Feasibility of accelerated partial breast irradiation with volumetric-modulated arc therapy in elderly and frail patients

Background Accelerated partial breast irradiation (APBI) is an option for adjuvant radiotherapy according to ASTRO and ESTRO recommendations. Among the available techniques, volumetric-modulated arc therapy (VMAT) is attractive but has not been extensively studied for APBI. This study assessed its feasibility, tolerance and early oncological outcomes. Methods We analysed the data of nine patients (median age 74 years) with ten lesions (one bilateral cancer) treated from May 2011 to July 2012 with APBI using VMAT. The radiation oncologist delineated the surgical tumour bed, and added an 18 mm isotropic margin to obtain the planning target volume (PTV). The dose was 40 Gy prescribed in 4 Gy fractions given twice a day over five days. Patients were regularly followed for toxicities and oncological outcomes. Results Mean PTV was 100.0 cm3 and 95 % of the PTV received a mean dose of 99.7 % of the prescribed dose. Hot spots represented 0.3 % of the PTV. 6.2 %, 1.6 % and 0.3 % of the ipsilateral lung volume received 5 Gy (V5Gy), 10 Gy (V10Gy) and 20 Gy (V20Gy), respectively. Regarding the contralateral lung, V5Gy was 0.3 %, and V10Gy and V20Gy were nil. V5Gy accounted for 3.1 % of the heart. An average 580 monitor units were delivered. No acute or late grade ≥ 2 toxicities were observed. With a median follow-up of 26 months, no relapses occurred. Conclusion In our study, VMAT allowed optimal dosimetry with consequential high therapeutic ratio in elderly and frail patients.


Background
Breast-conserving therapy followed by whole breast irradiation (WBI) equals radical surgery in terms of overall survival with limited long-term toxicity [1][2][3]. Even though the role of radiotherapy is well established, its use is sometimes challenged owing to accessibility, equipment and cost issues. Hypofractionated radiotherapy, such as accelerated partial breast irradiation (APBI), could be a response to certain WBI drawbacks. APBI allows to shorten treatment time and to limit the exposure of organs at risk (OAR) with a putative equivalent efficacy compared to standard fractionated WBI in patients with early breast cancer [4][5][6][7][8][9][10][11][12]. APBI is of special interest in elderly or frail patients who barely tolerate standard-course radiotherapy. A wide variety of APBI techniques are used such as brachytherapy (interstitial needles or balloon-based), intraoperative or external beam radiotherapy, especially 3-dimensional conformal radiotherapy (3D-CRT) [13]. The latter is mainly performed thanks to its availability, but the optimal delivery technique remains to be determined [6]. Recent studies have raised concerns regarding possible higher toxicity rates after APBI. In particular, after balloon catheter brachytherapy, a significant higher risk of rib fracture, breast pain and fat necrosis have been reported [14]. After external beam radiotherapy (intensity-modulated radiation therapy [IMRT] and/or 3D-CRT), a fair aesthetic outcome has also been noted, in specific clinical, technical and dose conditions [15,16]. On the contrary, another group has published improved toxicity results when using IMRT APBI as compared to WBI plus tumor bed boost [17,18]. These results call for new clinical studies on other delivery techniques of APBI, which might entail different types and rates of toxicity.
Volumetric-modulated arc therapy (VMAT) is an attractive IMRT technique that enables a fast delivery and an improved efficiency. It has been evaluated in a broad spectrum of tumours but has not been extensively studied for APBI [19][20][21]. Qiu et al. reported dosimetry feasibility of the VMAT approach compared to 3D-CRT treatment planning in 8 patients with breast cancer and showed that VMAT was more efficient, with equivalent or improved dose conformity and lower doses to OAR [22]. Essers et al. compared VMAT and 3D-CRT in a larger series of 37 patients [23] No clinical data has been yet reported with VMAT APBI. Here, we present the feasibility and early clinical results of BC patients treated with VMAT APBI.

Patient selection
Our study design was validated by our institutional ethical board (Comité d'éthique) and informed consent was obtained from all patients before treatment.
Nine patients with early breast cancer (ten lesions: 5 right-sided, 3 left-sided and 1 bilateral breast cancer) were prospectively recruited from May 2011 to July 2012. Patients' inclusion criteria were based on the guidelines of both work-task forces ASTRO and GEC/ ESTRO for APBI indications [24,25]. All patients were older than 50 years and had undergone breastconserving surgery with free margins followed by APBI using VMAT. They all had pT1N0 invasive ductal carcinoma, grade 1-2 SBR score, positive hormonal receptor, and negative HER2 expression. The patients were excluded in case of metastatic disease. Patients' characteristics are listed in Table 1. All patients were elderly (above 70) or presented with serious comorbidities including cardiovascular disease, chronic respiratory insufficiency or major scoliosis.

Acquisition and simulation
The patients underwent computed tomography (CT)based virtual simulation (CT Simulator, General Electric, Cleveland, OH) with 2.5 mm thick slices obtained at 2.5 mm intervals. Patients were in supine position with arms above the head (arms and knee support, Sinmed, The Netherlands) and within a personalized immobilization device (Mold Care, Bebig). The isocenter was set in the middle of the surgical tumour bed.

Contouring and volume definition
Target volumes and OAR were delineated on CT scan slices. The gross tumour volume and clinical target volume (CTV) were considered as equal and included the surgical bed, the surgical clips placed within the lumpectomy cavity, and/or the seroma. The planning target volume (PTV) was defined as an isotropic circumferential margin of 18 mm surrounding the CTV and excluded the first 5 mm under the skin surface, thoracic wall, ribs and pectoral muscles. OAR were automatically or manually contoured: ipsilateral and contralateral lungs, heart, ipsilateral and contralateral breast (using wires), thyroid, oesophagus, and humeral heads.

Treatment planning using RapidArc®
A maximum dose rate of 600 MU/min and 6 MV photon beams were used. The optimization process started with the constraints obtained with the IMRT plans. RapidArc® (RA, Eclipse software version 10.0.28, Helios, Varian, Palo Alto, CA) was delivered with two partial coplanar arcs (less than 240°of rotation) sharing the same isocenter and optimized independently and simultaneously. These two arcs were delivered with opposite rotations (clockwise and counterclockwise) so that the off-treatment time between the two beams was minimized to about 25 s. The field size and collimator rotation were determined using the automatic tool from Eclipse software to encompass the PTV. The first clockwise arc used a 45°collimator rotation in order to avoid the tongue-and-groove effect. The second arc rotated counterclockwise with a collimator rotation of 360°-X°( X°corresponding to the rotation of the collimator for the first arc). To improve results, we modified optimization constraints and priority factors of RA plans during optimization. These parameters were modified with regard to the DVH results for each patient.

Dose prescription, dose constraints, dosimetric evaluation and dose delivery
The radiotherapy was prescribed in fractions of 4.0 Gy "bis in die" (b.i.d.) over 5 consecutive days (40.0 Gy in total), with a minimal 6-hour interval between each fraction. 99 % and 95 % of PTV were to receive 38.0 Gy and 40.0 Gy, respectively. The total dose delivered wasn't to exceed 110 % of the prescribed dose. Volumes receiving more than 110 % of the prescribed dose (D) were considered as "hot spots". The homogeneity index (HI) was defined as: HI = (D2-D98 %)/D median. V x% was defined as the proportion of the total structure volume that received x% of the prescribed dose. To limit the ipsilateral lung exposure, volumes receiving 20.0 Gy (V 20Gy ) had to account for less than 3 % of the total structure volume; less than 10 % and 20 % for V 10Gy and V 5Gy , respectively. Regarding the contralateral lung exposure, respective thresholds for V 20Gy , V 10Gy and V 5Gy were 1 %, 2 % and 3 % of the lung volume. Moreover, to limit heart exposure, V 20Gy and V 5Gy were not to exceed 1 % and 70 % of the heart volume. Finally, exposure of the ipsilateral breast was expressed as V 50% and V 100% . The mean and maximal doses delivered to the contralateral breast were also determined. Image-guided radiotherapy with cone-beam computed tomography (CBCT) using soft-tissue matching was performed before each fraction. The γ-index methodology

Toxicity assessment
A clinical examination was performed before APBI. Acute and late adverse events were assessed 1, 2, and 6 months after APBI completion, then every 6 months until 5 years, and then annually, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0. The main expected toxicities included: breast pain, breast oedema, skin erythema, skin desquamation, radiation pneumonitis, telangiectasia, fat necrosis, skin pigmentation, skin atrophy, and breast fibrosis.

Treatment planning
Mean PTV and breast volumes were 100.0 cm 3 (range 38.9 cm 3 to 219. The Fig. 1 shows typical dose distribution using RA for right breast cancer (a) and bilateral breast cancer (b). Mean dose-volume histograms are presented in Fig. 2 (n = 10). The main dosimetric results are presented in Table 2 for ipsilateral breast, contralateral breast, heart, and ipsilateral and contralateral lung. An average of 580 monitor units (MU) was delivered with RapidArc ® (range 473 MU to 655 MU). The mean treatment time was 3.2 min.

Acute and late toxicity
As summarized in Table 3, acute toxicities were of grade 1 or less in all patients at any early time point (i.e. at APBI completion, 1 month and 2 months). Most observed Fig. 2 Mean dose-volume histograms for the ten lesions treated: planning target volume in violet, ispilateral breast in pink, contralateral breast in blue, homolateral lung in cyan, controlateral lung in yellow, heart in brown V x% proportion of the total structure volume that received x% of the prescribed dose, V xGy proportion of the total structure volume that received x Gy symptoms were breast pain, oedema and erythema. There were no grade 2 or more adverse events. No treatment discontinuations occurred. Late toxicities were collected with a median follow-up of 26 months (range 6-37 months). Only three grade 1 fibrosis and one grade 1 breast pain were observed. No toxicities of greater grade were reported.

Oncological outcomes
With a median follow-up of 26 months, no local or distant relapses were diagnosed.

Discussion
VMAT for APBI has not been extensively studied in the literature. We present here the first feasibility study including clinical results in this setting. VMAT, as a rotational IMRT technique, has the potential to deliver highly conformal and homogeneous dose to the targeted volumes. However, because of its rotational nature, it is thought to be less efficient at low and medium doses, thereby irradiating a larger OAR volume. On the one hand in our study, such dispersion was not observed and we obtained a dose distribution to the ipsilateral lung, contralateral lung and heart similar to the one reported in 3-dimensional (3D) conformal APBI [16,26]. On the other hand, we should remain aware of the low but not negligible dose delivered to the contralateral breast with this technique (Table 2). Indeed, this effect has not been reported when using tangential field 3D conformal APBI. Moreover, the ipsilateral breast exposure to a significant radiation dose seems to be a significant risk factor of unacceptable toxicity and impaired cosmesis [15]. The ipsilateral breast is considerably less irradiated with VMAT as compared to other external beam radiotherapy techniques: mean V 50% and V 100% being respectively of 25.8 % and 10.9 % in our study versus 47.9 % and 27.2 % in the IMRT study by Jagsi et al. [15], and 44.1 % and 23.8 % in the 3D-CRT study by Bourgier et al. [16,26] Our results remain competitive when compared with those obtained in other studies on VMAT for APBI published by Qiu et al. [22] and Essers et al. [23].: they reported ipsilateral breast V 50% of 45.9 and 19.7 % and V 100% of 20.9 % and not reported, respectively. However, in our study, a greater maximal dose was delivered to the contralateral breast: 3.  [17,18]. These differences in PTV can be explained by different surgical and remodelling techniques, entailing large variations in surgical bed and seroma cavity volumes. Indeed, APBI may not be the most suitable method to treat patients with large lumpectomy cavities.
Regarding exposure of OAR, especially lung, contralateral breast and heart, no comparison has yet been made between VMAT and static field IMRT. Whether the higher modulation possibilities of VMAT could improve OAR protection remains to be proven.
Acute toxicity was acceptable as all patients had grade ≤ 1 toxicities. With a median follow-up of 26 months, late toxicity was low, most of the patients experiencing none; and no grade 2 late toxicities occurred. Nevertheless, a longer follow-up and a larger cohort of patients are warranted to consider VMAT as a safe APBI modality. Our study has some limitations, including the low number of patients and the limited follow-up time. This is mainly due to the fact that APBI is not a standard treatment outside clinical trials in France; therefore we mainly recruited patients presenting clinical features that would not allow standard radiotherapy, such as advanced age, respiratory insufficiency or cardiovascular disease. The treatment tolerance seemed to be especially good in this population. This limited follow-up allowed us to consider the clinical toxicity only without drawing any conclusion regarding tumour control. If longer-term studies confirm its efficacy and tolerability, VMAT APBI might become a therapeutic alternative for patients otherwise not treated.

Conclusions
In this study performed in nine patients with breast cancer, VMAT offered a good OAR sparing while maintaining PTV coverage within acceptable levels for APBI. The early evaluation of oncological outcomes was promising.