Abstract
Objectives:
Intraoperative radiation therapy (IORT), a form of accelerated partial breast irradiation (APBI), is an appealing alternative to postoperative whole breast irradiation for early-stage breast cancer. The purpose of this study was to examine the toxicity and cosmetic outcomes of patients treated with a novel form of breast IORT (Precision-Breast-IORT; PB-IORT), that delivers a targeted, higher dose of radiation than conventional IORT.
Methods:
The first 204 patients treated with PB-IORT in a phase II clinical trial (NCT02400658) with 12 months of follow-up were included. Trial inclusion criteria were age ≥45 years, invasive or in situ breast cancer, tumor size ≤3 cm, and node negative. Toxicity and cosmetic scoring were performed at 6 and 12 months.
Results:
98 patients (48%, 95%CI 41-55%) experienced toxicity. Seven grade-3 toxicities occurred (3.4%, 95%CI 1.4-6.9%). The majority of patients (95%) had excellent or good cosmetic outcomes (95%CI 91-98%) at 12 months. The majority of patients (94%) had little or no pigmentation change (95%CI 90-97%), 88% little to no size change (95%CI 82-92%), and 87% experienced minimal shape change (95% CI 82-92%).
Conclusions:
Overall, grade 3+ toxicity was rare and cosmetic outcomes were excellent. Severe toxicity with PB-IORT is similar to that reported in the TARGIT trial (3.3% rate of major toxicity) but lower than APBI (NSABP-39, 10.1% grade-3/4 toxicities). We propose that the toxicity of PB-IORT compared to TARGIT and NSABP-39 is related to the radiation dose and delivery schedule. PB-IORT offers low toxicity and good cosmetic outcomes when compared to other forms of APBI.
Introduction
Breast-conserving therapy (BCT) consisting of breast conserving surgery (BCS) followed by adjuvant radiation therapy (RT) is the standard of care for patients diagnosed with early stage breast cancer. Adjuvant RT in the form of whole breast irradiation (WBI) is typically delivered daily over 3-6 weeks to reduce the likelihood of recurrence in the ipsilateral breast (1). WBI has well-established and acceptable toxicity and cosmetic outcome profiles, with most patients experiencing only minor toxicity and excellent or good long-term cosmetic outcomes (2, 3). However, up to a quarter of women who undergo lumpectomy do not receive postoperative breast irradiation (4). Numerous studies have sought to characterize the reasons for this omission. Difficulty traveling and patient preferences have been identified as common reasons, suggesting that optimizing the patient experience could improve radiotherapy utilization (4, 5). Accelerated partial breast irradiation (APBI) is a modern alternative to WBI that makes BCS a realistic and palatable option for more women as it involves treating a limited and targeted volume of breast tissue in a shorter course than WBI and with radiation exposure to smaller portions of the heart, lungs, skin and chest wall. Current evidence suggests small differences between these approaches for ipsilateral breast tumor recurrence (IBTR) and toxicity (6).
Intraoperative radiation therapy (IORT) is a form of APBI that consists of a single fraction of radiation delivered at the time of BCS. The primary advantages of IORT are reduced treatment time and decreased radiation to surrounding tissues. The targeted intraoperative radiation therapy trial (TARGIT) used the most commonly commercially available form of conventional breast IORT (CB-IORT) in the United States (INTRABEAM, Carl Zeiss Surgical, Oberkochen, Germany) to deliver 20Gy to the lumpectomy bed and 5-7 Gy to 1cm depth. The overall recurrence rate in the IORT cohort was slightly higher than in the WBI arm, but was still within the trial’s non-inferiority limit (7). Importantly, the patients treated with CB-IORT had a lower rate of grade 3 and 4 toxicities than the WBI patients (0.2% vs 0.8%, p=0.029) (8). We developed a novel form of breast IORT, (Precision Breast IORT; PB-IORT), that is composed of high-dose-rate (HDR) brachytherapy delivered through a multi-catheter brachytherapy balloon. PB-IORT takes place at the lead institution, in an integrated brachytherapy suite that houses a computed tomography (CT)-on-rails unit that allows for intraoperative CT images to be used to confirm catheter placement and to formulate individualized treatment plans. As the trial has expanded to additional sites, CT imaging is performed in a CT simulation unit on an ambulatory basis following the BCS procedure. Compared with CB-IORT, PB-IORT provides superior target volume coverage and a higher prescription dose (12.5 Gy) delivered to the lumpectomy bed while maintaining an applicator surface dose of ≤ 20 Gy (9). The multichannel brachytherapy balloon facilitates dose optimization and targeting so that the radiation delivered to critical structures (skin, ribs, heart, and chest wall) is well tolerated while not sacrificing coverage of the target volume. The feasibility and safety of this technique has been demonstrated in a prospective phase I clinical trial (10).
The purpose of the present study was to examine the toxicity and early cosmetic outcomes experienced by the first 204 patients treated in our ongoing, multi-institutional, phase II clinical trial. Considering that PB-IORT delivers a higher, although customized, radiation dose than CB-IORT, we hypothesized the PB-IORT would produce significantly less radiation toxicity and better cosmetic outcomes than WBI, and a different toxicity profile than other CB-IORT.
Methods
Patients treated with PB-IORT as part of an ongoing multi-institutional phase II clinical trial (NCT02400658) having completed a minimum of 12 months of follow up by November, 2018, were included in the study. The study was approved by the institutional review board and informed consent was signed by all participants before trial participation. Patients were eligible for treatment with PB-IORT if they were at least 45 years old, had invasive or in situ carcinoma ≤3 cm, and were node-negative (N0). All patients with invasive tumors underwent sentinel node biopsy at the time of or prior to the date of their IORT. Exclusion criteria included patients with history of ipsilateral breast cancer treated with radiation, lymph node involvement, BRCA gene mutation, breast implants, and treatment with neoadjuvant chemotherapy.
PB-IORT
At the primary center, all components of the PB-IORT procedures were performed in the brachytherapy suite, which is a dedicated, shielded suite with full anesthesia and HDR brachytherapy capabilities that contains an integrated CT-on-rails unit (Siemens Medical Solutions USA, Inc; Malvern, PA). We have previously reported the operative details of this system.(10) To determine if this novel technique could be easily translated to other centers, the phase II trial was opened at a secondary treatment site without a dedicated brachytherapy suite. At that institution, patients underwent breast conserving surgery and had the applicator placed at the time of surgery in the outpatient operating room; CT imaging was acquired later that day in a CT simulation unit. At both locations, the CT images were used by the radiation oncology teams to customize a radiation plan to deliver 12.5 Gy in a single fraction to the target volume (distance of 1 cm around the balloon surface) with an Iridium 192HDR brachytherapy source (11). Planning objectives included maximum skin and rib doses <145% of the prescription dose.
Toxicities and Cosmetic Outcomes
Patient assessments, including reported toxicity and cosmetic scoring, were performed at 6 months and 12 months postoperatively. The assessing physician used the Harvard Scale (Table 1) to grade cosmetic outcomes (12). Breast pigmentation, size, and shape were compared to the untreated breast at 6 and 12 months post treatment and change in these parameters scored as “none,” “little,” “some,” and “moderate.” Toxicities and adverse events were measured by the National Cancer Institute Common Toxicity Criteria for Adverse Events (13). Severe toxicity was defined as any grade ≥ 3 toxicity, the occurrence of skin breakdown or delayed wound healing, hematoma requiring surgical evacuation, seroma requiring more than 3 aspirations, or wound infection requiring intravenous antibiotics or surgical intervention.
Table 1.
The Harvard scale (4-point Likert)
| Score | Description |
|---|---|
| Excellent (E) | The treated breast is nearly identical to the untreated breast |
| Good (G) | The treated breast is slightly different from the untreated breast |
| Fair (F) | The treated breast clearly different from the untreated breast but not majorly distorted |
| Poor (P) | The treated breast is seriously distorted |
Data Analysis
Data were analyzed for all patients treated in the phase II trial who had achieved at least 12 months of postoperative follow-up. Summary measure for continuous variables are presented as median and interquartile range. Categorical variables are presented as n (%). Clopper-Pearson binomial confidence intervals were calculated for all reported proportions.
Results
Two-hundred and four patients underwent PB-IORT as part of our phase II clinical trial and had at least 12-month follow-up data. Median patient age was 64.2 years (IQR 11.9). Patient and tumor characteristics are summarized in Table 2. However, most patients had invasive ductal carcinoma (IDC) (135 tumors) or ductal carcinoma in-situ (DCIS) (54 tumors), which were largely ER+/PR+ and HER2−. Only 4 patients were ER−/PR− and HER2−. Surgical resection was performed with negative margins in 91% of patients (118) with 3.4% going back for re-excision. WBI is recommended and discussed with patients that are found to have positive margins on final pathology or a positive sentinel lymph node. WBI was performed in 7 (3.4%) patients after PB-IORT, 5 of whom underwent WBI after re-excision for positive margins.
Table 2.
Baseline Clinical/Tumor Characteristics
| n = 204 | |
|---|---|
| Median age (years) | 64.2 (IQR 11.9) |
| Histology | |
| IDC | 135 (66.2%) |
| DCIS | 54 (26.5%) |
| ILC | 11 (5.4%) |
| Other | 4 (2.0%) |
| Laterality | |
| Left | 86 (42.2%) |
| Right | 117 (57.4%) |
| Receptor Status | |
| ER+ | 195 (95.6%) |
| PR+ | 145 (71.1%) |
| *HER2+ | 10 (7.4%) |
| *ER− PR− HER2− | 4 (3.0%) |
| Postoperative | |
| Close or positive margins | 13 (6.4%) |
| Surgical re-excision | 7 (3.4%) |
| WBI after re-excision | 7 (3.4%) |
HER2 receptor status routinely only checked for patients with IDC. Positivity rate reported here is among patients with a primary diagnosis of IDC.
Toxicities
Overall, 98 of the 204 patients (48.0%; 95% CI 41-55%) experienced an adverse effect with 66 (32.4%; 95% CI 26-39%) patients experiencing a grade 1 toxicity, 27 (13.2%; 95% CI 8.9-18.7%) patients a grade 2 toxicity, and seven grade 3 toxicities observed in 5 patients (3.4%; 95% CI 1.4-6.9%) as their highest-grade adverse event. The grade 3 toxicities included two breast infections, one wound infection, one patient with generalized weakness, a thromboembolic event, and one patient with lymphocytopenia. There were no grade 4 or 5 toxicities reported. The most common toxicities included seroma (16.7%; 34 patients), breast pain (9.8%; 20 patients), and radiation dermatitis (7.8%; 16 patients). Table 3 summarizes the adverse effects and toxicities by grade.
Table 3.
Frequency of adverse effects and toxicities in patients undergoing PB-IORT.
| Total n=204 | ||||||
|---|---|---|---|---|---|---|
| Category | Adverse effect | G1 | G2 | G3 | G4 | G5 |
| Overall maximum toxicity | 66 (32.4%) | 27 (13.2%) | 5 (2.5%) | |||
| General | Fatigue | 9 (4.4%) | 3 (1.5%) | |||
| Fever | 1 (0.5%) | 1 (0.5%) | ||||
| Localized edema | 5 (2.5%) | |||||
| Pain | 2 (1.0%) | 1 (0.5%) | ||||
| Infection | Urinary tract infection | 1 (0.5%) | ||||
| Breast infection | 8 (3.9%) | 2 (1.0%) | ||||
| Wound infection | 2 (1.0%) | 1 (0.5%) | ||||
| Procedural | Radiation dermatitis | 13 (6.4%) | 3 (1.5%) | |||
| Radiation reaction | 2 (1.0%) | |||||
| Seroma | 29 (14.2) | 5 (2.5%) | ||||
| Wound dehiscence | 1 (0.5%) | |||||
| Other | 2 (1.0%) | |||||
| Hematologic | Lymphocytopenia | 1 (0.5%) | ||||
| Metabolic | Hyperglycemia | 1 (0.5%) | ||||
| Musculoskeletal | Fibrosis (deep) | 1 (0.5%) | ||||
| Fibrosis (superficial) | 8 (3.9%) | 1 (0.5%) | ||||
| Generalized muscle weakness | 1 (0.5%) | |||||
| Extremity pain | 1 (0.5%) | |||||
| Reproductive/breast | Breast pain | 18 (8.8%) | 2 (1.0%) | |||
| Other | 6 (2.9%) | 1 (0.5%) | ||||
| Respiratory | Cough | 1 (0.5%) | ||||
| Skin | Erythema multiforme | 7 (3.4%) | 1 (0.5%) | |||
| Pruritus | 4 (2.0%) | |||||
| Rash maculopapular | 3 (1.5%) | |||||
| Skin hyperpigmentation | 8 (3.9%) | |||||
| Skin induration | 1 (0.5%) | 1 (0.5%) | ||||
| Other | 14 (6.9%) | 5 (2.5%) | ||||
| Vascular | Lymphedema | 2 (1.0%) | ||||
| Superficial thrombophlebitis | 1 (05%) | 2 (1.0%) | ||||
| Thromboembolic event | 1 (0.5%) | |||||
| Other | 1 (0.5%) | |||||
| Unspecified | 1 (0.5%) | |||||
Categorical variables listed as n (%).
Overall maximum toxicity denotes the number of patients that experienced a maximum toxicity of that grade.
Cosmetic Outcomes
In the entire cohort of patients, 95% had excellent (E) or good (G) cosmetic outcomes as graded by the physician on the Harvard scale (95% CI 91-98%) at 12 months. With respect to breast pigmentation, 94% had little to no change (95% CI 90-97%) at 12 months. Most patients experienced little to no size (88%; 95% CI 82-92%) or shape change (87%; 95% CI 82-92%). Six and 12-month cosmetic outcomes are summarized in Table 4. For the majority of patients, cosmetic results were stable or improved between 6 and 12 months, with only a few patients experiencing worse cosmetic outcomes at 12 months compared to 6 months post-treatment (Table 5).
Table 4.
Physician scored cosmetic outcomes at 6 vs 12 months.
| Score at (6 months, 12 months) | Harvard n (%) N=149 | Score at (6 months, 12 months) | Pigmentation n (%) N=176 | Size n (%) N=176 | Shape n (%) N=175 |
|---|---|---|---|---|---|
| (E, E) | 60 (40%) | (N, N) | 85 (48%) | 83 (47%) | 56 (33%) |
| (G, E) | 24 (16%) | (L, N) | 35 (20%) | 19 (11%) | 25 (14%) |
| (F, E) | (S, N) | 2 (1.1%) | 1 (0.6%) | 2 (1.1%) | |
| (P, E) | (M, N) | ||||
| (E, G) | 27 (18%) | (N, L) | 12 (6.8%) | 24 (14%) | 25 (14%) |
| (G, G) | 28 (19%) | (L, L) | 21 (12%) | 22 (13%) | 43 (25%) |
| (F, G) | 3 (2.0%) | (S, L) | 10 (5.7%) | 6 (3.4%) | 4 (2.3%) |
| (P, G) | (M, L) | ||||
| (E, F) | (N, S) | 6 (3.4%) | 2 (1.1%) | ||
| (G, F) | 2 (1.3%) | (L, S) | 6 (3.4%) | 8 (4.6%) | 8 (4.6%) |
| (F, F) | 4 (2.7%) | (S, S) | 3 (1.7%) | 3 (1.7%) | 5 (2.9%) |
| (P, F) | 1 (0.7%) | (M, S) | 1 (0.6%) | 2 (1.1%) | |
| (E, P) | (N, M) | ||||
| (G, P) | (L, M) | 1 (0.6%) | |||
| (F, P) | (S, M) | 1 (0.6%) | 1 (0.6%) | ||
| (P, P) | (M, M) | 1 (0.6%) | 2 (1.1%) |
Scores at 6 and 12-months post-treatment. Harvard scale scoring: E = excellent; G = good; F = fair; P = poor. Appearance change scores: N = none; L = little; S = some; M = moderate.
Table 5.
Fraction of patients with improved or stable cosmetic results at 6 and 12-months post-treatment with PB-IORT.
| Cosmetic Variable | Fraction improved or stable n = 204 | Percent (95% CI) |
|---|---|---|
| Harvard Scale | 120/149 | 81% (73-87%) |
| Pigmentation | 157/176 | 89% (84-93%) |
| Size | 137/176 | 78% (71-84%) |
| Shape | 139/175 | 79% (73-85%) |
Discussion
In this study, we evaluated the adverse effects/toxicities and cosmetic outcomes in the first 204 patients treated with PB-IORT. Overall, the rate of severe toxicities was low, with no reported grade 4 or higher toxicities and only 3.4% of patients experiencing a grade 3 toxicity. The grade 3 toxicities were primarily infectious in nature, though one patient experienced a thromboembolic event and another experienced lymphocytopenia. Thromboembolism, though rare, is a well-known complication of surgery. It was surprising that a patient would develop lymphocytopenia after PB-IORT, though it is a known side effect in a minority of patients receiving radiation therapy (14, 15).
Cosmetic outcomes were also quite good, with over 95% scoring “excellent” or “good” at 12 months post-treatment. There were relatively few patients that experienced size, shape, or color changes compared to the un-treated breast.
It is informative to compare the results of PB-IORT to the published results of CB-IORT. CB-IORT was evaluated in the targeted intraoperative radiation therapy trial (TARGIT) (7, 8). In that trial, 20 Gy was delivered to the lumpectomy bed and 5-7 Gy to 1 cm depth using a low energy x-ray unit (50 kV maximum photons). Major toxicities (defined as skin breakdown, delayed wound healing, or grade 3-4 toxicity on the Radiation Therapy Oncology Group scale) were observed in 3.3% of subjects who received CB-IORT. This is similar to the rate of CTCAE grade 3 toxicities observed in the current study of PB-IORT. Since a higher radiation dose is delivered to 1cm depth with PB-IORT, it is encouraging that similar toxicity rates were observed when compared to CB-IORT. This finding suggests that the ability to tailor the treatment plan with PB-IORT allows for higher dose of IORT to be delivered with an acceptable level of toxicity. This may in turn result in a lower local recurrence rate than that observed in the CB-IORT arm of the TARGIT trial, which we are currently evaluating in the ongoing clinical trial. While intraoperative ultrasound was used in some patients at select institutions in the TARGIT trial, there is no routine use of intraoperative imaging in CB-IORT. CT imaging in PB-IORT serves two purposes: to confirm catheter placement and to allow for individualized treatment planning. Our prior work has demonstrated that in most patients that undergoing PB-IORT, catheter and dose adjustments are made in response to the CT images obtained, in order to limit radiation dose to normal tissues and improve tissue conformity (11).
Early results from NSABP-B39, which compared WBI to APBI, suggest that the toxicity of APBI is greater than WBI (9.6% grade 3 and 0.5% grade 4 toxicities for APBI) (16), but further data from that trial are anticipated in the near future. In B-39, APBI was delivered in 10 fractions of 3.4-3.85 Gy twice daily with either brachytherapy or 3D external beam radiation. In comparison, our findings suggest that PB-IORT results in significantly fewer severe adverse effects, likely due to the lower overall dose and because it is more targeted and tailored to the patient.
Cosmetic outcomes with PB-IORT were quite good, with 95% of patients having excellent or good results at 12 months post treatment. Published data from long-term outcomes studies of patients receiving hypofractionated WBI suggest that roughly 78% have excellent or good cosmetic outcomes at 5 years post treatment (17). In the B-39 trial, 3-year physician-reported cosmetic scores were worse for PBI when compared to WBI (18). The trial also reported patient-scored cosmetic outcomes, which interestingly did not differ between PBI and WBI. Results from the RAPID trial, which compared external beam APBI to WBI, suggest that cosmetic outcomes are significantly worse with external beam APBI (only 71% good or excellent results at 3 years post-treatment) (19).
While numerous trials have shown that cosmesis with APBI is inferior to WBI, there is evidence that Intensity-modulated radiotherapy (IMRT) may provide better cosmesis than WBI. IMRT is a form of APBI with higher dose conformity compared to three-dimensional techniques. The 5-year data from a study that randomized patients to APBI with IMRT (delivered in 5 doses over 5 days) to WBI, and reported the rate of excellent cosmetic outcomes to be higher in the IMRT group (95% vs 90%, p= 0.045). While IMRT does offer quite good cosmesis, it is delivered over 5 treatments which is a significant difference from PB-IORT which is delivered in one dose during surgery.
Trials of APBI in the form of IORT have been promising with respect to cosmetic outcomes, with over 90% of patients experiencing good or excellent results (21, 22). Though a limitation of the present trial is that it did not seek to directly compare cosmetic outcomes and toxicity with other forms of IORT, PB-IORT did have better physician reported cosmetic outcomes at 12 months post-treatment than other forms of IORT despite the higher radiation dose delivered. We propose that this difference is likely due to the ability to target the radiation dose in PB-IORT.
Conclusions
Adjuvant radiation in the form of WBI delivered over the course of 3-4 weeks remains the standard of care after BCS for early-stage breast cancer. APBI in the form of PB-IORT is an appealing alternative to WBI as it delivers one high dose of targeted, personalized radiation to the lumpectomy bed. While it is too early to compare local recurrence rates and mortality, results from our phase II clinical trial suggest that the rate of severe toxicity and adverse effects is significantly lower than in other forms of APBI, and similar to CB-IORT (which delivers a lower radiation dose). Interestingly, despite the higher radiation dose delivered with PB-IORT, cosmetic results seem to be better than with CB-IORT, potentially due to the targeted dose delivery.
Synopsis.
Toxicity and cosmetic outcomes of Precision-Breast IORT are reported. Toxicity is acceptable and cosmetic outcomes are excellent at 12 months post treatment. This form of IORT produces less toxicity than whole breast irradiation and comparable outcomes to other forms of IORT.
Acknowledgements
The National Institutes of Health provided support for this study under Award Number 1R01CA214594-01A1 and 5T32CA163177-08. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
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