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Optimizing treatment of low risk breast cancer patients

van der Leij, F.

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Download date: 19 Aug 2019

Chapter 4

Target volume delineation in external beam partial

breast irradiation: Less inter-observer variation with

preoperative- compared to postoperative delineation

Femke van der Leij

Paula H.M. Elkhuizen

Tomas M. Janssen

Philip Poortmans

Maurice van der Sangen

Astrid N. Scholten

Corine van Vliet-Vroegindeweij

Liesbeth J. Boersma

Radiotherapy and Oncology 2014; 110: 467-470

Chapter 4

52

Abstract

The challenge of adequate target volume definition in external beam partial breast irradiation

(PBI) could be overcome with preoperative irradiation, due to less inter-observer variation.

We compared the target volume delineation for external beam PBI on preoperative versus

postoperative CT scans of twenty-four breast cancer patients.

Target volume delineation in external beam partial breast irradiation

53

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Introduction

Accuracy of target volume delineation is of great importance in external beam partial breast

irradiation (PBI) in breast conserving therapy in early breast cancer because whole breast

irradiation is omitted. PBI should provide at least similar local control rates as the standard whole

breast irradiation. Whole breast irradiation after local excision of the tumor is associated with a

tumor control probability of more than 90% after 10 years. An additional boost dose after whole

breast irradiation increases the local control rate, with a local recurrence rate of 6% at 10 years 1. In order to result in similar local control rates, PBI should accurately irradiate the proper target

volume. However, delineation studies defining the postoperative clinical target volume (CTV)

for boost irradiation or PBI after lumpectomy have shown a large inter-observer variability 2-4.

Intra-operative (brachy) therapy, as PBI method, does not have this disadvantage. The absence

of pathology information during treatment may however lead to over- or under treatment of

the target area 5. 3D-external beam conformal radiotherapy (RT) has advantages in terms of

dose homogeneity and its’ wide availability, making it accessible to large groups of patients.

By delivering external beam PBI preoperatively, less inter-observer variation in target volume

delineation is expected. Therefore preoperative irradiation might prove to be a more effective

way of delivering PBI.

Preoperative RT for other tumors such as sarcomas and rectal carcinomas has led to smaller

treatment volumes and to less toxicity of the normal tissue compared to the postoperative setting 6, 7. Breast cancer studies suggests the same for preoperative PBI 8, 9. By reducing target volumes

in PBI, smaller volumes of normal breast tissue will be irradiated, probably leading to less adverse

effects and an improved cosmetic outcome. The aim of this study was to compare target volume

delineation for preoperative external beam PBI with that for postoperative external beam PBI,

with respect to inter-observer variation and difference in size of the delineated volumes.

Material and methods

Patient characteristics

For this study we used the dataset of 24 of the 26 patients from our previous study 10, where we

investigated the influence of the use of a preoperative CT scan on the inter-observer variation for

delineation of the boost CTV. Patients were scanned in RT position prior to and after surgery, as

described earlier 10. That study was approved by the Medical Ethics Committee of the Maastricht

University Medical Centre, according to the Dutch law and regulations. Written informed consent

to undergo an additional CT scan was given by all patients. Two patients were excluded from

the present study, since the tumor appeared to be multifocal. We excluded these patients to

make sure that patient selection was comparable with patient selection for PBI. In all 24 patients

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54

a mammography and ultrasound was available to guide delineation. Preoperative magnetic

resonance imaging (MRI) was available in 6 out of 24 patients. The radiological mean tumor size

was 12.6 mm (range, 6-23 mm), and the mean pathological tumor size was 10.4 mm (range, 3-17

mm). In the present study we used the postoperative delineated boost volumes as a surrogate for

postoperative PBI and compared these to preoperative target volume delineation.

Delineation

Five observers delineated the tumor bed on the postoperative scan, and expanded this

delineation with 15 mm minus the minimum histological free margin (CTV-post). At the time of

delineation, they did not have the information of the preoperative CT scan. Hereafter, the same

observers delineated the gross tumor volume (GTV) on the preoperative scan; this delineation

was expanded with 15 mm (CTV-pre). Both CTV-post and CTV-pre were, if required, adjusted

to exclude the chest wall and the first 5 mm underneath the surface of the skin. One observer

delineated the whole breast on the pre- and postoperative scans of all patients. All observers were

experienced radiation oncologists (5–20 years experience), specialized in radiation treatment of

breast carcinoma.

Delineation was performed using strict guidelines as described previously 10. In short, the CTV-

post was defined as the 15 mm rim of tissue that surrounded the primary tumor. To reconstruct

this rim of tissue on the planning CT scan, guidelines were developed for three postoperative

situations based on the presence of seroma; clear seroma cavity visible, no seroma cavity visible

or a partial seroma cavity present. Surgical clips were placed at the deepest resection border and

used for guidance 10. The mean number of surgical clips placed during surgery was 5.1 (range,

4–6).

Observation parameters

We tested the inter-observer variation by calculating the conformity index (CI = common volume

divided by encompassing volume; CI = 1 indicates perfect agreement) and the distance between

the centres of mass of the target (ComD) for each patient, for each observer pair and for both

volumes. We also calculated the standard deviation (sd) of all target volume delineations with

respect to the median delineation (in cm), defined per patient as an artificial median structure

on which at least half the observers agreed 11. The mean sd of the delineations of all observers

with respect to this median delineation is a measure of the inter-observer variation. Further,

we compared the mean volumes of the GTV and the tumor bed, the volumes of CTV-pre and

CTV-post and the CTV-pre- versus the CTV-post/whole breast volume ratio. We estimated the

mean GTV/tumor bed to CTV-pre/CTV-post expansion for each patient, by assuming that all

delineations are perfectly spherical but limited to the glandular tissue.

Target volume delineation in external beam partial breast irradiation

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Statistical parameters

Statistical significance was determined using a Wilcoxon test, with a significance level of α =

0.05. Correlations were studied using the Spearman rank correlation. All statistical tests were

performed using the SPSS for windows software (version 19).

Results

The mean CI, the mean ComD and the mean sd all show considerably less inter-observer variation

in the preoperative setting compared to the postoperative setting (all parameters: p<0.001). The

mean CI was preoperative 0.78 and 0.38 postoperative. The mean ComDs pre- and postoperatively

were 0.36 cm and 1.02 cm; the mean sds pre-and postoperatively were 0.30 cm and 0.57 cm,

respectively. Figure 1 shows examples of delineation of the CTV-post and the CTV-pre for two

patients with a clearly superior conformity in the preoperative situation.

The mean volumes of the GTV and the postoperative tumor bed were 0.97 cc (sd=0.83 cc, range

0.01-4.40 cc) and 8.68 cc (sd=9.16 cc, range 0.27-52.61 cc) respectively (p<0.001). The volume

of the CTV-pre was on average 36.8 cc (sd=12.1 cc) compared to CTV-post 41.0 cc (sd=34.6

cc) (p=0.789). CTV-pre- and CTV-post/whole breast volume ratio were similar as well (p=0.289).

The estimated average expansion of the mean GTV/tumor bed to the CTV was in the preoperative

situation 14.7 mm (SD), while in the postoperative situation the average expansion was only 8.4

mm (SD) (p < 0.001).

Discussion

We showed that preoperative external beam PBI leads to considerably less inter-observer variation

in target volume delineation compared to postoperative external beam PBI. While most other

studies focusing on target volume delineation investigated boost volumes, the clinical impact of

accurate target delineation is of even higher importance when using PBI. Tumor bed delineation

in boost studies have wide ranges of CI values depending on seroma size, clarity, delineated

volume size and target definition. The mean CI values reported in the literature are ranging

from 0.36 to 0.73 2-4, 10, 12. The mean CI, in our present study focusing on PBI, improved from

0.38 in the postoperative situation to 0.78 in the preoperative situation. This finding provides an

important argument in favour of treating patients with PBI preoperatively.

While in our study the delineated postoperative tumor bed volume was significantly larger than

the preoperative GTV, the CTV-pre and CTV-post volumes were comparable. This seemingly

contradictory finding can be explained by the fact that in postoperative CTV delineation, the

knowledge on histological margins was used, by subtracting the histological free margin from the

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56

prescribed CTV margin extension of 15 mm, as shown by the estimated expansion. We performed

this procedure in analogy to our clinical practice for boost delineation and this procedure results

in principle in the smallest acceptable CTV-post delineation. Other studies did not incorporate

the knowledge on the histological free margin in their postoperative CTV, and applied the full 15

mm as postoperative CTV margin 13-15, thus leading to an overestimate of the minimal CTV-post

volume.

Stroom et al 16 support our approach of subtracting the histological free margins in the

postoperative setting; they showed that CTVs can frequently be reduced when using excision

margins. Kirby et al 14, 17 also concluded that an anisotropic CTV margin should be applied in the

postoperative setting, but they reasoned that the total margin around a tumor should be 30 mm,

i.e. 15 mm to be removed by the surgeon, and 15 mm to be included in the CTV. Oncoplastic

breast conserving surgery techniques, with parenchymal rearrangement, causes challenges to

the localization and therefore delineation of the tumor bed. Due to more uncertainty a larger

area will be delineated or a larger CTV margin will be added. This problem will be avoided in

pre-operative RT.

Figure 1: Single CT slices of two patients (A and B) with delineated CTV-post (left) and CTV-pre (right) of all 5 observers.

Target volume delineation in external beam partial breast irradiation

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Palta et al 9 and Nichols et al 8 studied the impact of the CTV volume on the dose distribution

and planning target volume (PTV), respectively. In the preoperative PBI study of Palta et al 9 a

virtual plan was made for preoperative single fraction external beam PBI, which resulted in a

substantial reduction in ipsilateral breast tissue dose compared with postoperative PBI. Nichols et

al 8 showed in an analysis of a patient cohort of 40 patients that was treated postoperatively, that

preoperative PBI would decreased the PTV compared to postoperative PBI. They analyzed PTVs

based on preoperative tumor expansion compared to postoperative PTVs. The CTV margin of 15

mm in this study was expanded around the preoperative tumor and the postoperative tumor bed

respectively, without accounting for the histological tumor free margin. The PTV was a further

10 mm expansion around the CTV. In this study, the PTV based on preoperative tumor expansion

was associated with reduced amounts of irradiated non-target breast tissue. The volume of the

postoperative PTV exceeded the preoperative PTV in all cases.

The most applied PTV margins in PBI are 10 mm 8, 9, 14, 17, to account for both respiratory and

set-up errors, in addition to delineation uncertainty. Due to the considerably less inter-observer

variation in the preoperative situation we observed in our study, it would be interesting to consider

reducing the CTV-PTV margin in preoperative external PBI.

Irradiation of smaller volumes of normal breast tissue has been shown to lead to less adverse effects

of RT and improve the cosmetic outcome 18. Because the target volumes in the postoperative and

preoperative situation were comparable in our series there would probably be no difference

the degree of adverse effects of RT. Still, for breast cosmesis it might be an advantage to treat

preoperatively, because of surgical removal of that part of the breast receiving a high radiation

dose. In a study of primary whole breast RT in locally advanced breast cancer there was an

increased incidence of local wound infection, delayed wound healing, seroma formation, and

lymphedema after surgery 19. This is expected to be less pronounced in preoperative PBI given

the smaller treated volumes and the improved techniques of RT delivery. Further studies will be

needed to confirm this hypothesis.

In our institute a preoperative external beam PBI trial has been started (Preoperative Accelerated

Partial Breast Irradiation (PAPBI) trial, registered with clinicaltrials.gov NCT01024582). This trial

will contribute to the future knowledge on the accuracy of target volume delineation, volume

sizes, feasibility, treatment complications and cosmetic results of preoperative PBI.

Conclusion

In this study, preoperative external beam PBI leads to significantly less inter-observer variation

compared to postoperative external beam PBI. This supports the introduction of preoperative

external beam PBI.

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Conflict of interest statement

None.

Research support

This work is supported by a grant from the Dutch Cancer Society (Grant NKI 2009-4389) given to

F. van der Leij and P.H.M Elkhuizen.

Acknowledgement

We would like to thank Joop C. Duppen for his contribution.

Target volume delineation in external beam partial breast irradiation

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