Clinical impact of adjuvant radiation therapy delay after neoadjuvant chemotherapy in locally advanced breast cancer

Clinical impact of adjuvant radiation therapy delay after neoadjuvant chemotherapy in locally advanced breast cancer

The Breast 38 (2018) 39e44 Contents lists available at ScienceDirect The Breast journal homepage: www.elsevier.com/brst Original article Clinical ...

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The Breast 38 (2018) 39e44

Contents lists available at ScienceDirect

The Breast journal homepage: www.elsevier.com/brst

Original article

Clinical impact of adjuvant radiation therapy delay after neoadjuvant chemotherapy in locally advanced breast cancer Saulo Brito Silva a, Allan Andresson Lima Pereira a, Gustavo Nader Marta a, c, *, Kennya Medeiros Lopes de Barros Lima a, Thiago Brasileiro de Freitas a, ~o Matutino a, Manoel Carlos Leonardi de Azevedo Souza a, Adriana Reis Branda Renata Gondim Meira Velame de Azevedo a, Pedro Antonio Hermida de Viveiros a,  Roberto Filassi b, Heloísa de Andrade Carvalho a, Julianne Maria da Silva Lima a, Jose  Roberto Morales Piato b, Max S. Mano a, d Jose ~o Paulo (ICESP), Universidade de Sa ~o Paulo, Sa ~o Paulo, Brazil Department of Radiology and Oncology, Instituto do Cancer do Estado de Sa ~o Paulo, Brazil Department of Gynecology and Obstetrics, Breast Surgery Unit, Universidade de Sa c ^nes, Sa ~o Paulo, Brazil Department of Radiation Oncology, Hospital Sírio-Liba d ~o Paulo, Brazil Division of Medical Oncology, Hospital Sírio-Liban^ es, Sa a

b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 21 June 2017 Received in revised form 5 November 2017 Accepted 10 November 2017

Background: and Purpose: Post-operative radiation therapy (PORT) is usually indicated for patients with breast cancer (BC) after neoadjuvant chemotherapy (NAC) and surgery. However, the optimal timing to initiation of PORT is currently unknown. Material and methods: We retrospectively evaluated data from patients with BC who received PORT after NAC and surgery at our institution from 2008 to 2014. Patients were categorized into three groups according to the time between surgery and PORT: <8 weeks, 8e16 weeks and >16 weeks. Results: A total of 581 patients were included; 74% had clinical stage III. Forty-three patients started PORT within 8 weeks, 354 between 8 and 16 weeks and 184 beyond 16 weeks from surgery. With a median follow-up of 32 months, initiation of PORT up to 8 weeks after surgery was associated with better disease-free survival (DFS) (<8 weeks versus 8e16 weeks: HR 0.33; 95% CI 0.13e0.81; p ¼ 0.02; <8 weeks versus >16 weeks: HR 0.38; 95% CI 0.15e0.96; p ¼ 0.04) and better overall survival (OS) (<8 weeks versus 8e16 weeks: HR 0.22; 95% CI 0.05e0.90; p ¼ 0.036; <8 weeks versus >16 weeks: HR 0.28; 95% CI 0.07 e1.15; p ¼ 0.08). Conclusion: PORT started up to 8 weeks after surgery was associated with better DFS and OS in locallyadvanced BC patients submitted to NAC. Our findings suggest that early initiation of PORT is critically important for these patients. However, the low numbers of patients and events in this study prevent us from drawing firm conclusions. © 2017 Elsevier Ltd. All rights reserved.

Keywords: Breast neoplasms Radiation therapy Chemotherapy Time-to-treatment Disease-free survival Overall survival

1. Introduction Breast cancer (BC) leads in prevalence and death from cancer among females worldwide. However, the disease is diagnosed without metastatic disease in approximately 90% of cases [1]. In this scenario, cure is the ultimate goal, and a multidisciplinary

~o Paulo Universidade * Corresponding author. Instituto do Cancer do Estado de Sa ~o Paulo; Ave. Dr Arnaldo, 251, Sa ~o Paulo, SP, 01246-000, Brazil. de Sa E-mail address: [email protected] (G.N. Marta). https://doi.org/10.1016/j.breast.2017.11.012 0960-9776/© 2017 Elsevier Ltd. All rights reserved.

approach is critical to achieve it [2]. This includes coordinated and timely administration of systemic therapy, surgery and postoperative radiation therapy (PORT). PORT after breast conserving surgery (BCS) improves outcomes and has been established as an alternative to mastectomy [3,4]. While robust evidence supports PORT to women submitted to upfront mastectomy [5,6], it's use in patients treated with neoadjuvant chemotherapy (NAC) and mastectomy is still guided by retrospective analyses of prospective trials. As expected, the approaches differ significantly across cancer centers, but PORT tends to be indicated for patients with clinical stage III or T3 tumors, and to

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those with pathologic residual lymph nodes, an unfavorable scenario in which this treatment is more likely to improve outcomes [7e11]. Due to financial restrictions and/or overloaded oncology services, timely initiation of cancer treatments has been a concern worldwide, particularly in developing economies [12e14]. Of note, it has been shown that time to start adjuvant chemotherapy significantly influences survival outcomes [15e17]. However, the clinical impact of delayed PORT remains unclear, as data have been inconclusive [18e25]. In particular, no studies specifically evaluated the neoadjuvant scenario, in which patients have high-risk disease, and also had a considerably long treatment-free interval before initiation of PORT, to allow for definitive surgery to be performed. In theory, these patients could be at even greater risk from delays, and could represent a unique population to test this hypothesis. On that basis, we performed a retrospective analysis to evaluate the potential impact of the time to initiation of PORT in BC patients who underwent NAC followed by surgery. 2. Patients and methods 2.1. Patient population We performed a retrospective analysis of all patients diagnosed with BC who received NAC followed by potentially curative surgery and PORT between 2008 and 2014. We extracted data on relevant prognostic factors commonly associated with cancer recurrence. The electronic charts were reviewed by physicians (SBS, ARBM, JMSL, KMLBL, TBF, MCLAS, RGMVA, PAHV) who obtained information on age at diagnosis, clinical stage, histological grade [1e3], hormonal receptors status (positive or negative), HER-2 status (positive or negative), NAC schedule (anthracycline-based, anthracycline and taxane-based, or other), neoadjuvant and adjuvant trastuzumab if HER-2 positive (yes or no), adjuvant endocrine therapy if estrogen and/or progesterone receptor positive (yes or no), type of surgery (mastectomy or breast-conserving surgery[BCS]), axillary dissection (yes or no) and pathological complete response in both primary tumor and lymph nodes (pCR; yes or no). 2.2. Study endpoints The primary endpoint was the comparison of the disease-free survival (DFS) among three groups defined by the time for initiation of PORT (<8 weeks, 8e16 weeks, >16 weeks). DFS was defined as the time from date of surgery to the date of recurrence at any site or death from any cause. Secondary endpoints included overall survival (OS), defined as the time from date of surgery to death from any cause; and subgroup analyses of DFS and OS, stratifying results according to molecular profile, clinical stage and pCR. 2.3. Statistical methods and considerations Patients were categorized according to the time (in weeks) from definitive surgery to PORT into one of three groups: <8 weeks, 8e16 weeks, and >16 weeks. Demographics and baseline characteristics were summarized using descriptive statistics and compared using ANOVA, KruskaleWallis test for continuous variables and Fisher's exact test or c2-test for categorical variables, whenever appropriate. OS and DFS curves were estimated with the Kaplan-Meier method and compared them with the log-rank test adjusted for pCR. We used Cox proportional hazard regression models to estimate hazard ratios (HRs) and to investigate whether the effect of time to receive PORT was modified by adjustments for the following covariates (all of them well-known to be related to survival outcomes in breast cancer): age (as continuous variable),

pCR, molecular profile, clinical stage and histological grade. We also planned to include any other variable which is unbalanced among groups. An exploratory analysis to estimate survivals in subgroups adjusting for confounders was performed using Multivariate Cox Proportional Hazards Model. Multivariate analysis was also carried out using the binary logistic regression model with the covariates aforementioned to calculate the adjusted odds ratios for recurrence. All tests were two-sided and a p value of <0.05 was considered statistically significant. SPSS software (version 20.0; SPSS, Chicago, IL, USA) was used for statistical analyses. 3. Results 3.1. Patients characteristics A total of 581 patients were identified, with a median follow-up of 32 months (range: 2e82). Patients were properly staged according to institutional standards. Most patients had clinical stage III (74%) or IIB (18%). Almost all patients were treated with anthracycline and taxane-based NAC (95%), and the majority was treated with mastectomy (75%). All women with estrogen and/or progesterone receptor positive tumors received adjuvant endocrine therapy, and 96.3% of HER-2 positive patients received trastuzumab treatment. Patients who received breast-conserving surgery underwent PORT to the breast with or without nodal areas (supraclavicular in 87.1%; axillary levels II and III in 86.6%; axillary level I in 9.8% and internal mammary in 8.3%). Similarly, after mastectomy or adenomastectomy, all patients received PORT in the chest wall and most of them nodal areas were also included (supraclavicular in 95.1%; axillary levels II and III in 93.8%; axillary level I in 8.6% and internal mammary in 9.0%). Tumor and treatment characteristics were well balanced between the three groups (Table 1). Forty-three (7.4%) patients received PORT<8 weeks from surgery, 354 (60.9%) 8e16 weeks and 184 (31.7%) >16 weeks from surgery. The median time to start PORT was 3.2 months. 3.2. Analyses of disease-free and overall survival At the cut-point, with a median follow-up of 32 months, 96 patients had died and 160 had experienced a recurrence event. Seven patients had isolated locoregional recurrence, 94 only distant recurrence, and 59 patients both locoregional and distant recurrence events. Starting PORT within 8 weeks from surgery was associated with better DFS when compared to both 8e16 weeks (HR 0.33; 95% CI 0.13e0.81, p ¼ 0.02) and >16 weeks groups (HR 0.38; 95% CI 0.15e0.96; p ¼ 0.04e Fig. 1). There was no difference between 8 and 16 and > 16 weeks groups (HR 1.16; 95% CI 0.83e1.61; p ¼ 0.39). No recurrence events were reported in patients who had pCR and received PORT within 8 weeks of surgery (Supplementary Fig. 1). Starting PORT within 8 weeks also improved OS when compared to 8e16 weeks (HR 0.22; 95% CI 0.05e0.90; p ¼ 0.36) and >16 weeks (HR 0.28; 95% CI 0.07e1.15; p ¼ 0.08e Fig. 2), and, again, no difference between 8 and 16 and > 16 weeks was observed (HR ¼ 1.25; 95% CI 0.80e1.92; p ¼ 0.32). Due to the similarities between these two groups in terms of clinical outcomes, we combined them to allow for a comparison between <8weeks vs. > 8weeks, in which the benefit of starting PORT within 8 weeks was statistically significant both in terms of DFS (HR 0.34; 95% CI 0.14e0.84; p ¼ 0.02) and OS (HR 0.24; 95% CI 0.06e0.97; p ¼ 0.045). 3.3. Subgroup analyses As exploratory analyses, we estimated HRs for survival endpoints (DFS and OS) by time to initiation of PORT according to the

S.B. Silva et al. / The Breast 38 (2018) 39e44

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Table 1 Patient and Clinical characteristics. Characteristic Age at diagnostic, years Mean Range Clinical stagea I IIA IIB IIIA IIIB IIIC Missing Histological grade 1 2 3 Missing Hormonal and Her-2 status HR pos/Her-2 neg HR pos/Her-2 pos HR neg/Her-2 pos HR neg/Her-2 neg Neoadjuvant chemotherapy Anthracycline-taxane Others Trastuzumab in Her-2 pos Yes No Hormone therapy in HR-pos Yes No Surgery Mastectomy BCS Missing (1) Axillary dissection Yes No Missing pCR Yes No Missing

<8 weeks (N ¼ 43) No (%)

8-16 weeks (N ¼ 354) No (%)

>16 weeks (N ¼ 184) No (%)

50.79 25e78

50.96 24e84

49.51 23e76

0 (0%) 1 (2.3%) 10 (23.3%) 19 (44.2%) 9 (20.9%) 4 (9.3%) 0

0 (0%) 28 (7.9%) 61 (17.3%) 147 (41.6%) 86 (24.4%) 31 (8.8%) 1

1 (0.5%) 11 (6.0%) 35 (19.1%) 83 (45.4%) 40 (21.9%) 13 (7.1%) 1

4 (9.3%) 16 (37.2%) 23 (53.5%) 0

21 (6.0%) 146 (41.7%) 183 (52.3%) 4

13 (7.2%) 83 (45.8%) 85 (47.0%) 3

21 (48.8%) 6 (14.0%) 3 (7.0%) 13 (30.2%)

149 (42.1%) 52 (14.7%) 41 (11.6%) 112 (31.6%)

89 27 28 40

42 (97.7%) 1 (2.3%)

335 (94.6%) 19 (5.4%)

174 (94.6%) 10 (5.4%)

8 (88.9%) 1 (11.1%)

92 (99.0%) 1 (1.0%)

51 (92.7%) 4 (7.3%)

27 (100%) 0 (0%)

201 (100%) 0 (0%)

116 (100%) 0 (0%)

26 (60.5%) 17 (39.5%) 0

265 (75.1%) 88 (24.9%) 1

147 (79.9%) 37 (20.1%) 0

40 (93.0%) 3 (7.0%) 0

319 (90.4%) 34 (9.6%) 1

173 (94.0%) 11 (6.0%) 0

10 (23.3%) 33 (76.7%) 0

76 (21.5%) 277 (78.5%) 1

32 (17.4%) 152 (82.6%) 0

p 0.36

0.79

0.69

0.25 (48.4%) (14.7%) (15.2%) (21.7%) 0.74

0.053

1.00

0.03

0.34

0.47

HR, hormone receptor; HER2, human epidermal growth factor receptor 2; pCR, pathologic complete response; BCS, breast conserving surgery; pos, positive; neg, negative. a Clinical stage according to AJCC 2010.

Fig. 1. DFS curves according to group of time for PORT initiation.

Fig. 2. OS curves according to group of time for PORT initiation.

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S.B. Silva et al. / The Breast 38 (2018) 39e44

following subgroups: stage, hormone receptor, HER2 status, and pCR. The results after adjusting for confounders are presented in Table 2. Comparing to patients who started PORT after 8 weeks from surgery, a better DFS favoring treatment within 8 weeks was found in all subgroups. Statistical significance was found in the subsets with more patients: clinical stage III (HR 0.31; 95% CI 0.11e0.84; p ¼ 0.02), HR-positive (HR 0.28; 95% CI 0.09e0.91; p ¼ 0.03) and in those without pCR (HR 0.39; 95% CI 0.16e0.96; p ¼ 0.04). Table 2 summarizes the DFS and OS according to groups of time (in weeks) from definitive surgery to PORT. Subgroup analyses of patients with pCR who started PORT within 8 weeks were not presented due to the limited number of subjects in this subgroup. 3.4. Factors associated with recurrence In the multivariate analysis, adjusting for covariates, initiating PORT within 8 weeks of surgery (OR ¼ 0.29; 95% CI 0.11e0.80; p ¼ 0.02), stage I-II (OR ¼ 0.49; 95% CI 0.30e0.81; p ¼ 0.006) and pCR (OR ¼ 0.24; 95% CI 0.13e0.45; p < 0.001) were statistically associated with lower recurrence rates (Table 3). 4. Discussion To the best of our knowledge, our study is the largest addressing the clinical impact of delaying PORT in patients treated with NAC followed by surgery. Our cohort consisted mostly of women with clinical stage III, properly staged, and uniformly treated with standard systemic therapy (virtually all patients received anthracycline-taxane based NAC plus trastuzumab for HER2 positive tumors). In this setting, in which PORT is known to be associated with improved overall and recurrence-free survival (locoregional or distant) [10], our findings suggest that PORT initiation beyond 8 weeks from surgery was associated with worse clinical outcomes. Limited data is currently available on the impact of delaying PORT and prospective randomized trials are unlikely to be performed due to ethical constraints. Previous studies [18e24] addressed timing of PORT in patients with early BC treated with lumpectomy and possibly with adjuvant chemotherapy - which may have served as a sort of ‘bridge’ between surgery and PORT, potentially attenuating any deleterious effect of delaying treatment. It is difficult to compare those articles with the present study due to

Table 3 eMultivariate logistic regression adjusted for recurrence adjusted for PORT time for initiation, stage, molecular profile, pCR and histologic grade. Variable Time to Radiation therapy <8 weeks 8-16 weeks >16 weeks Clinical Stagea EC I or II ECIII Molecular profile Luminal Triple Positive HER-2 positive, ER negative Triple Negative Pathologic Complete Response Yes No Histologic Grade 1 2 3 Age Surgery Mastectomy BCS

OR (Odds Ratio)

95%CI

p-value

0.29 0.88 (reference)

0.11e0.80 0.59e1.33 e

0.02 0.93 e

0.49 (reference)

0.30e0.81 e

0.006 e

0.75 0.81 0.81 (reference)

0.46e1.25 0.42e1.53 0.41e1.60 e

0.26 0.51 0.54 e

0.24 (reference)

0.13e0.45 e

<0.001 e

0.74 0.78 (reference) 1.00

0.32e1.70 0.51e1.19 e 0.99e1.02

0.48 0.24 e 0.58

1.61 (reference)

0.96e2.69 e

0.07 e

HR, hormone receptor; HER2, human epidermal growth factor receptor 2; pCR, pathologic complete response; BCS, breast conserving surgery; pos, positive; neg, negative; BCS, breast conserving surgery. a Clinical stage according to AJCC 2010.

different study populations. Our study addressed the timing of PORT initiation in a homogeneous group of patients, though they were not exposed to post-operative chemotherapy and tended to harbor more advanced disease, potentially placing them at greater risk from PORT delays. Shiv Dasai et al. [25] also looked specifically at this population and, with a median follow up of 44 months from the start of NAC, did not find significant differences in locoregional outcome among the 248 patients who underwent PORT across different time-points [8 weeks vs. >8 weeks p ¼ 0.634, 12 vs > 12 weeks (p ¼ 0.332), or 16 vs > 16 weeks (p ¼ 0.549)], concluding that treatment should be offered regardless of the timing. We, in contrast, observed a statically significant benefit in both DFS and OS when comparing <8 weeks vs. > 8weeks, though we found no differences in outcome when comparing 8e16 weeks vs. > 16 weeks. This finding suggests that, in patients with locally advanced BC

Table 2 Subgroup analyses - multivariable Cox Proportional Hazards Model according to stage, pCR and BC subtypes. Time to Radiation therapy

All <8w vs. > 8w Stage I and II <8w vs. > 8w Stage III <8w vs. > 8w Hormone Receptor positive <8w vs. > 8w HER2 positive <8w vs. > 8w Triple Negative <8w vs. > 8w Without pCR <8w vs. > 8w

Events/N

DFS

Events/N

HR

95%CI

p

164/581 (11)

0.35

0.14e0.86

0.02

12/147 (2)

0.37

0.05e2.82

139/432 (7)

0.31

93/344 (7)

OS HR

95%CI

p

95/581 (12)

0.24

0.06e0.98

0.047

0.33

12/147 (3)

0.86

0.10e7.08

0.89

0.11e0.84

0.02

83/432 (8)

0.12

0.02e0.86

0.04

0.28

0.09e0.91

0.03

47/344 (8)

0.17

0.02e1.26

0.08

38/157 (4)

0.34

0.05e2.55

0.30

*

*

*

*

53/165 (2)

0.57

0.14e2.37

0.44

36/165 (3)

0.35

0.05e2.60

0.35

151/462 (8)

0.39

0.16e0.96

0.04

84/462 (9)

0.30

0.07e1.22

0.09

W, weeks; DFS, disease-free survival; OS, overall survival; HER2, human epidermal growth factor receptor 2; ER, estrogen receptor; pCR, pathologic complete response; HR, hazard ratio. *incomputable. - The numbers in brackets are the number of cases with missing values or censored before the earliest event.

S.B. Silva et al. / The Breast 38 (2018) 39e44

treated with NAC, most of the benefit from PORT can be lost if this treatment is not initiated within 8 weeks from surgery. Our study has limitations which might have affected the results and preclude drawing definitive conclusions. First, it has a retrospective design and could be susceptible to systematic errors like selection bias. Having this in mind, multivariable analyses adjusting for the main covariates related to clinical outcomes were carefully performed to control for confounding. However, it may not be completely free of residual confounders. Second, the low number of events in patients who started PORT within 8 weeks has affected the power of the subset analyses. Therefore, they can only be considered exploratory. Finally, the median follow-up time (<3 years) is not long enough to allow for definitive conclusions on recurrence rate or survival outcomes, especially for patients with the luminal BC subtype, who may present late recurrences. However, a difference in clinical outcomes is already suggested at this early point, and it is plausible to speculate that it could even increase with a longer follow up. The role of PORT in the subset of patients that achieved pCR after NAC and mastectomy is controversial [26]. In 2012, Mamounas and colleagues performed a combined analysis of the B-18 and B-27 trials and reported that women with clinically positive lymph nodes treated with NAC and mastectomy without PORT had no locoregional recurrence if they have achieved breast and axillary pCR [27]. On the other hand, a retrospective analysis of the National Cancer Database of United States reported improved overall survival (HR ¼ 0,729, 95% CI 0.566e0.939) in 3040 patients with cN1 disease who had converted to ypN0 following NAC and mastectomy if they received PORT [28]. Also, a recent pooled analysis of the randomized neoadjuvant trials GeparTrio, GeparQuattro and GeparQuinto, including a total of 3481 patients, suggested that omission of PORT in patients with pCR was associated with a worse 5-year DFS (HR 3.52, 95% CI 1.82e6.83; p < 0.001) [29,30]. Our study suggested a trend toward an increased recurrence ratio in patients that achieved pCR and delayed PORT more than 8 weeks (all of them with cN1 or T3), further stressing the importance of this treatment in this population. In fact, clone cells highly responsive to chemotherapy may respond to radiation as well, and although not present in the surgical pathology specimen, cancer cells can shed in tumor bed or in lymphatic vessels. An ongoing prospective randomized trial (NSABP B-51/RTOG 1304) is designed to clarify the role of PORT to women with cN1 disease who convert to ypN0 after NAC (clinicaltrials.gov: NCT01872975). The large number of patients who delayed the start of PORT in our study is troubling, and could be a consequence of limited resources that many developing (and some developed) countries deploy to cancer care. Our data suggest that early initiation of PORT may be critically important for these patients, and optimizing referrals might achieve disproportionally great returns in terms of improving in cancer outcomes. However, the low numbers of patients and events in this study prevent us from drawing firm conclusions. Although no prospective study will be performed due to ethical issues, further studies are needed to identify subgroups more likely to benefit from early initiation of PORT and determine an optimal time to start it. Conflict of interest statement All authors declare that they have no conflicts of interest in relation to the authorship or publication of this contribution. Financial support This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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