Timing of Radiotherapy and Outcome in Patients Receiving Adjuvant Endocrine Therapy

Int. J. Radiation Oncology Biol. Phys., Vol. 80, No. 2, pp. 398–402, 2011 Copyright Ó 2011 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$–see front matter

doi:10.1016/j.ijrobp.2010.02.042

CLINICAL INVESTIGATION

Breast

TIMING OF RADIOTHERAPY AND OUTCOME IN PATIENTS RECEIVING ADJUVANT ENDOCRINE THERAPY PER KARLSSON, M.D.,* BERNARD F. COLE, PH.D.,yz MARCO COLLEONI, M.D.,x MARIO RONCADIN, M.D.,{ BOON H. CHUA, M.D., PH.D.,k ELIZABETH MURRAY, M.D.,# KAREN N. PRICE, B.S.,** MONICA CASTIGLIONE-GERTSCH, M.D.,yy ARON GOLDHIRSCH, M.D.,zzxx AND GU¨NTHER GRUBER, M.D.{{ FOR THE INTERNATIONAL BREAST CANCER STUDY GROUP *Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden; yDepartment of Mathematics and Statistics, University of Vermont College of Engineering and Mathematical Sciences, Burlington, VT; zInternational Breast Cancer Study Group Statistical Center, Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA; xDepartment of Medicine, Research Unit in Medical Senology, European Institute of Oncology, Milan, Italy; {Department of Radiotherapy, Centro di Riferimento Oncologico, Aviano, Italy; kDepartment of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; # Department of Radiation Oncology, Groote Shuur Hospital and University of Cape Town, Cape Town, South Africa; **International Breast Cancer Study Group Statistical Center, Frontier Science and Technology Research Foundation, Boston, MA; yyInternational Breast Cancer Study Group Coordinating Center, Bern, Switzerland; zzEuropean Institute of Oncology, Milan, Italy; xxOncology Institute of Southern Switzerland, Bellinzona, Switzerland; {{Institut fuer Radiotherapie, Klinik Hirslanden, Zu¨rich, Switzerland Purpose: To evaluate the association between the interval from breast-conserving surgery (BCS) to radiotherapy (RT) and the clinical outcome among patients treated with adjuvant endocrine therapy. Patients and Methods: Patient information was obtained from three International Breast Cancer Study Group trials. The analysis was restricted to 964 patients treated with BCS and adjuvant endocrine therapy. The patients were divided into two groups according to the median number of days between BCS and RT and into four groups according to the quartile of time between BCS and RT. The endpoints were the interval to local recurrence, diseasefree survival, and overall survival. Proportional hazards regression analysis was used to perform comparisons after adjustment for baseline factors. Results: The median interval between BCS and RT was 77 days. RT timing was significantly associated with age, menopausal status, and estrogen receptor status. After adjustment for these factors, no significant effect of a RT delay #20 weeks was found. The adjusted hazard ratio for RT within 77 days vs. after 77 days was 0.94 (95% confidence interval [CI], 0.47–1.87) for the interval to local recurrence, 1.05 (95% CI, 0.82–1.34) for disease-free survival, and 1.07 (95% CI, 0.77–1.49) for overall survival. For the interval to local recurrence the adjusted hazard ratio for #48, 49–77, and 78–112 days was 0.90 (95% CI, 0.34–2.37), 0.86 (95% CI, 0.33–2.25), and 0.89 (95% CI, 0.33–2.41), respectively, relative to $113 days. Conclusion: A RT delay of #20 weeks was significantly associated with baseline factors such as age, menopausal status, and estrogen-receptor status. After adjustment for these factors, the timing of RT was not significantly associated with the interval to local recurrence, disease-free survival, or overall survival. Ó 2011 Elsevier Inc. Breast cancer, Radiotherapy, Radiotherapy timing, Breast-conserving surgery, Endocrine therapy.

INTRODUCTION Radiotherapy (RT) to the breast after breast-conserving surgery (BCS) reduces the risk of local recurrence and improves breast cancer-specific survival (1). The optimal interval between surgery and the start of RT is not known. Theoretically,

the risk of recurrence is related to the density of the clonogenic cells in the surgical bed. Therefore, a delay between surgery and the start of RT could increase the likelihood of tumor cell growth and the development of radioresistance (2). Several retrospective studies have yielded variable results (3–8).

Reprint requests to: Per Karlsson, M.D., Department of Oncology, University of Go¨teborg, Sahlgrenska University Hospital, Gothenburg S 413 45 Sweden. Tel: (+46) 31-342-2246; Fax: (+46) 31-820-114; E-mail: [email protected] Preliminary results were presented in a poster at the St. Gallen Breast Conference, St. Gallen, Switzerland, March 2009. The International Breast Cancer Study Group was funded in part by the Swiss Group for Clinical Cancer Research, the Frontier Science and Technology Research Foundation, the Cancer Council Australia, the Australian New Zealand Breast Cancer Trials Group

(National Health Medical Research Council), the National Cancer Institute (Grant CA-75362), the Swedish Cancer Society, the Cancer Association of South Africa, and the Foundation for Clinical Cancer Research of Eastern Switzerland (OSKK). Conflict of interest: none. Acknowledgments—We thank the patients, physicians, nurses, and data managers who participated in the International Breast Cancer Study Group trials. Received Oct 9, 2009, and in revised form Feb 3, 2010. Accepted for publication Feb 11, 2010. 398

Timing of RT for adjuvant breast cancer d P. KARLSSON et al.

Generally, on univariate analysis, an increased risk of local recurrence was observed with a longer delay between surgery and the start of RT. However, on multivariate analysis, this effect was not observed. Two systematic reviews showed an increase in the risk of local recurrence with RT delay of >8 weeks (9, 10). However, these reviews included all subtypes of breast cancer and a variety of study designs, rendering interpretation of the results difficult. The risk of local recurrence in relation to RT delay can vary by breast cancer subtype and systemic treatment. An International Breast Cancer Study Group (IBCSG) study has shown that delaying RT until the completion of chemotherapy did not adversely affect the treatment outcome (11). No study has examined the effect of RT delay on local recurrence in breast cancer exclusively in patients receiving endocrine therapy. The aim of the present study was to investigate the effect of a delay from BCS to the start of RT in patients treated with endocrine therapy in three IBCSG trials. PATIENTS AND METHODS Patient information was obtained from 1,108 patients who had undergone BCS and were randomized to selected treatment arms from IBCSG Trials VII, VIII, and IX. Of the 1,108 patients identified, 135 did not receive RT and an additional 9 did not have a record of RT start dates, leaving 964 patients in the analyzed cohort. Trial VII compared adjuvant tamoxifen alone vs. chemoendocrine treatment with tamoxifen with concurrent classic cyclophosphamide, methotrexate, and 5-fluorouricil (CMF) in postmenopausal patients with node-positive breast cancer (12). Trial VIII studied adjuvant ovarian function suppression with luteinizing hormonereleasing hormone analog for 2 years vs. six courses of CMF vs. six courses of CMF followed by 18 months of ovarian function suppression in premenopausal patients with node-negative disease (13). Trial IX compared adjuvant tamoxifen vs. three courses of CMF followed by tamoxifen in postmenopausal patients with node-negative disease (14). The present study was restricted to the following treatment groups receiving adjuvant endocrine therapy: Trial VII, Arm A, tamoxifen for 5 years (n = 69); Trial VIII, Arm B, luteinizing hormone-releasing hormone analog for 2 years ((n = 173); Trial IX, Arm A, tamoxifen for 5 years (n = 374); and Trial IX, Arm B, CMF3 followed by tamoxifen for 57 months (n = 370). Trial VII specified that RT was required for all patients who had undergone BCS. Although Trials VIII and IX did not mandate RT to the conserved breast, 88% of the patients who had undergone BCS were treated with RT. In all three trials, patients who had undergone BCS and RT and were randomized to receive endocrine therapy alone were required to begin RT within 3 months of randomization, and those randomized to receive CMF before tamoxifen in Trial IX were to begin RT 2 weeks after the end of the last cycle of chemotherapy. For the present study, the patients were divided into two groups according to the median number of days from surgery to the start of RT. Kaplan-Meier survival curves were plotted for the two groups, and the log–rank test was used to compare them. The endpoints were the interval to local recurrence, disease-free survival (DFS), and overall survival (OS), measured from the start of RT. This approach accounted for how the interval to an event had to exceed the number of days between surgery and the start of RT. In addition, the patients were divided into four groups according to the quartiles of days from surgery until the start of RT. Proportional

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hazards regression was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the two-group and four-group analyses following adjustment for baseline factors.. Wald tests were used to evaluate the heterogeneity among the HRs according to the four-group analysis. Of the 964 patients in the analytic cohort, 715 had estrogen receptor (ER)-positive disease. All analyses were repeated for the ER-positive cohort.

RESULTS The median number of days from surgery to the start of RT was 77 (mean, 84; standard deviation, 45; range, 14–436). A total of 409 patients (42%) received RT >90 days after surgery. Table 1 summarizes the baseline characteristics of the two groups of patients who started RT within or after the median of 77 days after surgery. Age, premenopausal status, and hormone receptor status were significantly associated with RT timing. However, it should be noted that some of these differences might have resulted from the CMF-tamoxifen arm of Trial IX in which patients underwent RT after chemotherapy. The median follow-up was 10.5 years. The total number of events was 37 local recurrences, 271 DFS events, and 161 deaths. Adjusting for the differences in baseline characteristics, the HR for starting RT within 77 days relative to after 77 days was 0.94 (95% CI, 0.47–1.87) for local recurrence, 1.05 (95% CI, 0.82–1.34) for DFS, and 1.07 (95% CI, 0.77–1.49) for OS (Tables 2 and 3). When patients were divided into Table 1. Baseline characteristics Characteristic Age (y) Menopausal status Pre Post ER status Negative Positive Unknown Tumor grade 1 2 3 Unknown Positive lymph nodes (n) 0 1–3 $4 Tumor size (cm) #2 >2 Unknown Vessel invasion No Yes Unknown

RT within 77 d (n = 492)

RT after 77 d (n = 472)

55.6  8.9

58.8  7.3

128 (26) 364 (74)

45 (10) 427 (90)

123 (25) 357 (73) 12 (2)

89 (19) 358 (76) 25 (5)

89 (18) 237 (48) 165 (34) 1 (0)

86 (18) 221 (47) 162 (34) 3 (1)

p* <.0001 <.0001 .042

.94

.62 454 (92) 25 (5) 13 (3)

441 (93) 23 (5) 8 (2)

371 (75) 118 (24) 3 (1)

366 (78) 100 (21) 6 (1)

378 (77) 94 (19) 20 (4)

364 (77) 67 (14) 41 (9)

.35

.098

Abbreviations: RT = radiotherapy; ER = estrogen receptor. Data presented as number of patients, with percentages in parentheses, except for age, which is given as mean +/ standard deviation. * Unknown data for given category excluded from calculation of p values.

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Table 2. Adjusted proportional hazards regression results dividing at median RT timing (from surgery) Local recurrence #77 d $78 d Disease-free survival #77 d $78 d Overall survival #77 d $78 d

Table 4. Adjusted proportional hazards regression results according to quartiles

HR

95% CI

p

0.94 1.00

0.47–1.87

.86

1.05 1.00

0.82–1.34

.73

1.07 1.00

0.77–1.49

.67

Abbreviations: RT = radiotherapy; HR = hazard ratio; CI = confidence interval. Adjustment factors: age, ER status, tumor grade, nodal status, tumor size and vessel invasion status.

quartiles according to the surgery-to-RT interval, the adjusted HRs were not significantly different (Tables 4 and 5). The Kaplan-Meier curves for the interval to local recurrence, DFS, and OS with the interval to an event from the start of RT for the two-group analysis and the four-group analysis are shown in Figs. 1 and 2, respectively. KaplanMeier analysis with the interval to event measured from Day 77 after surgery gave similar results (data not shown). The analyses were repeated for the ER-positive cohort (n = 715), with similar results (Tables 3 and 5), with no significant interactions found between RT timing and ER positivity (data not shown). The mean interval from surgery to the start of endocrine therapy was 33 days in the group that started RT within 77 days and 81 days in the group that started RT after 77 days. Of the 841 patients (89%) who began endocrine therapy before RT, the mean interval from the start of endocrine therapy to the start of RT was 26 days in the group that started RT within 77 days and 48 days in the group that started RT after 77 days.

After adjustment for differences in the baseline characteristics, RT timing was not significantly associated with the interval to local recurrence, DFS, or OS in patients receiving adjuvant endocrine therapy for RT delay of up to about 20 weeks. Postoperative RT after BCS reduces local failure rates Table 3. Estrogen receptor-positive cohort: adjusted proportional hazards regression results divided at median

Local recurrence #77 d $78 d Disease-free survival #77 d $78 d Overall survival #77 d $78 d

RT timing from surgery Local recurrence* #48 d 49–77 d 78–112 d $113 d Disease-free survivaly #48 d 49–77 d 78–112 d $113 d Overall survivalz #48 d 49–77 d 78–112 d $113 d

HR

95% CI

p

0.90 0.86 0.89 1.00

0.34–2.37 0.33–2.25 0.33–2.41

.83 .76 .81

0.78 0.95 0.68 1.00

0.55–1.10 0.68–1.32 0.47–0.97

.16 .75 .03

0.70 0.86 0.50 1.00

0.45–1.11 0.56–1.31 0.31–0.81

.13 .47 .005

Abbreviations as in Table 2. * Overall Wald p = .99. y Overall Wald p = .12. z Overall Wald p = .03. Adjustment factors as in Table 2.

substantially and thus has been well accepted (1). However, the optimal interval between surgery and the start of RT is controversial. A recent meta-analysis by Chen et al. (9) indicated an increasing relative risk of 1.11/month of RT delay for local recurrence in so-called high-quality series, irrespective of whether chemotherapy was given; however, no significant effect was found on distant metastasis or OS. That metaanalysis confirmed a previous systematic review (10), in which the 5-year local relapse rate was significantly greater in breast cancer patients starting adjuvant RT >8 weeks after surgery compared with patients treated within 8 weeks (odds ratio, 1.62; 95% CI, 1.21–2.16). However, these metaanalyses included patients with a variety of breast cancer subtypes and for whom the use of systemic therapy was Table 5. Estrogen receptor-positive cohort: adjusted proportional hazards regression results according to quartiles

DISCUSSION

RT timing from surgery

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HR

95% CI

p

0.84 1.00

0.38–1.89

.68

0.95 1.00

0.71–1.28

.73

1.16 1.00

0.77–1.74

.48

Abbreviations as in Table 2. Adjustment factors as in Table 2.

RT timing from surgery Local recurrence* #48 d 49–77 d 78–112 d $113 d Disease-free survivaly #48 d 49–77 d 78–112 d $113 d Overall survivalz #48 d 49–77 d 78–112 d $113 d

HR

95% CI

p

1.03 0.67 0.99 1.00

0.34–3.14 0.21–2.17 0.31–3.17

.96 .50 .99

0.72 0.82 0.65 1.00

0.48–1.09 0.55–1.22 0.42–0.99

.12 .32 .04

0.76 0.80 0.42 1.00

0.44–1.32 0.47–1.38 0.23–0.78

.33 .42 .005

Abbreviations as in Table 2. * Overall Wald p = .85. y Overall Wald p = .20. z Overall Wald p = .05. Adjustment factors as in Table 2.

Timing of RT for adjuvant breast cancer d P. KARLSSON et al.

A 100

Local recurrence free interval (%)

Local recurrence free interval (%)

A

80 60 40 Days Surgery to RT ≤ 77 days ≥ 78 days

20 0 0

1

2

N 492 472

10-Year Events Interval% ± SE p 21 95 ± 1 0.55 16 96 ± 1

3 4 5 6 7 8 9 10 Time from Start of Radiotherapy (Years)

11

80 60 40

Days Surgery to RT ≤ 48 days 49-77 days 78-112 days ≥ 113 days

20 0 0

1

2

N 234 258 226 246

10-Year Events Interval% ± SE p 0.91 11 95 ± 2 10 95 ± 2 8 95 ± 2 8 96 ± 1

3 4 5 6 7 8 9 10 Time from Start of Radiotherapy (Years)

11

12

B 100

100

80

80

60

60

DFS (%)

DFS (%)

100

12

B

40 Days Surgery to RT ≤ 77 days ≥ 78 days

20 0 0

1

2

N 492 472

Events 145 126

10-Year DFS% ± SE 72 ± 2 73 ± 2

3 4 5 6 7 8 9 10 Time from Start of Radiotherapy (Years)

p 0.55

40

Days Surgery to RT ≤ 48 days 49-77 days 78-112 days ≥ 113 days

20 0

11

0

12

C

1

2

N 234 258 226 246

Events 67 78 55 71

10-Year DFS% ± SE 72 ± 3 72 ± 3 75 ± 3 72 ± 3

3 4 5 6 7 8 9 10 Time from Start of Radiotherapy (Years)

p 0.39

11

12

C 100

100

80

80

60

60

OS (%)

OS (%)

401

40 Days Surgery to RT ≤ 77 days ≥ 78 days

20 0 0

1

2

N 492 472

Events 85 76

10-Year OS% ± SE 83 ± 2 84 ± 2

3 4 5 6 7 8 9 10 Time from Start of Radiotherapy (Years)

p 0.79

40

Days Surgery to RT ≤ 48 days 49-77 days 78-112 days ≥ 113 days

20 0

11

12

0

1

2

N 234 258 226 246

Events 39 46 29 47

10-Year OS% ± SE 83 ± 3 83 ± 3 86 ± 3 81 ± 3

3 4 5 6 7 8 9 10 Time from Start of Radiotherapy (Years)

p 0.22

11

12

Fig. 1. Kaplan-Meier curves for (A) interval to local recurrence, (B) disease-free survival (DFS), and (C) overall survival (OS) with interval to event from start of radiotherapy (RT) for patients with radiotherapy within or after 77 days after surgery. SE = standard error.

Fig. 2. Kaplan-Meier curves for (A) interval to local recurrence, (B) disease-free survival (DFS), and (C) overall survival (OS) with interval to event from start of radiotherapy (RT) in quartiles (#48, 49–77, 78–112, and $113 days). SE = standard error.

inconsistent. Both of these factors could have affected the local recurrence rate. Only a few studies have evaluated the interval of RT after surgery in the absence of chemotherapy. The more recent meta-analysis (9) identified only four studies (3, 5, 15, 16), all of which were observational. However, all had an adequate description of the distribution of relevant prognostic factors, which were either well balanced between the comparison groups or appropriately adjusted

for in the analyses. Of the individual studies, the largest by far (5) examined the effect of RT delay of <6, 6–8, 9–12, and $13 weeks on 1,962 patients who had undergone BCS. Of the 1,962 patients, 677 had received tamoxifen, and no patients had undergone chemotherapy. Of these patients, 23 had had a RT delay of >20 weeks. At a median follow-up of 71 months, the local recurrence rate was significantly associated with the omission of tamoxifen and a high

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histologic tumor grade. The interval between BCS and RT was not significantly associated with local recurrence in a model incorporating tamoxifen use and histologic grade, in contrast to the overall finding of the meta-analysis, but consistent with our results. A more recent publication from the British Columbia Cancer Agency examined different intervals between surgery and RT in early-stage breast cancer patients in the absence of chemotherapy (8). The study yielded results similar to those of the present study for an RT delay of #20 weeks. However, a RT delay of >20 weeks resulted in an inferior outcome. Patients who were not given endocrine therapy were analyzed separately, and the findings were similar to those for the entire cohort. However, no separate subgroup analysis was done for patients who were given endocrine therapy (8). In a recent study from Florence (4), the risk of developing breast cancer failure for patients without any systemic adjuvant treatment (n = 1,935) was inversely proportional to the interval between surgery and RT on univariate analysis. However, timing of RT was not statistically significance on multivariate analysis. Similar results were obtained in the RT/endocrine therapy group (n = 1,684) and RT/endocrine therapy/chemotherapy group (n = 529). RT timing was statistically significant on multivariate analysis only for the RT and chemotherapy group (n = 672; HR, 1.69; p = .045) (4). That report also did not provide separate analyses of patients undergoing RT and endocrine therapy. In a previous publication by our group, we analyzed the effect of RT delay resulting from chemotherapy in IBCSG Trials VI and VII (11). The

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present analysis was undertaken, because studies investigating RT timing in patients with endocrine therapy have been rare. Similar to others (4), we could not find any effect of the interval from surgery to RT on local control or other endpoints. However, the present study had too few events to provide an accurate estimate of the effect of RT delay of >20 weeks. In addition, a limitation of the present study was an insufficient power to reject an association between an RT delay of shorter intervals and a small increase in the local recurrence risk. Nevertheless, and despite its retrospective design, the present study included patients treated in a randomized study with defined inclusion/exclusion criteria, uniform adjuvant therapy, and rigid follow-up control, in contrast to most previously published observational series. The question of the effect of sequential or concurrent use of endocrine treatment and RT on tumor control could not be addressed in the present study. In IBCSG Trials VII–IX, most patients started endocrine therapy within 2 days after randomization, except for those assigned to receive CMF first, and RT was administered concurrently with endocrine therapy. A study of IBCSG Trials VI and VII showed that a delay of RT from BCS of #6.6 months (28 weeks), during which chemotherapy was given, did not adversely influence the treatment outcome (11). The results of the present IBCSG study have indicated that an interval of up to about 20 weeks between BCS and RT does not increase the risk of local recurrence in a cohort of patients receiving standard adjuvant endocrine treatment.

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