Prospective Study of Local Control and Late Radiation Toxicity After Intraoperative Radiation Therapy Boost for Early Breast Cancer

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation: Breast Cancer

Prospective Study of Local Control and Late Radiation Toxicity After Intraoperative Radiation Therapy Boost for Early Breast Cancer David W. Chang, MBBS,* Luc te Marvelde, PhD,y and Boon H. Chua, MBBS, PhD, FRANZCR*,z *Division of Radiation Oncology and Cancer Imaging and yCentre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; and zSir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia Received Jun 5, 2013, and in revised form Sep 21, 2013. Accepted for publication Sep 27, 2013.

Summary This is a prospective, singleinstitution study of local control and late radiation toxicity of tumor bed boost delivered using intraoperative radiation therapy via the Intrabeam System followed by external-beam whole-breast irradiation in 55 patients with early breast cancer. At a median followup of 3.3 years, intraoperative radiation therapy boost was associated with good local control but a clinically significant rate of grade 2 and 3 subcutaneous fibrosis.

Purpose: To report the local recurrence rate and late toxicity of intraoperative radiation therapy (IORT) boost to the tumor bed using the Intrabeam System followed by external-beam wholebreast irradiation (WBI) in women with early-stage breast cancer in a prospective singleinstitution study. Methods and Materials: Women with breast cancer 3 cm were recruited between February 2003 and May 2005. After breast-conserving surgery, a single dose of 5 Gy IORT boost was delivered using 50-kV x-rays to a depth of 10 mm from the applicator surface. This was followed by WBI to a total dose of 50 Gy in 25 fractions. Patients were reviewed at regular, predefined intervals. Late toxicities were recorded using the Radiation Therapy Oncology Group/ European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring systems. Results: Fifty-five patients completed both IORT boost and external-beam WBI. Median follow-up was 3.3 years (range, 1.4-4.1 years). There was no reported locoregional recurrence or death. One patient developed distant metastases. Grade 2 and 3 subcutaneous fibrosis was detected in 29 (53%) and 8 patients (15%), respectively. Conclusions: The use of IORT as a tumor bed boost using kV x-rays in breast-conserving therapy was associated with good local control but a clinically significant rate of grade 2 and 3 subcutaneous fibrosis. Ó 2014 Elsevier Inc.

Reprint requests to: David W. Chang, MBBS, Peter MacCallum Cancer Centre, Division of Radiation Oncology and Cancer Imaging, Melbourne, Victoria 3002, Australia. Tel: (þ61) 3-9656-1111; E-mail: David.Chang@ petermac.org Conflict of interest: none. Int J Radiation Oncol Biol Phys, Vol. 88, No. 1, pp. 73e79, 2014 0360-3016/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2013.09.049

AcknowledgmentdThe authors thank Dr Emma Link of the Centre for Biostatistics and Clinical Trials, Peter MacCallum Cancer Centre, Melbourne, Australia, for her contribution to statistical analysis.

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Introduction Radiation boost to the tumor bed using electrons, external-beam megavoltage photons, or interstitial brachytherapy after externalbeam whole-breast irradiation (WBI) following breast-conserving surgery has been shown to reduce the risk of local recurrence in randomized trials (1-3). A more novel approach to the delivery of tumor bed boost is intraoperative radiation therapy (IORT) using a miniature electron beam-driven kilovoltage (kV) x-ray source (4-9). In selected patients with early-stage breast cancer, partial-breast irradiation using a single dose of kV IORT can be an alternative to WBI, as demonstrated by the TARGIT-A trial (10). However, when IORT is applied as a tumor bed boost in addition to WBI, there may be an increased risk of long-term toxicity due to the higher total radiation dose delivered. The largest randomized, controlled trial assessing boost irradiation, European Organization for Research and Treatment of Cancer (EORTC) 2288110882, demonstrated an increased rate of severe fibrosis in the boost group, with a 10-year rate of 4.4% compared with 1.6% in the no-boost group (1). In this prospective, single-institutional study, we report the local recurrence rate and late toxicity of IORT boost followed by WBI in women with early-stage breast cancer managed with breast-conserving surgery.

Methods and Materials The method has been described previously (4). The study protocol was approved by the Human Research Ethics Committee of the Peter MacCallum Cancer Centre in Melbourne, Australia. Informed consent was provided by all study patients. Inclusion criteria included histologically proven nonmetastatic invasive carcinoma of the breast measuring 3 cm. Patients with clinical or radiologic evidence of extensive microcalcifications, multicentric disease, or tumor involvement of the chest wall or skin were excluded. A single 5-Gy dose of IORT boost was delivered via the Intrabeam System (Carl Zeiss, Oberkochen, Germany) to the tumor bed to a depth of 10 mm from the applicator surface using 50-kV x-rays after wide local excision of the primary breast cancer and sentinel node biopsy and/or axillary dissection during the same operative session. Re-excision was performed when surgical resection margins were positive or <1 mm. Postoperatively, participants received standard external-beam WBI using tangential photon beams to a total dose of 50 Gy in 25 fractions delivered over 5 weeks. Adjuvant chemotherapy, if indicated, was given before WBI. Adjuvant endocrine therapy for patients with hormone receptor-positive disease was started before or after WBI for 5 years. Patients were reviewed at 2, 4, and 8 weeks after IORT and at the 5th week of WBI. After WBI, clinical assessments were performed every 6 months for 3 years. Local recurrence was defined as recurrence or new disease within the treated breast, after breastconserving therapy. Late radiation toxicities were documented using the Radiation Therapy Oncology Group/EORTC Late Radiation Morbidity Scoring schemes (11). Logistic regression was used to identify predictors of fibrosis in 53 patients with 3 years of late toxicity evaluation. The following variables were considered: age, tumor location, tumor

International Journal of Radiation Oncology  Biology  Physics size, second surgery (re-excision and/or axillary dissection), hematoma, seroma, chemotherapy before radiation therapy, endocrine therapy, and time between IORT and WBI. Statistical analysis for predictors of fibrosis was performed with R version 2.15.3 (R Development Core Team 2009, Vienna, Austria).

Results Sixty patients were recruited between February 13, 2003 and May 13, 2005, with a median age of 57 years (range, 39-83 years). Fifty-eight patients completed IORT, and 55 patients received both IORT and WBI. The median pathologic primary tumor size was 13 mm (range, 4-62 mm). Forty-seven of the 55 patients (85%) were histologically node-negative. Adjuvant chemotherapy was administered in 13 patients (24%), and 37 patients (67%) received endocrine therapy. The clinical characteristics of the patients, acute adverse events, and cosmetic outcomes were reported previously (4, 12). Of the 55 patients who received both IORT boost and WBI, 53 patients completed the protocol-specified 3 years of follow-up. At a median follow-up of 3.3 years (range, 1.4-4.1 years), there was no reported locoregional recurrence or death. One patient developed distant metastases, 2.2 years after IORT boost and 2 years after WBI. Table 1 shows the late radiation toxicity in the 55 patients. One patient (2%) had grade 3 late skin toxicity with marked atrophy. Twenty-nine patients (53%) had moderate fibrosis, and 8 (15%) experienced severe induration of the subcutaneous tissue in the region of the tumor bed. One patient (2%) experienced moderately symptomatic late radiation lung toxicity. Table 2 outlines the potential predictors of fibrosis for the 53 patients who completed protocol-specified 3 years of follow-up. The median interval between IORT and WBI was 47 days (range, 23-223 days).

Discussion In the TARGIT-A trial, at 4 years, 6 local recurrences were reported out of the 996 patients who received partial-breast irradiation using the Intrabeam System (10). In our single-institution, prospective study, patients received IORT boost using the Intrabeam System followed by external-beam WBI. No local recurrence was observed at a median follow-up of 3.3 years, in comparison with the 5-year local recurrence rate of 1.73% in the largest series of IORT boost published to date involving 299 patients (9). The majority of studies of IORT boost using kV x-rays, including our study, demonstrated a higher rate of grade 2 or 3 subcutaneous fibrosis than in patients who received IORT alone in the TARGIT-A trial (Table 3). This was most likely due to the larger total dose of radiation administered in the IORT boost groups. In the TARGIT-A trial, only 14% of the patients who underwent IORT also received postoperative external-beam WBI. In a single-institution subset analysis of the TARGIT-A trial, these patients had a higher rate of grade 2 or 3 fibrosis (37.5%) than the patients who received IORT only (5.9%) (13). Similarly, in a matched-pair study by Welzel et al (14), the rate of grade 2 fibrosis was higher for patients who underwent IORT boost and WBI (32%) compared with those who received IORT alone (14%). The reported rates of moderate to severe subcutaneous fibrosis in patients treated with IORT boost using the Intrabeam System

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Table 1 Late radiation toxicities evaluated using the RTOG/EORTC Late Radiation Morbidity Scoring scheme in 55 patients treated with intraoperative radiation therapy boost after breast-conserving surgery followed by whole-breast irradiation Late toxicity

RTOG/EORTC grade (11)

Patients, n (%)

Skin: Late Radiation Morbidity Scoring

0: No change from baseline 1: Slight atrophy; pigmentation change; some hair loss 2: Patchy atrophy; moderate telangiectasia; total hair loss 3: Marked atrophy; gross telangiectasia 4: Ulceration Not assessed 0: No change from baseline 1: Slight induration (fibrosis) and loss of subcutaneous fat 2: Moderate fibrosis but asymptomatic; slight field contracture <10% linear reduction 3: Severe induration and loss of subcutaneous tissue; field contracture >10% linear measurement 4: Necrosis Not assessed 0: No change from baseline 1: Asymptomatic or mild symptoms (dry cough); slight radiographic appearances 2: Moderate symptomatic fibrosis or pneumonitis (severe cough); low grade fever; patchy radiographic appearances 3: Severe symptomatic fibrosis or pneumonitis; dense radiographic changes 4: Severe respiratory insufficiency/continuous O2/assisted ventilation Not assessed

0 41 (75) 12 (22) 1 (2) 0 1 (2) 0 16 (29) 29 (53)

Subcutaneous tissue: Late Radiation Morbidity Scoring

Lung: Late Radiation Morbidity Scoring

8 (15)

2 45 8 1

0 (4) (82) (15) (2)

0 0 1 (2)

Abbreviations: EORTC Z European Organization for Research and Treatment of Cancer; RTOG Z Radiation Therapy Oncology Group.

were generally higher than in patients who had tumor bed boost using external electron or photon beam, or intraoperative boost using electrons (1, 5-8, 13-15). These findings should be interpreted with caution given the limitations of interstudy comparisons. However, the higher observed rate of moderate to severe fibrosis in patients treated with an IORT boost using the Intrabeam System could not be fully accounted for by the hypofractionated nature of IORT. With administration of a single dose of 20 Gy at the applicator surface, the dose attenuates to <10 Gy at 5-mm and 5 Gy at 10-mm depth (16). Using an a/b ratio of 3.4 (17), a single dose of 5 Gy equates to 7.8 Gy in 2-Gy fractions, which is lower than the conventional 10- to 16-Gy external-beam boost delivered in 2-Gy fractions. Furthermore, although the risk of seroma requiring 3 or more aspirations was higher with IORT in the TARGIT-A trial, we found that postoperative seroma and hematoma were not significantly associated with the rate of fibrosis (10). It is possible that the elevated rate of subcutaneous fibrosis observed may be associated with the direct influence of Intrabeam radiation therapy on the tumor bed microenvironment after breastconserving surgery. Belletti et al (18) showed that the delivery of Intrabeam radiation therapy could have an impact on the level of cytokines in the surgical wound fluid, providing a possible biological rationale for the very low recurrence rates observed in TARGIT-A. This alteration in the molecular composition of the surgical wound fluid may also be associated with the increased rate of fibrosis in the IORT boost group. The rates of grade 2 and 3 fibrosis in our study were higher than in comparable IORT boost studies (Table 3) (5-8, 13-14). In our study, toxicity assessments were undertaken by a small group of senior radiation oncologists and breast surgeons at our institution. Although different toxicity scales were used in these studies for the evaluation of late toxicities (5-8, 13, 14), Hoeller et al (19) demonstrated that for fibrosis, there was a good

correlation between the Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force Subjective, Objective, Management, and Analytic scores (Spearman r Z 0.78) (19). Thus, this observed discrepancy in the fibrosis rates could not be explained by variation in the toxicity scoring systems alone. This discordance also could not be explained by differences in the duration of follow-up because the median follow-up of our study was comparable to most of the other IORT boost studies (Table 3). A possible explanation for the higher rate of fibrosis in our study is variation in methodology. We reported the worst grade of fibrosis observed during the 3 years of follow-up, whereas some of the other investigators graded fibrosis at a specific point in time. For example, Kraus-Tiefenbacher et al (6) documented fibrosis at multiple time points, and at 36 months the rate of grade 2 fibrosis was 16%. Wenz et al (7) evaluated fibrosis at 36 months. Nevertheless, this consideration would not explain the lower rates of fibrosis observed in the EORTC 22881-10882 trial, which reported a 10-year cumulative incidence of moderate to severe fibrosis of 28.1%, compared with 68% of patients who experienced grade 2 fibrosis at a median follow-up of 3.3 years in our study (1). In our analysis of the potential predictors of fibrosis, patients who received adjuvant chemotherapy before WBI were less likely to have grade 2 or 3 fibrosis compared with patients who did not have chemotherapy. In contrast, patients in the EORTC trial 22881-10882 who had concomitant chemotherapy experienced a greater rate of fibrosis (20). This finding was not reported in patients who had adjuvant chemotherapy before radiation therapy. In view of our small sample size, the effect of chemotherapy on the risk of fibrosis after IORT boost should be ascertained in a larger, adequately powered trial. The time interval between IORT and WBI was not shown to be significantly associated with the rate of fibrosis in our

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Table 2 surgery

Summary of variables considered in the logistic regression predicting the occurrence of grade 2 fibrosis within 3 years after Variable

n

Patients with fibrosis, n (%)

OR (95% CI)

P

Age (continuous) Location of tumor within breast Upper outer Lower outer 3 O’clock 9 O’clock Upper inner Lower inner 6 O’clock 12 O’clock Tumor size (continuous) Tumor size (mm) 10 >10 Second surgery (re-excision and/or axillary dissection) No Yes Hematoma No Yes Seroma No Yes Chemotherapy before radiation therapy* No Yes Endocrine treatment No Yes Time between IORT and WBI (mo) (continuous)

53

37 (70)

1.01 (0.95-1.07)

.84

24 3 1 2 11 2 4 6 53

17 3 1 2 5 2 4 3 37

29 24

20 (69) 17 (71)

(71) (100) (100) (100) (45) (100) (100) (50) (70)

.09 (7 df); 1 vs rest: PZ.88 (1 df)

0.97 (0.88-1.07)

.50 .88

1 1.09 (0.34-3.65) .44

46 7

33 (72) 4 (57)

1 0.53 (0.10-2.97)

42 11

30 (71) 7 (64)

1 0.70 (0.18-3.07)

25 28

18 (72) 19 (68)

1 0.82 (0.24-2.67)

41 12

32 (78) 5 (42)

1 0.20 (0.05-0.77)

16 37 53

12 (75) 25 (68) 37 (70)

1 0.69 (0.17-2.49) 0.74 (0.51-1.06)

.62

.74

.02

.59

.10

Abbreviations: CI Z confidence interval; IORT Z intraoperative radiation therapy; OR Z odds ratio; WBI Z whole-breast irradiation. * No patients received postoperative chemotherapy concurrently with whole-breast irradiation or after WBI.

analysis. Wenz et al (21) reported a link between shorter interval and late toxicities, which included not only fibrosis but also telangiectasia, edema, breast retraction, hyperpigmentation, and pain (21). Because we evaluated fibrosis only, a direct comparison between the 2 studies would not be valid. However, a possible explanation for this difference is the longer median interval of 47 days (range, 23-223 days) of our study, compared with 36 days (range, 14-197 days) reported by Wenz et al (21). This suggests that beyond approximately 5-6 weeks, further delays in WBI after IORT might not have a significant effect on the rate of fibrosis. To our knowledge, the longest reported median follow-up duration for evaluation of late toxicity in studies of IORT boost using the Intrabeam System was 47 months (5-8, 13, 14). With longer duration of follow-up, the rate of subcutaneous fibrosis is likely to increase. The EORTC 22881-10882 trial did not demonstrate a statistically significant higher rate of fibrosis for the boost group compared with the no-boost group at a median follow-up of 5.1 years (22). However, a statistically significant higher rate of fibrosis in the boost group was observed after a median follow-up of 10.8 years (1).

The safety and efficacy of the IORT boost delivered using the Intrabeam System are most appropriately assessed in a large, prospective study. The planned TARGIT-Boost randomized trial will test whether tumor bed boost delivered as a single dose of targeted IORT is superior to conventional external-beam boost, especially in women at high risk of local recurrence (9).

Conclusions Intraoperative radiation therapy using the Intrabeam System is a novel method of delivering boost irradiation to the tumor bed after breast-conserving surgery and followed by external-beam WBI. At a median follow-up of 3.3 years, our prospective study has shown a clinically significant rate of grade 2 and 3 subcutaneous fibrosis after IORT boost. Until results of a phase 3 trial become available, caution is warranted in the delivery of an IORT boost using the Intrabeam System outside of the clinical trial setting.

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Comparison of subcutaneous fibrosis rates after IORT tumor bed boost using 50-kV x-rays or electrons Study

n

Median follow-up

Classification scheme

55

3.3 y

RTOG/EORTC (11)

Joseph et al, 2004 (5)

35

8.9 mo

RTOG/EORTC (11)

Kraus-Tiefenbacher et al, 2006 (6)

73

25 mo

LENT/SOMA (23, 24)

Wenz et al, 2010 (7)

154

34 mo

LENT/SOMA (23, 24)

Blank et al, 2010 (8)

197

37 mo

LENT/SOMA (23, 24)

Welzel et al, 2010 (14)

23

47 mo

LENT/SOMA (23, 24)

Sperk et al, TARGIT-A subset analysis, 2012 (13)

20

40 mo

LENT/SOMA (23, 24)

IORT tumor bed boost using 50-kV x-ray Present study

IORT to tumor bed using 50-kV x-ray without whole-breast irradiation Welzel et al, 2010 (14) 23 47 mo Sperk et al, TARGIT-A subset analysis, 2012 (13) IORT tumor bed boost using electrons Lemanski et al, 2006 (15)

Grade of subcutaneous fibrosis

Worst grade of fibrosis during 3 y of follow-up 0: 0 1: 29% 2: 53% 3: 15% 4: 0 0: 73%* 1: 27% 2: 0 3: 0 4: 0 Tumor bed fibrosis at 36 mo 1: 4% 2: 16% 3: 0 Breast fibrosis at 36 mo 1: 0 2: 5% 3: 0 Fibrosis at 36 mo 0: 43% 1: 22% 2: 30% 3: 5% Fibrosis for 58 patients with 5 y of follow-up 0: 45%* 1: 17% 2: 34% 3: 3% 0 or 1: 68%* 2: 32% Cumulative incidence of fibrosis at 3 y 2 or 3: 37.5%

34

40 mo

LENT/SOMA (23, 24) 0 or 1: 86%* 2: 14% LENT/SOMA (23, 24) Cumulative incidence of fibrosis at 3 y 2 or 3: 5.9%

50

9.1 y

CTCAE v3.0 (25)

2: 14%* 3: 0 4: 0

5.1 y

Study-specific 4-point grading system

Rate of fibrosis at 5.1 y of median follow-up No fibrosis: 48% Minor: 37% Moderate: 9% Severe: 1% Unknown: 4%

Conventional external-beam tumor bed boost Bartelink et al, 2001 (22) 2657 WBI and 2007 (1)

(continued on next page)

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Table 3 (continued ) Study

n

Median follow-up

Conventional external-beam tumor bed boost Bartelink et al, 2001 (22) 2661 WBI þ boost and 2007 (1)

2657 WBI

10.8 y

2661 WBI þ boost

Classification scheme

Grade of subcutaneous fibrosis Rate of fibrosis at 5.1 y of median follow-up No fibrosis: 50% Minor: 34% Moderate: 10% Severe: 1% Unknown: 5% 10-y cumulative incidence of fibrosis Moderate/severe: 13.2% Severe: 1.6% 10-y cumulative incidence of fibrosis Moderate/severe: 28.1% Severe: 4.4%

Abbreviations: CTCAE Z Common terminology criteria for adverse events; LENT/SOMA Z Late Effects Normal Tissue Task Force Subjective, Objective, Management, and Analytic. Other abbreviations as in Tables 1 and 2. * The study did not indicate whether the figures represented the worst grade of fibrosis or fibrosis at a specific time point.

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