AAMD Journal Submission| Zoller , et al.

The dosimetric impact of seroma volume changes over the course of radiotherapy treatment on sequential boost planning (Arm I)
and a comparison of two concurrent hypofractionated boost methods (Arm II) for breast cancer patients eligible for RTOG protocol 1005.
BY WESLEY ZOLLER B.S.RT(T) AND LISA ZICKEFOOSE B.A.RT(R)(T)(CV)
CO-AUTH ORED BY ANDREW V ASSIL , MD, ANT ONIA F ANNIN B.A.RT(R)(T), PING X IA , PHD, AND ERIC MURRAY , CMD
THE DEPARTMENT OF RADIATION ONCOLOGY CLEVELAND CLINIC 9500 EUCLID AVENUE CLEVELAND, OHIO 44195

Abstract: Purpose: 1. Evaluate the effect of seroma volume changes over treatment to assess indications for adaptive boost planning. 2. Dosimetrically compare concurrent IMRT photon and electron cavity boosts for breast cancer patients eligible for RTOG 1005. Methods: Eleven patients with clinically evident seroma volumes at the time of initial CT (CT1) who received a second CT (CT2) prior t o sequential boost planning were chosen for this study. In Phase I, CT2 was fused onto CT1 for retrospective re -planning, with characteristics of both seroma volumes being recorded. As in RTOG 1005 Arm I, patients were planned to receive 50 Gray (Gy) in 25 fractions (fx) tangentially 1 with a 12 Gy/6 fx sequential electron boost to the cavity. Separate plans were optimized for each volume. For Phase II, patients were replanned using the CT1 volume receiving the RTOG 1005 Arm II dose of 40 Gy/15 fx with a concurrent 8 Gy/ 15 fx boost planned with both electron and IMRT tangential photons.1 Plans were evaluated based on dose to the heart, ipsilateral lung, and total ipsilateral breast tissue (Breast PTV Eval). Results: For Phase I, seroma volumes decreased on CT2 by an average of 57.06% +/- 8.96%, p= 0.001. The V56 of the Breast PTV Eval decreased on CT2 boost plans by an average of 9.16% +/- 3.26%, p= 0.001. In Phase II, the V 44.8 of the Breast PTV Eval was reduced for all electron boosts by an average of 16.24% +/- 8.08%, p= 0.001. Conclusions: For patients with clinically significant changes in seroma volumes, re-planning the sequential boost with a new CT may reduce excess dose to normal breast tissue, potentially reducing late effects. For concurrent hypofractionated methods, electron boost technique had improved conformality compared to IMRT plans with reduced dose to normal breast tissue.

KEYWORDS Seroma; Breast cancer; Radiation therapy; RTOG 1005 INTRODUCTION Breast conserving surgery with adjuvant radiation therapy is supported by mult iple clinical t rials as being a safe alternative to total mastectomy.2 Outlined by Arm I of RTOG Protocol 1005,1 one current standard of care for external beam radiation (EBRT) is delivery of 50 Gray (Gy) in 25 fract ions to the whole breast with a sequential 12 Gy photon or electron boost to the post-lumpectomy bed delivered in 6 fractions. The addition of such a tumor

bed boost has shown to further decrease recurrence rates for patients with invasive breast cancer.3 For early stage patients (stage I-II) undergoing breast-conservation therapy, the goal of EBRT is to deliver prescription dose to the target volumes while minimizing excess dose to surrounding normal structures. In terms of receiving boost dose in addition to the tangential 50 Gy, normal breast tissue is of particular area of interest and should be taken into account. By sparing this normal breast tissue of irradiation beyond standard whole breast doses, the potential exists to reduce sitespecific late effects, such as fibrosis.4,5 Excess dose may also increase the risk of hyperpig mentation and other acute side-effects.4,5 Despite being a reduced field, boost

Cleveland Clinic | Medical Dosi metry Program Class of 2013

Abstract-Title

AAMD Journal Submission| Zoller , et al.

portals can result in a significant portion of the breast receiving dose well beyond the tangential prescription. A potential difficulty with generating a boost portal fro m init ial simulat ion is the propensity for the p ostlu mpectomy seroma to change in size over the treatment course. The first objective of this study is to statistically quantify the volumetric extent of this change to assess consistency and significance. As a corollary, the second objective is to determine the impact of this seroma volume change on tumor bed dosimet ry. With significant decreases in tumor bed sizes, the possibility exists to minimize boost portals by generating the boost plan from a second computed tomography (CT) dataset acquired near completion of the whole breast course. This optimization may reduce excess irradiat ion to normal breast tissue. Currently, RTOG 1005 requires that all boost plans be rendered from the in itial CT simu lation. 1 This phase of the study will analy ze tu mor bed changes during radiation therapy as well as assess any advantages associated with acquiring a second CT prior to sequential boost planning. Hypofractionated courses for whole b reast radiation have been studied with the primary advantage of reducing total treatment time and associated cost. Arm II of the RTOG 1005 study is testing a radiation schedule of 40 Gy tangentially to the whole breast given in 15 fractions with a concurrent or integrated boost of 8 Gy in these same 15 fractions. This boost may be given by electron, conformal photon, or concomitant IMRT as preferred. 1 Based on this, the third and final objective of the study is to dosimetrically compare two hypofractionated concurrent boost methods for this course, electron versus tangential IMRT photon. Analysis of tumor bed coverage and critical structure avoidance may provide the means to assess preferability between the methods . MET HODS AND MATERIALS Phase I: In this study, eleven previously treated early stage breast cancer patients (stage I-II) with invasive carcinoma of either b reast were retrospectively re-planned using the standard fractionation schedule outlined in Arm I of RTOG Protocol 1005. Patients with clinically evident seroma volu mes at the time of initial CT simulat ion (CT1) were chose for this study sample. While each patient was receiving the conventional 50 Gy in 25 fractions under original radiat ion treatment, a secondary CT dataset (CT2) was acquired around the fourth week of treatment prior to boosting for the characterization of seroma volume changes and to assess a need for adaptive boost planning. All CT data was acquired using a Siemens SOMATOM CT-On-Rails Sensation Open system. Contours of both Lumpectomy gross tumor volumes (GTV) were delineated by a radiation oncologist in

accordance with RTOG Protocol 1005 guidelines using MIM Software Version 5.4 (Cleveland, OH). All contours and CT datasets were transferred to Philips Pinnacle3 with AcQSim t reat ment planning system version 9.0 for the purposes of retrospective re-planning as seen in Fig. 1. The CT2 data and GTV contour were then fused onto the CT1 data set using Philips Pinnacle3 Syntegra fusion system with box-limited cross-matching of mutual CT data of the affected breast and chest wall. Using the treatment planning system, the volumes of the two Lu mpectomy GTV contours were recorded for further analysis of volumetric changes over the course of treatment. Along with these volumes , the Lu mpectomy clinical target volu mes (CTV) , Lu mpectomy p lanning target volumes (PTV), Lu mpectomy PTV Eval, and Breast PTV Eval were delineated in this study for evaluation in accordance with the RTOG 1005 planning guidelines and can be seen in Fig. 2.1 Likewise, crit ical organs included the heart, ipsilateral lung, contralateral lung, and total lung volume; these structures were also generated within RTOG 1005 guidelines.1 The relation between initial GTV volu me (cc)

Cleveland Clinic | Medical Dosimetry Program Class of 2013

1|Page

AAMD Journal Submission| Zoller , et al.

and percent decrease, elapsed time between scans (days) and percent decrease, delta volume (cc), and the percent decrease were calculated. Pearson r regression and paired t-tests were performed to determine correlation strength and result significance. To quantify the dosimetric impact of sero ma volu me changes, tangential plans were rendered for each of the 11 patients in the treatment planning system for a Siemens Artiste linear accelerator with the capabilities to use both 6 and 10 megavolt potential as needed. Tangent fields

the RTOG 1005 Arm I-specified 95% V58.9 associated with each CTV.1 Electron boosts were planned at 100 cm Source-to-Skin Distance (SSD) and the available electron energies of 6, 9, 12, 15, 18, 21 megaelectron volts (MeV) were selected to achieve optimal coverage based on the protocol. Notable dose limiting volu mes for p lan acceptance specifically outlined in Arm I of the protocol involved the volume of ipsilateral lung receiv ing 20 Gray (V20 ), the mean dose to the heart (500 cGy Arm I), and the V56 for the Breast PTV Eval.1 These objectives were, therefore, the limits specifically analy zed in this study for statistical dosimetric comparison of the CT1 GTV and CT2 GTV p lans. In addition, the CT1 volume sequential boost was evaluated in terms of V58.9 coverage of the Lu mpectomy PTV Eval for CT2 to assess the possibility of CT1 lu mpectomy bed-optimized plans under-treating the seroma site due to changes throughout treatment. Phase II: In this phase, the same tangential whole breast fields optimized for phase I were re-prescribed to deliver 40 Gy in 15 fractions as in the hypofractionated schedule of Arm II of RTOG 1005.1 Along with this, the electron boost was represcribed to deliver 8 Gy in 15 fract ions concurrently to the CT1 volu me such that at least 95% of the Lumpecto my PTV Eval received 45.6 Gy as mandated by Arm II.1 To provide a direct comparison, an 8 Gy in 15 fraction concurrent tangential IMRT photon boost was generated compositely with the init ial 40 Gy tangent fields in a separate treatment plan. IMRT fields were limited to the same gantry angles as the tangent fields and were designed to be given

were designed to prescribe 50 Gy in 25 fractions to the whole breast while meet ing dose and coverage constraints outlined by Arm I of RTOG 1005.1 An examp le of these fields can be seen in Fig. 3.1 Forward-p lanned control point segmentation and/or dynamic wedging were used as necessary to meet these constraints. With the fused CT2 contour and the CT1 contour both present on the CT1 data set, it was then possible to generate composite sequential electron boost plans optimized individually for each volu me while maintaining identical whole breast tangential fields. The en-face electron boosts were independently given uniform expansions on each Lu mpectomy CTV (CT1 and CT2) such that each Lu mpectomy PTV Eval received

Cleveland Clinic | Medical Dosimetry Program Class of 2013

2|Page

AAMD Journal Submission| Zoller , et al.

concomitantly as the fields were inverse-planned with both prescriptions on for algorithmic evaluation. The total maximu m number of segments allowable for the two beams was twelve, and each beam was required to have at least three inverse-planned control points to qualify as IMRT per RTOG 1005.1 The same Lu mpecto my PTV Eval coverage constraints were used as in the concurrent electron boost, and some notable dose limiting volu mes for plan acceptance specifically outlined in A rm II o f the protocol included the V16 for the ipsilateral lung, the mean dose to the heart, and the V44.8 for the Breast PTV Eval.1 Analysis of these volumetric constraints was then used for a dosimetric evaluation of a concurrent electron cavity boost and a concurrent tangential IMRT photon boost by comparison of coverage and critical structure avoidance in identical manner to that of Phase I. RES ULTS Phase I: Based on the volume readings of the physiciancontoured CT1 Lu mpectomy GTV and the CT2 Lu mpectomy GTV, the seroma volumes decreased in size for each of the 11 patients with a mean reduction of 57.06% and standard deviation of 8.96% as shown in Table 1. The min imu m percentage decrease in volume among the population sample was 46.12% with the maximu m reduction being 77.34%. The decrease in seroma volume for the patients yielded a p-value of 0.001 and showed to be statistically significant over the course of treatment. The average of the elapsed days between CT1 and CT2 acquisition was 33.6 days +/- 5.14 days. The minimu m time separation between scans for the population was 22 days with the maximu m being 42 days. The Pearson r correlation coefficient between the number of elapsed days and the size decrease in percentage was found to be 0.4869, p=0.1287. Thus, no correlation between the two variables could be determined. For the patient population, the size of the Lu mpecto my GTV contour on CT1 ranged fro m a minimu m of 29.80 cubic centimeters (cc) to a maximu m of 116.85 cc. However, no relationship between the size of the initial GTV volume and the volume reduction percentage could be determined as the Pearson r correlation value between the variables was -0.0575, p =0.866. These results are shown in Table 1. The dosimetric impact of these volume changes was assessed between the CT1 Lu mpecto my GTV and CT2 Lu mpectomy GTV sequential electron boost plans and the results can be seen in Fig. 4. When compared to the CT1 retrospective boost plan, the CT2 plan showed to decrease the V56 Breast PTV Eval for all cases. The V56 for this structure was specifically outlined in Arm I of the RTOG 1005 Protocol as a dose constraint.1 On average, the V56 decreased by 9.16% +/ - 3.26% by re-planning with the new volu me, y ield ing a maximu m decrease of 14.74%

and a minimu m of 4.44%, p=0.001. This showed to be statistically significant in terms of dose reduction to normal breast tissue and results can be seen in Table 2. For the entire population, the maximu m change between the boost plans for mean heart dose was 17.2 cGy, wh ich was less for the CT2-optimized boost. This was minimal as all plans were well belo w the RTOG 1005 Arm I dose constraint of 500 cGy mean dose to the heart. 1 Likewise, the maximu m difference in V20 for the ipsilateral lung between the plans was 0.55%, which was also less for the CT2 Lu mpectomy CTV optimized boost plan. All plans accomplished greater than or equal to 95% coverage for the V58.9 of the Lu mpectomy PTV Eval, wh ich was specifically outlined as ideal in RTOG 1005. 1 When projected onto the CT2 volu me, the CT1 volu meoptimized sequential boost plan still maintained this coverage of the new contour for all cases, with the minimu m being 95.93%. Thus, this study did not show evidence that failure to repeat CT simu lation for boost planning would lead to under-treatment of the seroma volume.

Cleveland Clinic | Medical Dosimetry Program Class of 2013

3|Page

AAMD Journal Submission| Zoller , et al.

Phase II: Analysis of this phase showed a significant decrease in the Breast PTV Eval V44.8 for all concurrent electron boosts when compared to concurrent tangential IM RT photon boosts. The average V44.8 decrease was 16.24% +/- 8.08 for the electron plans, p=0.001 which indicates better dose conformity with the electron boost plan and can be seen in Fig. 5. The maximu m decrease between the methods was 28.07% with a minimu m of 4.62%. Results fro m this phase can be seen in Table 3. The Breast PTV Eval V44.8 was a constraint specifically outlined for the hypofractionated Arm II of RTOG 1005.1 For the mean heart dose, the maximu m variance was 53.5 cGy , wh ich was lower for the IMRT tangential photon boost. However, all mean heart doses were well below the mean dose constraint of 400 cGy outlined for the protocol.1 In accordance, the V16 for the ipsilateral lung yielded a maximu m variance of 1.85% wh ich was lower for the concurrent electron boost. Both of these variances were negligible in the planning process.

DISCUSS ION Multip le studies have looked to assess the volume changes of post-operative seromas throughout the course of radiation treatment.6,7 The first objective of this study was to evaluate the seroma volume changes during the course for patients receiving the standard treatment fractionation scheme (Arm I) outlined by RTOG protocol 1005.1 With this informat ion, it was then possible to evaluate the dosimetric impact of these potential volume changes as it pertains to cavity coverage and dose to critical structures for the standard of care as described in the protocol.1 The goal was to determine any indications for acquiring a second CT data set prior to the planning of a sequential boost. The results from Phase I showed a statistically significant decrease in the seroma volu me during whole breast treatment with an average decrease of 57.06% +/8.96% fro m CT1 to CT2. The average time between these CT acquisitions was 33.6 elapsed days with a standard deviation of 5.14 days. This time period is appropriate and falls at approximately the fourth week of t reat ment. This, in turn, would maintain the time necessary for a sequential boost to be planned on the new CT prior to complet ion of the standard whole breast fractionation course. The applicability of acquiring one additional CT to accurately delineate such a large change provides the benefit of reducing the treatment port volume by basing the marg ins of the sequential boost field off of the new reduced tumor bed volu me fro m CT2. Analysis of the individually optimized CT1 GTV versus CT2 GTV sequential electron boost plans indicated that the volume of normal breast tissue (Breast PTV Eval V56 ) treated was decreased by an average of 9.16% +/- 3.26% wh ile variances on mean heart dose and lung dose were minimal between the plans. This dose reduction to normal breast tissue was found to be statistically significant, and could play a role in decreasing associated acute and late effects of radiation treatment.4,5 50 Gy in 25 fract ions tangentially with a 12 Gy in 6 fract ion electron boost mimics the conventional standard of care, and by acquiring one additional CT dataset prior to boost planning, it could be possible to eliminate treating unnecessary normal tissue. By performing this adaptive re-planning, treat ment plans may have been able to more easily satisfy the dose constraints, or even change a structure dose from acceptable to ideal by trial compliance criteria. It was also necessary in this study to evaluate if the plans optimized for the orig inal volu me still p rovide adequate coverage of the new GTV volu me after the change over the treatment course. For all eleven patients, the original plan provided the necessary coverage of the CT2 Lu mpectomy PTV Eval set per RTOG 1005 Arm I.1 This indicated that although excess normal tissue may have been treated, plans from the original volume would

Cleveland Clinic | Medical Dosimetry Program Class of 2013

4|Page

AAMD Journal Submission| Zoller , et al.

not provide any potentially harmfu l under-dosing in this study. The second objective of this study was to compare dosimetric outcomes for concurrent IMRT photon boosts and concurrent electron cavity boosts given the hypofractionated scheme (Arm II) for breast cancer patients eligible for RTOG protocol 1005.1 In phase II, the Breast PTV Eval V44.8 showed a significant decrease for all electron boost plans when compared to IMRT tangential photon boosts. The V44.8 reduced by 16.24 % on average with a standard deviation of 8.08%. This indicates a potential benefit to concurrent electron boost planning as it reduced the dose to normal breast tissue while provid ing a plan which was mo re conformal to the target volume. Between the two methods, the dose discrepancies were minimal in terms of mean heart and ipsilateral lung dose. CONCLUS ION Tu mo r bed volumes may change significantly over the course of treatment for early-stage breast cancer

patients receiving post-lumpecto my radiotherapy. Due to the changes in the seroma volu me, there may be benefits in acquiring a second pre-boost CT dataset. Acquisition of this new scan would allow not only an assessment of seroma volu me changes, but also an opportunity to perform adaptive boost planning should the change render it necessary. Ultimately, this could decrease the volume of normal breast tissue receiving excess radiation, potentially decreasing acute and late side effects associated with this treatment site.4,5 The results from this patient population indicate merit for secondary CT acquisition for sequentially boosted breast cancer patients and provide a recommendation for its usage. For concurrent hypofractionated treatment methods, the electron boosts were shown to be more conformal to the target volume when co mpared with tangential IM RT photon boost fields, and this resulted in a decrease in dose to normal breast tissue. Again, this could potentially p lay a role in reducing side effects of radiation treatment and provide for better patient outcomes.

TABLES

Cleveland Clinic | Medical Dosimetry Program Class of 2013

5|Page

AAMD Journal Submission| Zoller , et al.

Cleveland Clinic | Medical Dosimetry Program Class of 2013

6|Page

AAMD Journal Submission| Zoller , et al.

REFERENCES 1. Vicini, F.; Freed man, G.; White, J.; et al . A Phase III trial of accelerated whole breast irradiation with hypofractionation plus concurrent boost versus standard whole breast irradiation plus sequential boost for early-stage breast cancer. RTOG protocol 1005; 2012. www.rtog.org Morrow, M .; Stro m, E.A.; Bassett, L.W.; et al. Standard for breast conservation therapy in the management of invasive breast carcinoma. Ca Cancer J Clin. 5: 277-300; 2002. Poortmans, P.M.; Co llette, L.; Bartelink, H.; et al. The addition of a boost dose on the primary tumour bed after lumpectomy in breast conserving treatment for breast cancer. A summary of the results of EORTC 22881-10882 boost versus no boost trial. Cancer Radiother. 6-7: 565-570; 2008. Collette, S.; Collette, L.; Budiharto, T.; et al. Predictors of the risk of fibrosis at 10 years after breast conserving therapy for early breast cancer; a study based on the EORTC Trial 22881-10882 boost versus no boost. Eur J Cancer. 17: 25872599; 2008. Mukesh, M.; Harris, E.; Jena, R.; Evans, P.; Coles, C. Relationship between irradiated breast volume and late normal t issue complications; a systemic rev iew. Radiother Oncol. 104: 1-10; 2012. Sharma, R.; Spierer, M.; Mutyala, S.; et al. Change in seroma volu me during whole-breast radiation therapy. Int J Radiat Oncol Biol Phys. 75: 89-93; 2009. Flannery, T.W.; Nichols, E.M.; Cheston, S.B; et al. Repeat computed tomography simulation to assess lumpectomy cavity volume during wholebreast irradiation. Int J Radiat Oncol Biol Phys. 75: 751-760; 2009.

2.

3.

4.

5.

6.

7.

Cleveland Clinic | Medical Dosimetry Program Class of 2013

7|Page