Effectiveness and toxicity of re-irradiation after breast conserving surgery for recurrent or new primary breast cancer: a multi-institutional study

doi:10.21203/rs.3.rs-2172644/v1

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Effectiveness and toxicity of re-irradiation after breast conserving surgery for recurrent or new primary breast cancer: a multi-institutional study

https://doi.org/10.21203/rs.3.rs-2172644/v1

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Journal Publication

published 05 Jan, 2023

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Purpose:

Breast reirradiation (reRT) after breast conserving surgery (BCS) has emerged as a viable alternative to mastectomy for women presenting with recurrent or new primary breast cancer. There are limited data on safety of different fractionation regimens. This multi-institutional study reports safety and efficacy among women treated with repeat BCS and reRT.

Methods and Materials:

Patients who underwent repeat BCS followed by RT from 2015–2021 at 2 institutions were analyzed. Univariate logistic regression models were used to identify predictors of acute and late toxicities. Kaplan Meier estimates were used to evaluate overall survival (OS), distant metastasis free survival (DMFS) and locoregional recurrence-free survival (LR-RFS).

Results:

Sixty-six patients were reviewed with median follow-up of 16 months (range: 3–60 months). At time of first recurrence, 41% had invasive carcinoma with a ductal carcinoma in situ (DCIS) component, 41% had invasive carcinoma alone and 18% had DCIS alone. All were clinically node negative. For the reirradiation course, 95% received partial breast irradiation (PBI) (57.5% with 1.5Gy BID; 27% with 1.8Gy daily; 10.5% with hypofractionation), and 5% received whole breast irradiation (1.8-2Gy/fx), all of whom had received PBI for initial course. One patient experienced grade 3 fibrosis, and one patient experienced grade 3 telangiectasia. None had grade 4 or higher late adverse events. We found no association between the fractionation of the second course of RT or the cumulative dose (measured as EQD2) with acute or late toxicity. At 2 years, OS was 100%, DMFS was 91.6%, and LR-RFS was 100%.

Conclusion:

In this multi-institutional series of patients with recurrent or new primary breast cancer, a second breast conservation surgery followed by reirradiation was effective with no local recurrences and an acceptable toxicity profile across a range of available fractionation regimens.

Breast reirradiation

toxicity

outcomes

fractionation regimens

The optimal treatment of recurrent or new primary early stage breast cancer is not well defined. Standard of care has been salvage mastectomy. Higher in-breast tumor recurrence (IBTR) rates were shown following breast conserving surgery (BCS) alone vs. mastectomy, ranging from 7–49% vs. 4–25%, respectively (1–5). Recent publications have shown equivalent tumor recurrence rates with the addition of partial breast reirradiation after BCS compared to salvage mastectomy (6–8). A recent SEER analysis of 3648 patients showed that the omission of radiation after re-BCS was associated with worse overall survival especially in patients with estrogen receptor negative IBTR and that the prognosis was comparable between re-BCS with radiation and salvage mastectomy, thus establishing the role of re-irradiation after BCS (8). A propensity score matched cohort analysis of the GEC-ESTRO breast cancer working group database including 1327 patients showed no difference in 5 year overall survival and cumulative incidence of third breast event between mastectomy and lumpectomy plus brachytherapy (9). While multi-catheter interstitial brachytherapy has historically been the most used partial breast irradiation (PBI) technique, EBRT is increasingly being used. RTOG 1014 was the first phase II trial evaluating 3D-conformal external beam partial breast reirradiation with conventional fractionation (45 Gy delivered in 1.5 Gy fractions twice daily) following repeat lumpectomy after previous BCS. At a median follow-up of 5.5 years in a cohort of 66 patients, the study reported excellent control rates with 5% in breast tumor recurrence, 95% DMFS and 95% OS, and only 7% late grade 3 toxicity events with no grade 4 or 5 events. (6, 7, 10–16). This fractionation scheme can be difficult for many patients because of both the twice-daily regimen and the absolute number of fractions. As such, there is increased interest in the use of once daily and hypofractionated regimens in the reirradiation setting, especially as increasing evidence emerges on the safety and efficacy of such techniques in the upfront setting (17, 18).

The aim of this study was to assess safety and efficacy in a large cohort of women with recurrent or new primary breast cancer treated with repeat BCS and different breast re-irradiation fractionation regimens.

We conducted an Institutional Review Board approved retrospective analysis from two institutions. We reviewed all electronic medical records of consecutive breast cancer patients treated with repeat breast conserving surgery followed by radiation from 2015–2021. Patients who underwent salvage mastectomy and those who received prior radiation to the contralateral breast or to the chest wall were excluded.

Patient and tumor characteristics, treatment planning parameters, adverse events, tumor control, and survival were recorded. Conventional fractionation was defined as ≤ 2Gy/fraction (1.8–2 Gy/fx for first course of radiation and 1.5Gy BID or 1.8 Gy daily for re-irradiation). Hypofractionation was defined as 2.6-2.7Gy/fraction. Ultrahypofractionation was defined as 6-8Gy/fraction. Acute toxicity was defined as ≤ 3 months and late toxicity > 3 months following reirradiation treatment. All were graded using the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0).

Statistical Analysis

The characteristics of subjects including demographics, patient, tumor, and treatment characteristics were first summarized using descriptive statistics in median (interquartile range (IQR)) for continuous variables or percentages (counts) for categorical variables.

We created Kaplan-Meier survival curves for locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS), which were measured from end date of second radiation course to first locoregional recurrence, distant recurrence or death.

Univariate logistic regression was performed to calculate odds ratio (OR) and characterize factors associated with acute and late toxicities where the null hypothesis was rejected for p < 0.05. All statistical analysis was conducted in R-statistical package (www.r-project.org).

Between 2015 and 2021, 66 patients (23 patients from one institution and 43 patients from the second institution) were identified who received breast reirradiation after second lumpectomy. The median time between radiation courses was 11 years (1–27 years). The median follow-up was 16.5 months (3–60 months).

Patient characteristics

Patient characteristics are summarized in Table 1. For both initial disease and recurrence, most patients had early-stage disease with > 70% of patients presenting with tumors ≤ 2 cm in size, about one third with high grade disease and most were hormone receptor positive and HER2 negative. There was no difference in histology between initial and recurrent disease: 80% of patients presented with invasive carcinoma (IDC) and 20% of patients presenting with ductal carcinoma in situ (DCIS). There were some difference in hormone status between initial and recurrent disease. Eight patients had initial ER negative disease and presented with ER positive disease at recurrence and four patients had initial ER positive disease and presented with ER negative disease. Two patients had initial HER2 positive disease and presented with HER2 negative disease at recurrence, and one patient had initial HER2 negative disease and presented with HER2 positive disease at recurrence. All patients at recurrence were clinically node negative, and all patients who had axillary sampling (72%) were pathologically node negative. Of the recurrences, 56% were located in a different quadrant, 36% were located in the same quadrant and 8% had unknown initial location of disease. Of those located in a different quadrant, 43% were invasive carcinoma with DCIS component, 40% were invasive without DCIS component and 16% were DCIS alone. The majority of patients (83%) did not undergo chemotherapy and 59% of patients did pursue hormone therapy for treatment of their recurrent or new primary disease.

Table 1

Patient characteristics
Table 1: Patient Characteristics (N = 66)
	Course 1	Course 2
Median age at time of recurrence (years, range)		68 (46–84)
Median follow up (months, range)		16.5 (3–60)
Laterality, (%)
Left	30 (45)	30 (45)
Right	36 (54)	36 (54)
Histologic subtypes, n (%)
Any invasive ductal carcinoma	52 (78)	54 (82)
invasive with DCIS component	20 (30)	27 (41)
invasive without DCIS component	32 (48)	27 (41)
DCIS	13 (20)	12 (18)
Clinical T stage, n (%)
Tis	13 (20)	12 (18)
T1	38 (57.5)	49 (74)
T2-T3	12 (18)	5 (8)
Clinical N stage, n (%)
Nx	21 (32)	22 (33)
N0	34 (51.5)	44 (66)
N1	9 (13.5)	0 (0)
N2-N3	2 (3)	0 (0)
DCIS grade, n(%)
Low-intermediate	5 (39)	5 (41.5)
High	2 (15)	4 (33.5)
Invasive grade, n (%)
Low-Intermediate	19 (36.5)	40 (74)
High	20 (38.5)	13 (24)
Invasive LVI, n (%)
Present	10 (19)	4 (7.5)
DCIS ER/PR status, n (%)
ER/PR negative	1 (8)	2 (17)
ER/PR positive	6 (46)	7 (58)
Unknown	6 (46)	3 (25)
Invasive ER/PR status, n (%)
ER/PR positive	28 (42)	38 (57)
ER positive / PR negative	7 (11)	9 (14)
ER/PR negative	11 (17)	10 (15)
Unknown	20 (30)	9 (14)
Invasive HER2, n (%)
Negative	39 (75)	54 (96)
Positive	2 (4)	2 (4)
Unknown	11 (21)	0 (0)
DCIS Axillary management
none	10 (77)	7 (58)
SLNB	3 (23)	5 (42)
Invasive Axillary management
none	11 (21)	15 (28)
SLNB	31 (56)	39 (72)
ALND	11 (21)	0 (0)
DCIS Hormone therapy
yes	3 (23)	5 (42)
Invasive Hormone therapy
yes	38 (72)	39 (59)
Invasive Chemotherapy
yes	23 (43)	9 (17)
Localization C1 + C2
Same quadrant		24 (36)
Different quadrant		37 (56)
Unknown		5 (8)
Abbreviations: DCIS = ductal carcinoma in situ; ER = estrogen receptor; PR = progesterone receptor; HER2 = human epidermal growth factor receptor 2; LVI = lymphovascular invasion

Radiation Treatment

Patient radiation treatment characteristics are summarized in Table 2. For the initial RT course, 54.5% received whole breast irradiation (WBI) with conventional fractionation (≤ 2Gy/fraction), 29% WBI with hypofractionation (2.6-2.7Gy/fraction), 6% received PBI with ultrahypofractionation (6-8Gy/fraction) and 10.5% had unknown initial course. With regard to reirradiation course, 95% received PBI (57.5% with 45Gy/1.5Gy BID; 27% with 45Gy/1.8Gy daily; 6% with hypofractionation and 4.5% with ultrahypofractionation) and 4.5% received WBI (44-46.8Gy in 1.8-2 Gy / fx). Prone position was utilized in 24% of patients at time of reirradiation. Median cumulative EQD2 dose was 100.5 Gy (IQR:93–105 Gy).

Table 2

Treatment characteristics
Table 2: Treatment Characteristics
	Course 1	Course 2
Median time between courses (yr) (range)	11 (1–27)
Radiation coverage (%)
Whole breast + RNI	3 (5)	0 (0)
Whole breast	59 (89)	3 (4.5)
Partial	4 (6)	63 (95.5)
Fractionation (%)
Whole breast conventional	36 (54.5)	3 (4.5)
Whole breast Hypofractionation	19 (29)	0
Partial ultrahypofractionation	4 (6)	3 (4.5)
Partial hypofraction	0 (0)	4 (6)
Partial conventional twice daily	0 (0)	38 (57.5)
Partial conventional daily	0 (0)	18 (27)
Unknown	7 (10.5)	0 (0)
Boost (%)
none	13 (20)	64 (97)
yes	47 (71)	2 (3)
unknown	6 (9)	0 (0)
Position (%)
Unknown	31 (47)	0
Prone	8 (12)	16 (24)
Supine	27 (41)	50 (76)
Cumulative EQD2 median (Gy) (Q1, Q3)	100.5 (93–105)

Of the patients who received PBI initially (n = 4), three had subsequent WBI and one had subsequent PBI. All of the women who had initial WBI (n = 62) had subsequent PBI reirradiation. Figure 1 illustrates the different course 2 fractionation regimens after initial WBI. Of the patients who initially received conventional fractionation WBI, 64% (n = 23) received PBI conventional fractionation twice daily, 25% (n = 9) received PBI conventional fractionation daily, and 11% (n = 4) received ultrahypofractionated PBI. Of the patients who initially received hypofractionated WBI, 58% (n = 11) received PBI conventional fractionation twice daily, 31.5% (n = 6) received PBI conventional fractionation daily and 10.5% (n = 2) received PBI hypofractionated. Of the patients with unknown initial WBI, 6% (n = 4) received PBI conventional fractionation BID and 6% (n = 3) received PBI conventional fractionation daily (Fig. 1).

Clinical Outcomes

Rates of adverse events are summarized in Table 3. Twenty-one patients (32%) experienced any acute ≥ grade 2 events. The most common acute event was grade 1–2 radiation dermatitis, with one patient experiencing grade 3 dermatitis, illustrated in Fig. 3. She initially presented with pT1N0 right breast invasive ductal carcinoma and underwent right PBI with mammosite balloon brachytherapy to 34 Gy in 1 fraction. Twelve years after her first radiation course, she presented with recurrent T3N0 IDC and underwent neoadjuvant chemotherapy and lumpectomy followed by WBRT to 46.8 Gy in 26 daily fractions with 14 Gy lumpectomy cavity boost in 7 fractions due to close margins. She experienced significant dermatitis during radiation treatment and subsequently developed worsening telangiectasia at 1- and 2-year follow-up, illustrated in Fig. 3. In addition to this patient’s grade 3 telangiectasia at 1 year, there was only one other grade 3 event in a patient who developed fibrosis at 3 years after completion of radiation. The latter patient initially received WBRT to 50 Gy in 25 fractions with a 10 Gy lumpectomy cavity boost in 5 fractions and partial breast reirradiation 45 Gy in 30 fractions twice daily to her recurrent disease with an 18 year interval between courses. For all patients, there were no grade 4 or 5 late events. The most common late events were breast fibrosis (grade 1–2, 28%) and atrophy (grade 1–2, 16%), with lower rates of breast pain and telangiectasia.

Table 3

Acute and late adverse events after course 2
Toxicity	Acute ≤ 3 months n = 66			Late > 3 months n = 61
Toxicity	Grade 1	Grade 2	Grade 3	Grade 1	Grade 2	Grade 3
Fatigue	10 (15)	6 (9)	0 (0)	0 (0)	0 (0)	0 (0)
Dermatitis	60 (91)	6 (9)	1 (1.5)	0 (0)	0 (0)	0 (0)
Breast pain	12 (18)	1 (1.5)	0 (0)	4 (6.5)	2 (3)	0 (0)
Fibrosis	7 (11)	3(4.5)	0 (0)	11 (18)	6 (10)	1 (1.5%)
Seroma	7 (11)	2 (3)	0 (0)	2 (3)	0 (0)	0 (0)
Breast atrophy	3 (4)	2(3)	0 (0)	5 (8)	5 (8)	0 (0)
Lymphedema	1 (1.5)	0 (0)	0 (0)	1 (1.5)	0 (0)	0 (0)
Telangiectasia	0 (0)	0 (0)	0 (0)	1 (1.5)	1 (1.5)	1 (1.5%)

On univariate analysis, age ≥ 70 years old was associated with a statistically significant increase in acute and late ≥ grade 2 events (p = 0.031). No other clinical or dosimetric parameters were found to be significant predictors of ≥ grade 2 events.

At a median follow-up of 16.5 months (range: 3–60 months), no patients developed local recurrence, and only one regional recurrence was identified. The patient initially presented with pT1bN0 high grade triple negative carcinoma of her right breast and underwent lumpectomy followed by adjuvant chemotherapy and hypofractionated WBRT to 42.4 Gy in 16 fractions with 10 Gy boost. She presented with a recurrence 1.4 years thereafter with a high grade triple negative invasive ductal carcinoma for which she underwent local excision and partial breast reirradiation to 45 Gy in 30 fractions twice daily. She was found to have recurrence in her right axilla 10 months after completing partial breast reirradiation, for which she underwent axillary lymph node dissection, regional nodal irradiation and chemotherapy. She was subsequently found to have recurrence in her left axilla and a malignant pleural effusions, 2.2 years and 4.9 years following completion of her partial breast reirradiation, respectively. Four patients presented with distant disease at 9 months, 10 months, 1.4 years and 2.2 years following completion of their second course of radiation. Of those four patients, the patient who presented with distant disease at 9 months after radiation died 4 years later from her metastatic disease. At 2 years, OS rate was 100%, distant metastasis free survival was 91.6% and locoregional recurrence-free survival was 100% (Fig. 2).

In this large multi-institutional series of 66 patients with recurrent or new primary breast cancer, our findings showed low rates of recurrence and toxicity in patients undergoing second breast conservation surgery followed by external beam breast reirradiation. At a median follow-up of 16.5 months, only one patient sustained a regional recurrence with subsequent distant disease and four patients developed distant disease with one patient subsequently dying from her disease. Our study showed an acceptable toxicity profile with only two late grade 3 events (3%) and no grade 4 or 5 events. Similarly, in RTOG 1014, only four patients had breast cancer recurrence, four patients had grade 3 and none had grade 4 or 5 adverse events (16). These findings are also consistent with those in the published literature with average rate of second local recurrence at 5 years of 12.5% ranging from 5–38% and average rate of ≥ grade 3 late adverse events of 10% ranging from 0–17% (7, 10–13, 19–22).

Studies of reirradiation with EBRT have used different irradiation techniques including electrons, protons and combination of electron/photon 3D fields (23–27). Given the concern for increased toxicity with hypofractionated and ultrahypofractionated regimens in these high-risk patients, EBRT is delivered with conventional dose fractionation regimens with total dose delivered ranging between 45 and 50 Gy. However, in the primary setting, the Florence trial showed improved acute and late adverse events and excellent to good cosmetic outcomes in 90% of patients treated with accelerated PBI (30 Gy in five 6 Gy/ fraction) vs WBI (17). This was further supported by Formenti et al. in a prospective trial using the same fractionation regimen which showed 1% local recurrence rate and good to excellent cosmetic outcomes in 89% of patients at a median follow up of 64 months (28).

Given these promising results, our study is one of the few studies to report clinical outcomes in a cohort that included patients treated with hypofractionated and ultrahypofractionated partial breast fractionation regimens in the setting of re-irradiation, albeit small numbers. Out of the 62 patients who received initial whole breast radiation, four patients (6%) received subsequent hypofractionated partial breast irradiation (2.6-2.7Gy/fx) and three patients (4.5%) received subsequent ultrahypofractionated partial breast irradiation (6 Gy/fx). Out of the three patients who received ultrahypofractionated partial breast irradiation, two subsequently presented with distant failure. One patient developed a metastatic pleural effusion 14 months after her second course of radiation. The second patient developed right breast IDC 26 months after completion of her second course of radiation to her left breast. Two patients experienced late grade 2 fibrosis. Out of the four patients who received hypofractionated partial breast irradiation, none presented with regional recurrence or distant failure. One patient experienced late grade ≥ 2 fibrosis and one patient experienced late grade ≥ 2 breast atrophy. No fractionation regimen was found to be a significant predictor of ≥ grade 2 events on univariate analysis though it was a small cohort of patients.

Furthermore, our study included three patients initially treated with PBI who were treated with WBI in the re-irradiation setting. Two patients had no late adverse events at 1 year follow up and patient and physician rated cosmesis was good. One patient developed grade 3 telangiectasia at her one year follow up which persistent until her 3 year follow up since radiation completion. Both patient and physician rated her cosmesis as poor. She was treated with partial breast mammosite balloon brachytherapy to 34 Gy initially followed by 46.8 Gy in 26 fraction with 14 Gy boost to her recurrent T3N0 invasive ductal carcinoma. There is currently no published data on the optimal management in the setting of recurrent or new primary breast cancer after PBI treated with repeat BCS. This is an area that needs further investigation.

There is also no standard approach for differentiating true recurrences from new primaries. Studies have used concordance of tumor location, time to occurrence, hormone receptor status, tumor grade to distinguish a new primary (NP) from a true recurrence (TP) (29–32). Given that half of the recurrences in our study were in a different quadrant than the initial disease, 15 patients (23%) had discordant hormone receptor status and the long median interval between course 1 and course 2, it is possible that a majority of these recurrences were NP as opposed to TR. Braunstein et al. showed that when classifying a new primary by the presence of an in situ component and a true recurrence by its absence, NPs had significantly better outcomes than TR, with 5-year DFS of 43% and 80% for TR and NP, respectively (31). Interestingly, in the patients who presented with a recurrence in a different quadrant that the primary disease, we did not find an increase in patients presenting with IDC with DCIS suggesting a new primary. Further research in tumor biology and molecular profiling to distinguish between a true recurrence and a new primary may help estimate prognosis in order to improve selection of patient who may be safely treated with a repeat BCS.

Although it is among the largest report to date, our study is limited by its retrospective nature and limited follow-up. Furthermore, only a minority of patients received hypofractionated and ultrahypofractionated PBI in the reirradiation setting, thus limiting our interpretation of clinical outcomes in this cohort. A larger cohort with longer follow up would likely have provided a more robust representation of the impact of different fractionation regimes on the development of late adverse events. Finally, the multi-institutional nature of our study leads to variability in reporting of adverse events and in radiation planning approaches. Some patients treated at one institution were treated prone given reduced skin toxicity observed in patients treated in the prone position. On univariate analysis, there was no significant increase in acute and late toxicity in patients treated prone versus supine. Despite these limitations, our study showed excellent local control and low rates of adverse events with hypofractionated, ultrahypofractionated and even whole breast radiation in the setting of reirradiation, further highlighting the need for additional outcomes data with these different fractionation regimens.

Our study demonstrates that a second breast conservation surgery followed by partial breast re-irradiation with conventional and hypofractionation appears to be safe and effective in this series of patients. It further explores safety and outcomes of partial breast ultrahypofraction and whole breast conventional fraction in the reirradiation setting. Longer follow-up and larger cohort size will help to further characterize dosimetric and clinical factors predictive of toxicity to optimize patient selection.

FUNDING SOURCES: None

CONFLICTS OF INTEREST: None

ETHICS APPROVAL: The study used retrospectively collected data from a publicly available database. No ethics approval was required.

CONSENT TO PARTICIPATE: The study did not enroll patients. No consent for participation was required.

AUTHORS: All authors contributed to the study conception and design. Data collection was performed by Camille Hardy Abeloos, Julia Xiao, David Barbee and Isabelle Choi. Data analysis was performed by Cheongeun Oh. The first draft of the manuscript was written by Camille Hardy Abeloos and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

DATA SHARING STATEMENT: Research data are stored in an institutional repository and will be shared upon request to the corresponding author.

This is a retrospective study. No ethical approval or informed consent was required.

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Effectiveness and toxicity of re-irradiation after breast conserving surgery for recurrent or new primary breast cancer: a multi-institutional study

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