This prospective study was designed to verify the technical feasibility of partial breast irradiation in breast cancer patients with small breasts, which are commonly encountered in Korean women.
A total of 40 Gy, administered in 10 fractions on consecutive days (one fraction per day), was prescribed to the isocenters of the fields using three-dimensional conformal radiotherapy (3-DCRT). For all patients, treatment planning and dose parameters strictly adhered to the constraints set forth in the Radiation Therapy Oncology Group (RTOG) 0319 protocol. This study was designed such that if fewer than five of the first 42 evaluable patients received unacceptable scores, the treatment would be considered reproducible.
Ten treatment plans (23.8%) were determined to have major variations. There was no major variation in planning target volume (PTV) coverage. The ipsilateral and contralateral breast dose limitations were not met in four (9.5%) and four cases (9.5%), respectively. Major variations in ipsilateral and contralateral lung dose limitations were observed in two cases (4.8%). Major variations in the heart and thyroid dose limitations were observed in one (2.4%) and one case (2.4%), respectively. In multivariate analysis, a ratio of PTV to ipsilateral breast volume (PTV/IB) > 0.16 was the only significant factor that statistically affected major variations.
We concluded that partial breast irradiation using 3-DCRT could not be reproduced in Korean breast cancer patients, particularly small-volumed breast surrogated as PTV/IB > 0.16. The dominant cause was the major variation in surrounding normal breast tissues.
A systematic review and meta-analysis of the current randomized trials to evaluate the role of accelerated partial breast irradiation (APBI) in eligible breast cancer patients suggested that APBI did not appear detrimental to survival and could be used as an alternative to whole breast irradiation (WBI) [
The high “elsewhere” failure throughout the review of APBI frontier studies indicated the importance of appropriate patient selection and optimal APBI techniques [
We need to determine whether the technical feasibility confirmed in Western breast cancer patients could be equally applicable to Korean women, who have relatively small breasts compared to Western women. Therefore, we designed phase I and II clinical trials to evaluate the technical feasibility of 3-DCRT in Korean breast cancer patients, using the technique confirmed by RTOG 0319, to determine the types of variations that occur during PBI with 3-DCRT in small-volumed breast cancer patients. This is the first report of the technical feasibility of PBI with 3-DCRT in Korea.
We defined the inclusion criteria more strictly than that of RTOG 0319; the criteria were postmenopausal women, a unifocal tumor, tumor size ≤ 2 cm with a resection margin (RM) > 2 mm, negative sentinel or axillary nodes, hormone receptor positivity, and a good to excellent postoperative cosmesis score [
Patients were immobilized in the supine position with both arms elevated upward, using a vacuum immobilization device. The ipsilateral whole breast and breast surgical scar were marked with a radiopaque rubber catheter. A treatment planning computed tomography (CT) scan (Hi-Speed FX/I, GE Medical Systems, Milwaukee, WI) was performed at a 3-mm scan width, and a contrast-enhanced image was obtained. The scan began at or above the mandible to beyond the breast tissue, including the entire lung. We used the Varian Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA). The following structures were contoured manually by the radiation oncologist: the lumpectomy cavity (LC) volume, PTV, ipsilateral breast, contralateral breast, thyroid, ipsilateral and contralateral lungs, and heart. We defined the target volume from the LC. To reduce the variability in LC contouring, radiation oncologists who participated in this study were educated and accustomed to the target volume definition guidelines. We assigned a clarity visualization score (CVS) to each patient, as follows; CVS-1, no cavity visualized; CVS-2, cavity visualized but significant uncertain margins; CVS-3, cavity visualized with some uncertain margins; CVS-4, cavity with mild heterogeneity on CT and mostly distinct margins; CVS-5, homogenous cavity with clearly identified margins [
The treatment was administered with three-dimensional conformal fields, and intensity-modulated radiation therapy was not allowed. Three or four non-coplanar beams that used 6-MV photons or a mixed-modality plan that used a photon field with an en face electron field were used. The maximum dose should not exceed 110% of the prescribed dose. We followed the radiotheraphy delivery technique and dosimetric guidelines for dose volume constraints set forth by the RTOG 0319 study. A thorough review of the dose volume histogram of each patient was performed by both the radiation oncologist and physicist, and a quality assurance evaluation of the treatment plans was performed to determine the variations.
Each plan was scored as acceptable (per protocol), marginally acceptable (minor variation), or unacceptable (major variation). An acceptable plan showed 95% isodose surface covers 100% of the PTV, and all specified critical normal tissue dose limits have been met. A marginally acceptable plan showed 95% isodose surface covers between ≥ 95% to < 100% of the PTV, and all specified critical normal tissue dose limits fall within 5%. An unacceptable plan showed 95% isodose surface covers < 95% of the PTV, or any critical normal tissue dose limit exceeding 5% of the specified value. Each dose limitation for normal tissues followed the criteria described in the RTOG 0319 protocol [
In brief, less than 50% of the ipsilateral whole breast should receive ≥ 50% of the prescribed dose and less than 25% of the whole breast should receive the prescribed dose. The contralateral breast should receive less than 3% of the prescribed dose to any point. At most, less than 10% of the ipsilateral lung can receive 30% of the prescribed dose and less than 10% of the contralateral lung should receive 5% of the prescribed dose. In right-sided lesions, less than 5% of the heart should receive 5% of the prescribed dose in a while the volume of the heart receiving 5% of the prescribed dose should be less than that for treatment using conventional whole breast radiation with tangential fields in left-sided lesions. Maximum point dose in thyroid should be less than 3% of the prescribed dose.
A total of 40 Gy, given in 10 fractions on consecutive days, one fraction per day, were prescribed to the isocenters of the fields. Electronic portal imaging was monitored for the first session and repeated at the sixth radiotherapy session. No patients received chemotherapy, and adjuvant endocrine therapy was combined with radiotherapy in all patients.
Technical feasibility was the primary end point in this study. A final review of the plan as acceptable or marginally acceptable indicated that the technique is reproducible. An optimal two-stage Simon design was used for this trial. Let p-value be the true probability that the final review is acceptable or marginally acceptable. A p-value close to 1 implies that the radiation therapy is reproducible in a multi-center setting. If p-value is ≤ 80%, the goal is to have at most a 5% probability of concluding that the technique is reproducible. On the other hand, if p-value is ≥ 95%, the desired level, the goal is to have at most a 10% probability (five cases) of concluding that the technique is not reproducible in the first 42 evaluable treatment plans. Associations with pretreatment factors, including the tumor location, tumor side, ipsilateral breast volume, PTV volume, and PTV volume to ipsilateral breast volume ratio (PTV/IB) were tested using the chi-square test and logistic regression. Fisher’s exact test was used with small sample sizes (< 5 in any cells) in univariate analysis. All statistical data were processed using SPSS ver. 19.0 (SPSS Inc., Chicago, IL), and null hypotheses were rejected at p < 0.05.
A total of 42 patients were enrolled in this study between January 2009 and July 2013. The pretreatment characteristics are shown in
Results of the plan evaluation with regard to dosimetric variations for the 42 patients, upon which the decision of feasibility was based, are shown in
We analyzed the relationship between the tumor or normal tissue parameters and major variations in the treatment plans (
Dose limitations in the ipsilateral and contralateral breast were not met in four (9.5%) and four cases (9.5%), respectively. Case no. 13 had major variations in both ipsilateral and contralateral breast dose limitations (
In the analysis of ipsilateral lung dose constraints, two cases (4.8%) showed major variations. Ipsilateral breast volumes < 900 mL and PTV/IB ratios > 0.16 were observed in both cases. In two cases with major variations in the contralateral lung dose limitation, we did not observe any specific features. Only one case (2.4%) had a major variation in the heart. In this case, the tumor was located in the lower central portion of the right breast. Although an electron beam was used in part in this case, more than 2 Gy were delivered to the right atrium. A thyroid dose limitation was observed in one case (2.4%). In this case, the LC was in the upper quadrant of the left breast, near the thyroid gland (
As clinical experiences with PBI increase, it is certain that patient subsets might be adequately treated with PBI, with acceptably low recurrence rates. As PBI currently remains an investigational approach and is not yet a standard therapy, we designed this study to include a more rigorously selected group of patients than would be allowed by the “suitable” criteria suggested in the American Society for Radiation Oncology consensus statement [
Delineation of the optimal treatment volume required to obtain equal or better local control rates, compared with WBI, after conservative surgery is crucial to the precision of conformal radiation therapy planning and the validity of clinical trial results [
The widespread acceptance of APBI using the 3-DCRT approach is likely because it is totally noninvasive and delivers a homogenous dose distribution to the target volume. In our study, PTV was defined to exclude the skin (5 mm beneath the skin surface) in order to reduce skin toxicity [
In our study, the ipsilateral breast dose limitations of V50% < 50% were not acceptable in four cases (9.5%), while, there was no violation of the ipsilateral breast dose limitation in the RTOG 0319 study [
Although we could not draw the same conclusion regarding technical feasibility as in the RTOG 0319 study, we can conclude that the PTV/IB ratio affects the technical feasibility of 3-DCRT planning for PBI and it can be performed in Korean breast cancer patients with PTV/IB ≤ 0.16, even those with small breasts. In addition, further study is needed in order to determine feasible dose limitations, particularly breast limitation, when PBI with external-beam irradiation is administered to small-breasted patients.
Conflict of interest relevant to this article was not reported.
Dose distribution of partial breast irradiation using two coplanar and two non-coplanar photon beams.
Dose volume histogram of partial breast irradiation using two coplanar and two non-coplanar photon beams. Lumpectomy cavity (purple), planning target volume (red), ipsilateral breast (yellow), contralateral breast (cyan), ipsilateral lung (blue), contralateral lung (green), and heart (orange) are depicted.
Patient characteristics
PBI (n=42) | |
---|---|
Age (yr) | |
Median | 62.0 |
Range | 50-76 |
pT stage | |
mi | 2 (4.8) |
1a | 2 (4.8) |
1b | 14 (33.3) |
1c | 24 (57.1) |
Tumor size (cm) | |
Median | 1.1 |
Range | 0.1-1.9 |
Tumor side | |
Right | 12 (28.6) |
Left | 30 (71.4) |
Tumor location | |
Upper outer | 26 (61.8) |
Upper inner | 3 (7.1) |
Lower outer | 4 (9.5) |
Lower inner | 2 (4.9) |
Upper central | 6 (14.3) |
Lower central | 1 (2.4) |
Cavity visualization score | |
2 | 1 (2.4) |
3 | 11 (26.2) |
4 | 19 (45.2) |
5 | 11 (26.2) |
Lumpectomy cavity (mL) | |
Median | 34.88 |
Range | 15.40-86.73 |
PTV (mL) | |
Median | 108.94 |
Range | 59.59-185.67 |
Ipsilateral breast volume (mL) | |
Median | 784.18 |
Range | 337.58-1,476.60 |
PTV/IB | |
Median | 0.1481 |
Range | 0.07-0.23 |
Values are presented as number (%). PBI, partial breast irradiation; pT stage, pathologic T stage; PTV, planning target volume; PTV/IB, planning target volume to ipsilateral breast volume ratio.
Technical feasibility of radiation treatment planning using three-dimensional conformal radiotherapy
PTV coverage | Ipsilateral breast | Contralateral breast | Ipsilateral lung | Contralateral lung | Heart | Thyroid | Overall | |
---|---|---|---|---|---|---|---|---|
No variation | 26 (61.9) | 36 (85.7) | 33 (78.6) | 37 (88.1) | 40 (95.2) | 41 (97.6) | 41 (97.6) | 18 (42.9) |
Minor variation | 16 (38.1) | 2 (4.8) | 5 (11.9) | 3 (7.1) | 0 | 0 | 0 | 14 (33.3) |
Major variation | 0 | 4 (9.5) | 4 (9.5) | 2 (4.8) | 2 (4.8) | 1 (2.4) | 1 (2.4) | 10 (23.8) |
Values are presented as number (%). PTV, planning target volume.
Pretreatment factors impacting technical feasibility using three-dimensional conformal radiotherapy
p-value |
||
---|---|---|
Univariate analysis |
Multivariate analysis |
|
Tumor location (lower) | 0.203 | - |
Tumor location (inner) | 0.341 | - |
Tumor side (left) | 0.600 | - |
Ipsilateral breast volume (> 900 mL) | 0.476 | - |
PTV (> 130 mL) | 0.020 | - |
PTV/IB (> 0.16) | 0.014 | 0.015 (OR, 7.0; 95% CI, 1.4-33.7) |
Values are presented as number (%). PTV, planning target volume; PTV/IB, planning target volume to ipsilateral breast volume ratio; OR, odds ratio; CI, confidence interval.
Fisher’s exact test was used due to small sample size (less than five cases in any cell),
Logistic regression test was performed.
Dosimetric features in cases with major variations of treatment planning using three-dimensional conformal radiotherapy
Case no. | PTV (mL) | IB (mL) | PTV/IB | Side | Location | Location (inner) | Major variation |
---|---|---|---|---|---|---|---|
2 | 120.82 | 818.22 | 0.147 | Left | Lower | No | Contralateral breast |
9 | 141.47 | 1,446.69 | 0.097 | Left | Upper | No | Thyroid |
13 | 148.16 | 763.54 | 0.194 | Left | Upper | No | Ipsilateral breast, contralateral breast |
18 | 155.32 | 864.37 | 0.179 | Right | Upper | No | Ipsilateral breast |
23 | 63.59 | 337.58 | 0.188 | Right | Upper | No | Contralateral breast |
27 | 134.42 | 807.71 | 0.166 | Right | Lower | No | Ipsilateral lung, contralateral lung, heart |
28 | 175.94 | 764.87 | 0.23 | Left | Lower | Yes | Ipsilateral breast |
31 | 88.28 | 528.81 | 0.166 | Left | Upper | Yes | Ipsilateral breast, ipsilateral lung |
36 | 74.08 | 487.98 | 0.151 | Left | Upper | No | Contralateral lung |
42 | 167.72 | 1,031.22 | 0.162 | Left | Upper | No | Contralateral breast |
PTV, planning target volume; IB, ipsilateral breast volume; PTV/IB, planning target volume to ipsilateral breast volume ratio.