Journal of the Egyptian National Cancer Institute (2016) 28, 163–168

Cairo University

Journal of the Egyptian National Cancer Institute

www.elsevier.com/locate/jnciwww.sciencedirect.com

Full Length Article

Volumetric-modulated arc therapy (VMAT) versus

3D-conformal radiation therapy in supra-

diaphragmatic Hodgkin’s Lymphoma with

mediastinal involvement: A dosimetric comparison

* Corresponding author at: Radiation Oncology & Nuclear Medicine Department, National Cancer Institute (NCI), Cairo University, 1

Al Aini Street, Misr Al Qadimah, Cairo 11796, Egypt. Tel: +20 1006679991/+20 2 23684423; fax: +20 2 23644720/+20 2 23684423.

E-mail addresses: higbycopeland@yahoo.com (C. Higby), ykhafaga@hotmail.com (Y. Khafaga), shabanah@kfshrc.edu.sa (M. Al-Sha

amrgabermousa@yahoo.com (A. Mousa), gnazer@kfshrc.edu.sa (G. Nazer), ehab.khalil@nci.cu.edu.eg, emkhalil2003@yahoo.com

Khalil).1 Oklahoma Cancer Center, Department of Radiation Oncology, Oklahoma City, Oklahoma, USA. Tel.: +1 405 919 8055.2 Tel.: +966 114424969 (Secretary), +966 115570434 (O), +966 506668124 (Mobile).3 Tel.: +966 114424969 (Secretary), +966 115570434 (O), +966 500645962 (Mobile).4 Tel.: +966 114424969 (Secretary), +966 115570434 (O), +966 505353430 (Mobile).

Peer review under responsibility of The National Cancer Institute, Cairo University.

http://dx.doi.org/10.1016/j.jnci.2016.04.0071110-0362 � 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Christine Higby b,1, Yasser Khafaga a,d,2, Mohammad Al-Shabanah a,2,

Amr Mousaa,d,3

, Mohamed Ilyasc,3, Ghadeer Nazer

b,4, Ehab M. Khalil

a,d,*

aSection of Radiation Oncology, Oncology Center, King Faisal Specialist Hospital & Research Centre, Riyadh, KSAbBiomedical Physics Department, Oncology Center, King Faisal Specialist Hospital & Research Centre, Riyadh, KSAcSection of Medical Oncology, Oncology Center, King Faisal Specialist Hospital & Research Centre, Riyadh, KSAdRadiation Oncology and Nuclear Medicine Department, National Cancer Institute (NCI), Cairo University, Cairo, Egypt

Received 8 March 2016; revised 28 April 2016; accepted 29 April 2016Available online 27 May 2016

KEYWORDS

VMAT;

3D CRT;

Mediastinum;

HL;

Dosimetry

Abstract Purpose: To compare volumetric-modulated arc therapy (VMAT) with 3D-conformal

radiation therapy (3D-CRT) mediastinal irradiation for stage I–II supra-diaphragmatic Hodgkin’s

Lymphoma (HL).

Patients and methods: Eleven patients were planned for RT after 4–6 cycles of ABVD chemother-

apy: conventional 3D-CRT (AP/PA) and VMAT plans were conformed to the same PTV. Objective

was to choose the best PTV coverage plan with the least OAR dose. The 2 plans were compared for:

PTV coverage, mean dose and V5,V20lung, mean dose and V30heart, V5, V10, V15breast (female

patients), and the integral body dose.

Results: Both techniques achieved adequate PTV coverage. Mean lung and heart dose was consis-

tently lower in VMAT plans. The lung V20 dose was acceptable for VMAT, but exceeded the tol-

erance threshold in 6 cases with 3DCRT plans. A mean difference of 15.9% for both lungs V20

favored VMAT plans; average MLD difference was 2.3 Gy less for VMAT plans. Similarly, lower

maximum and mean heart doses with a 3.3 Gy dose reduction and a 9.4% difference in V30 favored

Al Kasr

banah),

(E.M.

164 C. Higby et al.

VMAT plans. Mean V5lung/female breast and integral dose were invariably higher in VMAT plans

because of the low-dose spread.

Conclusions: VMAT is a valuable technique for treatment of large mediastinal HL. VMAT spares

the lung and heart compared to 3DCRT using ISRT in select HL cases. VMAT allows dose esca-

lation for post-chemotherapy residual disease with minimal dose to OARs. VMAT low radiation

dose (V5) to the normal tissues, and the increased integral dose should be considered.

� 2016 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an

open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Radiation therapy (RT) is the most effective single modality

for local control in Hodgkin’s Lymphoma (HL), and is com-monly used as a component of combined modality therapy(CMT) in many patients. Guidelines have been developed to

address the use of RT in the modern era of CMT, moving fromextended field (EF) to involved-field RT (IFRT), and morerecently to involved-site RT (ISRT), using 3D-CRT planning

and other advanced techniques such as intensity modulatedRT (IMRT), Rapidarc (RA), and optimized volumetric mod-ulated arc therapy (VMAT) for treatment delivery [1–3]. 3D-CRT generated AP/PA field plan, with field-in-field compensa-

tion for dose homogeneity still remains the standard tech-niques in many patients. There are situations where complexanatomy and tumor location make IMRT and VMAT supe-

rior to conventional 3D-CRT techniques [4,5].In this study, the intention was to explore the use of VMAT

in stage I–II patients with supra-diaphragmatic disease, partic-

ularly those presenting with large mediastinal disease volume,with or without neck/axillary involvement, where the OARdose constraints cannot be met using the conventional 3D-

CRT.

Patients and methods

The whole cohort included 11 patients with mediastinal HLwith or without involvement of the neck/axilla. There were 4females and 7 males. Three patients presented with mediastinaldisease only, and 8 with mediastinal, neck and/or axillary

involvement. Planning CT scan was acquired for the neckand chest in contiguous 3 mm thickness slices on a Philipslarge-bore CT simulator (Brilliance big bore V2.3.017184).

Patients were scanned in the supine position with the headand shoulders immobilized in a thermoplastic shell. 4-D CTsets were acquired in free breathing, deep inspiration and

expiration.Contouring the target volumes (GTV, CTV, ITV and PTV)

were done based on the pre- and post-chemotherapy PET-CT

imaging according to the International Lymphoma RadiationOncology Group (ILROG) recommendations and guidelinesfor involved-site irradiation (ISRT) [4]. Residual mediastinalmass were localized as the post-chemo GTV. CTV included

the pre chemo GTV superior and inferior disease extension,and edited for masses that initially encroached laterally onthe lungs, but regressed on chemotherapy. Internal target vol-

ume (ITV) was created on the free breathing CT, using theinformation acquired from expiration and deep inspirationCT scans, to account for respiratory movements. PTV was

then created by 1 cm margin isotropic expansion of the ITV,

except for the neck nodal area where a 0.5 cm margin was usedfor the CTV. The organs at risk were delineated (OARs: lungs,

heart, thyroid, salivary glands and spinal cord).Patients included in this study had pathologically proven

HL stage IB-IIBX. All patients were treated using combined

modality treatment; 4 and 7 patients were treated by 4 and 6cycles of ABVD (adriamycin, bleomycin, vinblastine, anddacarbazine) chemotherapy regimen respectively. Nine andtwo patients achieved complete (CR) and partial remission

(PR) respectively evidenced by PET-CT scans. Thereafter allpatients were treated by Involved Field RT (30.6 Gy/20Fx/3.5 weeks for CR patients and 36 Gy/20 Fx/4 weeks for

PR ones).VMAT plans were optimized using a complete 360 degree

arc or hemi-arcs or non-coplanar small arcs. The VMAT plans

were inversely planned using Pinnacle. Conventional RTopposed AP/PA plans were generated using 3D-CRT, fash-ioned to the same PTV in different clinical scenarios cases.The primary objective was to identify for each case the tech-

nique which provides an adequate PTV coverage with the leastdose to the OARs.

For all patients, the resulting plans were normalized to a

prescribed dose of 30.6 Gy in 1.8 Gy fractions with 95% ofthe dose to 100% of the PTV. Two patients hadpost-chemotherapy metabolic residual disease and received

additional 6 Gy boost to the site of residual disease.Dose-volume histograms (DVH) were used for evaluationand estimation of OAR doses. Comparison was made between

3D-CRT and VMAT for PTV coverage, V5, V20 and meanlung dose, as well as V30 heart, mean and maximum doses,and the integral dose. In addition V5, 10, 15 and mean doseto the breasts were estimated for female patients. Dose con-

straints to the heart, lungs and other OARs were definedaccording to the QUANTEC organ-specific dose/volume/out-come data, based on the QUANTEC reviews guidelines [6].

Results

Dose-volume parameters and mean dose value statistics for

3D-CRT and VMAT plans for the complete cohort of 11patients treated to the prescribed dose are displayed in Table 1.

The dose prescription was normalized to 30.6 Gy in all

cases except for two patients who had pot-chemotherapy resid-ual active disease, where the dose was prescribed to 30.6 Gywith an additional 5.4 Gy boost to area of residual disease

(total dose 36 Gy).Homogeneous dose coverage of PTV was achieved in both

3D-CRT and VMAT plans, with 100% of PTV covered by atleast 95% of the dose (Fig. 1). Only in one case who presented

with bulky mediastinal disease, sub-pectoral and axillary

VMAT versus 3D-CRT in Hodgkin’s Lymphoma 165

nodes, PTV coverage lower than the 95% dose normallyachieved was accepted because of the PTV-lungs overlap,and the 95% coverage plan would have exceeded the lung

metrics.The mean dose for lungs and heart was lower in VMAT

plans (Table 1). The V20 and mean dose to lungs were within

the acceptable range for VMAT, but exceeded the normalacceptable levels for the 3D-CRT plans in 6 cases with bulkymediastinal disease and/or sub-pectoral/axillary involvement.

For the whole cohort of patients, a mean difference of

Table 1 Dose-volume estimates and plan evaluation statistics for 3

Parameter 3D-CRT (mean) VMAT (mean)

Both lungs V20 35.4% 20.8%

V5 52.6% 67.8%

Mean 13 11.9

Right lung V20 36.7% 16.1%

V5 54.8% 68.7%

Mean 13.6 Gy 11.2 Gy

Left lung V20 38.5% 23.5%

V5 56.8 67%

Mean 14.3 Gy 12 Gy

Heart Max 33.1 Gy 31 Gy

Mean 15.8 Gy 12.8 Gy

V30 24.7% 17.7%

Body V5 23.3% 32.7%

V10 20.6% 20.5%

Right breast V5 4.6% 32.4%

V10 1.3% 11.2%

V15 0.5% 2.5%

Left breast V5 5.3% 39.5%

V10 4.5% 17.7%

V15 0% 4.8%

Figure 1 Same coverage using both 3D-CRT (a) and

15.9% was noticed for V20 of both lungs in favor of VMAT.The mean dose to both lungs was 2.3 Gy less for VMAT plans.Similarly, maximum and mean doses to the heart were much

lower with VMAT; there was an average reduction of 3.3 Gyof the mean heart dose and a 9.4% difference in V30 in favorof VMAT plans. An illustrative DVH comparison for a female

patient is shown in Fig. 2. The mean V5breast and lung for thewhole cohort of patients was lower in the conventional plan,because of the low-dose spread with VMAT (Fig. 3). Also,

the integral dose was invariably higher in the VMAT plans.

D-CRT and VMAT plans.

Difference

Max diff Minim diff Mean diff Median diff

29.2% 8% 15.9% 14.5%

25.3% 0% 13% 12%

3.8 Gy �0.8 Gy 1.8 Gy 2.8 Gy

51.2% 2.7% 20.6% 16.4%

45.5% �14% 14% 12.2%

11.8 Gy �4.3 Gy 2.3 Gy 2.7 Gy

31% 1.4% 15% 13.9%

32.3% �1.4% 10.2% 6.6%

6 Gy �1.9 Gy 2.2 Gy 2.75 Gy

8.4 Gy �1.4 Gy 2.8 Gy 1.5 Gy

6.9 Gy 0.1 Gy 3.3 Gy 3 Gy

26% 0.5% 9.4% 5.3%

20.7% 1.4% 9.4% 10.3%

7.7% �7.1% 0% �0.5%

51.4% 12.5% 27.8% 19.4%

18.8% �1.1% 9.8% 11.8%

6.6% �0.8% 1.9% 0

61% 7.4% 34.1% 34%

31.3% 0% 13.2% 8.2%

14.3% 0% 4.8 Gy 0%

VMAT (b) in a female patient with HL stage IIA.

166 C. Higby et al.

For the four female patients included in this cohort; the V5,10, 15 to the breasts were compared in both techniques with ahigher dose for VMAT, particularly for patients in whom the

disease involved the hilar and/or subcarinal region (Fig. 3).Hilar involvement and bulky disease at the mid-and lower

Figure 2 Dose volume histogram (DVH) and OARs for 3

Figure 3 Comparison between low dose spill for 3D-CRT (left) vs. V

for 3D-CRT vs. VMAT plans. (c) and (d) color wash of low dose lun

levels of mediastinum were however associated with unaccept-able high doses to the lungs with 3D-CRT plans. For patientswith non-bulky superior anterior mediastinal disease, the low-

dose volume for lungs and both breasts was much lower for theconventional plan as compared to VMAT (Fig. 3).

D-CRT and VMAT for a female patient with HL IIb.

MAT (right) plans. (a) and (b) color wash of breasts low dose spill

gs (V5) for in 3D-CRT vs. VMAT plans.

VMAT versus 3D-CRT in Hodgkin’s Lymphoma 167

In the four cases who presented with upper cervical disease,there was a better sparing of the parotid and thyroid with theVMAT as compared with 3D-CRT. The two patients with

post-chemotherapy residual active disease, the total RT dosewas escalated to 36 Gy, and it showed that the 3DCRT wasassociated with much higher V20 and mean dose to the lungs

and heart when compared to VMAT.

Discussion

Radiation therapy is an integral component of combinedmodality treatment (CMT) in HL. The RT delivery hasevolved over time, in an effort to reduce acute and long-term

toxicities while maintaining the excellent cure rate. Most ofHL cases can be managed with 3-DCRT using conventional3D-CRT (AP/PA) techniques. This is particularly true in pedi-

atric and adolescent cases where the prescribed RT dose is inthe low range of 20–25 Gy. In adult HL however, RT standarddoses range between 30 and 36 Gy, except for a small subset ofpatients with early-stage favorable HL where a lower dose of

20 Gy is used [1,7].The conventional dose constraints used in treatment plan-

ning for most solid tumors do not appear to apply for lym-

phomas, since the relatively low RT doses needed in HL willresult in most treatment plans being within the acceptable lim-its. However these may not constitute the optimal plan in

terms of keeping RT dose to the normal structures to a mini-mum, in order to minimize the long-term toxicity. The RT fieldsize was reduced over the last decades from extended field(EFRT) to involved-field (IFRT), and involved-nodal radia-

tion (INRT), in an attempt to decrease the potential RT-related toxicities. Based on clinical trials there is a generalagreement to replace EFRT with IFRT in the modern era of

CMT without compromising the outcome [8–10]. Recently,the International Lymphoma Radiation Oncology Group(ILROG) has developed guidelines for involved-field site

(ISRT), since INRT may not be applicable in most clinical sce-narios [4]. Nevertheless, there is still a wide variability betweenthe different centers as to the extent of RT field applied in the

current clinical practice (INRT, IFRT, or ISRT). Moreover,there is no agreement on the interpretation and implementa-tion of ISRT, not only among different centers, but alsoamong the most expert radiation oncologists, as has been

shown in a recent ILROG study [11]. The choice of RT deliv-ery technique depends on a number of factors: PTV coverage,dose to OARs, tumor volume, shape and location in relation

to the individual anatomy, as well as patient gender and age(children, young females with mediastinal and axillary dis-ease). Different clinical scenarios dictate the dose-priorities

with respect to the OARs (co-existing morbid conditions: lungdisease, bleomycin toxicity, heart disease). Finally, the choiceof RT treatment technique largely depends on the treatingradiation oncologist’s expertise and the center’s experience.

A recent ILROG study showed that for the same set of caseclinical scenarios, the treatment technique and planning meth-ods widely varied across the ILROG centers, techniques being

chosen according to the center’s best practice [12]. These vari-ations must be undoubtedly even greater among centers acrossthe world.

In mediastinal disease close to the heart, the prescribed RTdoses may not be achievable with 3D-CRT without potential

significant lung and heart toxicity. This is particularly true incases presenting with bulky mediastinal disease and chest wallor pericardial invasion. In these clinical situations, the conven-

tional 3D-CRT plan cannot deliver the required dose to thePTV while meeting the OAR constraints because of the targetanatomy overlapping with OARs. The use of more complex

techniques such as optimized VMAT or IMRT allows dose‘‘tailoring” and offers better sparing of the critical structures.The trade-off with VMAT is that a larger volume of normal

tissues being exposed to low-dose RT [2,12,13]. This increasedlow dose RT volume raises a major concern for a potentialincreased risk of developing second malignant tumor (SMT),especially breast cancer (BC) and thyroid cancer in female sur-

vivors [14–17]. In a recent study, optimized VMAT using nonco-planar arcs reduced the heart disease risk, as compared to3D-CRT, with comparable estimated risks of thyroid and

breast cancer, but with an increase in lung cancer inductionprobability [13]. The odds ratio for BC increases linearly withRT dose and decreases with the use of smaller RT volumes

[13]; hence the importance of reducing RT dose and volumein mediastinal irradiation, a finding which was proven in oneimportant study, where exclusion of axillae from supra-

diaphragmatic RT fields was associated with a substantialreduction of Breast Cancer risk among females previouslyreported with mantle fields [15].

In the current study, VMAT reduced the mean dose to

heart and lungs, V30heart and V20lungs, in all the resultingplans. It was however associated with an increased volumeof the normal tissues receiving low-dose radiation, due to

delivery of highly conformal treatment through a rotationalgeometry of 1 or 2 arcs or hemi-arcs, and to the increased mon-itor units required for treatment delivery. Our data are compa-

rable to the dose estimate comparison for ten patients withsupra-diaphragmatic HL, planned using (3D CRT andVMAT, INRT/ISRT) in five ILROG centers having vast expe-

rience in the treatment of lymphomas [11]. Also, the increase inV5 and low-dose normal tissues with VMAT in the currentstudy was comparable to other reports from similar studies[12,13,18–20].

Deep inspiration breath-hold (DBH) gadget is not availableat our center. Several studies have shown that DBH coupledwith VMAT, IMRT or 3D-CRT is associated with better spar-

ing of the heart and lungs than if the same techniques wereused alone [18].

In young female patients with disease limited to superior

anterior mediastinum, 3D-CRT plans could result in betterbreast sparing as compared to VMAT. VMAT would give bet-ter sparing of breast and lung when the disease extends to mid-or lower mediastinum with hilar involvement. A ‘‘butterfly”

IMRT technique for mediastinal disease in young femaleswas developed in MD Anderson Cancer Center (MDACC)[19]. This technique employs a special beam arrangement, daily

breath hold, and CT-on-rails verification to achieve adequatetarget coverage, while reducing the high- and low-dose radia-tion exposure of the breasts and other critical organs. This

technique is only applicable to disease confined to the medi-astinum without any axillary involvement. Though the doseto the breasts is lower, the V5lungs value for remains higher

for the ‘‘butterfly” as compared to 3DCRT AP/PA. VMAThas the advantage of a shorter treatment time and faster treat-ment delivery than IMRT. VMAT is also applicable in caseswith sub-pectoral and axillary involvement. Another new

168 C. Higby et al.

alternative is proton therapy, though the role of proton has notyet been defined in HL, and it is not widely used because of thetreatment cost, complexity, and availability.

Conclusions

This study shows that VMAT is a valuable technique for treat-

ment of large mediastinal HL. It allows maximal lung andheart sparing when compared to 3D-CRT in select Hodgkinlymphoma patients treated with ISRT. In addition, it allows

dose escalation when needed, with minimal increased dose toOARs. The main concern when using VMAT is the spreadingof low radiation dose to the normal tissue and hence an

increased integral dose. This raises concerns of possibleincreased risk of Second malignancy, particularly breast cancerwhen children and young female adolescent patients are trea-

ted. Long term data with regular follow up for treatment-induced late toxicity is necessary before final conclusions canbe made. ILROG guideline implementation and defining crite-ria for treatment plan evaluation for various clinical scenarios

will refine radiation treatment, and will hopefully improve clin-ical outcomes for patients.

Conflict of interest

We have no conflict of interest to declare.

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