mm. The CTV (blue dotted line) includes the

GTV plus 5mm margin in all directions.



Figure 4: CTV-ISRT / COPDAC-28 treatment arm and Boost volume in patients with COPDAC-28 (TL-2 and TL-3) based on initial PET/CT and LRA-qPET Axial and coronal view of the initial PET/CT and LRA-qPET. The blue line demonstrates the

CTV based on primary tumour extension. The red line demonstrates the boost target based

on LRA-qPET.



Figure 5: CTV-ISRT and E-lesions in patients with COPDAC-28 (TL-2 and TL-3) based on ERA-qPET.

Axial view of the initial PET/CT and ERA-qPET. The CTV includes the primary tumour

extension (E-lesion of the chest wall) plus the precardiaclymph nodes after chemotherapy.



Figure 6: Organs at Risk (OAR)

Target delineation of lungs (green), breast (blue), heart (red), and liver (yellow). For details

please see chapter 4.



LIST OF ABBREVIATIONS:

CBCT Cone Beam Computer tomography

CD Compact Disc

CTV Clinical Target Volume

CTV-INRT Clinical target volume –Involved Node Radiotherapy

CTV-ISRT Clinical target volume- Involved Side Radiotherapy

CD Compact Disc

DVH Dose Volume Histogram

EPID Electronic Portal Imaging Device

ERA Early Response Assessment

ERA-qPET Early Response Assessment quantitative PET

GTV Gross Tumor Volume

Gy Gray

ICRU 50/62 International Commission of Radiation units

IM Internal Margin

INRT Involved Node Radiotherapy

LINAC Linear Accelerator

LN Lymph node

LRA Late Response Assessment

LRA-qPET Late Response Assessment quantitative PET

mIFRT modified involved field Radiotherapy

OAR Organ At Risk

PTV Planning Target Volume

SM Setup Margin

TL Treatment Level

Documents

Radiotherapy Manual...2017/05/15 · Radiotherapy Manual Confidential EuroNet-PHL-C2 final 4.0 2017-05-15 Page 6 of 32 as demonstrated on the staging PET-CT scans at the time of diagnosis