Sequential Volumetric Modulated Arc Therapy (VMAT) Boost in Hybrid Plan with Tangential Beams for Whole Breast Treatment: a Dosimetric Study

1. Introduction:

Breast conservative surgery followed by whole breast radiation therapy (WBRT) and a boost to the tumor bed is the treatment of choice for most patients with stages I–II breast cancer (BC) (1–3).

Breast radiotherapy (RT) has been historically performed by two tangential fields for a total dose of about 50 Gy with a conventional fractionation of 1.8-2 Gy (4). More recent evidence have demonstrated the non-inferiority of hypofractionated RT also showing a reduction in acute toxicity (5–9).

Breast conservative approaches have increased significantly in the last decades and techniques have improved with greater awareness of the impact of radiation on the heart (10).

The tumor bed boost can be performed in different modalities, electrons beam radiotherapy, particles RT, photons beam RT or brachytherapy (BT). Electrons beam RT and photons beam RT delivered in sequential boost (SB) have been shown to be the most common modalities (11,12).

Even though particles RT and photons beam RT seem to guarantee better planning solutions, no randomized trials have been designed to identify the best modality to use (13,14).

In recent years, static fields three-dimensional Conformal Radiotherapy (3D-CRT) modality has been replaced by Intensity-Modulated Radiation Therapy (IMRT) modality assuring more conforming doses and volumes. Experience have also showed that IMRT could also provide a minimization of unwanted radiation dose inhomogeneity in the breast leading to late adverse effects reduction (15,16).

Volumetric modulated arc therapy (VMAT) technique is preferred to conventional direct electron in tumor bed boost both for better conformation of the dose and for lung sparing (17).

Electrons should be reserved to very superficially located tumor bed without contact with the thoracic wall (18).

To our knowledge, in literature no studies have analyzed a hybrid treatment with static tangential fields for WBRT and with the use of VMAT technique for the sequential boost.

The aim of this study is to demonstrate the feasibility and dosimetric advantages of SB delivered with VMAT technique in hybrid plans with tangential beams for whole breast treatment.

2. Material and Methods:

Patients characteristics:

Thirty-one patients from a single institution who received RT following conservative surgery for early BC from June to October 2020 were retrospectively enrolled. Patients enrolled signed a consent for data collection according to the study design requirements and also to department regulation.

Patients had stage I disease according to the 7th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system (19).

In this study 12 left-sided and 19 right-sided tumors were evaluated.

A heterogeneous patient population was considered for analysis with large or small breast volume and deeply or superficially located tumors.

The boost regions were sixteen in upper outer quadrant (UOQ), two in upper-lower inner quadrants (UIQ – LIQ), two in lower outer quadrant (LOQ), eleven in central quadrant (CQ).

Patients characteristics are reported in table 1.

Table 1 – Patients characteristics

R: right; L: left; UOQ: upper outer quadrant; LOQ: lower outer quadrant. UIQ: upper inner quadrant; LIQ: lower inner quadrant; CQ: central quadrant;

Contouring:

The patients underwent a 2.5-mm slice thickness, free-breathing computed tomography (CT) scan in supine position on breast board (C-qual) with both arms raised above the head.

The clinical target volume of whole breast (CTVbreast) was contoured according to European Society for Radiotherapy and Oncology (ESTRO) guidelines (20).

The CTVboost was defined as the tumor bed identified through the study of pre-operative mammography and/or MRI images and the visualization of the surgical alteration, with the help of a metal marker on the scar; any seromas near the tumor bed were included.

The PTVbreast andPTVboost were created by adding an isotropic 5 mm margin expansion to CTVbreast and CTVboost respectively.

The PTVs were cropped to 5 mm from the body as Italian guideline recommendation (1).

The organs at risk (heart, ipsilateral lung, contralateral lung and lungs) were delineated according to National guidelines (1).

Planning:

31 hybrid treatment plans were generated characterized by a 3D-CRT plan using tangential mediolateral and lateromedial fields for the irradiation of the PTVbreast and a sequential VMAT plan with 2 coplanar arches for PTVboost irradiation with an amplitude of 120° (240°- 40° for right breast, 320°- 120° for left breast).

All treatment plans were calculated using the Pinnacle3 vers.16.02 from Philips, collapsed cone algorithm and 3x3x2.5 mm calculation grid and were optimized for Elekta Synergy® linear accelerator equipped with an 80 leafs multi-lamellar collimator.

The dose prescribed to the whole breast was 50 Gy in 2 Gy daily fractions according to internal department regulamentation. The dose to the tumor bed was 10-16 Gy in 2 Gy daily fractions, higher boost dose was prescribed for patients with close margins status at pathological examination. The total delivered dose was 60-66 Gy.

The target volume and prescription dose were defined according Report 50, 62 and 83 recommendations of the International Commission on Radiation Units and Measurements (ICRU) (21–23).

Both plans aimed to PTV V95% and CTV 98% higher than 95% of the prescribed dose, and also to PTV V107% inferior to 5% and PTV Dmax not exceeding 110%.

The conformity index (CI95%) was calculated as

$$CI = frac{TV_{RI}}{TV} cdot frac{TV_{RI}}{V_{RI}}$$

where TVRI represents the target volume covered by the reference isodose (95% of the prescription dose); TV is the target volume, VRI is the volume of the reference isodose. The value of CI ranges from 0-1, with a value closer to 1 indicating better conformity of the dose to the PTV (24).

The dose constraints considered for Organs at risk (OARs) were:

• Heart V10Gy < 10%, V40Gy < 4% and Dmean < 3 Gy
• Ipsilateral lung Dmean < 18 Gy and V20Gy < 25%
• Contralateral lung Dmax < 5 Gy
• Bilateral lungs V5Gy < 60%
• Contralateral breast Dmax < 5 Gy and V10 Gy < 5%. (25–27)

Plan evaluation:

The dosimetric data of the individual and the sum plans considered were:

• CTV boost bed V95% and V107%
• PTV boost bed V95%, V107% and CI95%
• Ipsilateral lung mean dose and V20Gy
• Contralateral lung max dose and mean dose
• Bilateral lungs V5Gy
• Heart V20Gy, V40Gy and mean dose
• Contralateral breast max dose and V10Gy

3. Results:

Plan evaluation resulted in homogeneous dosimetric values for target coverage as Mean PTV boost V95% resulted in 98,2% ± 1,8 DS with a mean PTV boost CI 95% result of 1,0 ± 0,0 DS. Coverage of both PTVbreast and PTVboost are shown in Figure 1 and 2.

A

PTV: planning target volume

Figure 1 – Dose Volumes Histograms for PTVbreast (A) and PTVboost (B)

PTV: planning target volume

Figure 2 – Dose coverage for PTVbreast (A) and PTVboost (B)

Heart constraints were respected as mean heart V20 Gy resulted in 1,4 Gy ± 2,5 DS and 1,5 Gy ± 2,7 DS in WBRT plans and boost plans sum. Also constraints for the other OARs were respected.

Table 2 and 3 resume data of target coverage and OARs doses in both WBRT and boost plans sum.

Table 2 – Target coverage values

CTV: Clinical Target Volume; PTV: Planning Target Volume; CI: Conformity Index; ST. DEV: Standard Deviation

Table 3 – OARs dose constraints values

ST. DEV: Standard Deviation; WBRT: Whole Breast Radiotherapy

No statistically significant differences in Heart Dmean of PTV boost (p=0,14) were shown. Dose volume histograms for OARs ais shown Figure 3.

OARs: Organs at risk

Figure 3 – Dose Volumes Histograms for OARs

4. Discussion:

This study analyzes the dosimetric data of adjuvant radiation treatment plans in patients with early stage BC, using hybrid plans delivered through a 3D-CRT plan for WBRT and a sequential VMAT plan for tumor bed boost.

The use of hybrid plans could allow us to improve the dose homogeneity without exceeding the low doses rates typical of WBRTs performed entirely with the IMRT / VMAT technique.

In addition, the delivery of the single boost with the VMAT technique proved to be really simple and fast, with excellent visualization and reproducibility of the target through daily cone beam computed tomography (CBCT).

A recent experience showed that whole breast IMRT and Hypofractionated VMAT RT are feasible and well tolerated in elderly patients affected by early-stage BC, also showing lower risks of acute and late RT-related side effects (28).

Several experiences have been published regarding RT treatments with IMRT-VMAT technique with simultaneous integrated boost (SIB) and Accelerated Partial Breast Irradiation (APBI) (28–31; 47). Further studies also compared sequential boost with simultaneous boost.

A significant reduction in the severity of acute radiation dermatitis in IMRT-SIB RT compared to 3D-CRT-SB was shown (32).

Preliminary data from the prospective IMRT-MC2 trial, reported a non-inferiority of IMRT-SIB versus 3D-CRT sequential boost with respect to cosmesis and LC at 2 years of follow up (33).

IMRT planning also has been shown to provide higher dose conformity and to assure shorter treatment duration, even though with a slightly higher planning maximum and increased lung doses (34).

Other experiences showed a significantly reduced surface dose with IMRT compared to 3D-CRT, in the adjuvant treatment of BC (35).

However, many authors have shown tangential fields RT approach delivered with modern techniques such as IMRT and tomotherapy could be an optimal modality especially for minimizing organs at risk (OAR) low-doses. Nissen et al have demonstrated as deep inspiration breath hold (DIBH) in conjunction with tangential-field, forward-planned IMRT treatment plans can lead to a significant reduction in heart and lung dose while optimizing PTV coverage (36). Other experience showed as tangential fields tomotherapy could result in better dose coverage and OARs constraints compliance compared to other RT modalities (37,38).

A recent experience from Joseph et al, recently showed that IMRT SIB does not seem to have any dosimetric advantage compared to field-in-field 3D-CRT (39). Significantly higher doses to contralateral lung and heart and radiation exposure in terms of Monitor Units were also shown in IMRT SIB treatments (39).

Limited benefits of IMRT have been shown in specific patients subsets, mainly in treatments with large boost planning tumor volume (PTV) and an overlap between heart and breast PTV (40).

Several authors have proposed hybrid plans with SIB to take advantages of both 3D technique and IMRT(41,42). Onal et al demonstrated that the D2, D98, and V107 values for PTVbreast and PTVboost, and Homogeneity Index of PTVbreast with VMAT technology were higher with SB technique compared to the SIB technique (43).

In the frame of dosimetric analysis, an excellent target coverage and dose homogeneity is shown with mean values of PTV boost CI 95% 1.0 and media of CTV boost V95% 99.8%. Mean PTV boost V107% is always less than 5% except in 1 case where it is 5.1%.PTV boost V110% is always less than 1% and almost always is 0%. This high homogeneity of dose distribution is typical of IMRT / VMAT techniques.

As regarding to OARs, the dosimetric data show that the dose contribution of the boost plan is minimal and does not lead to large variations in the costraints used in clinical practice for treatment plan approvement.

In particular the difference of the heart V20 values between WBRT performed by 3D-CRT technique alone and the plan sum, is always less than 0.5% exception a case that is 1.4%; in most cases the difference is 0%.

Given the latest evidence in the article by Killander et al (26), where no correlation was found between cardiac toxicity and Dmean value inferior to 4 Gy, we have verified that the VMAT boost low doses did not go to affect the increase of this constraint.

We performed a subset analysis of patients with left BC and found no statistically significant differences between right and left side. The mean value of Heart Dmean was 1.0 Gy ± 0.7 SD and allowed not to exceed 3-4 Gy in the plan sum. Authors are aware of the limitations of this study such as the small simple size and the limited number of patients with internal quadrants for whom hearth doses could be increased.

In literature there are no studies investigating the use of hybrid plans with 3D-CRT plan with tangential fields for WBRT and with VMAT / IMRT plan for boosting the tumor bed. Balaji et al demonstated the feasibility of flattening filter-free (FFF) photon beams in hybrid volumetric modulated arc therapy (23). (41).

However, we have found studies that support the use of the VMAT technique for the boost (17,18). Most of the recent literature regarding BC tumor bed boost focuses on SIB studies in full IMRT/VMAT plans. (30,32,33,40,43–46). But some studies suggest that the low doses given by many fractions in IMRT / VMAT may not justify the use of this technique for the entire treatment (34,39).

5. Conclusions:

This study aimed to demonstrate the very low impact of boost with VMAT technique on constraints and low doses, to suggest the use of hybrid plans that can avoid the low doses of many fractions with IMRT / VMAT technique but exploit their potential in few fractions of the boost.

Comparative dosimetric studies on this hybrid technique applied in different modalities of treatment and large-scale studies to evaluate clinical outcomes should be designed to address the potential benefit of hybrid treatments.

Abbreviations:

WBRT – whole breast radiation therapy

BC – breast cancer

VMAT – volumetric modulated arc therapy

OARs – organs at risk

3D-CRT – three-dimensional Conformal Radiotherapy

SB – sequential boost

CTV – clinical target volume

PTV – planning tumor volume

RT – radiotherapy

BT – brachytherapy

IMRT – intensity-modulated radiation therapy

AJCC – American Joint Committee on Cancer

UICC – Union for International Cancer Control

UOQ – upper outer quadrant

UIQ – LIQ – lower inner quadrants

CQ – central quadrant

CT – computed tomography

ESTRO – European Society for Radiotherapy and Oncology

ICRU – International Commission on Radiation Units and Measurements

CI – conformity index

CBCT – cone beam computed tomography

SIB – simultaneous integrated boost

APBI – accelerated partial breast irradiation

DIBH – deep inspiration breath hold

Statements:

Authors’ contribution – AP: Conceptualization, Writing – Review & Editing; LB: Conceptualization, Supervision; A D’A: Writing – Original Draft, Writing – Review & Editing; AS: Investigation, Data Curation; SM: Investigation, Data Curation; MM: Writing – Review & Editing Supervisio; MS: Writing – Review & Editing; GP: Writing – Review & Editing; TA: Writing – Review & Editing; AD: Supervision.

Funding – This research received no external funding.

Conflicts of Interest – No actual or potential conflicts of interest exist regarding this article.

Data Availability Statement – The data presented in this study are available on request from the corresponding author.

Ethics approval – The study was conducted according to the guidelines of the declaration of Helsinki. Patients enrolled signed a consent for data collection according to the study design requirements and also to department regulation.

Aknowlegments – The Authors are grateful to Dr. Diepriye Charles-Davies for the linguistic revision of this manuscript

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