INTRODUCTION
Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death among females worldwide, with an estimated 2,088,849 new cases and 626,679 deaths.[ 1 ] It is the commonest cancer in urban Indian females and the second commonest in the rural Indian females and data has shown a trend toward increase in the incidence of breast cancer in India. According to the National Cancer Registry Programme in India, 1,62,468 new cases of breast cancer and about 87,090 deaths attributed to it were reported in 2018.[ 2 ]
Radiotherapy is one of the integral components in the multidisciplinary management of breast cancer patients. There is considerable evidence available for node-positive breast cancer patients that locoregional radiotherapy after mastectomy results in improved local control, significant reduction in distant metastases, and absolute increase in breast cancer survival.[ 3 ] Danish Breast Cancer Cooperative Group’s (DBCG) trial 82b, DBCG 82c, and British Columbia Cancer Agency Randomized Radiation trial were the first prospective randomized trials using uniform modern radiation techniques to show not only a locoregional control advantage but also a survival advantage associated with postmastectomy radiotherapy.[ 4–6 ] Traditionally, conventional radiotherapy plan based on clinical Landmarks is used to deliver radiation to postmastectomy patients. Conventional fields are placed based on radiopaque markers applied over chest wall (CW) to delineate targets to be irradiated solely based on anatomical landmarks at the time of the simulation. Most commonly, a mono-isocentric photon technique is used whereby opposed tangent split beams are employed for CW irradiation and are matched at isocenter to a superior angled antero-posterior supraclavicular (SCV) field. The medial border of wide tangent field is typically set at lateral opposite border of sternum to include internal mammary nodes (IMNs), and lateral border is at the mid or posterior axillary line as clinically indicated. The inferior edge is two centimeters inferior to the level of where the inframammary fold existed. The contralateral breast (if it is intact), can be used to estimate the level of the inframammary fold. The superior border of the CW fields serves as the match plane for SCV field and should be marked at the inferior edge of the clavicular head. The gantry angles of the tangent fields are then designed with half-beam block technique to limit posterior divergence into the lungs.[ 7 ]
As the planning evolved from two-dimensional (2-D) to three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated radiotherapy (IMRT) need of precise delineation of clinical target volumes and organs at risk became more prudent. And now, in the current scenario also, planning techniques are continuously evolving to achieve more homogeneous dose distribution to the target and sparing of normal tissues at the same time. Computed tomography (CT) simulation scans are preferably used nowadays in most of the institutions in India to decide placement of the treatment fields, and contouring of target volumes to be used for treatment planning in either 3D-CRT or IMRT treatments. Few randomized trials of IMRT and volume-based planning in breast cancer demonstrated reduction in moist desquamation and better cosmetic outcomes with volume-based planning compared to clinically derived 3-D and 2-D planning.[ 8 , 9 ] This has led clinicians to adopt suitable contouring guidelines of breast cancer .
Need to standardize the radiotherapy treatment plans and ease to compare treatment plans among different institutions gave way to prepare guidelines to contour postmastectomy and post breast-conserving surgery of breast cancer patients. The Radiation Therapy Oncology Group (RTOG) published a consensus guideline for CT-based target delineation for breast cancer patients that give anatomically based definitions for target volumes.[ 10 ] Variation in target volume delineation will practically be reduced while following the same guideline by physicians and among different institutions.
Since published results of trials of adjuvant radiotherapy in breast cancer patients treated during the 2D planning era and clinically derived planning era have demonstrated a very low rate of loco-regional relapse, it was ensured in guideline that no significant changes in the field arrangements and sizes of the fields during the shift from 2D to 3D were introduced.
The objective of this study was to evaluate coverage of the RTOG consensus guideline-defined volumes of CW and draining lymphatics with a standard clinically derived treatment plan in which lymphatics were not contoured. At present, there is no literature available suggesting the better outcome of patients treated with this RTOG defined volumes and better or optimal sparing of organ at risks (OARs).
SUBJECTS AND METHODS
Unilateral breast cancer patients who have underwent Radical Mastectomy and have received adjuvant radiation therapy to CW and draining lymphatics from January to June 2016 were selected for the study. Female breast cancer patients, 18–70 years of age with histologically confirmed infiltrating ductal carcinoma without evidence of distant metastasis or second malignancy were eligible for the study. Twenty consecutive breast cancer patients were selected to complete ten patients each of right and left-sided breast cancer . CT simulation images and radiation treatment planning information of all patients were used for the analysis. Before undergoing radiation treatment, patients were simulated on CT-based treatment simulator in supine position on a commercially available angled breast board to make sternum parallel to the table, with both arms fully abducted (90° or greater) and externally rotated, and head tilted to opposite direction.
Two-to-three-millimeter (mm) slice thickness of contrast-enhanced CT images were generated and transferred to treatment planning system. The field borders for treatment were clinically decided with the help of radiopaque wires placed during the simulation process and delineation of CW done. The beam arrangement was uniform among all patients and involved a single-isocentric technique. Superiorly tangent beams were matched to a half-beam oblique SCV photon beam. All treatment plans had been modified based on patient’s anatomy and tumor factors, and approved by a radiation oncologist before treatment. Typical beam arrangements for SCV and CW are shown in representative images of right-sided breast cancer cases in [Figure 1 ].
Figure 1: Clinically designed radiotherapy beam arrangements for a post-mastectomy right breast cancer patient in axial view. (a) Supra-clavicular beam (b) medial and lateral tangential beams
The prescription doses for all patients were 42.4 Gray (Gy) in 16 fractions over 3 weeks to the iso-center for the CW and supraclavicular fields. A commercial treatment planning system, XIO (Version 5.0; Elekta Medical System, Crawley, UK), was used to generate the treatment plans. All plans were generated using 6 MV photons. Actual treatment plans were clinically designed using CT images to achieve full coverage of the regions at risk of recurrence and sparing of normal structures without routine contouring of all targets. Forward planned 3D-CRT planning was done, employing two tangents with field-in-field segments to reduce hot spots for each patient.
Dose-volume histograms (DVHs) were generated from clinically designed plans that had actually been delivered to each patient after contouring of targets volumes and OARs according to RTOG contouring guideline, but coverage of these contours was not prime objective. For comparing dose to target volumes, new radiotherapy plans based on RTOG contouring guideline were generated with the goal of covering 95% of target volume to 90% (38.16 Gy) of prescribed dose, and new DVHs were generated to compare with the DVHs of clinically designed plan. Target volumes were defined according to the specifications of the RTOG Breast Cancer Atlas for Radiation Therapy Planning: Consensus Definitions.[ 10 ] The following structures were contoured on the planning CT scans: CW; level I, level II, and level III axillae (Ax1, Ax2, and Ax3); SCV, IMN; heart (H); and ipsilateral and whole lung.
An average DVH was generated for each structure from all the 20 patients with both radiation treatment plans for comparison. The mean V90 (Volume of the target receiving 90% of the prescribed radiation dose) values of each target were noted for each case. The mean heart V5 Gy and V20 Gy (volume of the heart receiving 5 and 20 Gy) were calculated for 20 patients and also separately for the 10 right-sided and the 10 left-sided cases. The mean ipsilateral and whole lung V20 values were also calculated separately for right- and left-sided cases.
Treatment plans were forward-planned, and adjustments were made to meet planning goals. In addition to coverage of target volumes specified, radiation plans were optimized to minimize the dose received to normal structures, including heart and lung. CW contours were contoured by removing the superficial 5 mm of volume to account for the build-up region. With this modification, it is practical to meet greater than 95% coverage of CW volume.
Dose constraints used in this analysis were based on the Quantitative Analyses of Normal Tissue Effects in the Clinic published in 2010. We ensured that 95% of the CTV should be covered by the 90% of the prescribed dose. The maximum point dose was kept under 105%–107% of prescribed dose. The volume of ipsilateral and total lung receiving 20 Gy or more (V20 Gy) were restricted under 45% and <25%. The mean heart dose was mandated to be V5 Gy <40% and V20 Gy <20% regardless of right- or left-sided breast cancer . As a wide tangent is used to include IMN, the lung and heart doses were critical evaluation before finalization of these plans.
Statistical analysis
Continuous variables were compared with Paired t -test analysis as the sample size was small. DVH parameters of mean value of each structure; V90 values for CW, SCV, Ax1, Ax2, and Ax3, IMN; V20 for lung, and V5 and V20 for heart dose with both radiation plans were compared.
RESULTS
Clinically derived radiation treatment plans: How well it covered radiation therapy oncology group-defined target volumes?
The calculated mean V90 of each target volume and V5 Gy, V20 Gy of OAR of all patients were plotted on DVH for comparison. The mean V90 values for the RTOG consensus volumes in clinically derived plans were as follows: CW 89.8% (standard deviation [SD]: 4.56%), SCV 83% (8.95%), Ax3 86.67% (14.03%), Ax2 85.92% (11.87%), Ax1 80.35% (8.95%), and IMN 81% (11.42%) [Table 1 ].
Table 1: Mean volume receiving 90% of prescribed dose (V90=3816 cGy)
The mean heart V5 and V20 values were 7.82% (8.11%) and 3.42% (4.53%), respectively, mean ipsilateral and total lung V20 were 23.87% (5.44%) and 12.33% (1.83%), respectively. The mean dose to the opposite breast was 0.66 Gy (0.69%) Table 2 .
Table 2: Organ at risk dose comparison according to radiation plan type
There was a considerable difference in dose received by OARs when laterality is considered. For patients treated for left-sided breast cancer , the mean heart V5 and V20 values were 14.52% and 6.55%, the mean left lung and total lung V20 were 22.34% and 11.34%, respectively. While for patients of right-sided breast cancer , the mean heart V5 and V20 values were 1.13% and 0.29%, mean right lung and total lung V20 were 25.41% and 13.32%, respectively [Table 3 ].
Table 3: Heart and lung radiation dose comparison taking laterality into account
Regions of the CW, SCV, and Ax3, contoured as per RTOG consensus guidelines, receiving 38.16 Gy in right-sided breast cancer patient is shown in a representative case [Figure 2 ]. Notably, portions of the contoured CW in the posterior and deep border of the caudal aspect of the field did not receive 38.16 Gy, nor did the superficial aspect of the CW in the build-up region. The medial and deep aspect of the contoured SCV also did not receive 38.16 Gy.
Figure 2: Representative clinically derived plan in sagittal view showing coverage of radiation therapy oncology group defined target contours
Radiation therapy oncology group defined target volumes directed radiation plans: Does better coverage is at the expense of higher dose to organ at risks?
New radiation treatment plans according to RTOG consensus guideline were generated for all the same patients. In these contoured plans, goals were to achieve 95% coverage of RTOG-defined target volumes to cover with 38.16 Gy of radiation dose (90% of the prescribed dose). The calculated mean V90 values for the RTOG consensus volumes in contour-derived plans were as follows: CW 95.26% (SD: 3.96%), SCV 94.9% (4.29%), Ax3 98.6% (1.75%), Ax2 97.09% (4.36%), Ax1 96.40% (5.07%), and IMN 95.42% (2.95%). As shown in Table 1 , the mean heart V5 and V20 values were 8.95% (9.02%) and 4.07% (4.89%) respectively, mean ipsilateral and total lung V20 were 28.73% (4.28%) and 14.06% (1.68%), respectively. The mean dose to opposite breast was 1.12 Gy (1.27%) [Table 2 ].
When these contour-based treatment plans were compared with clinically derived treatment plans, coverage improved for all target volumes; CW (V90 = 89.8 vs. 95.2%, P < 0.05), SCV (V90 = 83 vs. 94.9%, P < 0.05), IMN (V90 = 81.0 vs. 95.42%, P < 0.05) and axillary nodal coverage for Level-I (V90 = 80.35% vs. 96.40%, P < 0.05), Level-II (V90 = 85.9%3 vs. 97.09%, P < 0.05), and Level III (V90 = 86.67% vs. 98.6%, P < 0.05).
Low dose to heart is increased in left-sided cases (V5 = 14.52% vs. 16.72%, P < 0.05), but it was within specified dose constraints while it was same in right-sided cases. The dose to the ipsilateral lung was increased (V20 = 23.87% vs. 28.73%, P < 0.05). The dose to the total lung was increased in left sided cases (V20 = 11.34% vs. 13.88%, P < 0.05) [Table 3 ].
Therefore, doses shown to be increased in RTOG based plans are acceptable as these are within the dose constraints limit. Improved dose coverage can be seen in representational sagittal view of contours in right-sided breast cancer patient [Figure 3 ].
Figure 3: Representative Radiation Therapy Oncology Group contour derived plan in sagittal view showing coverage of Radiation Therapy Oncology Group defined target contours: Note, Better supraclavicular coverage in superior portion and chest wall coverage in posterior caudal aspects
DISCUSSION
The use of 3D-CRT technique for adjuvant radiation of breast cancer has lagged substantially owing to its complex target volumes and historical encouraging results of clinically derived radiation planning. Many randomized trials and systematic reviews on postmastectomy adjuvant radiation with conventional planning showed excellent long-term locoregional control, progression-free survival, and overall survival in breast cancer . As we adopt 3D-CRT in breast cancer , designing a conformal radiation plan to cover adequate target volume at risk of recurrence and plan evaluation becomes streamlined and standard if single contouring guideline is followed.
In this analysis, we found adequate coverage of RTOG defined target volumes with contour-based plans that are theoretically supposed to be covered with clinically derived plans. With contour-based plans, although OARs received more doses than clinically derived plans but were found to be within the dose constraints specified. Conversely, it is also proved in this analysis that conventional planned radiation therapy is not adequate to provide full coverage of RTOG defined target volumes. Improved dose coverage with contour-based plans is evident in all targets: CW (V90 = 89.8 vs. 95.2%, P < 0.05), SCV (V90 = 83 vs. 94.9%, P < 0.05), Axillary Level-I (V90 = 80.35 vs. 96.40%, P < 0.05), Axillary Level-II (V90 = 85.93 vs. 97.09%, P < 0.05), Axillary Level III (V90 = 86.67 vs. 98.6%, P < 0.05), and IMN (V90 = 81.0 vs. 95.42%, P < 0.05) [Figure 4 ].
Figure 4: Diagrammatic representation of differences in target volume percentage receiving 90% of prescribed dose in both plans
Fontanilla et al . in 2012, conducted analysis with the same parameters of RTOG defined contour on 20 postmastectomy patients with 50 Gy prescription dose showed, CW coverage 74% and nodal coverage ranging from 80% to 96%.[ 11 ] Improvement in target volume coverage with contour-based plan was shown, CW 94% and nodal volumes 95%–98% except IMN coverage which was not improved. In our study CW, all axillary levels and IMN coverage were better than this study and all coverages improved with RTOG contoured plans. The mean V20 Ipsilateral lung V45 value for right- and left-sided breast cancer was 32% and 45%, respectively in Fontanilla et al . while in our study with 42.4 Gy prescription dose, the same parameters were 29.48% and 28.00%, respectively. The mean heart V10 values were significantly more for both left-sided (14% vs. 11%, P = 0.007), and right-sided cases (10% vs. 6%, P < 0.001) in this study. In our study, only heart V5 value of left-sided breast cancer was significantly increased, although heart V5 of right-sided and V20 of left-sided breast cancer cases were increased in RTOG-derived plans in comparison to clinically derived plans differences were not statistically significant [Figure 5 ].
Figure 5: Diagrammatic representation of differences in radiation dose received by heart and lungs
Rudra et al . in 2012 conducted a randomized trial comparing BCS and postmastectomy (79%) patients treated with clinically derived plan or RTOG contour-derived plans.[ 12 ] Statistically significant coverage was improved for SCV (V90 = 78.0% vs. 93.6%, P = 0.02) and intact breast V95 (95.6% vs. 99.3%, P = 0.007) with the targets delineated plans. The low dose for the ipsilateral lung (V5 Gy = 84.5% vs. 69.3%, P = 0.001) and whole lung (V5 Gy = 44.0% vs. 35.7%, P = 0.03) was increased. Surprisingly, low dose to the heart in RTOG plans was decreased with mean V5 Gy of 48.7% versus 27.3% (P = 0.02) and mean V10 Gy = 33.5% versus 17.5% (P = 0.01). This difference was also seen for left-sided tumors. As shown in Table 3 , in our study, the absolute differences in dose coverage were improved for all the nodal volumes.
CONCLUSIONS
The study shows that radiotherapy using the RTOG consensus contouring guidelines improves coverage of target volumes with a slight increase in OARs dose, compared to that are traditionally used. Current clinically designed treatment plans, which are the proven standard, are not able to cover any of the anatomically based RTOG consensus target volumes. This study will facilitate further discussion about RTOG guideline utility or selection from other available breast contouring guidelines. Further, mapping pattern of recurrence studies and future clinical trials will be encouraged with this analysis.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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