Forward Intensity-Modulated Radiotherapy Planning in Breast Cancer to Improve Dose Homogeneity: Feasibility of Class Solutions

Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 1, pp. 394–400, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter

doi:10.1016/j.ijrobp.2010.09.005

CLINICAL INVESTIGATION

Physics

FORWARD INTENSITY-MODULATED RADIOTHERAPY PLANNING IN BREAST CANCER TO IMPROVE DOSE HOMOGENEITY: FEASIBILITY OF CLASS SOLUTIONS HEIKE PEULEN, M.D., BIANCA HANBEUKERS, M.A., LIESBETH BOERSMA, M.D., PH.D., ANGELA VAN BAARDWIJK, M.D., PH.D., PIET VAN DEN ENDE, M.D., RUUD HOUBEN, M.SC., JOS JAGER, M.D., PH.D., LARS MURRER, PH.D., AND JACQUES BORGER, M.D., PH.D. Department of Radiation Oncology, MAASTRO Clinic, Maastricht, The Netherlands Purpose: To explore forward planning methods for breast cancer treatment to obtain homogeneous dose distributions (using International Commission on Radiation Units and Measurements criteria) within normal tissue constraints and to determine the feasibility of class solutions. Methods and Materials: Treatment plans were optimized in a stepwise procedure for 60 patients referred for postlumpectomy irradiation using strict dose constraints: planning target volume (PTV)95% of >99%; V107% of <1.8 cc; heart V5 Gy of <10% and V10 Gy of <5%; and mean lung dose of <7 Gy. Treatment planning started with classic tangential beams. Optimization was done by adding a maximum of four segments before adding beams, in a second step. A breath-hold technique was used for heart sparing if necessary. Results: Dose constraints were met for all 60 patients. The classic tangential beam setup was not sufficient for any of the patients; in one-third of patients, additional segments were required (<3), and in two-thirds of patients, additional beams (<2) were required. Logistic regression analyses revealed central breast diameter (CD) and central lung distance as independent predictors for transition from additional segments to additional beams, with a CD cut-off point at 23.6 cm. Conclusions: Treatment plans fulfilling strict dose homogeneity criteria and normal tissue constraints could be obtained for all patients by stepwise dose intensity modification using limited numbers of segments and additional beams. In patients with a CD of >23.6 cm, additional beams were always required. Ó 2012 Elsevier Inc. Radiotherapy, Breast-conserving therapy, Treatment planning, Class solutions.

forward planning methods to obtain a homogeneous dose distribution (using International Commission on Radiation Units and Measurements [ICRU] criteria) (10), within dose constraints and tried to define class solutions.

INTRODUCTION Postoperative whole-breast irradiation after breastconserving therapy is standard treatment for early-stage breast cancer (BC). Usually, two opposing tangential beams are used to cover the planning target volume (PTV). This approach gives excellent local control, with a local recurrence rate of <1% per year (1), but generally, dose homogeneity is poor. Overdosage may result in poor cosmetic outcome and more acute side effects (2–4). Homogeneity becomes more important in hypofractionation schemes (5). Dose homogeneity is difficult to achieve due to the shape of the breast (6, 7). PTV coverage with a minimal dose of 95% often leads to overdosage (8). Underdosage often is a problem in large breasts. Intensity-modulated radiotherapy (IMRT) for breast cancer improves dose homogeneity (9). However, inverse treatment planning requires sophisticated technical resources and contouring of target and organ volumes. We explored simple

METHODS AND MATERIALS Patients Thirty-eight patients with left-sided BC and 22 patients with right-sided BC were randomly selected from our database. All patients had stage I or II disease, the mean age was 56 years old (95% confidence interval [CI], 38-74), and patients had been recently referred to our department for postlumpectomy irradiation. To evaluate heart dose, we deliberately selected more left-sided patients. Computed tomography (CT) scans obtained in 3-mm-thick slice intervals without contrast and were available for all patients. Leftsided BC patients were scanned using voluntary, moderately deep-inspiration breathhold (vmDIBH) if necessary for heart protection (maximum heart distance, >1 cm) (11). In short, patients were coached to hold their breath for 30 sec after two cycles of

Acknowledgment—We thank Colette Dijcks, Truus Hooijen, Nicole Menten, Anke van der Salm, Jennifer Strijbos, Cissy Stultjens, Lieke Verhoeven, Doreen Verstappen, and Mireille Westbroek. Received Feb 11, 2010, and in revised form June 14, 2010. Accepted for publication Sept 14, 2010.

Reprint requests to: Heike Peulen, NKI-AVL, Department of Radiation Oncology, Postbox 90203, 1006 BE Amsterdam, The Netherlands. Tel: +3120-5127860; Fax: +3120-5121592; E-mail: [email protected] Conflict of interest: none. 394

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deep respiration. Set-up verification was done with electronic portal images (of bone anatomy) and copper skin markers (12). Evaluation (n = 60) of reproducibility with and without vmDIBH, using a shrinking action level protocol, revealed nonsignificant random and systematic errors in the range of 2 mm.

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tissue, we defined dose points: centrally in the vertebral body at the level of the central plane, in the thoracic 12th vertebral body (T12), centrally in the ipsilateral upper abdomen at the level of T12, and in the isthmus of the thyroid gland. We calculated the conformity index as defined by the Radiation Therapy Oncology Group protocol: irradiated volume 95% /PTV95% (13).

Delineation of target volumes and organs at risk Target volumes. Whole-breast clinical target volume (CTV) was indicated by a radioopaque wire on the skin, based on contour and palpation. Breast CTV was defined at 5 mm under the skin surface, in front of the major pectoral muscle and chest wall (Fig. 1); borders were determined largely by the radioopaque wire. Cranially, the CTV did not extend above the superior border of the sternoclavicular joint, and medially, not beyond the lateral edge of the sternum. CTV-planning target volume (PTV) expansion was 5 mm in all directions, except toward the skin surface where no CTV-PTV margin was taken. If standard tangential fields were set up, this PTV often extended beyond standard fields. The irradiated volume of the tangential fields was taken as the ‘‘gold standard,’’ and we created an auxiliary PTV (PTVaux) with medial and lateral adjustments according to the 95% isodose lines of the standard tangential beam setup (Fig. 1). We clipped the PTV at 7 mm under the skin, due to random underdosage directly under the skin if it were clipped at 5 mm, using two standard tangential 6-MV beams (data not shown). This definition of the PTVaux was used for all study patients and is referred to in this study as PTV from here on. Boost CTV was defined by adding surgical (lumpectomy) and radiotherapy margins up to 15 mm around the excision cavity, applying anatomical borders (chest wall). CTV-PTV expansion was 5 mm in all directions, clipped at 7 mm below the skin. Normal tissues. Contralateral breasts, hearts, and lungs were contoured. Delineation of the heart started at one slice below the pulmonary trunk; pericardium was excluded. All delineations were checked by one investigator (HP) to limit interobserver variation. To evaluate radiation exposure to other surrounding normal

Treatment planning Standard tangential fields were applied. If dose homogeneity was not achieved, a stepwise optimization procedure was started, with strict criteria for homogeneity and normal tissue constraints. The first optimization step consisted of applying only additional segments (maximum of four segments). If the optimized plan fulfilled all criteria (see below), the treatment plan was accepted. If criteria were not met, a second optimization procedure was started, in which beams (maximum of four) were added to the existing plan with segments. Results were evaluated according to the planning procedure: standard tangential versus final optimized plan, in which each patient served as her own control. For all plans, a dose of 50 Gy in 25 fractions was prescribed, specified at the intersection of the beam axes in the central plane according to ICRU guidelines (10). Treatment planning was performed using a superposition algorithm (XiO version 4.2.2 software: CMS, St. Louis, MO). A Siemens Oncor 82-leaf collimator was used for optimization. Standard tangential fields. Treatment planning started with a classic open, tangentially opposing beam setup using (motor) mediolateral wedges and alignment of the dorsal field borders, with beam energy levels of 6 MV. Dose constraints for tangential setup were a central lung distance (CLD) of <30 mm (14) and a maximum heart distance of <10 mm (15). Reduction of field width or shielding with leaves to reduce heart and lung doses was permitted; no additional beams were allowed. A craniocaudal wedge was permitted and scored as a segment.

Fig. 1. Auxiliary PTV (PTVaux): medial and lateral planning target volumes are shown adjusted according to classical tangential beam setup. Purple = breast CTV; red = PTV.

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Criteria for optimization. Dose homogeneity had to meet ICRU criteria. Minimum dose is 95% of the reference dose and should cover 99% of the PTV. Maximum dose within the body contour was only allowed to be >107% of the reference dose if it occurred in a volume with a diameter of less than 15 mm, measured in craniocaudal, mediolateral, and ventral-dorsal directions ‘‘(corresponding to a volume of 1.8cc)’’. (10). Although the optimal parameter for predicting late cardiac toxicity is not well established, low dose may increase the incidence of cardiovascular disease (16). Therefore, we chose to apply strict heart constraints: V5 Gy of <10% and V10 Gy of <5%. The CLD of <3 cm is the most widely used lung constraint in tangential field irradiation (14). We used the mean lung dose (MLD) for three-dimensional (3D) evaluation of radiation-induced lung toxicity (17) and induction of secondary tumors (18). In a subset analysis, the CLD of <3 cm correlated with an MLD of <7 Gy. Therefore, the lung constraint was set at an MLD of <7 Gy. Dose constraints were applied rigorously, with concessions to whole-breast PTV coverage if necessary. No such concessions were allowed for boost PTV coverage. Heart constraints were overruled only when boost PTV coverage was compromised. Optimization procedure 1: applying additional segments. PTV coverage and dose homogeneity were optimized with the same tangential open or wedged beam setup by adding a maximum of two segments per beam (procedure 1) (Fig. 2). A segment was defined as an additional beam with an angle difference of #5 from standard tangential angles and was considered a component of the total intensity-modulated beam. Beams with larger differences in beam angles were qualified as additional beams (procedure 2). Optimization with additional segments was done with 6 or 10 MV. Optimization procedure 2: applying additional beam(s). PTV coverage and dose homogeneity were further optimized by applying additional beams to the additional segments (Fig. 2). A maximum of four additional beams of 6 or 10 MV was used for optimization.

Statistical analysis Average differences in dose-volume parameters between three treatment planning procedures (standard tangents vs. additional segments or additional beams) were tested with a Wilcoxon

Fig. 2. Beam setup after optimization with additional segments and beams in a patient treated for left-sided breast cancer. Solid line = tangential classical beams; dotted line = additional segments; dashed line = additional beam; yellow = 95% isodose line; magenta = 105% isodose line; blue = heart.

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signed-rank test. The level of (two-tailed) statistical significance was set at 0.05. Because of multiple pairwise comparisons, a Holm-Bonferroni (two-tailed) correction was applied. Univariate analysis was performed to test the impact of central breast diameter (CD, i.e., distance between dorsal entry points of two opposing beams in the central plane), CLD, breast radius (BR, i.e., distance between chest wall and skin surface in the central plane perpendicular to the CD), and whole-breast PTV (PTV) on the choice of treatment planning procedure. Correlation of these parameters was tested using a Pearson test. The most significant factors were included in a logistic regression analysis.

RESULTS 3D dose distributions meeting all criteria were obtainable for all patients. In none of the patients did standard tangential angles yield an adequate treatment plan fulfilling all constraints. An optimized 3D dose distribution could be reached in 21 patients (35%) by applying additional segments, whereas in 39 patients (65%) application of an additional beam(s) was required (Table 1). Plan characteristics A mean of 2.9 segments was added to standard tangents for optimization with additional segments (Table 2). In case of further optimization, a mean of 1.5 additional beams was applied. Higher beam energy levels were more often used in additional beams than in additional segments: 26% versus 4%, respectively. Dose homogeneity Differences between plans: additional segments versus standard tangents. Median PTV coverage by the 95% isodose line (PTV95%) was 99.0% with standard tangents and increased to 99.4% after optimization with additional segments (p = 0.114) (Table 3). One patient with the smallest CD (17.8 cm) had no overdosage in the standard tangential plan. After optimization with additional segments, PTV95% increased from 98% to 99% (Fig. 3). Although the median PTV95% was >99% after optimization, PTV was underdosed due to heart shielding in 1 of 21 patients with PTV95% values of 98.3%, with standard tangential angles, and 96.8%, with additional segments. Differences between plans: additional beams versus standard tangents. The median PTV95% was 96.9% with standard tangents and 99.2% after optimization with additional beams (p < 0.001) (Table 3). Underdosage of the PTV occurred in 10 of 39 patients. In 9 cases, the PTV was compromised to reach cardiac constraints: median PTV95% was 93.5% (range, 84.2%–99.3%) for tangents versus 96.5% (range, 88.4%–97.9%) after optimization. In 1 case, PTV underdosage was caused by loss of an adequate build-up region due to small-volume slices of caudal breast tissue. Heart dose. In all patients, heart constraints were met. No differences were seen in maximum heart doses between tangential planning and optimized plans (Table 3). After plans were optimized with additional segments, there were no significant increases in median heart dose,

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Table 1. Patient characteristics according to treatment plan Additional segments

Additional beams

Characteristics

Tangents

Optimized

Tangents

Optimized

Number of patients Number of left-sided BC* Median age (years) Median Breast Diameter (cm) Median Breast Radius (cm) Median Central Lung Distance (cm) Median Maximum Heart Distance (cm) Median Breast PTV volume (cc) Median Boost PTV volume (cc)

21 13

21 13 53 20.4 7.7 1.8 0.4 569 88

39 25

39 25 56 23.3 9.2 2.2 0.7 904 147

Abbreviation: BC = breast cancer.

V5 Gy, and V10 Gy. When plans were optimized using additional beams, the median heart dose increased from 1.3 Gy with tangents to 1.8 Gy after optimization (p < 0.001). The V5 Gy increased from 1.9% in tangential planning to 4.5% after optimization (p = 0.004). Differences in V10 Gy were not significant. Lung dose. In all patients, the MLD (both lungs) was <7 Gy after optimization: MLD was 3.2 Gy with additional segments and 3.8 Gy with additional beams. For optimization with additional segments, the mean ipsilateral lung dose was increased from 5.5 Gy in standard tangents to 5.8 Gy after optimization (p = 0.003) (Table 3). Contralateral mean lung doses remained unchanged. After optimization with additional beams, mean ipsilateral lung dose was 6.8 Gy in tangential plans and 7.7 Gy after optimization (p < 0.001). Contralateral lung dose increased from 0.2 Gy in tangential plans to 0.3 Gy after optimization (p < 0.001). Contralateral breast dose. After optimization with segments, maximum and median contralateral breast doses showed no significant difference (Table 3). With additional beams, maximum and median contralateral breast doses increased from 2.7 Gy to 3.7 Gy (p = 0.001) and from 0.2 Gy to 0.4 Gy (p < 0.001), respectively. Dose to other normal tissues. With respect to dose points used to estimate dose to the central plane of the spine, T12, the ipsilateral upper abdomen at the T12 level, and the isthmus of the thyroid gland, all values were <1 Gy and not significantly different between standard and optimized plans. The conformity index did not significantly change after op-

timization and remained at about 1.5 for both optimization procedures (Table 3). Predictive factors for selection of the optimization procedure. Univariate analysis showed CD, CLD, BR, and PTV values were significantly related to the type of optimization procedure: the larger the values of these parameters, the larger the probability that additional segments were insufficient and additional beams were required. Since CD, BR, and PTV were closely correlated (Pearson test range, 0.670.91), of these parameters only CD, the parameter with the highest statistical significance in univariate analysis, was tested using multivariate analysis. Multivariate logistic regression analysis showed CD (odds ratio [OR] = 1.7; 95% CI, 1.2-2.3; p = 0.002) and CLD (OR = 6.2; 95% CI, 1.6-23.9; p = 0.008) were independent predictors for transition from additional segments to additional beams. In our patient group, additional beams were required for all patients with a CD of >23.6 cm. In the case of a CD of > 22.4 cm, additional beams were necessary for optimization in 87% of the cases. DISCUSSION We showed that by using a stepwise forward intensitymodulated treatment planning procedure, we could make excellent treatment plans fulfilling our strict dose homogeneity criteria and normal tissue constraints in all 60 patients. Optimal plans were relatively simple to obtain, with fewer than three additional segments in one-third of the cases.

Table 2. Plan characteristics according to treatment plan Additional segments (n = 21)

Additional beams (n = 39)

Characteristics

Tangents

Optimized

Tangents

Optimized

Beam energy 6 MV (%) Mean total number of beams and segments Mean number of beams without segments Mean number of total segments Total Monitor Units Medio-lateral wedge (number) Weight of tangentials (mean %) Cranio-caudal wedge (number)

100 2.3 2 0.3 221 37 79 7

96 5.2 2 3.2 230 22 81 4

100 2.3 2 0.3 224 75 85 10

74 6.7 3.5 3.2 246 30 63 8

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Table 3. Dose-volume parameters according to treatment plan Parameters

Additional segments (n = 21)

Additional beams (n = 39)

Dosimetric outcome

Tangents

Optimized

p value

Tangents

Optimized

p value

Treated Volume (median cc) Conformity Index (median) PTV95% 7 mm (median %) PTV95% 5 mm (median %) Median overdosage V107% (cc) Boost PTV coverage (median %) Median dose PTV 7mm Median MLD ipsilateral (%) Median MLD contralateral (%) Maximum contralateral breast dose (Gy) Median contralateral breast dose (Gy) Maximum heart dose (median in Gy) Median heart dose (Gy) Median V5Gy (%) Median V10Gy (%)

833(328–1413) 1.55(1.21–2.1) 99.0(94.0–100) 98.0(93.2–99.6) 31.8(0.0–224.5) 99.6(94.3–100) 50.7(49.9–51.8) 5.5(3.0–9.8) 0.2(0.1–0.3) 3.6(0.5–8.4) 0.4(0.1–0.6) 38.2(1.5–50.5) 1.0(0.3–2.9) 2.0(0.0–9.7) 0.8(0.01–6.6)

873(379–1394) 1.57(1.33–1.81) 99.4(96.8–99.9) 98.3(93.8–99.2) 0.4(0.0–2.2) 99.7(98.5–100) 50.5(49.9–51.0) 5.8(3.1–9.8) 0.2(0.1–0.3) 4.2(0.5–20.1) 0.4(0.1–0.6) 40.2(1.6–49.9) 1.2(0.3–2.6) 3.0(0.0–8.6) 1.1(0.0–4.3)

NS NS NS NS < 0.001 NS NS 0.003 NS NS NS NS NS NS NS

1452(407–2794) 1.52(1.24–2.52) 96.9(84.2–99.9) 96.6(82.6–99.5) 99.9(5.0–493.5) 99.6(58.4–100) 50.8(46.6–52.0) 6.8(2.7–9.9) 0.2(0.1–0.3) 2.7(0.6–53.2) 0.2(0.1–0.9) 32.1(2.1–52.6) 1.3(0.3–5.2) 1.9(0.0–14.7) 0.7(0.0–9.9)

1316(464–2432) 1.53(1.26–2.22) 99.2(88.4–99.9) 97.3(86.6–99.3) 0.8(0.0–2.6) 99.7(98.5–100) 50.4(48.9–51.1) 7.7(2.9–10.7) 0.3(0.1–0.9) 3.7(1.1–51.6) 0.4(0.1–1.5) 41.7(2.4–50.5) 1.8(0.4–3.2) 4.5(0.0–10.3) 0.9(0.0–5.2)

NS NS < 0.001 NS < 0.001 NS NS < 0.001 < 0.001 0.001 < 0.001 NS < 0.001 0.004 NS

Abbreviations: MLD = mean lung dose, T12 = thoracic 12th vertebral body; NS = not significant. Heart parameters shown only for leftsided treatments: n = 13 for additional segments, and n = 25 for additional beams. Data in median with range between brackets. p = significant if < 0.05.

Two-thirds of our patients required fewer than two beams in addition to the beam segment plan. In patients with a CD of >23.6 cm, additional beams were always necessary. Plans for patients with this characteristic should be made directly with procedure 2. Dose homogeneity Planning studies with multiple segments or fields in the literature report PTV95% values ranging from 90% to 97% (6, 8, 15, 19–24), whereas all our optimized plans had PTV95% values of >99%. This can be explained partly by differences in PTV definition; most studies use a PTV delineation of 0 to 5 mm under the skin surface, whereas we chose 7 mm. This depth was chosen because tangential beam setup using 6-MV photons always resulted in random underdosage of the PTV defined at 5 mm in the subcutis, making systematic evaluation of underdosage elsewhere in the PTV difficult. Since there is no clinical

evidence for high recurrence rates, in the subcutaneous area in particular, we believe this PTV definition is acceptable. The general conclusions of our study with regard to the procedures required to optimize dose homogeneity and whole-breast PTV coverage remained the same when the breast PTV was defined at 5 mm under the skin, albeit the PTV95% is <99% for both optimization approaches: 98% with additional segments and 97% with additional beams (Table 3). Possible differences in breast size can influence the outcome of dose homogeneity. We reported median breast volumes of 569 cm3 in optimization with segments and 904 cm3 with additional beams (Table 1), which are comparable to other reports (7, 15, 20–26). Most studies expressed overdosage as the percentage of volume receiving >105%, 107%, or 110% of the prescribed dose, with values ranging from 0.3% to 14% (7–9, 15, 19– 23, 26, 27). We only took overdosage into account when >107% was found in at least 15 mm of a continuous tissue

Fig. 3. Absolute differences in volume within the body contour receiving >107% of the prescription dose according to procedures.

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volume (1.8 cc), since larger regions of overdosage can result in acute and late toxicity such as skin reactions and fibrosis but also radiation-induced pain and sometimes rib fractures (28). The presence of regions with overdosage are significantly correlated with worse cosmetic outcome (2, 3). In addition, Pignol et al. (4) concluded that moist desquamation was reduced when high doses were avoided and that moist desquamation was correlated with increased pain and reduction of quality of life. Heart dose The clinical significance of heart exposure to low doses has not been fully explored, but some studies suggest that this might have important consequences with respect to morbidity and mortality (29, 30). We reported low median heart doses of 1.2 Gy and 1.8 Gy after optimization with segments and additional beams, respectively, whereas the literature reports values in the range of 5 to 8.5 Gy (19–21). Median values of V5 Gy were <5% irrespective of optimization procedure compared with studies reporting V30Gy values in the range of 2% to 5% (22). Our strict heart constraints could be met by applying vmDIBH. Lung dose Ipsilateral MLD was 5.8 Gy after optimization with segments, whereas in the literature, mean lung doses are reported from 6.4 to 11 Gy (7, 19–22, 27). Optimization with additional beams resulted in an ipsilateral MLD of 7.7 Gy, which is similar to values reported in the literature (19, 22, 27), although some studies report MLD values of >10 Gy (21, 24). One explanation may be that we applied vmDIBH and used a superposition algorithm for treatment planning, predicting a lower lung dose (31). Induction of secondary malignancies Some investigators suggest that IMRT might increase the incidence of secondary cancer from 1% in conventional

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planning to 1.75% in IMRT planning for patients surviving 10 years (32). Median contralateral (calculated) breast dose with additional beams doubled from 0.2 Gy to 0.4 Gy after optimization, which is negligible. With respect to lung cancer induction, postoperative radiotherapy for breast-conserving therapy appears to have an effect in women under 50 years of age (hazard ratio = 2.31) and smokers (OR = 10.5 in contralateral lung cancer; OR = 37.6 in ipsilateral lung cancer) (33, 34). The average excess relative risk for females at 1 sievert (Sv), according to the United Nations Scientific Committee on the Effects of Atomic Radiation, is 1.48 (absolute excess risk = 2.38 [104 PY Sv -1]) (35). The only relevant increase seems to be 0.9 Gy in the ipsilateral MLD after optimization with additional beams. This would result in an excess relative risk of 1.43 and an absolute excess risk of 2.14/104 PY in ipsilateral lung cancer, representing only a slightly increased risk in a worst-case scenario.

CONCLUSIONS In almost all cases, it is impossible to meet ICRU criteria for whole-breast irradiation with standard tangential beams. Homogeneous dose distribution, according to ICRU standards, can be easily obtained by stepwise adjustment of dose intensity. The addition of a mean of 2.9 segments to two standard tangents resulted in good coverage and no overdosage in one-third of the patients. In two-thirds of the patients, further optimization was necessary by applying a mean of 1.5 additional beams. After optimization there was an acceptable dose increase to heart, lungs, and contralateral breast tissue but no additional dose to other normal tissues. In case of a CD of >23.6 cm, optimization with additional segments was not sufficient and additional beams were always required.

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