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The influence of the boost in breast-conserving therapy on cosmetic outcome in the eortc “boost versus no boost” trial
Int. J. Radiation Oncology Biol. Phys., Vol. 45, No. 3, pp. 677– 685, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter
PII S0360-3016(99)00211-4
CLINICAL INVESTIGATION
Breast
THE INFLUENCE OF THE BOOST IN BREAST-CONSERVING THERAPY ON COSMETIC OUTCOME IN THE EORTC “BOOST VERSUS NO BOOST” TRIAL CONNY VRIELING, M.D.,* LAURENCE COLLETTE, M.SC.,† ALAIN FOURQUET, M.D.,‡ WILLEM J. HOOGENRAAD, M.D.,§ JEAN-CLAUDE HORIOT, M.D.,㛳 JOS J. JAGER, M.D., PH.D.,¶ MARIANNE PIERART, M.SC.,† PHILIP M. POORTMANS, M.D.,# HENK STRUIKMANS, M.D., PH.D.,兰 MARLEEN VAN DER HULST,# EMMANUEL VAN DER SCHUEREN, M.D., PH.D.,⬁ HARRY BARTELINK, M.D., PH.D.* ON BEHALF OF THE EORTC RADIOTHERAPY AND BREAST CANCER COOPERATIVE GROUPS** *Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; †EORTC, Brussels, Belgium; Department of Radiation Oncology, Institut Curie, Paris, France; §Department of Radiation Oncology, Joint Center for Radiotherapy Arnhem/Nijmegen, St. Radboud Hospital, Nijmegen, The Netherlands; 㛳Department of Radiation Oncology, Centre Georges-Franc¸ois Leclerc, Dijon, France; ¶Department of Radiation Oncology, Radiotherapeutisch Instituut Limburg, Heerlen, The Netherlands; # Department of Radiation Oncology, Dr. Bernard Verbeeten Instituut, Tilburg, The Netherlands; 兰Department of Radiation Oncology, University Hospital Utrecht, Utrecht, The Netherlands; ⬁Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven, Belgium ‡
Purpose: To evaluate the influence of a radiotherapy boost on the cosmetic outcome after 3 years of follow-up in patients treated with breast-conserving therapy (BCT). Methods and Materials: In EORTC trial 22881/10882, 5569 Stage I and II breast cancer patients were treated with tumorectomy and axillary dissection, followed by tangential irradiation of the breast to a dose of 50 Gy in 5 weeks, at 2 Gy per fraction. Patients having a microscopically complete tumor excision were randomized between no boost and a boost of 16 Gy. The cosmetic outcome was evaluated by a panel, scoring photographs of 731 patients taken soon after surgery and 3 years later, and by digitizer measurements, measuring the displacement of the nipple of 3000 patients postoperatively and of 1141 patients 3 years later. Results: There was no difference in the cosmetic outcome between the two treatment arms after surgery, before the start of radiotherapy. At 3-year follow-up, both the panel evaluation and the digitizer measurements showed that the boost had a significant adverse effect on the cosmetic result. The panel evaluation at 3 years showed that 86% of patients in the no-boost group had an excellent or good global result, compared to 71% of patients in the boost group (p ⴝ 0.0001). The digitizer measurements at 3 years showed a relative breast retraction assessment (pBRA) of 7.6 pBRA in the no-boost group, compared to 8.3 pBRA in the boost group, indicating a worse cosmetic result in the boost group at follow-up (p ⴝ 0.04). Conclusions: These results showed that a boost dose of 16 Gy had a negative, but limited, impact on the cosmetic outcome after 3 years. © 1999 Elsevier Science Inc. Breast cancer, Breast-conserving therapy, Radiotherapy boost, Cosmetic result.
Accepted for publication 26 May 1999. **Trial participants and responsible physicians: Tilburg NL (Poortmans), Utrecht NL (Struikmans), Leuven B (Van den Bogaert), Dijon F (Horiot), Paris F (Fourquet), Amsterdam NL (Borger), Heerlen NL (Jager), Nijmegen NL (Hoogenraad), Cologne D (Mu¨ller), Geneva CH (Kurtz), Nottingham GB (Morgan), Montpellier F (Dubois), Namur B (Salamon), Lausanne CH (Mirimanoff), Leiden NL (Leer), Grenoble F (Bolla), Haifa IS (Kuten), La Louviere B (Renaud), Krefeld D (Schulz), Rotterdam NL (Koper), Antwerp B (Van den Weyngaert), Brussels B (Storme), Creteil F (Calitchi), Berlin D (Budach), Du¨sseldorf D (Roth), Brisbane AUS (Poulsen), Pamplona ES (Dominguez), Vannes F (Monpetit), Tel Aviv IS (Kovner), Barcelona ES (Biete Sola), Madrid ES (Calvo)
Reprint requests to: Harry Bartelink, Department of Radiation Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] Acknowledgments—The authors thank all the participating institutions for their cooperation, the panel members Jacques H. Borger, Stefan J. Brenninkmeyer, Marianne Pierart, Joop A. Van Dongen, and Erik Van Limbergen for their great effort in scoring the photographs, Ellen Bartelink for performing all the digitizer measurements, and Abram Recht for reviewing the manuscript. This work was partially supported by a grant from the European Commission (DGXII) within the framework of BIOMED I and by Grants 3U10CA11488-18S1 through 2U10CA11488-28 from the National Cancer Institute (Bethesda, Maryland, USA). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. 677
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INTRODUCTION Over the last decade, breast-conserving therapy (BCT) has been established as the treatment of choice for patients with early-stage breast cancer (1– 4). However, specific details of the surgical, radiotherapeutic, and systemic adjuvant approaches are not generally agreed upon. In this paper we will concentrate on one of the controversial items of radiotherapy technique, namely the effects of giving a boost dose to the tumor bed. The two major endpoints of BCT are good local control and good cosmetic outcome. The influence of the radiotherapy boost on both endpoints, however, is controversial. Pezner et al. (5, 6) claimed that omitting the local boost in patients with tumor-free specimen margins resulted in local control rates comparable to those of other institutions that routinely used a boost. On the other hand, the Lyon trial (7) showed that the delivery of a 10-Gy boost (given in fractions of 2.5 Gy) to the tumor area significantly reduced the risk of early local recurrence in patients with tumor-free margins from 4.5% to 3.6% at 5 years, compared to treatment of the whole breast with a dose of 50 Gy in 2.5-Gy fractions. A similar controversy exists concerning the influence of the radiation boost on the cosmetic result after BCT. Some studies have concluded that the boost had no effect on the cosmetic outcome, in terms of the degree of breast retraction or the proportion of patients having an excellent or good cosmetic result, although patients treated with a boost may have had an increased frequency of telangiectasia (5, 7, 8). Others have demonstrated a negative effect of the boost on the global cosmetic result (9 –12). One factor that might determine whether or not the boost can be shown to worsen the cosmetic outcome is the time following radiotherapy at which the cosmetic result is evaluated. It is well known that the cosmetic changes progress over the first years after BCT and that the cosmetic outcome is evaluable only after at least 3 years (13–16). Two of the above-mentioned studies which found no adverse effect of the boost evaluated cosmetic outcome at a median follow-up of 2 years or less (5, 7). The European Organization for Research and Treatment of Cancer (EORTC) Phase III trial 22881/10882 for Stage I and II breast cancer was created to unequivocally answer the question of the impact of the radiation boost on local control, survival, and cosmesis. The current analysis focuses on the influence of the boost on the cosmetic outcome.
METHODS AND MATERIALS Trial design and treatment From May 1989 to June 1996, 5569 early-stage breast cancer patients were entered in the “boost versus no boost” trial. Patients with T1-2 N0-1 M0 invasive breast cancer were eligible. Exclusion criteria were: age over 70 years; carcinoma in situ (CIS) without invasive tumor; residual microcalcifications on mammogram or gross residual dis-
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ease in the breast after tumorectomy (unless reexcision had been performed); tumor foci in more than one quadrant; a prior history of malignant disease; or an Eastern Cooperative Oncology Group (ECOG) performance score of greater than 2. The patients were treated with tumorectomy (with a macroscopic tumor-free margin of 1 cm) and axillary dissection, followed by tangential irradiation of the whole breast of 50 Gy, with a dose per fraction of 2 Gy, in 5 weeks. Patients with a microscopically complete excision were randomized to receive either no further treatment or a boost of 15 or 16 Gy (15 Gy for interstitial and 16 Gy for external beam therapy). Patients with a microscopically incomplete excision were randomized to receive either a 10 Gy boost or a boost of 25 or 26 Gy (25 Gy for interstitial and 26 Gy for external beam therapy). The completeness of excision of a possible CIS component has not been taken into account in the definition of a complete excision. The volume to be treated by the boost was defined as the site of the primary tumor, with a safety margin of 1.5 cm around the primary tumor after a microscopically complete excision and of 3 cm after incomplete excision or in patients with an extensive intraductal component (EIC). The following techniques were accepted: (a) two external photon beams: cobalt-60 or X-ray beams in the range of 4 to 8 MV, the boost dose being specified in the center of the tumor excision area; (b) one electron beam: the energy of the electron beams being chosen in such a way that the 85% isodose surface encompassed the boost target volume, with the dose specified as the maximum dose; or (c) interstitial therapy: iridium-192 wires or cesium-137 wires, the dose being prescribed according to the Paris system and specified at the reference isodose (defined as 85% of the mean basal dose), preferably delivered at a dose rate of about 50 cGy per hour. In order to avoid late radiation telangiectasia, it was recommended that the most superficially located needles should be located at least 5 mm below the overlying skin surface. For this analysis, only the boost dose itself has been taken into account. In the prognostic factor analysis for cosmetic outcome (to be published), other factors such as boost modality and boost volume will be analyzed as well, together with various other treatment parameters. Cosmetic assessment The original design of the “boost versus no boost” trial aimed at assessing the influence of the boost on local control and cosmesis. It was estimated that 330 patients should be treated in each treatment arm to provide an 80% power for detecting a difference of 10% in the rate of overall excellent/good results between the treatment arms. However, as it was demonstrated that a recruitment rate of 1000 patients a year could be achieved, it was decided to add survival as an endpoint. It was estimated that at least 5000 patients should be entered to be able to detect a 5% difference in the 10-year survival rates, with an ␣ of 0.01 and  of 0.1. However, this large a number of patients would not be needed to prove beyond any doubt the influence of the boost on cosmesis. It was therefore decided to analyze the number of patients as
Influence of the boost in BCT on cosmesis
originally calculated for the evaluation of the influence of the boost on cosmesis. Because the surgical excision of invasive disease was microscopically complete for 95% of patients, the cosmetic outcome was evaluated only for patients randomized to receive either no boost or a boost of 15 or 16 Gy. The panel scored 731 patients, both postoperatively and after 3 years of follow-up. These patients were not randomly selected, but were the first patients evaluable at both time points. Because the quantitative cosmetic evaluation (digitizer measurements) was much less time-consuming, it was decided to analyze all available pictures (postoperative and at 3-year follow-up) by means of the digitizer. A total of 3201 patients were scored with the digitizer. In 2060 patients, only a baseline picture was measured; in 201 patients, only a 3-year follow-up picture was measured; and in 940 patients both baseline and 3-year follow-up pictures were scored. A review panel consisting of 5 persons (see Acknowledgments) scored the cosmetic results, based on the photographs taken after surgery (before radiotherapy was started) and after 3 years of follow-up. The following items were evaluated by comparing the treated breast with the untreated breast: global cosmetic result; appearance of the surgical scar; breast size; breast shape; nipple position; and shape of areola. In scoring these items, a 4-point scale was used, classifying the results into one of the following categories: “0” represented an excellent result; “1” a good result; “2” a fair result; and “3” a poor result (17). A photograph or slide with a frontal view of the patient standing with both arms alongside the body was used for measurements of the nipple position in order to calculate the breast retraction assessment (BRA) values (18). The absolute value of the BRA as well as the relative BRA [defined as (BRA/reference length) ⫻ 100, see Fig. 1] are measures of lack of symmetry between the nipple positions. The relative BRA (or percentage BRA, pBRA) was used in this analysis instead of the absolute BRA for technical reasons as explained in a publication concerning the methods of cosmetic evaluation used in this trial (19). The measurements were performed by one person (see Acknowledgments) using a digitizer of a radiotherapy treatment planning system. The reliability of the panel evaluation as well as the digitizer measurements have been described previously (19). Statistical methods The distribution of patient, tumor, and treatment characteristics of panel patients was compared to the remainder of the population and, similarly, patients with any digitizer measurements available were compared to patients without, in order to check for significant differences. To account for the very large sample size of the overall population and to correct for the multiplicity of testing according to the Bonferroni method (20), a significance level of 0.001 or less is used for claiming significance of any of the comparisons made. The scores given by the 5 reviewers for each patient at each occasion have been combined into a single average. Such score can be interpreted as the score assigned to a
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Fig. 1. Illustration of the BRA measurements.
BRA ⫽ 冑共a1 ⫺ b1 兲2 ⫹ 共a2 ⫺ b2 兲2 ; reference length 共ref.兲 ⫽ 冑b 12 ⫹ b 22; pBRA ⫽ 共BRA/reference length兲 ⫻ 100 picture by an “average observer.” This average score takes values between 0 and 3, with a score close or equal to 0 indicating an excellent result and a score close or equal to 3 indicating a poor result. For the purposes of presentation and tabulation, these averages have been rounded to the closest integer. Comparison of the distribution of the scores between the two treatment arms was performed, for each cosmetic item at both evaluation times, using the WilcoxonMann-Whitney test (21). The cosmetic score after 3 years was described in relation to the initial cosmetic aspect of the breast. This was done in order to account for the fact that, due to the limited range of possible score values, patients with a score of 0 at their first evaluation can only remain stable or worsen, whereas patients who start with a score of 3 can only remain stable or improve. To test for the presence of a significant change in the cosmetic outcome after 3 years, a chi-square test for marginal homogeneity (22) was applied to the tables of initial versus 3-year follow-up scores. A significance level of 0.05 or less was used. The treatment effect according to the digitizer measurements was assessed by means of an analysis of variance (ANOVA) I model. The change in the pBRA between baseline and the 3-year follow-up evaluation was calculated as follows: pBRA3 years ⫺ pBRAbaseline. The time effect was assessed by means of a linear mixed model (23) which takes into account the natural correlation between two measurements made on the same subject. RESULTS Patient population An overview of the distribution of the patient, tumor, and treatment characteristics of the different patient populations is given in Table 1. The p-values in this table relate to the
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Table 1. Patient, tumor and treatment characteristics Panel patients
Age (median and range in years) Tumor location Lateral Central/superior Medial Inferior Unknown T clinical T1 T2 T3 T pathological ⱕ 10 mm 11–20 mm ⬎ 20 mm unknown Reexcision Yes No Unknown Volume of excision ⱕ 100 cm3 101–200 cm3 201–300 cm3 ⬎ 300 cm3 unknown Type of axillary dissection Discontinuous En bloc No dissection or unknown Postoperative breast complications Present Absent Unknown Postoperative axilla complications Present Absent Unknown Radiation quality of WBI Cobalt-60 X-ray Combination or unknown Dose WBI in isocenter ⱕ 49.5 Gy 49.5–50.5 Gy ⬎ 50.5 Gy Unknown Boost treatment received No boost Electron boost Cobalt-60 boost X-ray boost Interstitial boost Unknown
Others
Digitizer patients
No boost
Boost
Overall
No boost
N ⫽ 367 N (%)
N ⫽ 364 N (%)
N ⫽ 4567 N (%)
p-value*
55 (23–72)
56 (26–72)
55 (26–83)
NS†
Boost
Others Overall
N ⫽ 1580 N ⫽ 1621 N (%) N (%)
N ⫽ 2099 N (%)
p-value*
55 (23–80)
54 (26–83)
NS†
55 (26–79)
196 (53) 51 (14) 58 (16) 62 (17) 0 (0)
185 (51) 43 (12) 64 (17) 72 (20) 0 (0)
2215 (48) 727 (16) 771 (17) 854 (19) 0 (0)
NS‡
790 (50) 244 (15) 266 (17) 280 (18) 0 (0)
803 (50) 214 (13) 295 (18) 307 (19) 2 (0)
1003 (48) 363 (17) 332 (16) 401 (19) 0 (0)
NS‡
193 (53) 174 (47) 0 (0)
189 (52) 175 (48) 0 (0)
2360 (52) 2205 (48) 2 (0)
NS‡
809 (51) 771 (49) 0 (0)
849 (52) 770 (48) 2 (0)
1084 (52) 1013 (48) 2 (0)
NS‡
81 (22) 208 (57) 69 (19) 9 (2)
83 (23) 193 (53) 78 (21) 10 (3)
1152 (25) 2451 (54) 888 (19) 76 (2)
NS§
408 (26) 827 (52) 321 (20) 24 (2)
393 (24) 869 (54) 324 (20) 35 (2)
515 (24) 1156 (55) 390 (19) 38 (2)
NS§
95 (26) 272 (74) 0 (0)
100 (27) 264 (73) 0 (0)
1111 (24) 3456 (76) 0 (0)
NS‡
368 (23) 1212 (77) 0 (0)
405 (25) 1214 (75) 2 (0)
533 (25) 1566 (75) 0 (0)
NS‡
99 (27) 110 (30) 45 (12) 45 (12) 68 (19)
113 (31) 87 (24) 51 (14) 41 (11) 72 (20)
1649 (36) 1078 (24) 427 (9) 468 (10) 945 (21)
⬍ 0.001§ 530 (34) 406 (26) 160 (10) 180 (11) 304 (19)
570 (35) 400 (25) 168 (10) 168 (10) 315 (20)
761 (36) 469 (23) 195 (9) 206 (10) 468 (22)
NS§
309 (85) 56 (15) 2 (0)
304 (84) 59 (16) 1 (0)
3926 (86) 614 (13) 27 (1)
NS‡
1340 (85) 229 (14) 11 (1)
1401 (87) 215 (13) 5 (0)
1798 (86) 285 (13) 16 (1)
NS‡
39 (11) 327 (89) 1 (0)
57 (16) 307 (84) 0 (0)
571 (13) 3992 (87) 4 (0)
NS‡
200 (13) 1379 (87) 1 (0)
198 (12) 1421 (88) 2 (0)
269 (13) 1826 (87) 4 (0)
NS‡
52 (14) 315 (86) 0 (0)
57 (16) 306 (84) 1 (0)
793 (17) 3771 (83) 3 (0)
NS‡
244 (15) 1336 (85) 0 (0)
259 (16) 1359 (84) 3 (0)
399 (19) 1697 (81) 3 (0)
NS‡
55 (15) 307 (84) 5 (1)
75 (21) 289 (79) 0 (0)
1304 (29) 3165 (69) 98 (2)
⬍ 0.001‡ 292 (18) 1258 (80) 30 (2)
331 (21) 1254 (77) 36 (2)
811 (39) 1249 (59) 39 (2)
0.001‡
11 (3) 344 (94) 12 (3) 0 (0)
13 (4) 343 (94) 8 (2) 0 (0)
117 (3) 4046 (88) 367 (8) 37 (1)
NS§
36 (2) 1507 (96) 31 (2) 6 (0)
40 (2) 1549 (96) 24 (2) 8 (0)
65 (3) 1677 (80) 332 (16) 25 (1)
0.001§
361 (98) 3 (1) 0 (0) 2 (1) 1 (0) 0 (0)
3 (1) 202 (55) 35 (10) 84 (23) 39 (11) 1 (0)
2234 (49) 1458 (32) 214 (5) 438 (9) 187 (4) 36 (1)
NS‡
1552 (99) 15 (1) 2 (0) 5 (0) 1 (0) 5 (0)
14 (1) 1082 (67) 118 (7) 272 (17) 126 (8) 9 (0)
1032 (49) 566 (27) 129 (6) 247 (12) 100 (5) 25 (1)
NS‡
continued
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Table 1. (Cont’d) Panel patients
Volume of external boost ⱕ 100 cm3 101–200 cm3 201–300 cm3 ⬎ 300 cm3 Unknown Volume of interstitial boost ⱕ 50 cm3 ⬎ 50 cm3 Unknown Axillary irradiation Yes No Unknown IMC irradiation Yes No Unknown Chemotherapy Yes No Unknown Tamoxifen, postmenopausal patients Yes No
Others
No boost
Boost
Overall
N ⫽ 367 N (%)
N ⫽ 364 N (%)
N ⫽ 4567 N (%)
46 (14) 128 (40) 80 (25) 68 (21) 0 (0)
365 (17) 954 (46) 422 (20) 362 (17) 7 (0)
14 (36) 25 (64) 0 (0) 27 (7) 340 (93) 0 (0)
Digitizer patients No boost
Boost
Others Overall
N ⫽ 1580 N ⫽ 1621 N (%) N (%)
N ⫽ 2099 N (%)
NS§
238 (16) 668 (45) 319 (22) 247 (17) 1 (0)
172 (18) 406 (43) 181 (20) 178 (19) 5 (0)
NS§
70 (38) 116 (62) 1 (0)
NS‡
38 (30) 89 (70) 0 (0)
46 (46) 53 (54) 1 (0)
NS‡
24 (7) 340 (93) 0 (0)
220 (5) 4307 (94) 40 (1)
NS‡
82 (5) 1491 (95) 7 (0)
85 (5) 1528 (95) 8 (0)
104 (5) 1968 (94) 27 (1)
NS‡
48 (13) 319 (87) 0 (0)
53 (15) 311 (85) 0 (0)
986 (22) 3543 (77) 38 (1)
⬍ 0.001‡
248 (16) 1326 (84) 6 (0)
271 (17) 1342 (83) 8 (0)
568 (27) 1505 (72) 26 (1)
0.001‡
31 (8) 336 (92) 0 (0)
32 (9) 332 (91) 0 (0)
584 (13) 3944 (86) 39 (1)
⬍ 0.001‡
174 (11) 1400 (89) 6 (0)
205 (13) 1408 (87) 8 (0)
268 (13) 1804 (86) 27 (1)
NS‡
50 (22) 175 (78)
56 (24) 174 (76)
855 (30) 1949 (70)
NS‡
276 (28) 724 (72)
285 (28) 715 (72)
400 (32) 859 (68)
NS‡
p-value*
p-value*
Abbreviations: N ⫽ number of patients; NS ⫽ not significant; T ⫽ tumor size; WBI ⫽ whole-breast irradiation; IMC ⫽ internal mammary chain. * Panel patients versus others and digitizer patients versus others. † t test. ‡ Chi-square test. § Chi-square test for linear trend.
comparison of panel patients to the remainder of the population (“others”) and of digitizer patients to patients without any digitizer measurements available (“others”). The characteristics of the no-boost and the boost patients are reported separately for the panel and digitizer patients. There were no significant differences between the two treatment groups within both populations. Small imbalances were found between the patients scored by the panel and those not scored by the panel. Differences were significant for the excision volume, for the radiation quality of the whole-breast irradiation (WBI), for internal mammary chain (IMC) irradiation, and for chemotherapy. The panel-scored patients had relatively larger excision volumes, were less frequently irradiated with cobalt-60, and received less often IMC irradiation or chemotherapy. The panel-scored patients were entered in the first years of the study, which might explain why they received less often IMC irradiation as well as chemotherapy. Since some of these differences favored a better and others a worse cosmetic outcome for the panel patients, we assumed that these imbalances would not affect the results of the comparison.
Comparing the patients with at least one digitizer evaluation to those without any showed significant differences for the radiation quality of the WBI, with the digitizer patients being less frequently irradiated with cobalt-60; for the dose of the WBI at the isocenter, with the digitizer patients less frequently receiving a dose greater than 50.5 Gy; and for IMC irradiation, with digitizer patients less frequently receiving IMC irradiation. These factors may have resulted in a better outcome in the patients with available digitizer measurements than in the entire population. These differences between the two patient populations could be due to interinstitutional variations in treatment equipment and policy, as some institutions made photographs of the patients whereas others did not. Cosmetic results in each treatment arm, based on the panel scoring Overall, 82% of patients had an excellent or good global cosmetic result following surgery. Sixteen percent had a fair result, and only a small proportion of the patients had a poor result. The global cosmetic results between the two treat-
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Fig. 2. Global score in each treatment arm after surgery. 0 ⫽ excellent; 1 ⫽ good; 2 ⫽ fair; 3 ⫽ poor.
ment arms were very similar (Fig. 2). For the 6 cosmetic items (Table 2), only the evaluation of the scar appeared to differ significantly between the two arms, with patients in the boost group having a slightly higher score (median, 1.0) than the patients in the no-boost group (median, 0.8; p ⫽ 0.04). After 3 years, 86% of patients in the no-boost group had an excellent or good global result, compared to 71% in the boost group; and only 13% of patients in the no-boost group had a fair global result, compared to 26% of those receiving a boost (p ⫽ 0.0001; Fig. 3). The boost group had significantly worse results than the no-boost group with respect to all cosmetic items scored (Table 2). In the boost group the proportion of patients with an excellent result was decreased while more patients had a fair outcome, compared to the no-boost group. However, very few patients in either arm had a poor result. The proportion of patients in this category ranged from 0% to 1.6% in the no-boost group and from 0.6% to 3.3% in the boost group. The distributions of the global score and of the breast shape score after 3 years, according to the initial score in each treatment arm, are shown in Fig. 4. A trend towards having better scores for these 2 items over time in the no-boost group, compared to the boost group, was seen (the number of patients with a score 3 after surgery was very small, and therefore the results observed in this subgroup
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Fig. 3. Global score in each treatment arm at 3-year follow-up. 0 ⫽ excellent; 1 ⫽ good; 2 ⫽ fair; 3 ⫽ poor.
should not be overemphasized). This trend could also be seen for the other cosmetic items (data not shown). In the no-boost arm, the global cosmetic aspect worsened in 21% of the patients with a score 0 after surgery, whereas in the boost arm 35% of patients with score 0 worsened to either score 1 or 2. Eleven percent of the patients with a postoperative score of 1 in the no-boost arm had a score 2 or 3 after 3 years, whereas 25% in the boost arm changed to score 2 or 3. Of the patients with a postoperative score of 2, 50% in the no-boost arm improved their score, whereas only 29% in the boost arm improved. The changes in time with regard to the global score, the breast size, breast shape, the nipple position, and shape of areola were significant only in the boost arm (p ⬍ 0.001 for all items, using the test for marginal homogeneity). Taking the breast size score as an example, it appeared that the distributions of the scores immediately after surgery and after 3 years were almost identical in the no-boost group, indicating that as many patients had an improved as a worsened cosmetic result (16%) after 3 years, while 68% of patients had an unchanged result. However, in the boost group, 63% of patients had an unchanged cosmetic result, but more patients had a worsened result (27%) compared to an improved result (10%) at follow-up. The same trend could be seen in the boost group for the other items (except for the appear-
Table 2. Cosmetic result after surgery and at 3-year follow-up Postoperative
Global score Surgical scar Breast size Breast shape Nipple position Shape areola
No boost
Boost
median (range)
median (range)
0.8 (0–3.0) 0.8 (0–2.8) 0.6 (0–2.6) 0.6 (0–3.0) 0.6 (0–2.4) 0.4 (0–2.8)
0.8 (0–3.0) 1.0 (0–3.0) 0.4 (0–3.0) 0.6 (0–3.0) 0.6 (0–2.6) 0.4 (0–3.0)
* Wilcoxon-Mann-Whitney test.
At 3-year follow-up No boost
Boost
p-value*
median (range)
median (range)
p-value*
0.23 0.04 0.66 0.23 0.64 0.39
0.6 (0–3.0) 0.4 (0–3.0) 0.4 (0–3.0) 0.4 (0–3.0) 0.6 (0–3.0) 0.2 (0–2.6)
0.8 (0–3.0) 0.6 (0–3.0) 0.6 (0–3.0) 0.6 (0–3.0) 0.8 (0–2.8) 0.4 (0–3.0)
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
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Table 4. Change in pBRA, for the boost group Time
N
Mean pBRA
95% CI
p-value
Postoperative After 3 years
1518 595
7.74 8.26 ratio: ⫻ 1.07
7.48–8.01 7.82–8.72 1.00–1.14
0.05
CI ⫽ confidence interval.
crease in nipple position asymmetry), resulting in a borderline significant difference (Table 4). DISCUSSION Fig. 4. Change with time in global result and breast shape score in each treatment arm. N ⫽ number of patients; *100% range is indicated by length of line and 90% range by cross-lines.
ance of the scar): most patients had an unchanged cosmetic result at 3 years, but if the cosmetic score changed, more patients had a poorer result than a better result. The only item that was significantly influenced by time in both treatment arms was the scar score (p ⬍ 0.0001, using the test for marginal homogeneity). Analysis of the scar score showed an overall improvement. However, the trend towards the scar score improving with time was more striking in the no-boost arm: 45% of patients had an improved scar score after 3 years, compared to 34% in the boost arm. Cosmetic results in each treatment arm, based on the digitizer scoring The mean pBRA postoperative was 7.6 pBRA. It was not different between the no-boost group and the boost group (p ⫽ 0.27). The difference in mean pBRA after 3 years between both treatment arms was small (less than 1 pBRA); however, the larger mean pBRA in the boost group at 3 years indicated a worse result in this group compared to the no-boost group. This difference was of borderline statistical significance (Table 3). The median change in pBRA over a 3-year period was 0.3 pBRA, with a range from ⫺12.8 to ⫹31.0; 80% of the patients had a change ranging from ⫺6.2 to ⫹7.0 pBRA. In the no-boost group the change in pBRA over time was not significant, with a mean pBRA of 7.5 postoperatively and 7.6 at 3-year follow-up (p ⫽ 0.94). In the boost group there was an increase in mean pBRA of 0.6 (indicating an in-
Table 3. Cosmetic result in each treatment arm at follow-up, based on digitizer measurements Treatment
N
Mean pBRA
95% CI
p-value
No boost Boost
546 595
7.55 8.26 ratio: ⫻ 1.09
7.11–8.02 7.79–8.75 1.05–1.19
0.04
CI ⫽ confidence interval.
The EORTC trial 22881/10882 was launched to investigate in BCT, the influence of the boost on local control, survival, and cosmesis. In this study we have shown that the boost slightly impairs the cosmetic outcome 3 years after BCT. Because the local recurrence rate is only 3.9% so far for the overall population after a median follow-up of 3.8 years, more follow-up is needed before the influence of the boost on local control and survival can be reliably evaluated. Therefore, the answers to these research questions might not be available until the median follow-up is 10 years. However, an interim analysis will be performed at a median follow-up of 5 years and an independent datamonitoring committee may recommend publication of these results. There was no significant difference in the cosmetic outcome between the two treatment arms immediately after surgery. After 3 years of follow-up, a difference appeared in the cosmetic result between the treatment arms. The panel review showed that more patients in the no-boost group had excellent results compared to the boost group, and more patients in the boost group had fair results compared to the no-boost group. This difference was present for all cosmetic items scored. However, the proportion of patients with a poor cosmetic outcome was small in both treatment arms. It appeared that the cosmetic results of most patients in the no-boost group were unchanged at 3-year follow-up. For those patients whose cosmetic result changed in this treatment arm, as many patients improved as worsened. In the boost group, a somewhat smaller proportion of patients had stable results; and more patients had a worsened than an improved cosmetic result at 3 years. This difference between treatment arms was seen for all cosmetic items evaluated by the panel except the scar score. The appearance of the scar improved in both treatment groups, but the improvement was far greater in the no-boost group than in the boost group. Thus, the cosmetic evaluation by the panel at 3-year follow-up clearly demonstrated the negative impact of the boost on cosmetic outcome. The digitizer measurements showed a difference in mean pBRA between the no-boost and the boost group at 3-year follow-up, but this difference was rather small. The measurements showed no time trend in the mean pBRA in the no-boost group, but there was a borderline significant time trend in the mean
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pBRA in the boost group, with slightly worse cosmetic results after 3 years. An interesting, but so far unanswered question is, how does this difference in cosmetic outcome caused by the impact of the boost affect the patient? This question cannot be answered based on this trial because patient self-assessment was not incorporated in the study. Therefore, it cannot be determined whether the assessed difference in cosmetic outcome is significant for the patient in terms of resemblance of both breasts, body image, or satisfaction with treatment. However, the study of Patterson et al. (24) showed that 94% of patients rated the overall appearance of the treated breast as good or excellent, although 50% of patients reported moderate to large differences between the treated and the untreated breast. This seems to indicate that differences in specific cosmetic items do not influence the evaluation of the overall appearance very much, and it suggests that the rating of the overall appearance of the treated breast is influenced by more factors than the perceived differences between the treated and the untreated breast only. In our previous study evaluating both methods of cosmetic assessment, it appeared that the digitizer evaluation was more accurate than the panel evaluation with regard to intra- and interobserver variability. Correlation between the results of the two methods was significant, though moderate (19). One of the questions that remained unanswered was whether both methods were able to identify the same treatment parameters as resulting in a worsened cosmesis. In this present study it was shown that both methods were able to assess the adverse effect of the boost on cosmesis. One of
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the shortcomings of the digitizer evaluation is that this method is unable to measure skin changes. This might be important in assessing the influence of the boost since a boost can cause telangiectasia. However, the outcome of the panel evaluation showed that very few patients had visible skin changes at 3-year follow-up. Therefore, this limitation of the digitizer was not considered a major disadvantage in this cosmetic evaluation (19). In deciding whether or not to give a boost, its impact on both local control and cosmesis must be considered. It might be better to consider this issue with regard to subgroups with favorable and more unfavorable prognostic factors separately, rather than for the population as a whole. The first subgroup will likely benefit less from the boost in terms of local control than the latter subgroup. Therefore, it might not be appropriate to give these patients a treatment that influences the cosmetic result negatively and that prolongs the overall treatment time, with consequences for patients’ convenience and treatment costs. The latter group will likely benefit more from the boost in terms of local control, and this group most probably should receive a boost despite its negative effect on cosmesis. The optimal treatment schedule should be chosen by the physician together with the patient, considering the prognostic risk factors involved, the local control probability aimed at, and the acceptable degree of cosmetic damage. However, in weighing the different treatment options against each other, it should be realized that the boost has a small but definite negative effect on the cosmetic outcome.
REFERENCES 1. Sarrazin D, Leˆ MG, Arriagada R, et al. Ten-year results of a randomized trial comparing a conservative treatment to mastectomy in early breast cancer. Radiother Oncol 1989;14:177– 184. 2. Blichert-Toft M, Rose C, Andersen JA, et al. Danish randomized trial comparing breast conservation therapy with mastectomy: Six years of life-table analysis. J Natl Cancer Inst Monogr 1992;11:19 –25. 3. Veronesi U, Salvadori B, Luini A, et al. Breast conservation is a safe method in patients with small cancer of the breast: Long-term results of three randomized trials on 1,973 patients. Eur J Cancer 1995;31A:1574 –1579. 4. Fisher B, Anderson S, Redmond CK, et al. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1995;333:1456 –1461. 5. Pezner RD, Patterson MP, Lipsett JA, et al. Factors affecting cosmetic outcome in breast-conserving cancer treatment— objective quantitative assessment. Breast Cancer Res Treat 1991;20:85–92. 6. Pezner RD. Cosmetic breast fibrosis: It’s the local boost! Int J Radiat Oncol Biol Phys 1994;30:1251–1252. 7. Romestaing P, Lehingue Y, Carrie C, et al. Role of a 10-Gy boost in the conservative treatment of early breast cancer: Results of a randomized clinical trial in Lyon, France. J Clin Oncol 1997;15:963–968.
8. Taylor ME, Perez CA, Halverson KJ, et al. Factors influencing cosmetic results after conservation therapy for breast cancer. Int J Radiat Oncol Biol Phys 1995;31:753–764. 9. Fagundes MA, Fagundes HM, Brito CS, et al. Breast-conserving surgery and definitive radiation: A comparison between quadrantectomy and local excision with special focus on local–regional control and cosmesis. Int J Radiat Oncol Biol Phys 1993;27:553–560. 10. Wazer DE, DiPetrillo T, Schmidt-Ullrich R, et al. Factors influencing cosmetic outcome and complication risk after conservative surgery and radiotherapy for early-stage breast carcinoma. J Clin Oncol 1992;10:356 –363. 11. Sarin R, Dinshaw KA, Shrivastava SK, et al. Therapeutic factors influencing the cosmetic outcome and late complications in the conservative management of early breast cancer. Int J Radiat Oncol Biol Phys 1993;27:285–292. 12. Beadle GF, Silver B, Botnick L, et al. Cosmetic results following primary radiation therapy for early breast cancer. Cancer 1984;54:2911–2918. 13. Gray JR, McCormick B, Cox L, et al. Primary breast irradiation in large-breasted or heavy women: Analysis of cosmetic outcome. Int J Radiat Oncol Biol Phys 1991;21:347–354. 14. Van Limbergen E, Rijnders A, Van der Schueren E, et al. Cosmetic evaluation of breast conserving treatment for mammary cancer. 2. A quantitative analysis of the influence of radiation dose, fractionation schedules and surgical treatment
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15.
16.
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18.
techniques on cosmetic results. Radiother Oncol 1989;16: 253–267. De la Rochefordie`re A, Abner AL, Silver B, et al. Are cosmetic results following conservative surgery and radiation therapy for early breast cancer dependent on technique? Int J Radiat Oncol Biol Phys 1992;23:925–931. Markiewicz DA, Schultz DJ, Haas JA, et al. The effects of sequence and type of chemotherapy and radiation therapy on cosmesis and complications after breast conservation therapy. Int J Radiat Oncol Biol Phys 1996;35:661– 668. Harris JR, Levene MB, Svensson G, et al. Analysis of cosmetic results following primary radiation therapy for stages I and II carcinoma of the breast. Int J Radiat Oncol Biol Phys 1979;5:257–261. Pezner RD, Patterson MP, Hill LR, et al. Breast retraction assessment: An objective evaluation of cosmetic results of
19. 20. 21. 22. 23. 24.
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patients treated conservatively for breast cancer. Int J Radiat Oncol Biol Phys 1985;11:575–578. Vrieling C, Collette L, Bartelink E, et al. Validation of the methods of cosmetic assessment after breast-conserving therapy in the EORTC “boost versus no boost” trial. Submitted. Miller RG Jr. Simultaneous statistical inference. New York: Springer Verlag; 1981. Lehmann EL. Nonparametrics: statistical methods based on ranks. San Francisco: Holden-Day; 1975. Agresti A. Categorical data analysis. New York: John Wiley and Sons; 1990. Diggle PJ, Liang KY, Zeger SL. Analysis of longitudinal data. Oxford: Clarendon Press; 1994. Patterson MP, Pezner RD, Hill LR, et al. Patient self-evaluation of cosmetic outcome of breast-conserving cancer treatment. Int J Radiat Oncol Biol Phys 1985;11:1849 –1852.
PII S0360-3016(99)00211-4
CLINICAL INVESTIGATION
Breast
THE INFLUENCE OF THE BOOST IN BREAST-CONSERVING THERAPY ON COSMETIC OUTCOME IN THE EORTC “BOOST VERSUS NO BOOST” TRIAL CONNY VRIELING, M.D.,* LAURENCE COLLETTE, M.SC.,† ALAIN FOURQUET, M.D.,‡ WILLEM J. HOOGENRAAD, M.D.,§ JEAN-CLAUDE HORIOT, M.D.,㛳 JOS J. JAGER, M.D., PH.D.,¶ MARIANNE PIERART, M.SC.,† PHILIP M. POORTMANS, M.D.,# HENK STRUIKMANS, M.D., PH.D.,兰 MARLEEN VAN DER HULST,# EMMANUEL VAN DER SCHUEREN, M.D., PH.D.,⬁ HARRY BARTELINK, M.D., PH.D.* ON BEHALF OF THE EORTC RADIOTHERAPY AND BREAST CANCER COOPERATIVE GROUPS** *Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; †EORTC, Brussels, Belgium; Department of Radiation Oncology, Institut Curie, Paris, France; §Department of Radiation Oncology, Joint Center for Radiotherapy Arnhem/Nijmegen, St. Radboud Hospital, Nijmegen, The Netherlands; 㛳Department of Radiation Oncology, Centre Georges-Franc¸ois Leclerc, Dijon, France; ¶Department of Radiation Oncology, Radiotherapeutisch Instituut Limburg, Heerlen, The Netherlands; # Department of Radiation Oncology, Dr. Bernard Verbeeten Instituut, Tilburg, The Netherlands; 兰Department of Radiation Oncology, University Hospital Utrecht, Utrecht, The Netherlands; ⬁Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven, Belgium ‡
Purpose: To evaluate the influence of a radiotherapy boost on the cosmetic outcome after 3 years of follow-up in patients treated with breast-conserving therapy (BCT). Methods and Materials: In EORTC trial 22881/10882, 5569 Stage I and II breast cancer patients were treated with tumorectomy and axillary dissection, followed by tangential irradiation of the breast to a dose of 50 Gy in 5 weeks, at 2 Gy per fraction. Patients having a microscopically complete tumor excision were randomized between no boost and a boost of 16 Gy. The cosmetic outcome was evaluated by a panel, scoring photographs of 731 patients taken soon after surgery and 3 years later, and by digitizer measurements, measuring the displacement of the nipple of 3000 patients postoperatively and of 1141 patients 3 years later. Results: There was no difference in the cosmetic outcome between the two treatment arms after surgery, before the start of radiotherapy. At 3-year follow-up, both the panel evaluation and the digitizer measurements showed that the boost had a significant adverse effect on the cosmetic result. The panel evaluation at 3 years showed that 86% of patients in the no-boost group had an excellent or good global result, compared to 71% of patients in the boost group (p ⴝ 0.0001). The digitizer measurements at 3 years showed a relative breast retraction assessment (pBRA) of 7.6 pBRA in the no-boost group, compared to 8.3 pBRA in the boost group, indicating a worse cosmetic result in the boost group at follow-up (p ⴝ 0.04). Conclusions: These results showed that a boost dose of 16 Gy had a negative, but limited, impact on the cosmetic outcome after 3 years. © 1999 Elsevier Science Inc. Breast cancer, Breast-conserving therapy, Radiotherapy boost, Cosmetic result.
Accepted for publication 26 May 1999. **Trial participants and responsible physicians: Tilburg NL (Poortmans), Utrecht NL (Struikmans), Leuven B (Van den Bogaert), Dijon F (Horiot), Paris F (Fourquet), Amsterdam NL (Borger), Heerlen NL (Jager), Nijmegen NL (Hoogenraad), Cologne D (Mu¨ller), Geneva CH (Kurtz), Nottingham GB (Morgan), Montpellier F (Dubois), Namur B (Salamon), Lausanne CH (Mirimanoff), Leiden NL (Leer), Grenoble F (Bolla), Haifa IS (Kuten), La Louviere B (Renaud), Krefeld D (Schulz), Rotterdam NL (Koper), Antwerp B (Van den Weyngaert), Brussels B (Storme), Creteil F (Calitchi), Berlin D (Budach), Du¨sseldorf D (Roth), Brisbane AUS (Poulsen), Pamplona ES (Dominguez), Vannes F (Monpetit), Tel Aviv IS (Kovner), Barcelona ES (Biete Sola), Madrid ES (Calvo)
Reprint requests to: Harry Bartelink, Department of Radiation Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. E-mail: [email protected] Acknowledgments—The authors thank all the participating institutions for their cooperation, the panel members Jacques H. Borger, Stefan J. Brenninkmeyer, Marianne Pierart, Joop A. Van Dongen, and Erik Van Limbergen for their great effort in scoring the photographs, Ellen Bartelink for performing all the digitizer measurements, and Abram Recht for reviewing the manuscript. This work was partially supported by a grant from the European Commission (DGXII) within the framework of BIOMED I and by Grants 3U10CA11488-18S1 through 2U10CA11488-28 from the National Cancer Institute (Bethesda, Maryland, USA). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. 677
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INTRODUCTION Over the last decade, breast-conserving therapy (BCT) has been established as the treatment of choice for patients with early-stage breast cancer (1– 4). However, specific details of the surgical, radiotherapeutic, and systemic adjuvant approaches are not generally agreed upon. In this paper we will concentrate on one of the controversial items of radiotherapy technique, namely the effects of giving a boost dose to the tumor bed. The two major endpoints of BCT are good local control and good cosmetic outcome. The influence of the radiotherapy boost on both endpoints, however, is controversial. Pezner et al. (5, 6) claimed that omitting the local boost in patients with tumor-free specimen margins resulted in local control rates comparable to those of other institutions that routinely used a boost. On the other hand, the Lyon trial (7) showed that the delivery of a 10-Gy boost (given in fractions of 2.5 Gy) to the tumor area significantly reduced the risk of early local recurrence in patients with tumor-free margins from 4.5% to 3.6% at 5 years, compared to treatment of the whole breast with a dose of 50 Gy in 2.5-Gy fractions. A similar controversy exists concerning the influence of the radiation boost on the cosmetic result after BCT. Some studies have concluded that the boost had no effect on the cosmetic outcome, in terms of the degree of breast retraction or the proportion of patients having an excellent or good cosmetic result, although patients treated with a boost may have had an increased frequency of telangiectasia (5, 7, 8). Others have demonstrated a negative effect of the boost on the global cosmetic result (9 –12). One factor that might determine whether or not the boost can be shown to worsen the cosmetic outcome is the time following radiotherapy at which the cosmetic result is evaluated. It is well known that the cosmetic changes progress over the first years after BCT and that the cosmetic outcome is evaluable only after at least 3 years (13–16). Two of the above-mentioned studies which found no adverse effect of the boost evaluated cosmetic outcome at a median follow-up of 2 years or less (5, 7). The European Organization for Research and Treatment of Cancer (EORTC) Phase III trial 22881/10882 for Stage I and II breast cancer was created to unequivocally answer the question of the impact of the radiation boost on local control, survival, and cosmesis. The current analysis focuses on the influence of the boost on the cosmetic outcome.
METHODS AND MATERIALS Trial design and treatment From May 1989 to June 1996, 5569 early-stage breast cancer patients were entered in the “boost versus no boost” trial. Patients with T1-2 N0-1 M0 invasive breast cancer were eligible. Exclusion criteria were: age over 70 years; carcinoma in situ (CIS) without invasive tumor; residual microcalcifications on mammogram or gross residual dis-
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ease in the breast after tumorectomy (unless reexcision had been performed); tumor foci in more than one quadrant; a prior history of malignant disease; or an Eastern Cooperative Oncology Group (ECOG) performance score of greater than 2. The patients were treated with tumorectomy (with a macroscopic tumor-free margin of 1 cm) and axillary dissection, followed by tangential irradiation of the whole breast of 50 Gy, with a dose per fraction of 2 Gy, in 5 weeks. Patients with a microscopically complete excision were randomized to receive either no further treatment or a boost of 15 or 16 Gy (15 Gy for interstitial and 16 Gy for external beam therapy). Patients with a microscopically incomplete excision were randomized to receive either a 10 Gy boost or a boost of 25 or 26 Gy (25 Gy for interstitial and 26 Gy for external beam therapy). The completeness of excision of a possible CIS component has not been taken into account in the definition of a complete excision. The volume to be treated by the boost was defined as the site of the primary tumor, with a safety margin of 1.5 cm around the primary tumor after a microscopically complete excision and of 3 cm after incomplete excision or in patients with an extensive intraductal component (EIC). The following techniques were accepted: (a) two external photon beams: cobalt-60 or X-ray beams in the range of 4 to 8 MV, the boost dose being specified in the center of the tumor excision area; (b) one electron beam: the energy of the electron beams being chosen in such a way that the 85% isodose surface encompassed the boost target volume, with the dose specified as the maximum dose; or (c) interstitial therapy: iridium-192 wires or cesium-137 wires, the dose being prescribed according to the Paris system and specified at the reference isodose (defined as 85% of the mean basal dose), preferably delivered at a dose rate of about 50 cGy per hour. In order to avoid late radiation telangiectasia, it was recommended that the most superficially located needles should be located at least 5 mm below the overlying skin surface. For this analysis, only the boost dose itself has been taken into account. In the prognostic factor analysis for cosmetic outcome (to be published), other factors such as boost modality and boost volume will be analyzed as well, together with various other treatment parameters. Cosmetic assessment The original design of the “boost versus no boost” trial aimed at assessing the influence of the boost on local control and cosmesis. It was estimated that 330 patients should be treated in each treatment arm to provide an 80% power for detecting a difference of 10% in the rate of overall excellent/good results between the treatment arms. However, as it was demonstrated that a recruitment rate of 1000 patients a year could be achieved, it was decided to add survival as an endpoint. It was estimated that at least 5000 patients should be entered to be able to detect a 5% difference in the 10-year survival rates, with an ␣ of 0.01 and  of 0.1. However, this large a number of patients would not be needed to prove beyond any doubt the influence of the boost on cosmesis. It was therefore decided to analyze the number of patients as
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originally calculated for the evaluation of the influence of the boost on cosmesis. Because the surgical excision of invasive disease was microscopically complete for 95% of patients, the cosmetic outcome was evaluated only for patients randomized to receive either no boost or a boost of 15 or 16 Gy. The panel scored 731 patients, both postoperatively and after 3 years of follow-up. These patients were not randomly selected, but were the first patients evaluable at both time points. Because the quantitative cosmetic evaluation (digitizer measurements) was much less time-consuming, it was decided to analyze all available pictures (postoperative and at 3-year follow-up) by means of the digitizer. A total of 3201 patients were scored with the digitizer. In 2060 patients, only a baseline picture was measured; in 201 patients, only a 3-year follow-up picture was measured; and in 940 patients both baseline and 3-year follow-up pictures were scored. A review panel consisting of 5 persons (see Acknowledgments) scored the cosmetic results, based on the photographs taken after surgery (before radiotherapy was started) and after 3 years of follow-up. The following items were evaluated by comparing the treated breast with the untreated breast: global cosmetic result; appearance of the surgical scar; breast size; breast shape; nipple position; and shape of areola. In scoring these items, a 4-point scale was used, classifying the results into one of the following categories: “0” represented an excellent result; “1” a good result; “2” a fair result; and “3” a poor result (17). A photograph or slide with a frontal view of the patient standing with both arms alongside the body was used for measurements of the nipple position in order to calculate the breast retraction assessment (BRA) values (18). The absolute value of the BRA as well as the relative BRA [defined as (BRA/reference length) ⫻ 100, see Fig. 1] are measures of lack of symmetry between the nipple positions. The relative BRA (or percentage BRA, pBRA) was used in this analysis instead of the absolute BRA for technical reasons as explained in a publication concerning the methods of cosmetic evaluation used in this trial (19). The measurements were performed by one person (see Acknowledgments) using a digitizer of a radiotherapy treatment planning system. The reliability of the panel evaluation as well as the digitizer measurements have been described previously (19). Statistical methods The distribution of patient, tumor, and treatment characteristics of panel patients was compared to the remainder of the population and, similarly, patients with any digitizer measurements available were compared to patients without, in order to check for significant differences. To account for the very large sample size of the overall population and to correct for the multiplicity of testing according to the Bonferroni method (20), a significance level of 0.001 or less is used for claiming significance of any of the comparisons made. The scores given by the 5 reviewers for each patient at each occasion have been combined into a single average. Such score can be interpreted as the score assigned to a
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Fig. 1. Illustration of the BRA measurements.
BRA ⫽ 冑共a1 ⫺ b1 兲2 ⫹ 共a2 ⫺ b2 兲2 ; reference length 共ref.兲 ⫽ 冑b 12 ⫹ b 22; pBRA ⫽ 共BRA/reference length兲 ⫻ 100 picture by an “average observer.” This average score takes values between 0 and 3, with a score close or equal to 0 indicating an excellent result and a score close or equal to 3 indicating a poor result. For the purposes of presentation and tabulation, these averages have been rounded to the closest integer. Comparison of the distribution of the scores between the two treatment arms was performed, for each cosmetic item at both evaluation times, using the WilcoxonMann-Whitney test (21). The cosmetic score after 3 years was described in relation to the initial cosmetic aspect of the breast. This was done in order to account for the fact that, due to the limited range of possible score values, patients with a score of 0 at their first evaluation can only remain stable or worsen, whereas patients who start with a score of 3 can only remain stable or improve. To test for the presence of a significant change in the cosmetic outcome after 3 years, a chi-square test for marginal homogeneity (22) was applied to the tables of initial versus 3-year follow-up scores. A significance level of 0.05 or less was used. The treatment effect according to the digitizer measurements was assessed by means of an analysis of variance (ANOVA) I model. The change in the pBRA between baseline and the 3-year follow-up evaluation was calculated as follows: pBRA3 years ⫺ pBRAbaseline. The time effect was assessed by means of a linear mixed model (23) which takes into account the natural correlation between two measurements made on the same subject. RESULTS Patient population An overview of the distribution of the patient, tumor, and treatment characteristics of the different patient populations is given in Table 1. The p-values in this table relate to the
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Table 1. Patient, tumor and treatment characteristics Panel patients
Age (median and range in years) Tumor location Lateral Central/superior Medial Inferior Unknown T clinical T1 T2 T3 T pathological ⱕ 10 mm 11–20 mm ⬎ 20 mm unknown Reexcision Yes No Unknown Volume of excision ⱕ 100 cm3 101–200 cm3 201–300 cm3 ⬎ 300 cm3 unknown Type of axillary dissection Discontinuous En bloc No dissection or unknown Postoperative breast complications Present Absent Unknown Postoperative axilla complications Present Absent Unknown Radiation quality of WBI Cobalt-60 X-ray Combination or unknown Dose WBI in isocenter ⱕ 49.5 Gy 49.5–50.5 Gy ⬎ 50.5 Gy Unknown Boost treatment received No boost Electron boost Cobalt-60 boost X-ray boost Interstitial boost Unknown
Others
Digitizer patients
No boost
Boost
Overall
No boost
N ⫽ 367 N (%)
N ⫽ 364 N (%)
N ⫽ 4567 N (%)
p-value*
55 (23–72)
56 (26–72)
55 (26–83)
NS†
Boost
Others Overall
N ⫽ 1580 N ⫽ 1621 N (%) N (%)
N ⫽ 2099 N (%)
p-value*
55 (23–80)
54 (26–83)
NS†
55 (26–79)
196 (53) 51 (14) 58 (16) 62 (17) 0 (0)
185 (51) 43 (12) 64 (17) 72 (20) 0 (0)
2215 (48) 727 (16) 771 (17) 854 (19) 0 (0)
NS‡
790 (50) 244 (15) 266 (17) 280 (18) 0 (0)
803 (50) 214 (13) 295 (18) 307 (19) 2 (0)
1003 (48) 363 (17) 332 (16) 401 (19) 0 (0)
NS‡
193 (53) 174 (47) 0 (0)
189 (52) 175 (48) 0 (0)
2360 (52) 2205 (48) 2 (0)
NS‡
809 (51) 771 (49) 0 (0)
849 (52) 770 (48) 2 (0)
1084 (52) 1013 (48) 2 (0)
NS‡
81 (22) 208 (57) 69 (19) 9 (2)
83 (23) 193 (53) 78 (21) 10 (3)
1152 (25) 2451 (54) 888 (19) 76 (2)
NS§
408 (26) 827 (52) 321 (20) 24 (2)
393 (24) 869 (54) 324 (20) 35 (2)
515 (24) 1156 (55) 390 (19) 38 (2)
NS§
95 (26) 272 (74) 0 (0)
100 (27) 264 (73) 0 (0)
1111 (24) 3456 (76) 0 (0)
NS‡
368 (23) 1212 (77) 0 (0)
405 (25) 1214 (75) 2 (0)
533 (25) 1566 (75) 0 (0)
NS‡
99 (27) 110 (30) 45 (12) 45 (12) 68 (19)
113 (31) 87 (24) 51 (14) 41 (11) 72 (20)
1649 (36) 1078 (24) 427 (9) 468 (10) 945 (21)
⬍ 0.001§ 530 (34) 406 (26) 160 (10) 180 (11) 304 (19)
570 (35) 400 (25) 168 (10) 168 (10) 315 (20)
761 (36) 469 (23) 195 (9) 206 (10) 468 (22)
NS§
309 (85) 56 (15) 2 (0)
304 (84) 59 (16) 1 (0)
3926 (86) 614 (13) 27 (1)
NS‡
1340 (85) 229 (14) 11 (1)
1401 (87) 215 (13) 5 (0)
1798 (86) 285 (13) 16 (1)
NS‡
39 (11) 327 (89) 1 (0)
57 (16) 307 (84) 0 (0)
571 (13) 3992 (87) 4 (0)
NS‡
200 (13) 1379 (87) 1 (0)
198 (12) 1421 (88) 2 (0)
269 (13) 1826 (87) 4 (0)
NS‡
52 (14) 315 (86) 0 (0)
57 (16) 306 (84) 1 (0)
793 (17) 3771 (83) 3 (0)
NS‡
244 (15) 1336 (85) 0 (0)
259 (16) 1359 (84) 3 (0)
399 (19) 1697 (81) 3 (0)
NS‡
55 (15) 307 (84) 5 (1)
75 (21) 289 (79) 0 (0)
1304 (29) 3165 (69) 98 (2)
⬍ 0.001‡ 292 (18) 1258 (80) 30 (2)
331 (21) 1254 (77) 36 (2)
811 (39) 1249 (59) 39 (2)
0.001‡
11 (3) 344 (94) 12 (3) 0 (0)
13 (4) 343 (94) 8 (2) 0 (0)
117 (3) 4046 (88) 367 (8) 37 (1)
NS§
36 (2) 1507 (96) 31 (2) 6 (0)
40 (2) 1549 (96) 24 (2) 8 (0)
65 (3) 1677 (80) 332 (16) 25 (1)
0.001§
361 (98) 3 (1) 0 (0) 2 (1) 1 (0) 0 (0)
3 (1) 202 (55) 35 (10) 84 (23) 39 (11) 1 (0)
2234 (49) 1458 (32) 214 (5) 438 (9) 187 (4) 36 (1)
NS‡
1552 (99) 15 (1) 2 (0) 5 (0) 1 (0) 5 (0)
14 (1) 1082 (67) 118 (7) 272 (17) 126 (8) 9 (0)
1032 (49) 566 (27) 129 (6) 247 (12) 100 (5) 25 (1)
NS‡
continued
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Table 1. (Cont’d) Panel patients
Volume of external boost ⱕ 100 cm3 101–200 cm3 201–300 cm3 ⬎ 300 cm3 Unknown Volume of interstitial boost ⱕ 50 cm3 ⬎ 50 cm3 Unknown Axillary irradiation Yes No Unknown IMC irradiation Yes No Unknown Chemotherapy Yes No Unknown Tamoxifen, postmenopausal patients Yes No
Others
No boost
Boost
Overall
N ⫽ 367 N (%)
N ⫽ 364 N (%)
N ⫽ 4567 N (%)
46 (14) 128 (40) 80 (25) 68 (21) 0 (0)
365 (17) 954 (46) 422 (20) 362 (17) 7 (0)
14 (36) 25 (64) 0 (0) 27 (7) 340 (93) 0 (0)
Digitizer patients No boost
Boost
Others Overall
N ⫽ 1580 N ⫽ 1621 N (%) N (%)
N ⫽ 2099 N (%)
NS§
238 (16) 668 (45) 319 (22) 247 (17) 1 (0)
172 (18) 406 (43) 181 (20) 178 (19) 5 (0)
NS§
70 (38) 116 (62) 1 (0)
NS‡
38 (30) 89 (70) 0 (0)
46 (46) 53 (54) 1 (0)
NS‡
24 (7) 340 (93) 0 (0)
220 (5) 4307 (94) 40 (1)
NS‡
82 (5) 1491 (95) 7 (0)
85 (5) 1528 (95) 8 (0)
104 (5) 1968 (94) 27 (1)
NS‡
48 (13) 319 (87) 0 (0)
53 (15) 311 (85) 0 (0)
986 (22) 3543 (77) 38 (1)
⬍ 0.001‡
248 (16) 1326 (84) 6 (0)
271 (17) 1342 (83) 8 (0)
568 (27) 1505 (72) 26 (1)
0.001‡
31 (8) 336 (92) 0 (0)
32 (9) 332 (91) 0 (0)
584 (13) 3944 (86) 39 (1)
⬍ 0.001‡
174 (11) 1400 (89) 6 (0)
205 (13) 1408 (87) 8 (0)
268 (13) 1804 (86) 27 (1)
NS‡
50 (22) 175 (78)
56 (24) 174 (76)
855 (30) 1949 (70)
NS‡
276 (28) 724 (72)
285 (28) 715 (72)
400 (32) 859 (68)
NS‡
p-value*
p-value*
Abbreviations: N ⫽ number of patients; NS ⫽ not significant; T ⫽ tumor size; WBI ⫽ whole-breast irradiation; IMC ⫽ internal mammary chain. * Panel patients versus others and digitizer patients versus others. † t test. ‡ Chi-square test. § Chi-square test for linear trend.
comparison of panel patients to the remainder of the population (“others”) and of digitizer patients to patients without any digitizer measurements available (“others”). The characteristics of the no-boost and the boost patients are reported separately for the panel and digitizer patients. There were no significant differences between the two treatment groups within both populations. Small imbalances were found between the patients scored by the panel and those not scored by the panel. Differences were significant for the excision volume, for the radiation quality of the whole-breast irradiation (WBI), for internal mammary chain (IMC) irradiation, and for chemotherapy. The panel-scored patients had relatively larger excision volumes, were less frequently irradiated with cobalt-60, and received less often IMC irradiation or chemotherapy. The panel-scored patients were entered in the first years of the study, which might explain why they received less often IMC irradiation as well as chemotherapy. Since some of these differences favored a better and others a worse cosmetic outcome for the panel patients, we assumed that these imbalances would not affect the results of the comparison.
Comparing the patients with at least one digitizer evaluation to those without any showed significant differences for the radiation quality of the WBI, with the digitizer patients being less frequently irradiated with cobalt-60; for the dose of the WBI at the isocenter, with the digitizer patients less frequently receiving a dose greater than 50.5 Gy; and for IMC irradiation, with digitizer patients less frequently receiving IMC irradiation. These factors may have resulted in a better outcome in the patients with available digitizer measurements than in the entire population. These differences between the two patient populations could be due to interinstitutional variations in treatment equipment and policy, as some institutions made photographs of the patients whereas others did not. Cosmetic results in each treatment arm, based on the panel scoring Overall, 82% of patients had an excellent or good global cosmetic result following surgery. Sixteen percent had a fair result, and only a small proportion of the patients had a poor result. The global cosmetic results between the two treat-
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Fig. 2. Global score in each treatment arm after surgery. 0 ⫽ excellent; 1 ⫽ good; 2 ⫽ fair; 3 ⫽ poor.
ment arms were very similar (Fig. 2). For the 6 cosmetic items (Table 2), only the evaluation of the scar appeared to differ significantly between the two arms, with patients in the boost group having a slightly higher score (median, 1.0) than the patients in the no-boost group (median, 0.8; p ⫽ 0.04). After 3 years, 86% of patients in the no-boost group had an excellent or good global result, compared to 71% in the boost group; and only 13% of patients in the no-boost group had a fair global result, compared to 26% of those receiving a boost (p ⫽ 0.0001; Fig. 3). The boost group had significantly worse results than the no-boost group with respect to all cosmetic items scored (Table 2). In the boost group the proportion of patients with an excellent result was decreased while more patients had a fair outcome, compared to the no-boost group. However, very few patients in either arm had a poor result. The proportion of patients in this category ranged from 0% to 1.6% in the no-boost group and from 0.6% to 3.3% in the boost group. The distributions of the global score and of the breast shape score after 3 years, according to the initial score in each treatment arm, are shown in Fig. 4. A trend towards having better scores for these 2 items over time in the no-boost group, compared to the boost group, was seen (the number of patients with a score 3 after surgery was very small, and therefore the results observed in this subgroup
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Fig. 3. Global score in each treatment arm at 3-year follow-up. 0 ⫽ excellent; 1 ⫽ good; 2 ⫽ fair; 3 ⫽ poor.
should not be overemphasized). This trend could also be seen for the other cosmetic items (data not shown). In the no-boost arm, the global cosmetic aspect worsened in 21% of the patients with a score 0 after surgery, whereas in the boost arm 35% of patients with score 0 worsened to either score 1 or 2. Eleven percent of the patients with a postoperative score of 1 in the no-boost arm had a score 2 or 3 after 3 years, whereas 25% in the boost arm changed to score 2 or 3. Of the patients with a postoperative score of 2, 50% in the no-boost arm improved their score, whereas only 29% in the boost arm improved. The changes in time with regard to the global score, the breast size, breast shape, the nipple position, and shape of areola were significant only in the boost arm (p ⬍ 0.001 for all items, using the test for marginal homogeneity). Taking the breast size score as an example, it appeared that the distributions of the scores immediately after surgery and after 3 years were almost identical in the no-boost group, indicating that as many patients had an improved as a worsened cosmetic result (16%) after 3 years, while 68% of patients had an unchanged result. However, in the boost group, 63% of patients had an unchanged cosmetic result, but more patients had a worsened result (27%) compared to an improved result (10%) at follow-up. The same trend could be seen in the boost group for the other items (except for the appear-
Table 2. Cosmetic result after surgery and at 3-year follow-up Postoperative
Global score Surgical scar Breast size Breast shape Nipple position Shape areola
No boost
Boost
median (range)
median (range)
0.8 (0–3.0) 0.8 (0–2.8) 0.6 (0–2.6) 0.6 (0–3.0) 0.6 (0–2.4) 0.4 (0–2.8)
0.8 (0–3.0) 1.0 (0–3.0) 0.4 (0–3.0) 0.6 (0–3.0) 0.6 (0–2.6) 0.4 (0–3.0)
* Wilcoxon-Mann-Whitney test.
At 3-year follow-up No boost
Boost
p-value*
median (range)
median (range)
p-value*
0.23 0.04 0.66 0.23 0.64 0.39
0.6 (0–3.0) 0.4 (0–3.0) 0.4 (0–3.0) 0.4 (0–3.0) 0.6 (0–3.0) 0.2 (0–2.6)
0.8 (0–3.0) 0.6 (0–3.0) 0.6 (0–3.0) 0.6 (0–3.0) 0.8 (0–2.8) 0.4 (0–3.0)
⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001
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Table 4. Change in pBRA, for the boost group Time
N
Mean pBRA
95% CI
p-value
Postoperative After 3 years
1518 595
7.74 8.26 ratio: ⫻ 1.07
7.48–8.01 7.82–8.72 1.00–1.14
0.05
CI ⫽ confidence interval.
crease in nipple position asymmetry), resulting in a borderline significant difference (Table 4). DISCUSSION Fig. 4. Change with time in global result and breast shape score in each treatment arm. N ⫽ number of patients; *100% range is indicated by length of line and 90% range by cross-lines.
ance of the scar): most patients had an unchanged cosmetic result at 3 years, but if the cosmetic score changed, more patients had a poorer result than a better result. The only item that was significantly influenced by time in both treatment arms was the scar score (p ⬍ 0.0001, using the test for marginal homogeneity). Analysis of the scar score showed an overall improvement. However, the trend towards the scar score improving with time was more striking in the no-boost arm: 45% of patients had an improved scar score after 3 years, compared to 34% in the boost arm. Cosmetic results in each treatment arm, based on the digitizer scoring The mean pBRA postoperative was 7.6 pBRA. It was not different between the no-boost group and the boost group (p ⫽ 0.27). The difference in mean pBRA after 3 years between both treatment arms was small (less than 1 pBRA); however, the larger mean pBRA in the boost group at 3 years indicated a worse result in this group compared to the no-boost group. This difference was of borderline statistical significance (Table 3). The median change in pBRA over a 3-year period was 0.3 pBRA, with a range from ⫺12.8 to ⫹31.0; 80% of the patients had a change ranging from ⫺6.2 to ⫹7.0 pBRA. In the no-boost group the change in pBRA over time was not significant, with a mean pBRA of 7.5 postoperatively and 7.6 at 3-year follow-up (p ⫽ 0.94). In the boost group there was an increase in mean pBRA of 0.6 (indicating an in-
Table 3. Cosmetic result in each treatment arm at follow-up, based on digitizer measurements Treatment
N
Mean pBRA
95% CI
p-value
No boost Boost
546 595
7.55 8.26 ratio: ⫻ 1.09
7.11–8.02 7.79–8.75 1.05–1.19
0.04
CI ⫽ confidence interval.
The EORTC trial 22881/10882 was launched to investigate in BCT, the influence of the boost on local control, survival, and cosmesis. In this study we have shown that the boost slightly impairs the cosmetic outcome 3 years after BCT. Because the local recurrence rate is only 3.9% so far for the overall population after a median follow-up of 3.8 years, more follow-up is needed before the influence of the boost on local control and survival can be reliably evaluated. Therefore, the answers to these research questions might not be available until the median follow-up is 10 years. However, an interim analysis will be performed at a median follow-up of 5 years and an independent datamonitoring committee may recommend publication of these results. There was no significant difference in the cosmetic outcome between the two treatment arms immediately after surgery. After 3 years of follow-up, a difference appeared in the cosmetic result between the treatment arms. The panel review showed that more patients in the no-boost group had excellent results compared to the boost group, and more patients in the boost group had fair results compared to the no-boost group. This difference was present for all cosmetic items scored. However, the proportion of patients with a poor cosmetic outcome was small in both treatment arms. It appeared that the cosmetic results of most patients in the no-boost group were unchanged at 3-year follow-up. For those patients whose cosmetic result changed in this treatment arm, as many patients improved as worsened. In the boost group, a somewhat smaller proportion of patients had stable results; and more patients had a worsened than an improved cosmetic result at 3 years. This difference between treatment arms was seen for all cosmetic items evaluated by the panel except the scar score. The appearance of the scar improved in both treatment groups, but the improvement was far greater in the no-boost group than in the boost group. Thus, the cosmetic evaluation by the panel at 3-year follow-up clearly demonstrated the negative impact of the boost on cosmetic outcome. The digitizer measurements showed a difference in mean pBRA between the no-boost and the boost group at 3-year follow-up, but this difference was rather small. The measurements showed no time trend in the mean pBRA in the no-boost group, but there was a borderline significant time trend in the mean
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pBRA in the boost group, with slightly worse cosmetic results after 3 years. An interesting, but so far unanswered question is, how does this difference in cosmetic outcome caused by the impact of the boost affect the patient? This question cannot be answered based on this trial because patient self-assessment was not incorporated in the study. Therefore, it cannot be determined whether the assessed difference in cosmetic outcome is significant for the patient in terms of resemblance of both breasts, body image, or satisfaction with treatment. However, the study of Patterson et al. (24) showed that 94% of patients rated the overall appearance of the treated breast as good or excellent, although 50% of patients reported moderate to large differences between the treated and the untreated breast. This seems to indicate that differences in specific cosmetic items do not influence the evaluation of the overall appearance very much, and it suggests that the rating of the overall appearance of the treated breast is influenced by more factors than the perceived differences between the treated and the untreated breast only. In our previous study evaluating both methods of cosmetic assessment, it appeared that the digitizer evaluation was more accurate than the panel evaluation with regard to intra- and interobserver variability. Correlation between the results of the two methods was significant, though moderate (19). One of the questions that remained unanswered was whether both methods were able to identify the same treatment parameters as resulting in a worsened cosmesis. In this present study it was shown that both methods were able to assess the adverse effect of the boost on cosmesis. One of
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the shortcomings of the digitizer evaluation is that this method is unable to measure skin changes. This might be important in assessing the influence of the boost since a boost can cause telangiectasia. However, the outcome of the panel evaluation showed that very few patients had visible skin changes at 3-year follow-up. Therefore, this limitation of the digitizer was not considered a major disadvantage in this cosmetic evaluation (19). In deciding whether or not to give a boost, its impact on both local control and cosmesis must be considered. It might be better to consider this issue with regard to subgroups with favorable and more unfavorable prognostic factors separately, rather than for the population as a whole. The first subgroup will likely benefit less from the boost in terms of local control than the latter subgroup. Therefore, it might not be appropriate to give these patients a treatment that influences the cosmetic result negatively and that prolongs the overall treatment time, with consequences for patients’ convenience and treatment costs. The latter group will likely benefit more from the boost in terms of local control, and this group most probably should receive a boost despite its negative effect on cosmesis. The optimal treatment schedule should be chosen by the physician together with the patient, considering the prognostic risk factors involved, the local control probability aimed at, and the acceptable degree of cosmetic damage. However, in weighing the different treatment options against each other, it should be realized that the boost has a small but definite negative effect on the cosmetic outcome.
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