Abstract
Purpose:
Breast cancer patients requiring postmastectomy radiation therapy (PMRT) often desire breast reconstruction. Reconstructions can be adversely affected by PMRT, and fear of reconstruction complications has discouraged adoption of short-course radiation therapy used after lumpectomy. To fill the evidence gap, we conducted a non-inferiority trial of hypofractionated vs conventional PMRT in patients undergoing breast reconstruction. The primary outcome was reconstruction complication rate, a composite of wound healing, re-admission, capsular contracture, unplanned re-operation, and reconstruction failure.
Patients and Methods:
Women with unilateral invasive breast cancer with planned immediate or delayed reconstruction and PMRT were randomized (1:1) to 50 Gy (25 fractions/5 weeks) or 42.56 Gy (16 fractions/3 weeks). This study was designed with a non-inferiority margin of 10%, assuming a 2-year reconstruction complication rate of 25% with conventional PMRT. Randomization was stratified by immediate vs delayed and autologous vs implant-only reconstruction.
Results:
Between 2018 and 2021, 898 patients enrolled with a median follow-up of 3.9 years; 825 patients were evaluable for the primary endpoint. The 24-month reconstruction complication rates were 12.3% (52/422) with hypofractionated PMRT and 10.2% (41/403) with conventional PMRT, estimated difference −2.1% (95% confidence interval: −6.5%, 2.2%). The complication rate was higher (regardless of arm) with implant-only vs autologous reconstruction, odds ratio = 1.65. There was no statistically significant difference in 36-month locoregional recurrence rates: 1.5% (95% CI: 0.7–3.2%) with hypofractionated and 2.2% (95% CI: 1.1–4.3%) with conventional PMRT. Acute and late toxicity rates were not statistically different.
Conclusions:
A 16-fraction course of hypofractionated PMRT is safe and non-inferior to conventional PMRT in women undergoing breast reconstruction after mastectomy.
Trial registration
ClinicalTrials.gov Identifier: NCT03414970
Full Protocol document available on https://www.ctsu.org
Keywords: mastectomy, PMRT, hypofractionation, reconstruction, breast cancer
Introduction
Postmastectomy radiation therapy (PMRT) improves local control and breast cancer survival and is a critical component of comprehensive oncological treatment for many breast cancer patients.1–3 In the patient-level meta-analysis of PMRT trials reported by The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG),4 PMRT was important even in patients with 1–3 positive lymph nodes, decreasing the 10-year local recurrence from 20% to 4% (p<0.00001) and reducing 20-year breast cancer mortality from 50% to 42% (p=0.01).5
Radiation is shifting toward shorter, more convenient, and more cost-effective treatment schedules, referred to as hypofractionation.6 Numerous prospective trials have demonstrated that hypofractionation is safe and effective in women undergoing breast-conserving therapy.7–10 Hypofractionation may even improve oncological outcomes by simply increasing access to radiation therapy (RT).11,12 Following mastectomy, the majority of women in the United States are treated with breast reconstruction,13 which can be associated with increased complications such as infection, delayed wound healing, contraction, prosthesis exposure, and failed reconstruction.14–21 There has been a reluctance to apply hypofractionation after mastectomy because of concern for these complications. Small studies of hypofractionated PMRT (+/− reconstruction) suggest acceptable complication rates with moderately hypofractionated PMRT.22–25 Based on these preliminary data, we conducted a non-inferiority trial to assess the safety of this approach compared to conventional fractionation.
Methods
Study design and participants
Alliance for Clinical Trials in Oncology (Alliance) A221505, RT CHARM (Radiation Therapy, Conventional vs. Hypofractionation, Accelerated, after Reconstruction and Mastectomy), was designed with assistance from the Canadian Cancer Trials Group and NRG Oncology investigators. 209 academic and community sites in the United States and Canada enrolled patients. The study was a two-arm, unblinded, non-inferiority trial testing the control schedule (50 Gy in 25 daily treatments) against the experimental arm (42.56 Gy in 16 daily treatments). All patients were provided with and signed written consent before trial enrollment. This trial was monitored through the National Cancer Institute (NCI) Central Institutional Review Board (CIRB) and Alliance Data and Safety Monitoring Board, and registered with ClinicalTrials.gov (https://clinicaltrials.gov/NCT03414970). The Imaging and Radiation Oncology Core Group (IROC) performed RT plan quality assurance.
Eligible patients were ≥ 18 years of age, had an Eastern Cooperative Oncology Group performance status 0–1, with a completed mastectomy for invasive carcinoma of the breast, and American Joint Committee on Cancer (AJCC Ver 8) staging of T0N1–2a, T1N1–2a, T2N1–2a, or T3N0–2a, and all M0. Patients must have had a completed, ongoing, or intent for future breast reconstruction. Patients were not eligible if they had T4, or N3 disease, positive margins, active collagen vascular disease, synchronous bilateral or prior ipsilateral breast cancer, or prior thoracic RT.
Given the absence of prospective, level 1 evidence on interventions affecting chest wall reconstructions, we intentionally allowed all reconstruction types, timing sequences, and combinations used in community and academic practice. Reconstructions could occur before or after RT, provided the intent was to complete the process within 18 months of finishing RT.
Randomization and masking
Patients were randomized, non-blinded, to conventional vs. hypofractionation radiation 1:1 using dynamic allocation algorithm with sub-stratification for intent of immediate versus delayed and autologous versus implant-only reconstruction. If all reconstruction was completed before RT, it was classified as immediate; otherwise, it was categorized as delayed. Immediate tissue expander at mastectomy and a second stage final procedure was also considered delayed. Autologous reconstruction included the use of autologous tissue with or without a breast implant.
Procedures
PMRT was delivered in the conventional arm to a dose of 50 Gy in 25 daily fractions over 5–6 weeks or hypofractionated arm to a dose of 42.56 Gy in 16 daily fractions over 3–4 weeks. The treating radiation oncologist had to certify intent to treat regional lymphatics prior to registration. Margins were to be negative, defined as no tumor on ink. Mastectomy and nodal evaluation had to be completed within 56 days of neoadjuvant chemotherapy. Lymph nodes were evaluated per standard of care. Neoadjuvant or adjuvant chemotherapy, biological or endocrine therapy was given per treating physician based on standard of care. If adjuvant chemotherapy was given, it could be delivered before or after RT. RT treatment was to begin no sooner than 21 days and no later than 84 days after mastectomy or the completion of adjuvant chemotherapy, whichever was later. RT was delivered with 3D-defined volumes and proton radiotherapy was not allowed. The PMRT methods and dose volume parameters were adapted from RTOG criteria: http://www.rtog.org/corelab/contouringatlases/breastcanceratlas.aspx.26 PMRT was delivered to the reconstructed breast/CW, undissected axilla, supraclavicular fossa and IM nodal chain (first 3 intercostal spaces). The use of skin bolus was per the treating physician’s discretion. The use of chest wall or scar boosts was not allowed. Every case was reviewed centrally for quality and uniformity by the Quality Assurance Review Center (QARC) at Imaging and Radiation Oncology Core (IROC), Rhode Island. Dosimetric RT planning constraints are available in Supplemental Table 1.
Outcomes
The primary endpoint was the proportion of patients with one or more ipsilateral reconstruction complications in 24 months after PMRT, using a composite definition that included unplanned re-admission for reconstruction complications (including, but not limited to, infection, wound healing, or pain), re-operation (for complications including, but not limited to, infection, prosthesis exposure, failed reconstruction, unplanned implant removal, wound healing complications, or contracture management), Baker grades III–IV capsular contracture, or total loss of the reconstructed breast (reconstruction failure). Routine revisions, such as dog-ear corrections, fat grafting, and revising the contralateral breast, were recorded, but not scored, as an adverse reconstruction event. Additionally, a contracture that was corrected when the tissue expander was exchanged for an implant or autologous tissue flap was not scored as an event. Secondary endpoints included non-reconstruction toxicity attributable to PMRT, locoregional recurrences, and reconstruction complications based on the timing and type of reconstruction technique. Toxicity was graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and considered a late event if it occurred or was still present ≥ 6 months from the completion of RT. Additional endpoints include the European Organization for Research and Treatment of Cancer (EORTC) photographic assessment, detailed lymphedema analysis, patient-reported outcomes (Breast-Q), and an economic analysis – will be reported separately.
Statistical Analysis
Based on available data, we assumed a 2-year reconstruction complication rate of 25% in the control arm (Arm 1: standard fractionation). The experimental arm would be considered inferior if the complication rate was 10% higher than that of the control arm. This non-inferiority margin was selected after discussion and consensus with radiation oncologist, breast surgeons, plastic surgeons and patient advocates representing all NCTN groups, the Alliance Breast Committee and the NCI Breast Cancer Steering Committee. A sample size of 792 (396 per arm) evaluable patients provided a 90% power at a one-sided Type I error rate of 0.025 to reject the null hypothesis of inferiority. The design included 1 interim analysis for futility when 30% of evaluable patients had reached two years post RT follow-up. To account for a 10% drop-out due to cancellations or protocol violations, the total target accrual was 880 patients (440 per arm). The primary analysis was based on the intent-to-treat principle, regardless of the actual RT schedule received or reconstruction performed. The 24-month post-RT reconstruction complication rates were compared between treatment arms using a one-sided two-sample test of proportions, based on a normal approximation of the binomial distribution, with a non-inferiority margin of 10%. Acute and late RT complication rates were compared using a two-sided two-sample test of proportions based on normal approximation. Local and local regional recurrence-free survival was estimated using the Kaplan-Meier estimator and compared using the log-rank test. Local and local regional recurrences were estimated using the cumulative incidence function and compared using Gray’s test. Local or local regional recurrence was the event of interest and death without recurrence as the competing risk. The time to event for both endpoints was time from end of radiation to recurrence or death, whichever occurred first. Patients who were alive and recurrence free were censored at their last follow-up. Multivariable logistic regression was used to investigate the relationship between the type and timing of reconstruction and the occurrence of complications.
Statistical analyses were conducted by the Alliance Statistics and Data Management Center. Data quality was ensured by review of data by the Alliance Statistics and Data Management Center and by the study chairperson, following Alliance policies. Multiple layers of review and monitoring were conducted to ensure data quality including a dedicated data manager review 100% of cases to ensure data timeliness and consistency, the trial PI confirmed and verified 20% of cases through record review, and routine site audits for clinical trial compliance, including independent review of all medical records that might indicate a missed primary event. All analyses were based on the study database frozen on December 12th, 2024.
Results
A total of 898 patients were enrolled between February 1, 2018, and August 11, 2021. Enrollment was stopped when the trial met the target accrual goal. Thirty-eight patients withdrew before RT and 35 patients were deemed ineligible, resulting in 825 evaluable subjects for the intention to treat analysis. The study trial profile is presented in Figure 1.
Figure 1.
Consort Diagram
Table 1 summarizes the demographics of the study cohort. Patient median age was 49 years (range: 24–79 years), with 49% premenopausal, 14% with known genetic predisposition syndromes, 66% with a body mass index of overweight or obese (≥ 25 kg/m2), and 6% with a history of diabetes. Patient race was reported as 79% White, 8% Hispanic, 9% Black, 4% Asian, and 7% not reported. Most patients had N1 nodal disease (76%), and 14% of patients who received neoadjuvant chemotherapy had a pathological complete response. Fifty-one percent of patients received neoadjuvant chemotherapy before surgery, and 37% received adjuvant chemotherapy after mastectomy and before PMRT. With the median follow-up of 46.4 months from completion of PMRT, 84% of evaluable patients had completed reconstruction, 76% within 18 months of completing RT. With respect to our pre-specified strata, 219 (27%) were immediate vs 474 (58%) delayed (median 252-day interval); 400 (49%) were implant only vs 293 (41%) autologous tissue (+/− implant) reconstructions. Table 1 displays additional details of breast reconstruction, including implant placement (pre- or subpectoral), as well as temporary tissue expander and acellular dermal matrix utilization. Supplemental Tables 2–4 provide additional details, including baseline characteristics of evaluable patients by reconstruction status at the time of data analysis.
Table 1:
Patient Characteristics of evaluable patients, intention to treat
| Evaluable (intent) | Conventional (n=403) | Hypofractionated (n=422) | Total (n=825) |
|---|---|---|---|
| Age, median years (range) | 49.0 (26–78) | 49.0 (24–79) | 49.0 (24–79) |
| Median follow-up after RT, months | 40.7 | 47.0 | 46.4 |
| ECOG 0 | 317 (78.7%) | 313 (74.4%) | 630 (76.4%) |
| BMI, kg/m2 | |||
| < 18.5, underweight | 9 (2.2%) | 7 (1.7%) | 16 (1.9%) |
| 18.5–24.9, normal | 137 (34.0%) | 125 (29.6%) | 262 (31.8%) |
| ≥ 25, overweight | 145 (36.0%) | 138 (32.7%) | 283 (34.3%) |
| ≥ 30, obese | 112 (27.8%) | 152 (36.0%) | 264 (32.0%) |
| History of Diabetes | 26 (6.5%) | 24 (5.7%) | 50 (6.1%) |
| Hemoglobin A1c w/diabetes, mg/dl (SD) | 6.9 (1.18) | 8.7 (10.75) | 7.8 (7.47) |
| Known Predisposition syndrome | 56 (13.9%) | 62 (14.7%) | 118 (14.3%) |
| BRCA1 | 14 (3.5%) | 15 (3.6%) | 29 (3.5%) |
| BRCA2 | 10 (2.5%) | 23 (5.5%) | 33 (4.0%) |
| ATM | 1 (0.2%) | 2 (0.5%) | 3 (0.4%) |
| CHEK2 | 18 (4.5%) | 7 (1.7%) | 25 (3.0%) |
| Other | 18 (4.5%) | 7 (1.7%) | 36 (4.4%) |
| Menopause status | |||
| Perimenopausal | 22 (5.5%) | 24 (5.7%) | 46 (5.6%) |
| Postmenopausal | 172 (42.7%) | 186 (44.1%) | 358 (43.4%) |
| Premenopausal | 199 (49.4%) | 204 (48.3%) | 403 (48.8%) |
| Unknown | 10 (2.5%) | 8 (1.9%) | 18 (2.2%) |
| Histology | |||
| Ductal | 325 (80.6%) | 333 (78.9%) | 660 (80.0%) |
| Lobular | 61 (15.1%) | 65 (15.4%) | 126 (15.3%) |
| Mammary | 15 (3.7%) | 24 (5.7%) | 39 (4.7%) |
| Histologic Grade | |||
| High | 144 (35.7%) | 148 (35.2%) | 292 (35.5%) |
| Intermediate | 188 (46.7%) | 214 (51.0%) | 402 (48.8%) |
| Low | 44 (10.9%) | 41 (9.8%) | 85 (10.3%) |
| Unknown | 27 (6.7%) | 17 (4.0%) | 44 (5.3%) |
| Missing | 0 | 2 | 2 |
| Clinical T Stage (Neoadj chemo only) | |||
| T0 | 1 (0.5%) | 2 (0.9%) | 3 (0.7%) |
| T1 | 28 (13.8%) | 37 (17.0%) | 65 (15.4%) |
| T2 | 95 (46.8%) | 104 (47.7%) | 199 (47.3%) |
| T3 | 79 (38.9%) | 75(34.4%) | 154 (36.6%) |
| Clinical N Stage (Neoadj chemo only) | |||
| N0 | 23 (11.3%) | 31(14.2%) | 54 (12.8%) |
| N1 | 165(81.3%) | 172 (78.4%) | 337 (80.0%) |
| N2a | 14 (5.9%) | 15 (7.3%) | 29 (6.9%) |
| NX | 1 (0.5%) | 0 (0%) | 1 (0.2%) |
| Final T Stage 1 | |||
| T0 | 0 (0%) | 1 (<1%) | 1 (< 1%) |
| T1 | 70 (17.4%) | 103 (24.4%) | 173 (21.0%) |
| T2 | 207 (51.4%) | 195 (46.2%) | 402 (48.7%) |
| T3 | 126 (31.3%) | 122 (28.9%) | 248 (30.1%) |
| Final N Stage 1 | |||
| N0 | 16 (4.0%) | 24 (5.7%) | 40 (4.8%) |
| N1 | 304 (75.4%) | 322 (76.3%) | 626 (75.9%) |
| N2a | 83 (20.6%) | 75 (17.8%) | 158 (19.2%) |
| Reconstruction Completed | 331 (82.3%) | 362 (85.8%) | 693 (84.0%) |
| Immediate (before RT) | 105 (26.1%) | 114 (27.0%) | 219 (26.5%) |
| Delayed (after RT) | 226 (56.1%) | 248 (58.8%) | 474 (57.5%) |
| Reconstruction not completed or reported | 72 (17.9%) | 60 (14.2%) | 132 (16.0%) |
| Temporary Tissue Expander Use | 219 (54.3%) | 245 (58.1%) | 464 (56.2%) |
| Acellular dermal matrix2 | 139 (65.9%) | 146 (61.3%) | 285 (63.5%) |
| Implant used | 240 (70.4%) | 264 (71.0%) | 504 (70.7%) |
| Implant used without autologous | 191 (47.4%) | 209 (49.5%) | 400 (48.5%) |
| Pre-pec implant3 | 114 (48.5%) | 133 (52.0%) | 247 (50.3%) |
| Sub-pec implant3 | 121 (51.5%) | 123 (48.0%) | 244 (49.7%) |
| Autologous (+/− implant) | 140 (41.1%) | 153 (41.1%) | 293 (41.1%) |
| RT to final reconstruction, days (Median, range) | 254.0 (28.0, 1531.0) | 252.0 (35.0, 1755.0) | 252.0 (28.0, 1755.0) |
| Chemotherapy use | |||
| Neoadjuvant | 203 (50.4%) | 218 (51.7%) | 421 (51.0%) |
| Adjuvant | 152 (37.7%) | 152 (36.0%) | 304 (36.8%) |
Higher of clinical or pathological stage.
Expressed as a percentage of tissue expander use.
Expressed as a percentage of any implant use
The primary endpoint of composite reconstruction toxicity events at 24 months after finishing RT was seen in 11.3% of all evaluable patients. The reconstruction complication rate was 10.2% in the conventional fractionation arm and 12.3% in the hypofractionation arm, difference of −2.1%, 95% CI: (−6.5%–2.2%) with the non-inferiority p-value = 0.0001, thus rejecting the null hypothesis that the experimental arm is inferior to the control, Figure 2a. The effect of radiation fractionation on complication rates do not appear to differ by type and timing of reconstruction. In all study patients, there was a 5.2% rate of unplanned hospital admission, 7.8% unplanned re-operation, 3.6% Baker grade 3–4 capsular contracture, and 1.2% rate of complete failure of reconstruction, Supplemental Tables 5–6. Supplemental Table 7 details the cosmetic reconstruction revisions not counted toward the primary event.
Figure 2a.
Forest plot, intention to treat, reconstruction complications (n=825)
Of the 132 patients that did not report reconstructions at the time of the data were frozen for the primary analysis, it was confirmed that 80 patients did not have reconstruction, 17 were reconstructed after 18 months, and 35 patients (4% of the 825 evaluable) did not have reconstruction form completed and being queried. We thus performed an analysis limited to patients who completed breast reconstruction within 18 months of RT, Figure 2b. Non-inferiority was also demonstrated in this analysis using the same method as primary analysis, with a 10.4% rate of complications with conventional fractionation and 12.6% with hypofractionation, a difference of −2.2%, 95% CI: (−7.2%–2.8%), p = 0.001. Results across six subgroups of reconstruction (combination of type and timing of reconstruction and use of tissue expander) do not appear to differ by radiation treatment arm, but the groups become too small to declare statistical non-inferiority, Table 2.
Figure 2b.
Forest plot, as reconstructed, reconstruction complications by type and timing for patients who completed reconstruction within 18 months of finishing radiation therapy (n=631)
Table 2.
Reconstruction complications by type and timing (as treated by radiation and reconstruction type) for the 631 patients who completed reconstruction within 18 months of finishing radiation therapy.
| Frequency of Use | Proportion with 24-month Complications | |||
|---|---|---|---|---|
| Conventional PMRT | Hypofractionated PMRT | Overall Complication Rate | ||
| Immediate TE & Delayed Implant | 31.7% | 15.4% (n = 91) | 19.3% (n = 109) | 17.5% (n = 200) |
| All Delayed Implant +/− TE | 4.1% | 10% (n = 10) | 18.8% (n = 16) | 15.4% (n = 26) |
| Immediate TE & Delayed Autologous +/− Implant | 18.4% | 13.8% (n = 58) | 13.8% (n = 58) | 13.8% (n = 116) |
| All Delayed Autologous +/− Implant +/− TE | 11.1% | 5.9% (n = 34) | 13.9% (n = 36) | 10% (n = 70) |
| Immediate Implant only | 23.3% | 8.3% (n = 72) | 5.3% (n = 75) | 6.8% (n = 147) |
| All Immediate Autologous+/− Implant | 11.4% | 0.0% (n = 33) | 2.6% (n = 39) | 1.4% (n = 72) |
In a pre-planned multivariate analysis of patients who completed reconstruction, we found that treatment arm, body mass index, and history of diabetes were not significant predictors of reconstruction complications, Table 3. Delayed reconstruction was associated with increased odds of complications compared to immediate reconstruction, regardless of treatment arm (OR 2.96, 95% CI: 1.4–6.2, p=0.004). Slightly increased odds were observed but did not reach statistical significance with implant-only reconstruction compared to autologous (+/− implant) reconstruction (OR 1.65, 95% CI: 1.0–2.8, p = 0.07). Although complication differences were noted by type and timing of breast reconstruction, no difference was demonstrated between the two RT fractionation schedules.
Table 3.
Multivariable regression analysis for a reconstruction complication (as treated by radiation and reconstruction type)
| Variable | Estimated Odds ratio (95% CI) | p-value |
|---|---|---|
| Treatment arm (hypofractionated vs. conventional) | 1.172 (0.708, 1.938) | 0.537 |
| Timing reconstruction received (Delayed vs. immediate) | 2.960 (1.421, 6.166) | 0.004 |
| Reconstruction received (Implant only vs. Autologous +/− implant) | 1.651 (0.958, 2.846) | 0.071 |
| Temporary Tissue Expander placement (Yes vs. No) | 1.456 (0.724, 2.933) | 0.291 |
| BMI | 1.006 (0.983, 1.029) | 0.628 |
| History of Diabetes (No vs. Yes) | 1.416 (0.411, 4.880) | 0.582 |
The median follow-up time, calculated using the reverse Kaplan-Meier method, was 3.9 years from end of RT. The 3-year local and locoregional recurrence-free survival was 96.2%, 95% CI: (94.3–98.2%) with conventional fractionation, and 97.0%, 95% CI: (95.4–98.7%) with hypofractionation, HR 1.01, 95% CI: (0.53–1.96), p = 0.97, Figure 3a. Local and locoregional recurrences were low overall, with a total of 8 recurrences reported in conventional fractionation arm and 10 in the hypofractionation arm. The estimated 3-year cumulative incidence of local and local regional recurrence was 2.2%, 95% CI: (1.1–4.3%) in the conventional fractionation arm and 1.5%, 95% CI: (0.7–3.2%) in the hypofractionation arm, Figure 3b. A Gray’s test indicates there was no significant difference between the two treatment arms.
Figure 3a.
Kaplan Meier estimate for local or local regional recurrence free survival
Figure 3b.
Cumulative incidence for local and local regional recurrences
Evaluating acute non-reconstruction related toxicity, regardless of RT attribution, there was no difference by treatment arm for grade 3 or greater toxicity with a rate of 7.7% with conventional fractionation and 5.0% with hypofractionation, 2.7% difference, 95% CI: (−0.6%–6.0%), p = 0.11, Supplemental Figure 1. Evaluating toxicity by attribution of possibly or likely related to RT, the toxicity rate was low without an apparent difference between treatment arms, except acute dermatitis, occurring less frequently with hypofractionation, Supplemental Table 8. The rates of acute dermatitis with conventional RT were grade 2 in 171 (42%) patients and grade 3 in 11 (3%) patients, while in the hypofractionated arm, grade 2 dermatitis was seen in 84 (20%) patients and grade 3 in 3 (1%). The p-values were < .0001 for Grade 2 comparison and 0.048 for Grade 3.
Radiation quality was considered good, with 805 (90%) of cases reviewed rated as per-protocol or with acceptable variations. 40 (4%) of cases were considered unacceptable per protocol and 53 (6%) not submitted for review.
Discussion
RT CHARM has demonstrated non-inferiority of breast reconstruction complications with no difference observed in locoregional recurrences and RT toxicity with abbreviated PMRT, regardless of the timing or technique of reconstruction used. RT CHARM is a notable study given its requirement for comprehensive nodal coverage, central RT quality assurance, and the inclusion of a broad spectrum of reconstruction techniques.27,28 Indeed, we believe this is the only study of its type that has collected reconstruction outcomes with this level of detail in a prospective randomized trial. Thus, RT CHARM offers an unprecedented examination of PMRT-associated reconstruction complications.
Our overall reconstruction complication rate was 11.3%, significantly lower than our a priori assumption of 25% based on published literature.14,15,18,29–31 The lower rate may reflect improved surgical techniques over the past decade, or our exclusion of patients who had experienced any reconstruction complication prior to radiation therapy. Overall, our results show that regardless of radiation protocol, delayed reconstruction had a higher complication rate, however, it is important to note that this study was not designed to randomize patients based on reconstructive timing. Nevertheless, there are several possible explanations for this finding. Patients with delayed reconstruction undergo at least one additional surgery compared to patients receiving immediate reconstruction. This additional surgical intervention could put them at risk for additional complications such as scarring, delayed wound healing or infection. Additionally, patients undergoing delayed reconstruction often have a contracted or scarred skin envelope that can compromise healing.
While the study findings are consistent with those of two other randomized studies of hypofractionated PMRT,27,28 this report addresses critical evidence gaps. We note the consistency of the finding in our immediate implant cohort with the results from FABREC,28 lending credence to the observation. The FABREC study demonstrated no significant difference in patient-reported outcomes, local recurrence, and reconstruction complications between similarly randomized patients, at a median follow-up of 40 months. The study recruited 400 subjects across 16 United States centers, reporting an overall complication rate of 9.8% at 15 months (excluding capsular contracture). The study exclusively allowed implant-only reconstructions, with 21% of patients receiving irradiation with a permanent implant and 79% with tissue expanders. A separate phase 3 randomized trial from China also tested hypofractionated PMRT, but this study completely excluded patients with chest wall reconstructions and delivered comprehensive radiotherapy (but without IMN coverage) with en face electrons to the flat chest wall (a very uncommon practice in the US and Canada).27 Eight-hundred and twenty patients were randomized to either 43.5 Gy in 15 fractions or 50 Gy in 25 fractions, and with a median of 58.5 months, they reported non-inferiority for local control and similar toxicity. This trial was clearly too restrictive to be broadly practice changing and had limited impact on practice patterns in the US.
Limitations
Our results reveal a significantly lower incidence of reconstruction complications than was supported by the literature when the trial was designed in 2015, thus the 10% margin for non-inferiority could be criticized. Although the observed complication rate was lower than the rate assumed in the original trial design, the resulting 95% confidence interval for the absolute difference in complication rates between the conventional arm and the hypofractionated arm (−6.5%, 2.2%) indicates that the null hypothesis would be rejected and non-inferiority of hypofractionation would be concluded for any non-inferiority margin of 6.5% or higher. Although we report 16% of patients without breast reconstruction for the primary analysis, only (35) 4% of patients had missing data, with 80 (10%) of patients confirmed to not undergo breast reconstruction and 17 (2%) completing their breast reconstructed beyond the 18-month planned time interval. This is not unusual for larger cooperative group trials. To account for this, we performed secondary as-reconstructed analyses (Figure 2b, Tables 2a and 2b). While we felt there was a benefit to utilizing a comprehensive composite reconstruction endpoint, this approach could underestimate the true toxicity burden by focusing on only one event. We hope this will be reflected better when we publish our patient reported outcomes.
We urge caution in applying this data to all PMRT patients, as the published randomized data excludes patients with various combinations of T4 and N3 disease, as well as proton radiation therapy. Additionally, one should carefully interpret the reconstruction subgroup analyses, as the trial did not randomize for type or timing of breast reconstruction. While not part of our randomization, we reiterate that this is the first prospective, multi-institutional trial of this size and quality that allows for comparison of different breast reconstruction techniques. While we believe these data are unprecedented and useful, it is unlikely that we will ever have randomized data directly comparing reconstruction techniques. As such, this study will likely remain a very important source of information for patients and providers in the coming years. We also note that reconstruction complication rates must be viewed with the perspective of patient-reported outcomes and cosmetic outcomes, which will be forthcoming. The strength of RT CHARM lies in its largest sample size to date, the diversity of enrolling institutions, RT quality control, uniform internal mammary node coverage, and the inclusion of all current reconstruction techniques and methods.
Conclusion
A 16-fraction course of hypofractionated PMRT is non-inferior to conventional radiation in women undergoing breast reconstruction after mastectomy. Together with prior prospective evidence, these results support hypofractionated PMRT for the majority of patients who require PMRT, including those undergoing breast reconstruction.
Supplementary Material
Acknowledgments
We’d like to thank the patients who agreed to participate in this trial, as well as the physicians and staff at their respective institutions for enrolling those patients on this trial. This manuscript is the result of funding in whole or in part by the National Cancer Institute of the National Institutes of Health (NIH) under Award Numbers U10CA180821 and UG1CA189823 (Alliance for Clinical Trials in Oncology NCORP Grant), UG1CA233290, UG1CA233178, UG1CA233180, UG1CA233337, UG1CA233373, UG1CA239767, U10CA180863 and CCS 707213 (CCTG); and U10CA180868 (NRG Oncology). It is subject to the NIH Public Access Policy. Through acceptance of this federal funding, NIH has been given a right to make the Author Accepted Manuscript publicly available in PubMed Central upon the Official Date of Publication, as defined by NIH.
Declaration of Interests
MMP Alliance and NIH/NCORP salary support for protocol development and travel. JLR NCI U24 grant and Alliance NCORP research grant. MKL NCI/NCORP
TJW Research funding from Exact Sciences/Genomic Health
AJK Research grants from Merck, Clovis Oncology and Varian.
MBB Paid consultant for Prime Therapeutics
All other authors declare no competing interests
Footnotes
Previous Presentation: plenary oral presentation at ASTRO’s 2024 annual meeting
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. https://acknowledgments.alliancefound.org.
Data Sharing
De-identified patient data may be requested from Alliance for Clinical Trials in Oncology via Datasharing@alliancenctn.org if data are not publicly available. A formal review process includes verifying the availability of data, conducting a review of any existing agreements that may have implications for the project, and ensuring that any transfer is in compliance with the IRB. The investigator will be required to sign a data release form prior to transfer.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
De-identified patient data may be requested from Alliance for Clinical Trials in Oncology via Datasharing@alliancenctn.org if data are not publicly available. A formal review process includes verifying the availability of data, conducting a review of any existing agreements that may have implications for the project, and ensuring that any transfer is in compliance with the IRB. The investigator will be required to sign a data release form prior to transfer.