uva-dare (digital academic repository) optimizing ... · we also calculated the standard deviation...
TRANSCRIPT
UvA-DARE is a service provided by the library of the University of Amsterdam (http://dare.uva.nl)
UvA-DARE (Digital Academic Repository)
Optimizing treatment of low risk breast cancer patients
van der Leij, F.
Link to publication
Citation for published version (APA):van der Leij, F. (2017). Optimizing treatment of low risk breast cancer patients.
General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s),other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons).
Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, statingyour reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Askthe Library: https://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam,The Netherlands. You will be contacted as soon as possible.
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
4
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
Chapter 4
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
55
4
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
Chapter 4
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
57
4
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.
Chapter 4
58
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
59
4
References
1. Bartelink H, Horiot JC, Poortmans PM, Struikmans H, Van den Bogaert W, Fourquet A, Jager JJ, Hoogenraad WJ, Oei SB, Warlam-Rodenhuis CC et al: Impact of a higher radiation dose on local control and survival in breast-conserving therapy of early breast cancer: 10-year results of the randomized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol 2007, 25(22):3259-3265.
2. Landis DM, Luo W, Song J, Bellon JR, Punglia RS, Wong JS, Killoran JH, Gelman R, Harris JR: Variability among breast radiation oncologists in delineation of the postsurgical lumpectomy cavity. Int J Radiat Oncol Biol Phys 2007, 67(5):1299-1308.
3. van Mourik AM, Elkhuizen PH, Minkema D, Duppen JC, Vliet-Vroegindeweij C: Multiinstitutional study on target volume delineation variation in breast radiotherapy in the presence of guidelines. Radiother Oncol 2010, 94(3):286-291.
4. Petersen RP, Truong PT, Kader HA, Berthelet E, Lee JC, Hilts ML, Kader AS, Beckham WA, Olivotto IA: Target volume delineation for partial breast radiotherapy planning: clinical characteristics associated with low interobserver concordance. Int J Radiat Oncol Biol Phys 2007, 69(1):41-48.
5. Bartelink H, Bourgier C, Elkhuizen P: Has partial breast irradiation by IORT or brachytherapy been prematurely introduced into the clinic? Radiother Oncol 2012, 104(2):139-142.
6. O’Sullivan B, Davis AM, Turcotte R, Bell R, Catton C, Chabot P, Wunder J, Kandel R, Goddard K, Sadura A et al: Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002, 359(9325):2235-2241.
7. Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004, 351(17):1731-1740.
8. Nichols EM, Dhople AA, Mohiuddin MM, Flannery TW, Yu CX, Regine WF: Comparative analysis of the post-lumpectomy target volume versus the use of pre-lumpectomy tumor volume for early-stage breast cancer: implications for the future. Int J Radiat Oncol Biol Phys 2010, 77(1):197-202.
9. Palta M, Yoo S, Adamson JD, Prosnitz LR, Horton JK: Preoperative single fraction partial breast radiotherapy for early-stage breast cancer. Int J Radiat Oncol Biol Phys 2012, 82(1):37-42.
10. Boersma LJ, Janssen T, Elkhuizen PH, Poortmans P, van der Sangen M, Scholten AN, Hanbeukers B, Duppen JC, Hurkmans C, van Vliet C: Reducing interobserver variation of boost-CTV delineation in breast conserving radiation therapy using a pre-operative CT and delineation guidelines. Radiother Oncol 2012.
11. Deurloo KE, Steenbakkers RJ, Zijp LJ, de Bois JA, Nowak PJ, Rasch CR, van Herk M: Quantification of shape variation of prostate and seminal vesicles during external beam radiotherapy. Int J Radiat Oncol Biol Phys 2005, 61(1):228-238.
12. Struikmans H, Warlam-Rodenhuis C, Stam T, Stapper G, Tersteeg RJ, Bol GH, Raaijmakers CP: Interobserver variability of clinical target volume delineation of glandular breast tissue and of boost volume in tangential breast irradiation. Radiother Oncol 2005, 76(3):293-299.
13. Berrang TS, Olivotto I, Kim DH, Nichol A, Cho BC, Mohamed IG, Parhar T, Wright JR, Truong P, Tyldesley S et al: Three-year outcomes of a canadian multicenter study of accelerated partial breast irradiation using conformal radiation therapy. Int J Radiat Oncol Biol Phys 2011, 81(5):1220-1227.
14. Kirby AM, Coles CE, Yarnold JR: Target volume definition for external beam partial breast radiotherapy: clinical, pathological and technical studies informing current approaches. Radiother Oncol 2010, 94(3):255-263.
15. Lewin AA, Derhagopian R, Saigal K, Panoff JE, Abitbol A, Wieczorek DJ, Mishra V, Reis I, Ferrell A, Moreno L et al: Accelerated Partial Breast Irradiation is Safe and Effective Using Intensity-Modulated Radiation Therapy in Selected Early-Stage Breast Cancer. Int J Radiat Oncol Biol Phys 2011.
Chapter 4
60
16. Stroom J, Schlief A, Alderliesten T, Peterse H, Bartelink H, Gilhuijs K: Using histopathology breast cancer data to reduce clinical target volume margins at radiotherapy. Int J Radiat Oncol Biol Phys 2009, 74(3):898-905.
17. Kirby AM, Evans PM, Nerurkar AY, Desai SS, Krupa J, Devalia H, della Rovere GQ, Harris EJ, Kyriakidou J, Yarnold JR: How does knowledge of three-dimensional excision margins following breast conservation surgery impact upon clinical target volume definition for partial-breast radiotherapy? Radiother Oncol 2010, 94(3):292-299.
18. Immink JM, Putter H, Bartelink H, Cardoso JS, Cardoso MJ, MH vdH-V, Noordijk EM, Poortmans PM, Rodenhuis CC, Struikmans H: Long-term cosmetic changes after breast-conserving treatment of patients with stage I-II breast cancer and included in the EORTC ‘boost versus no boost’ trial. Ann Oncol 2012, 23(10):2591-2598.
19. Badr el Din A, Coibion M, Guenier C, Nogaret JM, Lorent I, Van Houtte P, Tueni E, Mattheiem W: Local postoperative morbidity following pre-operative irradiation in locally advanced breast cancer. Eur J Surg Oncol 1989, 15(6):486-489.