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Accelerated Partial Breast Irradiation With Interstitial Implants: Risk Factors Associated With Increased Local Recurrence
Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 5, pp. 1458–1463, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter
doi:10.1016/j.ijrobp.2010.04.032
CLINICAL INVESTIGATION
Breast
ACCELERATED PARTIAL BREAST IRRADIATION WITH INTERSTITIAL IMPLANTS: RISK FACTORS ASSOCIATED WITH INCREASED LOCAL RECURRENCE OLIVER J. OTT, M.D.,* GUIDO HILDEBRANDT, M.D.,yz RICHARD PO¨TTER, M.D.,x JOSEF HAMMER, M.D.,k MARION HINDEMITH, M.D.,y ALEXANDRA RESCH, M.D.,x KURT SPIEGL, M.D.,k MICHAEL LOTTER, PH.D.,* WOLFGANG UTER, M.D.,{ ROLF-DIETER KORTMANN, M.D.,y MICHAEL SCHRAUDER, M.D.,# MATTHIAS W. BECKMANN, M.D.,# RAINER FIETKAU, M.D.,* AND VRATISLAV STRNAD, M.D.* *University Hospital Erlangen, Department of Radiation Oncology, Erlangen, Germany; yUniversity Hospital Leipzig, Department of Radiation Oncology, Leipzig, Germany; zUniversity Hospital Rostock, Department of Radiation Oncology, Rostock, Germany; x University Hospital AKH Vienna, Department of Radiation Oncology and Radiobiology, Vienna, Austria; kBarmherzige Schwestern Hospital, Department of Radiation Oncology, Linz, Austria; {Departments of Medical Informatics, Biometry and Epidemiology, University Erlangen-Nuremberg, Erlangen, Germany; and #University Hospital Erlangen, Department of Gynecology, Erlangen, Germany Purpose: To analyze patient, disease, and treatment-related factors regarding their impact on local control after interstitial multicatheter accelerated partial breast irradiation (APBI). Methods and Materials: Between November 2000 and April 2005, 274 patients with early breast cancer were recruited for the German–Austrian APBI Phase II trial (ClinicalTrials.gov identifier: NCT00392184). In all, 64% (175/274) of the patients received pulsed-dose-rate (PDR) brachytherapy and 36% (99/274) received high-doserate (HDR) brachytherapy. Prescribed reference dose for HDR brachytherapy was 32 Gy in eight fractions of 4 Gy, twice daily. Prescribed reference dose in PDR brachytherapy was 49.8 Gy in 83 consecutive fractions of 0.6 Gy each hour. Total treatment time was 3 to 4 days. Results: The median follow-up time was 64 months (range, 9–110). The actuarial 5-year local recurrence free survival rate (5-year LRFS) was 97.7%. Comparing patients with an age <50 years (49/274) vs. $50 years (225/274), the 5-year LRFS resulted in 92.5% and 98.9% (exact p = 0.030; 99% confidence interval, 0.029–0.032), respectively. Antihormonal treatment (AHT) was not applied in 9% (24/274) of the study population. The 5-year LRFS was 99% and 84.9% (exact p = 0.0087; 99% confidence interval, 0.0079–0.0094) in favor of the patients who received AHT. Lobular histology (45/274) was not associated with worse local control compared with all other histologies (229/274). The 5-year LRFS rates were 97.6% and 97.8%, respectively. Conclusions: Local control at 5 years is excellent and comparable to therapeutic successes reported from corresponding whole-breast irradiation trials. Our data indicate that patients <50 years of age ought to be excluded from APBI protocols, and that patients with hormone-sensitive breast cancer should definitely receive adjuvant AHT when interstitial multicatheter APBI is performed. Lobular histology need not be an exclusion criterion for future APBI trials. Ó 2011 Elsevier Inc. Accelerated partial breast irradiation, Local control, In-breast recurrence, Interstitial brachytherapy, Risk factors.
INTRODUCTION
on the safety and efficacy of this treatment approach for a highly selected subgroup of breast cancer patients with an intrinsically low risk of local recurrence (4–10). As clinical data accumulate, a deeper understanding of the impact of several factors related to treatment outcome becomes possible. The aim of the present analysis was to detect predictive patient-, disease-, or treatment-related conditions significantly associated with local control rates.
Recently, accelerated partial breast irradiation (APBI) has become a field of high interest in radio-oncological research (1, 2). During the past few years, six large randomized trials with a total accrual number of more than 11.600 patients had been initiated to compare various APBI techniques to standard whole breast irradiation (3). Data from quality controlled Phase II trials on interstitial multicatheter APBI with a median follow-up reaching 10 years increasingly provided evidence Reprint requests to: Oliver J. Ott, M.D., University Hospital Erlangen, Department of Radiation Oncology, Universita¨tsstr. 27, D91054 Erlangen, Germany. Tel: +49 9131 8544204; Fax: +49 9131 8535969; E-mail: [email protected]
Conflicts of interest: none. Received Jan 28, 2010, and in revised form April 13, 2010. Accepted for publication April 14, 2010. 1458
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METHODS AND MATERIALS Study patients Between April 2001 and January 2005, 274 consecutive patients with early breast cancer were recruited for this prospective Phase II trial. At the time of radiotherapy, the median age was 60.5 years (range, 39–84 years). Per protocol, patients were eligible for APBI if they had histologically confirmed breast cancer, tumor diameter #3 cm, complete resection with clear margins $2 mm, postsurgical negative axillary lymph nodes (pN0) or singular nodal micrometastasis (pN1 mi), no distant metastasis or contralateral breast cancer, European Cooperative Oncology Group (ECOG) performance status #2, estrogen and/or progesterone sensitive tumors (ER+/PR+; ER+/PR; ER/PR+), and were at least 35 years of age. Patients were excluded from the protocol if they mammographically showed a multifocal invasive growth pattern or poorly differentiated tumors, had postoperative residual micro-calcifications, had an extensive intraductal component (EIC), had vessel invasion (L1, V1), had involved or unknown margins (R1/Rx), or were pregnant. Before recruitment, the protocol was approved by each of the four appropriate ethical committees of Erlangen, Leipzig (Germany), Linz, and Vienna (Austria). All patients gave informed consent before protocol specific treatment. More detailed information on the trial is available elsewhere (7, 8, 10–13).
Treatment Patients received closed cavity breast conserving surgery and axillary staging. Titan clip marking of the tumor bed was present in 58% (159/274) and absent in 37% (102/274) of the patients; data on tumor bed clips were not available for 5% (13/274) of the patients. The median interval between the definitive surgical procedure and the implantation of the brachytherapy catheters for APBI was 57 days (standard deviation [SD], 39–75 days). This time interval facilitated complete wound healing and obtaining of a comprehensive histological report for proper patient selection. Of the patients, 64% (175/274) received PDR , and 36% (99/274) HDR brachyther-
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apy. Prescribed reference dose for HDR brachytherapy was 32 Gy in eight fractions of 4 Gy, twice daily, at an interval of 6 h at least. Total treatment time was 4 days. Prescribed reference dose in PDR brachytherapy was 49.8 Gy in 83 consecutive fractions of 0.6 Gy each hour. Total treatment time was 4 days. Antihormonal treatment (usually with tamoxifen during this time) was administered in 91% (250/274) and adjuvant chemotherapy in 7% (19/274) of the patients. Further information on patient- and treatment-related characteristics is given in Table 1. More information on protocol design and treatment variables had been summarized in previous publications (7, 8, 10).
Follow-up Patients were followed up every 3 months for 2 years after breast conserving surgery, at 6-month intervals thereafter, and at yearly intervals after completion of 5-year follow-up. Local control and survival parameters, as well as acute and late toxicity rates and cosmetic outcome, were assessed by clinical examination and combined mammogram and breast ultrasound examination. For this analysis, we focused on risk factors associated with ipsilateral in-breast recurrence.
Statistical analysis Data management and statistical analysis were carried out with PASW Statistics for MS Windows, release 17.0.2 (SPSS Inc., Chicago, IL). For statistical comparisons between groups the Mann–Whitney U test and Pearson’s’ Chi-square test were used as appropriate. Survival probability was estimated using the Kaplan–Meier method (14), using the log-rank test to compare two or more groups. In view of the rareness of events and of the partly small size of a subgroup, an approximation of the exact permutation log-rank test based on 100,000 chance permutations was used with R, version 2.8.1, software (15), in particular the package coin (16). To examine the association of continuous factors with local recurrence, the distribution of these factors was compared between patients with local recurrence vs. patients without local recurrence using a Monte Carlo approximation of the exact p value of
Table 1. Patient, disease, and treatment related factors analyzed for their impact on local control Age (<50 vs. $50)* Bra cup sizey Type of surgery* Study center* Number of removed axillary lymph nodesz Localization (involved quadrant, upper vs. lower, medial vs. lateral)* Histological subtype* Accompanying DCIS (Y/N)* pT Categoryy Tumor size (mm)z pN Categoryy UICC stagey Safety margin (mm)z Gradingy Lateralization (involved breast)* ER/PR receptor statusy Her2/neu overexpression status* Prior radiotherapy (Y/N)*
Chemotherapy (Y/N)* Antihormonal treatment (Y/N)* PDR vs. HDR brachytherapy* Number of implant planesz Number of pulsesz Reference dose (Gy)z Mean central dose (Gy)z V150 (ml)z Dose homogeneity indexz Dose nonuniformity ratioz Interval BCS–APBI (days)z Single pulse dose (Gy)z Vref (ml)z High dose (Gy)z D150 (Gy)z Vmax (ml)z
Acute toxicity (Y/N)* Late toxicity (Y/N)* Breast tissue fibrosis (LSC)y Telangiectasia (LSC)y Fat necrosis (Y/N)* Breast pain (LSC)y Hyperpigmentation (CTCAE)y
Abbreviations: APBI = accelerated partial breast irradiation; BCS = breast-conserving surgery; CTCAE = common terminology criteria for adverse events v3.0; ER = estrogen receptor; LSC = lent soma classification; N = no; PR = progesterone receptor; UICC = International Union Against Cancer; Y/N = yes/no. * Log-rank test. y Log-rank test (in case of ordered categorical variables as trend test). z Exact Mann–Whitney U test, comparing distribution of continuous factor between patients with vs. without local recurrence.
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the Wilcoxon U test. In view of the exploratory nature of statistical analyses in this study, no alpha adjustment techniques for multiple testing were used.
RESULTS The median follow-up time was 64 months (range, 9–110 months). During follow up, 2.9% (8/274) of patients experienced local recurrence in the treated breast. The actuarial 5year LRFS was 97.7%. Younger age had been found to be a risk factor for increased ipsilateral in-breast failure. Comparing patients with age <50 years (49/274) vs. $50 years (225/274), the 5-year LRFS were 92.5% and 98.9% (approximated exact p value of logrank test: p = 0.030; 99% CI, 0.029–0.032), respectively (Fig. 1). At the time of breast-conserving treatment, the agea of the 8 patients with local relapses were 42, 44, 45, 46, 56, 69, 70, and 74 years. Table 2 shows the distribution of disease and treatment characteristics between both age groups. With exception of higher use of adjuvant chemotherapy in younger patients (20% vs. 4%; p < 0.001), no other significant differences had been found. Comparing the risk for local recurrence in patients with age 50–59 years (82/ 274) vs. $60 years (143/274), we found no significant differences at 5 years (5-year LRFS, 100% vs. 98.2%). Among 24 patients without AHT, 50% (4/8) of the total number of local recurrences appeared. For all patients, the 5-year LRFS was 99% and 84.9% in favor of the patients who received AHT. The patient group without AHT showed a significantly higher proportion of hormone receptor–negative tumors (13% vs. 0%; p < 0.001) as well as a borderline significance for a greater use of chemotherapy (17% vs. 6%; p = 0.049), which is also an indirect sign for a higher proportion of hormone-insensitive tumors (Table 2). Excluding patients with hormone-insensitive tumors (n = 3) and unknown hormone receptor status (n = 7) from Kaplan–Meier
Fig. 1. Impact of age on local control. Five-year local recurrance for patients <50 years of age was 7.5%, and for patients $50 years was 1.1% (log-rank test; approximated exact p = 0.030; 99% confidence interval, 0.029–0.032).
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analysis and thus considering patients with hormonesensitive tumors only (n = 264), the 5-year LRFS were 98.9% and 88% (approximated exact p value of log-rank test: p = 0.0087; 99% CI, 0.0079–0.0094), respectively (Fig. 2). The lobular histological subtype (45/274) was not associated with local control compared with all other histologies (229/274). The 5-year LRFS rates at were very similar (97.6% vs. 97.8%). Table 2 shows balanced disease and treatment characteristics with exception of tumor grading (p = 0.007). The majority of the additional variables considered were not significantly associated with local control (Table 1). Because age and AHT, both found to be significantly associated with LRFS, were not significantly associated (Table 2), mutual confounding was regarded as unlikely, and an adjusted, multifactorial analysis was not deemed necessary. DISCUSSION In this analysis the actuarial local recurrence rate was 2.3% at 5 years, which is very well comparable to trials on highly selected subgroups of patients with early breast cancer, after breast-conserving surgery and subsequent whole breast irradiation in the treatment arm (17–22). The averaged annual risk for in-breast recurrence was 0.46% in this large Phase II trial (n = 274), which underlines that APBI with interstitial implants is safe for this subgroup of breast cancer patients. Despite efforts to identify appropriate selection criteria for this subgroup, many questions are still open. Therefore, we analyzed our study population regarding factors associated with local failure, and found age and antihormonal treatment to be significant predictors for local control (Figs. 1 and 2). Because of the low number of ipsilateral in-breast failures in our trial (8/274), there may be some concern regarding the statistical precision of the presented results. Nevertheless, our findings are in accordance with available data, underlining that even in a highly selected subgroup of early-stage breast cancer, patient age of <50 years represents a crucial risk factor. The results of large randomized APBI studies such as the Groupe Europe´en de Curiethe´rapie (GEC)/European Society for Therapeutic Radiology (ESTRO) Trial or the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39/Radiation Therapy Oncology Group (RTOG) 0413 Trial may generate a deeper understanding regarding the conclusions of our presentation. It is a well-known fact that despite extensive treatment younger age is associated with a worse local and distant control of breast cancer (23). In a recently published subgroup analysis of the European Organisation for Research and Treatment of Cancer (EORTC) Boost Versus No Boost Trial, age <50 years has been found to be one of two negative predictive factors for local relapse in multifactorial analysis (24). The cumulative incidence of local relapse at 10 years was significantly higher for patients <50 years of age compared with patients $50 years (14.8% vs. 6.2%). Because of a limited number of cases and follow-up, as well as a lack of mature
Table 2. Distribution of risk factors with potential impact on local control in the analyzed subgroups (age, antihormonal treatment, and histological subtype) Age <50 Years
$50 Years
p value
45 (39–49)
63 (50–84)
18 (9/49) 76 (37/49) 6 (3/49)
Histological subtype
No
Yes
p value
Lobular
Others
p value
—
56 (40–78)
61 (39–84)
NS*
58 (39–84)
61 (39–82)
NS*
17 (39/225) 73 (163/225) 10 (23/225)
NSy
17 (4/24) 71 (17/24) 12 (3/24)
18 (44/250) 73 (183/250) 9 (23/250)
NSy
16 (7/45) 75 (34/45) 9 (4/45)
18 (41/229) 72 (166/229) 10 (22/229)
NSy
35 (17/49) 4 (2/49) 55 (37/49) 6 (3/49)
35 (78/225) 12 (27/225) 48 (109/225) 5 (11/225)
NSy
43 (11/24) 8 (2/24) 42 (10/24) 4 (1/24)
34 (84/250) 11 (27/250) 50 (126/250) 5 (13/250)
NSy
31 (14/45) 7 (3/45) 51 (23/45) 11 (5/45)
35 (81/229) 12 (26/229) 49 (113/229) 4 (9/229)
NSy
— 6 (3/49) 35 (17/49) 51 (25/49) 8 (4/49)
3 (6/225) 12 (26/225) 28 (64/225) 50 (112/225) 8 (17/225)
NSy
4 (1/24) 21 (5/24) 29 (7/24) 38 (9/24) 8 (2/24)
2 (5/250) 9 (24/250) 51 (74/250) 30 (128/250) 8 (19/250)
NSy
— 9 (4/45) 33 (15/45) 56 (25/45) 2 (1/45)
2 (6/229) 11 (25/229) 29 (66/229) 50 (112/229) 8 (20/229)
NSy
90 (44/49) 8 (4/49) 2 (1/49) —
85 (191/225) 10 (23/225) 2 (5/225) 3 (6/225)
NSy
84 (20/24) 8 (2/24) 8 (2/24) —
86 (215/250) 10 (25/250) 2 (4/250) 2 (6/250)
NSy
82 (37/45) 14 (6/45) — 4 (2/45)
86 (198/229) 9 (21/229) 3 (6/229) 2 (4/229)
NSy
16 (8/49) 84 (41/49)
16 (37/225) 84 (188/225)
NSy
17 (4/24) 83 (20/24)
16 (41/250) 84 (209/250)
NSy
100 (45/45) —
— 100 (229/229)
—
33 (16/49) 65 (32/49) 2 (1/49) — 20 (10/49) 86 (42/49)
32 (71/225) 64 (144/225) 3 (7/225) 1 (3/225) 4 (9/225) 92 (208/225)
NSy
38 (9/24) 58 (14/24) 4 (1/24) — 17 (4/24) —
31 (68/250) 65 (172/250) 3 (7/250) 1 (3/250) 6 (15/250) 100 (250/250)
NSy
13 (6/45) 87 (39/45) — — 11 (5/45) 91 (41/45)
35 (81/229) 60 (137/229) 4 (8/229) 1 (3/229) 6 (14/229) 91 (209/229)
0.007y
86 (42/49) 6 (3/49) 2 (1/49) 2 (1/49) 4 (2/49)
84.5 (190/225) 12 (27/225) 0.5 (1/225) 1 (2/225) 2 (5/225)
58 (14/24) 17 (4/24) 4 (1/24) 13 (3/24) 8 (2/24)
87 (218/250) 10 (26/250) 1 (1/250) — 2 (5/250)
91 (41/45) 7 (3/45) — — 2 (1/45)
84 (191/229) 12 (27/229) 1 (2/229) 1 (3/229) 2 (6/229)
NSy
0.000y NSy NSy
0.049y — 0.000y
NSy NSy
Risk factors associated with increased local recurrence after APBI d O. J. OTT et al.
Median age (y) Type of surgery (%) Tumorectomy Segmental mastectomy quadrantectomy Resection margins (%) #5 mm 6–9 mm $10 mm Not available pT Category (%) pT1mic pT1a pT1b pT1c pT2 pN Category (%) pN0 pN0 sn cN0 pN1mi Typing (%) Lobular Nonlobular Grading (%) G1 G2 G3 Not available Chemotherapy (%) AHT (%) ER/PR status (%) ER+/PR+ ER+/PR ER-/PR+ ER-/PR Not available
Antihormonal treatment
Abbreviations: AHT = antihormonal treatment; ER = estrogen receptor; PR = progesterone receptor. * Whitney-Mann U test. y Chi-square test. 1461
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Fig. 2. Impact of adjuvant antihormonal treatment (AHT) on local control. Five-year local recurrance for hormone-sensitive patients (n = 264) with AHT was 1.1%, and without AHT was 12% (logrank test; approximated exact p = 0.0087; 99% CI, 0.0079–0.0094).
full-powered Phase III trials, data on risk factors associated with higher in-breast failure is rare in APBI research. Recently, Antonucci et al. (1) reported on differences in patterns of failure in patients treated with interstitial multicatheter APBI vs. WBI in a matched-pair analysis with 10 years follow-up. A total of 199 patients with early-stage breast cancer were treated prospectively with breast-conserving surgery and APBI were matched with 199 patients treated with WBI. Match criteria included tumor size, nodal status, age at diagnosis, margins of excision, estrogen receptor status, and use of adjuvant tamoxifen therapy. Median followup for surviving patients was 9.6 years (range, 0.3–13.6 years). Eight ipsilateral breast tumor recurrences (IBTR) were observed in patients treated with APBI. The cumulative incidence at 10 years was 5%. On matched-pair analysis, the rate of IBTR was not statistically significantly significantly different between the patient groups (4% for WBI therapy patients vs. 5% for APBI patients). All patients (n = 398) were analyzed for variables associated with local failure. Young age had been found to be a significant predictor of in-breast
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recurrence in Cox proportional hazards regression analysis, which is in perfect accordance with findings in our trial. Furthermore, Antonucci et al. (1) found the lack of adjuvant tamoxifen therapy use to be significantly associated with a higher rate of ipsilateral in-breast failures. Adjuvant tamoxifen was administered in 57% (228/398) of their cases, as positive receptor status was no inclusion criteria for that study. In contrast, in our trial, estrogen receptor–negative and progesterone receptor–negative tumors (ER/PR) were prospectively excluded by eligibility criteria (Table 2). Therefore, the lack of adjuvant AHT led to even more pronounced differences regarding local control. At 5 years, the probability of in-breast recurrence was approximately 11 times higher for the subgroup of hormone-sensitive patients who received no AHT (Fig. 2). On the other hand, the 5-year LRFS was excellent (1.1%) in the group of hormone-sensitive patients with breast-conserving surgery, adjuvant interstitial multicatheter APBI, and AHT. Lobular histology had been discussed as a predictor of local recurrence (25) and therefore had been excluded in some contemporary APBI trials (1, 26). At present, among published APBI trials, no evidence on the effect of different histological subtypes on local control is available. In the present trial, no significant difference of 5-year LRFS had been found for patients with lobular histology. Lobular histology was definitely not associated with a higher rate of in-breast failures. This finding is confirmed by a large retrospective analysis by Yale University (25). CONCLUSION With increasing follow-up, more and more Phase II trials with interstitial multicatheter brachytherapy have demonstrated that local control rates comparable to those obtained with standard whole breast irradiation are safely achievable. The 5-year LRFS rates in contemporary Phase II trials are very good. Beyond that, our data indicate that patients <50 years should be excluded from APBI protocols, and that patients with hormone-sensitive breast cancer should definitely receive adjuvant AHT when interstitial multicatheter APBI is performed. Lobular histology might not be an exclusion criterion in future APBI trials.
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doi:10.1016/j.ijrobp.2010.04.032
CLINICAL INVESTIGATION
Breast
ACCELERATED PARTIAL BREAST IRRADIATION WITH INTERSTITIAL IMPLANTS: RISK FACTORS ASSOCIATED WITH INCREASED LOCAL RECURRENCE OLIVER J. OTT, M.D.,* GUIDO HILDEBRANDT, M.D.,yz RICHARD PO¨TTER, M.D.,x JOSEF HAMMER, M.D.,k MARION HINDEMITH, M.D.,y ALEXANDRA RESCH, M.D.,x KURT SPIEGL, M.D.,k MICHAEL LOTTER, PH.D.,* WOLFGANG UTER, M.D.,{ ROLF-DIETER KORTMANN, M.D.,y MICHAEL SCHRAUDER, M.D.,# MATTHIAS W. BECKMANN, M.D.,# RAINER FIETKAU, M.D.,* AND VRATISLAV STRNAD, M.D.* *University Hospital Erlangen, Department of Radiation Oncology, Erlangen, Germany; yUniversity Hospital Leipzig, Department of Radiation Oncology, Leipzig, Germany; zUniversity Hospital Rostock, Department of Radiation Oncology, Rostock, Germany; x University Hospital AKH Vienna, Department of Radiation Oncology and Radiobiology, Vienna, Austria; kBarmherzige Schwestern Hospital, Department of Radiation Oncology, Linz, Austria; {Departments of Medical Informatics, Biometry and Epidemiology, University Erlangen-Nuremberg, Erlangen, Germany; and #University Hospital Erlangen, Department of Gynecology, Erlangen, Germany Purpose: To analyze patient, disease, and treatment-related factors regarding their impact on local control after interstitial multicatheter accelerated partial breast irradiation (APBI). Methods and Materials: Between November 2000 and April 2005, 274 patients with early breast cancer were recruited for the German–Austrian APBI Phase II trial (ClinicalTrials.gov identifier: NCT00392184). In all, 64% (175/274) of the patients received pulsed-dose-rate (PDR) brachytherapy and 36% (99/274) received high-doserate (HDR) brachytherapy. Prescribed reference dose for HDR brachytherapy was 32 Gy in eight fractions of 4 Gy, twice daily. Prescribed reference dose in PDR brachytherapy was 49.8 Gy in 83 consecutive fractions of 0.6 Gy each hour. Total treatment time was 3 to 4 days. Results: The median follow-up time was 64 months (range, 9–110). The actuarial 5-year local recurrence free survival rate (5-year LRFS) was 97.7%. Comparing patients with an age <50 years (49/274) vs. $50 years (225/274), the 5-year LRFS resulted in 92.5% and 98.9% (exact p = 0.030; 99% confidence interval, 0.029–0.032), respectively. Antihormonal treatment (AHT) was not applied in 9% (24/274) of the study population. The 5-year LRFS was 99% and 84.9% (exact p = 0.0087; 99% confidence interval, 0.0079–0.0094) in favor of the patients who received AHT. Lobular histology (45/274) was not associated with worse local control compared with all other histologies (229/274). The 5-year LRFS rates were 97.6% and 97.8%, respectively. Conclusions: Local control at 5 years is excellent and comparable to therapeutic successes reported from corresponding whole-breast irradiation trials. Our data indicate that patients <50 years of age ought to be excluded from APBI protocols, and that patients with hormone-sensitive breast cancer should definitely receive adjuvant AHT when interstitial multicatheter APBI is performed. Lobular histology need not be an exclusion criterion for future APBI trials. Ó 2011 Elsevier Inc. Accelerated partial breast irradiation, Local control, In-breast recurrence, Interstitial brachytherapy, Risk factors.
INTRODUCTION
on the safety and efficacy of this treatment approach for a highly selected subgroup of breast cancer patients with an intrinsically low risk of local recurrence (4–10). As clinical data accumulate, a deeper understanding of the impact of several factors related to treatment outcome becomes possible. The aim of the present analysis was to detect predictive patient-, disease-, or treatment-related conditions significantly associated with local control rates.
Recently, accelerated partial breast irradiation (APBI) has become a field of high interest in radio-oncological research (1, 2). During the past few years, six large randomized trials with a total accrual number of more than 11.600 patients had been initiated to compare various APBI techniques to standard whole breast irradiation (3). Data from quality controlled Phase II trials on interstitial multicatheter APBI with a median follow-up reaching 10 years increasingly provided evidence Reprint requests to: Oliver J. Ott, M.D., University Hospital Erlangen, Department of Radiation Oncology, Universita¨tsstr. 27, D91054 Erlangen, Germany. Tel: +49 9131 8544204; Fax: +49 9131 8535969; E-mail: [email protected]
Conflicts of interest: none. Received Jan 28, 2010, and in revised form April 13, 2010. Accepted for publication April 14, 2010. 1458
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METHODS AND MATERIALS Study patients Between April 2001 and January 2005, 274 consecutive patients with early breast cancer were recruited for this prospective Phase II trial. At the time of radiotherapy, the median age was 60.5 years (range, 39–84 years). Per protocol, patients were eligible for APBI if they had histologically confirmed breast cancer, tumor diameter #3 cm, complete resection with clear margins $2 mm, postsurgical negative axillary lymph nodes (pN0) or singular nodal micrometastasis (pN1 mi), no distant metastasis or contralateral breast cancer, European Cooperative Oncology Group (ECOG) performance status #2, estrogen and/or progesterone sensitive tumors (ER+/PR+; ER+/PR; ER/PR+), and were at least 35 years of age. Patients were excluded from the protocol if they mammographically showed a multifocal invasive growth pattern or poorly differentiated tumors, had postoperative residual micro-calcifications, had an extensive intraductal component (EIC), had vessel invasion (L1, V1), had involved or unknown margins (R1/Rx), or were pregnant. Before recruitment, the protocol was approved by each of the four appropriate ethical committees of Erlangen, Leipzig (Germany), Linz, and Vienna (Austria). All patients gave informed consent before protocol specific treatment. More detailed information on the trial is available elsewhere (7, 8, 10–13).
Treatment Patients received closed cavity breast conserving surgery and axillary staging. Titan clip marking of the tumor bed was present in 58% (159/274) and absent in 37% (102/274) of the patients; data on tumor bed clips were not available for 5% (13/274) of the patients. The median interval between the definitive surgical procedure and the implantation of the brachytherapy catheters for APBI was 57 days (standard deviation [SD], 39–75 days). This time interval facilitated complete wound healing and obtaining of a comprehensive histological report for proper patient selection. Of the patients, 64% (175/274) received PDR , and 36% (99/274) HDR brachyther-
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apy. Prescribed reference dose for HDR brachytherapy was 32 Gy in eight fractions of 4 Gy, twice daily, at an interval of 6 h at least. Total treatment time was 4 days. Prescribed reference dose in PDR brachytherapy was 49.8 Gy in 83 consecutive fractions of 0.6 Gy each hour. Total treatment time was 4 days. Antihormonal treatment (usually with tamoxifen during this time) was administered in 91% (250/274) and adjuvant chemotherapy in 7% (19/274) of the patients. Further information on patient- and treatment-related characteristics is given in Table 1. More information on protocol design and treatment variables had been summarized in previous publications (7, 8, 10).
Follow-up Patients were followed up every 3 months for 2 years after breast conserving surgery, at 6-month intervals thereafter, and at yearly intervals after completion of 5-year follow-up. Local control and survival parameters, as well as acute and late toxicity rates and cosmetic outcome, were assessed by clinical examination and combined mammogram and breast ultrasound examination. For this analysis, we focused on risk factors associated with ipsilateral in-breast recurrence.
Statistical analysis Data management and statistical analysis were carried out with PASW Statistics for MS Windows, release 17.0.2 (SPSS Inc., Chicago, IL). For statistical comparisons between groups the Mann–Whitney U test and Pearson’s’ Chi-square test were used as appropriate. Survival probability was estimated using the Kaplan–Meier method (14), using the log-rank test to compare two or more groups. In view of the rareness of events and of the partly small size of a subgroup, an approximation of the exact permutation log-rank test based on 100,000 chance permutations was used with R, version 2.8.1, software (15), in particular the package coin (16). To examine the association of continuous factors with local recurrence, the distribution of these factors was compared between patients with local recurrence vs. patients without local recurrence using a Monte Carlo approximation of the exact p value of
Table 1. Patient, disease, and treatment related factors analyzed for their impact on local control Age (<50 vs. $50)* Bra cup sizey Type of surgery* Study center* Number of removed axillary lymph nodesz Localization (involved quadrant, upper vs. lower, medial vs. lateral)* Histological subtype* Accompanying DCIS (Y/N)* pT Categoryy Tumor size (mm)z pN Categoryy UICC stagey Safety margin (mm)z Gradingy Lateralization (involved breast)* ER/PR receptor statusy Her2/neu overexpression status* Prior radiotherapy (Y/N)*
Chemotherapy (Y/N)* Antihormonal treatment (Y/N)* PDR vs. HDR brachytherapy* Number of implant planesz Number of pulsesz Reference dose (Gy)z Mean central dose (Gy)z V150 (ml)z Dose homogeneity indexz Dose nonuniformity ratioz Interval BCS–APBI (days)z Single pulse dose (Gy)z Vref (ml)z High dose (Gy)z D150 (Gy)z Vmax (ml)z
Acute toxicity (Y/N)* Late toxicity (Y/N)* Breast tissue fibrosis (LSC)y Telangiectasia (LSC)y Fat necrosis (Y/N)* Breast pain (LSC)y Hyperpigmentation (CTCAE)y
Abbreviations: APBI = accelerated partial breast irradiation; BCS = breast-conserving surgery; CTCAE = common terminology criteria for adverse events v3.0; ER = estrogen receptor; LSC = lent soma classification; N = no; PR = progesterone receptor; UICC = International Union Against Cancer; Y/N = yes/no. * Log-rank test. y Log-rank test (in case of ordered categorical variables as trend test). z Exact Mann–Whitney U test, comparing distribution of continuous factor between patients with vs. without local recurrence.
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the Wilcoxon U test. In view of the exploratory nature of statistical analyses in this study, no alpha adjustment techniques for multiple testing were used.
RESULTS The median follow-up time was 64 months (range, 9–110 months). During follow up, 2.9% (8/274) of patients experienced local recurrence in the treated breast. The actuarial 5year LRFS was 97.7%. Younger age had been found to be a risk factor for increased ipsilateral in-breast failure. Comparing patients with age <50 years (49/274) vs. $50 years (225/274), the 5-year LRFS were 92.5% and 98.9% (approximated exact p value of logrank test: p = 0.030; 99% CI, 0.029–0.032), respectively (Fig. 1). At the time of breast-conserving treatment, the agea of the 8 patients with local relapses were 42, 44, 45, 46, 56, 69, 70, and 74 years. Table 2 shows the distribution of disease and treatment characteristics between both age groups. With exception of higher use of adjuvant chemotherapy in younger patients (20% vs. 4%; p < 0.001), no other significant differences had been found. Comparing the risk for local recurrence in patients with age 50–59 years (82/ 274) vs. $60 years (143/274), we found no significant differences at 5 years (5-year LRFS, 100% vs. 98.2%). Among 24 patients without AHT, 50% (4/8) of the total number of local recurrences appeared. For all patients, the 5-year LRFS was 99% and 84.9% in favor of the patients who received AHT. The patient group without AHT showed a significantly higher proportion of hormone receptor–negative tumors (13% vs. 0%; p < 0.001) as well as a borderline significance for a greater use of chemotherapy (17% vs. 6%; p = 0.049), which is also an indirect sign for a higher proportion of hormone-insensitive tumors (Table 2). Excluding patients with hormone-insensitive tumors (n = 3) and unknown hormone receptor status (n = 7) from Kaplan–Meier
Fig. 1. Impact of age on local control. Five-year local recurrance for patients <50 years of age was 7.5%, and for patients $50 years was 1.1% (log-rank test; approximated exact p = 0.030; 99% confidence interval, 0.029–0.032).
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analysis and thus considering patients with hormonesensitive tumors only (n = 264), the 5-year LRFS were 98.9% and 88% (approximated exact p value of log-rank test: p = 0.0087; 99% CI, 0.0079–0.0094), respectively (Fig. 2). The lobular histological subtype (45/274) was not associated with local control compared with all other histologies (229/274). The 5-year LRFS rates at were very similar (97.6% vs. 97.8%). Table 2 shows balanced disease and treatment characteristics with exception of tumor grading (p = 0.007). The majority of the additional variables considered were not significantly associated with local control (Table 1). Because age and AHT, both found to be significantly associated with LRFS, were not significantly associated (Table 2), mutual confounding was regarded as unlikely, and an adjusted, multifactorial analysis was not deemed necessary. DISCUSSION In this analysis the actuarial local recurrence rate was 2.3% at 5 years, which is very well comparable to trials on highly selected subgroups of patients with early breast cancer, after breast-conserving surgery and subsequent whole breast irradiation in the treatment arm (17–22). The averaged annual risk for in-breast recurrence was 0.46% in this large Phase II trial (n = 274), which underlines that APBI with interstitial implants is safe for this subgroup of breast cancer patients. Despite efforts to identify appropriate selection criteria for this subgroup, many questions are still open. Therefore, we analyzed our study population regarding factors associated with local failure, and found age and antihormonal treatment to be significant predictors for local control (Figs. 1 and 2). Because of the low number of ipsilateral in-breast failures in our trial (8/274), there may be some concern regarding the statistical precision of the presented results. Nevertheless, our findings are in accordance with available data, underlining that even in a highly selected subgroup of early-stage breast cancer, patient age of <50 years represents a crucial risk factor. The results of large randomized APBI studies such as the Groupe Europe´en de Curiethe´rapie (GEC)/European Society for Therapeutic Radiology (ESTRO) Trial or the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39/Radiation Therapy Oncology Group (RTOG) 0413 Trial may generate a deeper understanding regarding the conclusions of our presentation. It is a well-known fact that despite extensive treatment younger age is associated with a worse local and distant control of breast cancer (23). In a recently published subgroup analysis of the European Organisation for Research and Treatment of Cancer (EORTC) Boost Versus No Boost Trial, age <50 years has been found to be one of two negative predictive factors for local relapse in multifactorial analysis (24). The cumulative incidence of local relapse at 10 years was significantly higher for patients <50 years of age compared with patients $50 years (14.8% vs. 6.2%). Because of a limited number of cases and follow-up, as well as a lack of mature
Table 2. Distribution of risk factors with potential impact on local control in the analyzed subgroups (age, antihormonal treatment, and histological subtype) Age <50 Years
$50 Years
p value
45 (39–49)
63 (50–84)
18 (9/49) 76 (37/49) 6 (3/49)
Histological subtype
No
Yes
p value
Lobular
Others
p value
—
56 (40–78)
61 (39–84)
NS*
58 (39–84)
61 (39–82)
NS*
17 (39/225) 73 (163/225) 10 (23/225)
NSy
17 (4/24) 71 (17/24) 12 (3/24)
18 (44/250) 73 (183/250) 9 (23/250)
NSy
16 (7/45) 75 (34/45) 9 (4/45)
18 (41/229) 72 (166/229) 10 (22/229)
NSy
35 (17/49) 4 (2/49) 55 (37/49) 6 (3/49)
35 (78/225) 12 (27/225) 48 (109/225) 5 (11/225)
NSy
43 (11/24) 8 (2/24) 42 (10/24) 4 (1/24)
34 (84/250) 11 (27/250) 50 (126/250) 5 (13/250)
NSy
31 (14/45) 7 (3/45) 51 (23/45) 11 (5/45)
35 (81/229) 12 (26/229) 49 (113/229) 4 (9/229)
NSy
— 6 (3/49) 35 (17/49) 51 (25/49) 8 (4/49)
3 (6/225) 12 (26/225) 28 (64/225) 50 (112/225) 8 (17/225)
NSy
4 (1/24) 21 (5/24) 29 (7/24) 38 (9/24) 8 (2/24)
2 (5/250) 9 (24/250) 51 (74/250) 30 (128/250) 8 (19/250)
NSy
— 9 (4/45) 33 (15/45) 56 (25/45) 2 (1/45)
2 (6/229) 11 (25/229) 29 (66/229) 50 (112/229) 8 (20/229)
NSy
90 (44/49) 8 (4/49) 2 (1/49) —
85 (191/225) 10 (23/225) 2 (5/225) 3 (6/225)
NSy
84 (20/24) 8 (2/24) 8 (2/24) —
86 (215/250) 10 (25/250) 2 (4/250) 2 (6/250)
NSy
82 (37/45) 14 (6/45) — 4 (2/45)
86 (198/229) 9 (21/229) 3 (6/229) 2 (4/229)
NSy
16 (8/49) 84 (41/49)
16 (37/225) 84 (188/225)
NSy
17 (4/24) 83 (20/24)
16 (41/250) 84 (209/250)
NSy
100 (45/45) —
— 100 (229/229)
—
33 (16/49) 65 (32/49) 2 (1/49) — 20 (10/49) 86 (42/49)
32 (71/225) 64 (144/225) 3 (7/225) 1 (3/225) 4 (9/225) 92 (208/225)
NSy
38 (9/24) 58 (14/24) 4 (1/24) — 17 (4/24) —
31 (68/250) 65 (172/250) 3 (7/250) 1 (3/250) 6 (15/250) 100 (250/250)
NSy
13 (6/45) 87 (39/45) — — 11 (5/45) 91 (41/45)
35 (81/229) 60 (137/229) 4 (8/229) 1 (3/229) 6 (14/229) 91 (209/229)
0.007y
86 (42/49) 6 (3/49) 2 (1/49) 2 (1/49) 4 (2/49)
84.5 (190/225) 12 (27/225) 0.5 (1/225) 1 (2/225) 2 (5/225)
58 (14/24) 17 (4/24) 4 (1/24) 13 (3/24) 8 (2/24)
87 (218/250) 10 (26/250) 1 (1/250) — 2 (5/250)
91 (41/45) 7 (3/45) — — 2 (1/45)
84 (191/229) 12 (27/229) 1 (2/229) 1 (3/229) 2 (6/229)
NSy
0.000y NSy NSy
0.049y — 0.000y
NSy NSy
Risk factors associated with increased local recurrence after APBI d O. J. OTT et al.
Median age (y) Type of surgery (%) Tumorectomy Segmental mastectomy quadrantectomy Resection margins (%) #5 mm 6–9 mm $10 mm Not available pT Category (%) pT1mic pT1a pT1b pT1c pT2 pN Category (%) pN0 pN0 sn cN0 pN1mi Typing (%) Lobular Nonlobular Grading (%) G1 G2 G3 Not available Chemotherapy (%) AHT (%) ER/PR status (%) ER+/PR+ ER+/PR ER-/PR+ ER-/PR Not available
Antihormonal treatment
Abbreviations: AHT = antihormonal treatment; ER = estrogen receptor; PR = progesterone receptor. * Whitney-Mann U test. y Chi-square test. 1461
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Fig. 2. Impact of adjuvant antihormonal treatment (AHT) on local control. Five-year local recurrance for hormone-sensitive patients (n = 264) with AHT was 1.1%, and without AHT was 12% (logrank test; approximated exact p = 0.0087; 99% CI, 0.0079–0.0094).
full-powered Phase III trials, data on risk factors associated with higher in-breast failure is rare in APBI research. Recently, Antonucci et al. (1) reported on differences in patterns of failure in patients treated with interstitial multicatheter APBI vs. WBI in a matched-pair analysis with 10 years follow-up. A total of 199 patients with early-stage breast cancer were treated prospectively with breast-conserving surgery and APBI were matched with 199 patients treated with WBI. Match criteria included tumor size, nodal status, age at diagnosis, margins of excision, estrogen receptor status, and use of adjuvant tamoxifen therapy. Median followup for surviving patients was 9.6 years (range, 0.3–13.6 years). Eight ipsilateral breast tumor recurrences (IBTR) were observed in patients treated with APBI. The cumulative incidence at 10 years was 5%. On matched-pair analysis, the rate of IBTR was not statistically significantly significantly different between the patient groups (4% for WBI therapy patients vs. 5% for APBI patients). All patients (n = 398) were analyzed for variables associated with local failure. Young age had been found to be a significant predictor of in-breast
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recurrence in Cox proportional hazards regression analysis, which is in perfect accordance with findings in our trial. Furthermore, Antonucci et al. (1) found the lack of adjuvant tamoxifen therapy use to be significantly associated with a higher rate of ipsilateral in-breast failures. Adjuvant tamoxifen was administered in 57% (228/398) of their cases, as positive receptor status was no inclusion criteria for that study. In contrast, in our trial, estrogen receptor–negative and progesterone receptor–negative tumors (ER/PR) were prospectively excluded by eligibility criteria (Table 2). Therefore, the lack of adjuvant AHT led to even more pronounced differences regarding local control. At 5 years, the probability of in-breast recurrence was approximately 11 times higher for the subgroup of hormone-sensitive patients who received no AHT (Fig. 2). On the other hand, the 5-year LRFS was excellent (1.1%) in the group of hormone-sensitive patients with breast-conserving surgery, adjuvant interstitial multicatheter APBI, and AHT. Lobular histology had been discussed as a predictor of local recurrence (25) and therefore had been excluded in some contemporary APBI trials (1, 26). At present, among published APBI trials, no evidence on the effect of different histological subtypes on local control is available. In the present trial, no significant difference of 5-year LRFS had been found for patients with lobular histology. Lobular histology was definitely not associated with a higher rate of in-breast failures. This finding is confirmed by a large retrospective analysis by Yale University (25). CONCLUSION With increasing follow-up, more and more Phase II trials with interstitial multicatheter brachytherapy have demonstrated that local control rates comparable to those obtained with standard whole breast irradiation are safely achievable. The 5-year LRFS rates in contemporary Phase II trials are very good. Beyond that, our data indicate that patients <50 years should be excluded from APBI protocols, and that patients with hormone-sensitive breast cancer should definitely receive adjuvant AHT when interstitial multicatheter APBI is performed. Lobular histology might not be an exclusion criterion in future APBI trials.
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