The risk factors and the relationship between radiation dose and complications and prosthetic reconstruction failure in patients with post-mastectomy breast implant reconstruction: a retrospective cohort study

Introduction

Breast cancer has become the most common malignant tumor in the world (1). Along with tumor control, radical mastectomy may negatively affect a woman’s body image and sexual function, thus aggravating their psychological trauma and increasing social burden. However, this may be improved by breast implant reconstruction (2), which has risen in popularity globally (3). While the number of patients undergoing reconstruction in China is less than that in some Western countries, the numbers have gradually increased in recent years (4).

Physicians and patients have traditionally focused on complications, aesthetic outcomes of reconstructed breasts, and tumor control. Post-mastectomy radiotherapy (PMRT) can reduce the local recurrence rate and prolong disease-free survival and overall survival. In recent years, its indications have been gradually expanded with the publication of several large-scale clinical studies (5-8). However, the risk of complications after breast implant reconstruction, such as capsular contracture, infection, hematoma, seroma, bleeding, wound dehiscence, and breast implant reconstruction failure may increase with radiotherapy (RT) (9-11). Some studies have reported risk factors for reconstruction complications other than RT, but their results are currently inconclusive (12-14). Chemotherapy has been reported to be associated with a high rate of complications and reconstruction failure (10,15), but several studies showed the opposite result (14,16). Whether diabetes and hypertension (HT) are associated with postoperative complications is conflicting in implant-based breast reconstruction (12,17,18). It is well established that a high body mass index (BMI) increases the risk for surgical complications (12-14,19,20). Smoking is also considered as risk factor for complications, although some studies have failed to establish this relationship (13,14,16,20,21). Very little has been published on the association between complication and inflation volume (16,19). In the case of the implant-based reconstruction method, there is no agreement regarding its effect on complications (22,23). Besides, some research showed smoking, axillary lymph node dissection would increase the risk of prosthetic reconstruction failure (22,24,25).

The relationship between radiation dose distribution, radiation technology, clinical target volume (CTV), and reconstruction complications is currently unclear. Three studies reported that patients with reconstruction complications following PMRT have a higher degree of hot spots (radiation dose reaching 105–107% of the prescribed dose in the CTV) compared to those without complication, but their conclusions have not been consistent (26-28). In addition, Chinese women have relatively small breast volume compared to those in Western countries, which may influence the degree and location of hot spot doses. Therefore, this current investigation explored other risk factors for reconstruction complications and analyzed the relationship between dose distribution and reconstruction complications in Chinese women. We present the following article in accordance with the STARD reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-22-633/rc).

Methods

Patients

Women with breast ductal carcinoma in situ (DCIS) or clinical stage I–III invasive breast cancer who underwent mastectomy and breast reconstruction with or without PMRT at the First Affiliated Hospital of Chongqing Medical University between January 2012 and June 2020, were retrospectively identified. Patients with the following conditions were excluded: (I) loss to follow-up or deceased; (II) incomplete expander-implant replacement; (III) implant removal for reasons unrelated to surgery; (IV) completed postoperative adjuvant RT in other medical institutions; and (V) presented with benign tumors. After excluding ineligible patients, a total of 275 patients were enrolled, including 59 patients who received PMRT (59 breast reconstructions) and 216 patients who did not receive PMRT (221 breast reconstructions). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the First Affiliated Hospital of Chongqing Medical University Ethics Committee (No. 2021-377) and individual consent for this retrospective analysis was waived.

Demographic data

Their medical charts were reviewed, data on demographic parameters registered were age, BMI, smoking history, drinking history, breastfeeding history, menstrual history, concurrent morbidity (diabetes, hypertension), clinical data (including tumor type and stage, and adjuvant therapy), perioperative parameters (nipple and areola complex sparing, autologous fat filling, reconstruction stage, axillary lymph node dissection, implant volume) as well as follow-up-time.

Follow up

Complications were assessed by two surgeons through telephone interviews with patients, patient history database, physical examinations, and imaging examinations. Complications included postoperative bleeding, incision dehiscence, upper limb edema, nipple areolar complex (NAC) necrosis, flap necrosis, extrusion, hematoma, and seroma required unplanned surgery or medication. Breast implant reconstruction failure was defined as the removal of the prosthesis due to complications; 11 and 19 patients suffered from breast implant reconstruction failure among patients received with and without RT, respectively. The radioactive dermatitis was graded by physicians according to the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0). The follow-up time was defined from the date of completion of the mastectomy to the time of the last record.

Breast reconstruction

There were two types of prosthesis reconstructions, namely, immediate prosthesis reconstruction (immediate placement of a permanent implant after the subcutaneous breast resection) and immediate-delayed prosthesis reconstruction (expanders inserted immediately after the subcutaneous breast resection with an expander-implant exchange after adjuvant RT). During RT, the expander was partially inflated and the inflation was suspended to maintain dose homogeneity throughout the treatment. After completion of postoperative adjuvant chemoradiotherapy, expander-implant exchange was performed after more than 3 months of RT. All implants were placed between the pectoralis major and pectoralis minor/serratus anterior muscles without acellular dermal matrix (ADM) or other tissue patches. Antibiotics were used for three days to prevent infections.

Radiation therapy

RT was provided less than eight weeks after mastectomy or completion of the last cycle of adjuvant chemotherapy. The treatment plans were generated using the Varian Eclipse treatment planning system with simulation computed tomography (CT) scans. Patients were treated with 3-dimensional conformal radiation therapy (3DCRT) until 2017, after which they received 3DCRT or intensity-modulated radiation therapy (IMRT) according to the target area. The CTV includes the chest wall (including the marked mastectomy scar on the skin) and regional lymph nodes, including supraclavicular lymph nodes, with/without internal mammary lymph nodes. These were delineated according to the tumor characteristics and guidelines of the Radiation Therapy Oncology Group (RTOG). The European Society for Radiotherapy and Oncology-Advisory Committee in Radiation Oncology Practice (ESTRO-ACROP) published a consensus guideline in 2019 for target volume delineation in the setting of PMRT after implant-based immediate reconstruction for early-stage breast cancer. It suggested that in reconstructed breasts with expander/prosthesis placed below pectoralis major, the bottom of the implant should not be included in the CTV (29). Therefore, there is no uniform standard on whether to include the bottom of the expander/prosthesis in CTV. Most of the CTV delineated by physicians in this study included the bottom of the implant. The planning target volume (PTV) is the CTV plus a 5 mm expansion, except for the frontier edge of the chest wall. 6-MV X-rays were used for both IMRT and 3DCRT plans. The prescription dose was 50 Gy/25 F, except for 1 case of 50.4 Gy/28 F and 1 case of 46 Gy/23 F + 11 Gy/5 F. No bolus was used.

In general, 95% of the PTV should receive at least 95% of the prescription dose. Ipsilateral lung volumes at or exceeding 5 Gy (V5) and 20 Gy (V20) were mandated to ≤45% and ≤30%, respectively. For patients with left breast cancer, the mean cardiac doses with or without internal mammary lymph node radiotherapy (IMNI) were defined as <6 and <4 Gy, respectively. For patients with right breast cancer, the mean cardiac doses were defined as <2 and <0.5 Gy, depending on whether IMNI was performed.

Statistical analysis

Pearson’s chi-square tests or Fisher’s exact tests were used to compare the complication rates between the RT and non-RT groups. Univariate and multivariate logistic regression analyses were performed to assess the correlation between complications and age, BMI, personal history, history, adjuvant therapy, reconstruction type, and implant volume, so as to determine the risk factors for complications and breast implant reconstruction failure.

Patients in the RT group were divided into two subgroups according to the presence or absence of complications. Independent samples t-tests, Mann-Whitney U tests, Pearson’s chi-square tests, or Fisher’s exact tests were selected according to the sample type to compare the characteristics of RT between the two groups, including RT techniques (IMRT/3DCRT), CTV (chest wall, supraclavicular lymph nodes, internal mammary lymph nodes), whether surgical scars were exposed to high-dose radiation, and radiation dose distribution.

The radiation dose distribution was collected by examining the dose-volume histogram and analyzed. The maximum point dose (Dmax), the mean dose to 0.03, 1, 2, 5, and 10 cc in the PTV (represented by D0.03cc, D1cc, D2cc, D5cc, and D10cc, respectively), the irradiation volume with the doses of 105% and 107% of prescription dose (represented by V105% and V107%, the unit is milliliters), and their ratio to the total PTV (represented by V%105% and V%107%) were selected to reflect radiation dose distribution and obtained from dose-volume histograms. The predictive values of each parameter for the development of complications were tested by the receiver operating characteristic (ROC) method. All significance tests were two-sided. A value of P<0.05 was considered statistically significant. Data analysis was performed using SPSS software (version 22.0, IBM Corporation, Armonk, NY, USA).

Results

Baseline characteristics

Figure 1 shows the selection process of the patients enrolled in this study. Patients who were excluded (and the associated reasons) or who withdrew from the study have been noted. A total of 275 patients undergoing 280 reconstructions were finally included. The baseline characteristics are shown in Table 1. The median follow-up time was 47.7 months (range, 11.7 to 108.8 months). Patients who were irradiated and those who were not irradiated differed significantly in pathological type, tumor stage, and pathological grade. Patients with RT were less likely to have grade 1 tumors (8.3% vs. 0%, P=0.019) and carcinoma in situ (21.3% vs. 0%, P<0.001), but more likely to receive axillary lymph node dissection (ALND); 94.9% vs. 21.3%, P<0.001), neoadjuvant chemotherapy (39.0% vs. 12.5%, P<0.001), and adjuvant chemotherapy (100.0% vs. 76.9%, P<0.001). There were no significant differences in molecular subtypes, anti-human epidermal growth factor receptor 2 (anti-HER2) targeted therapy, and endocrine therapy. Immediate-delayed implant reconstruction may be recommended when there is a confirmed indication of PMRT, so as to reduce the adverse effects of RT on the permanent implant. Accordingly, the proportion of patients who received immediate-delayed implant reconstruction in the RT group was higher (74.6% vs. 38.5%, P<0.001). In addition, there were no significant differences in prosthesis volume nor NAC preservation between the two groups.

Figure 1 A flowchart showing the inclusion process of the breast cancer patients with implant-based reconstructions.

Reconstruction related complications

The incidence of complications is shown in Table 2. Complications occurred in 103 (36.7%) reconstructed breasts, including 30 (10.7%) prosthetic reconstruction failure. The overall complications in the irradiated and the non-irradiated groups were 50.8% and 33%, respectively (P=0.012). The incidences of upper limb edema, wound dehiscence, and infection in the irradiated group were significantly higher than those in the non-irradiated group (10.2% vs. 2.3%, P=0.013; 15.3% vs. 6.8%, P=0.039; and 22% vs. 9.5%, P=0.009, respectively). The rate of prosthesis reconstruction failure due to complications was 18.6% in the irradiated group and 8.6% in the non-irradiated group (P=0.027). After excluding patients without axillary dissection, the proportion of upper limb edema in the irradiated group was not significantly different from that in the non-irradiated group (10.7% vs. 4.3%, P=0.223).

The reasons for prosthetic reconstruction failure in patient with RT were infection (7/11), wound dehiscence (3/11), and prosthesis exposure (1/11), and in patients without RT, the causes of reconstruction failure were infection (9/19), wound dehiscence (5/19), prosthesis exposure (3/19), hematoma (1/19), and wound infection (1/19).

Risk factors for complications

In univariate analysis (Table 3), RT [odds ratio (OR) =2.197; 95% confidence interval (CI): 1.231–3.922; P=0.008] and adjuvant chemotherapy (OR =2.804; 95% CI: 1.338–5.875; P=0.006) were significant predictors of overall complications. Multivariate analysis (Table 4) also showed that RT (OR =2.000; 95% CI: 1.065–3.754; P=0.031) and chemotherapy (OR =2.226; 95% CI: 1.032–4.799; P=0.041) were associated with overall complications.

To avoid the ratio of RT as a confounding factor, the correlation between reconstruction type and complications in the irradiated and non-irradiated groups were analyzed. The results demonstrated that the reconstruction type was not associated with overall complications, regardless of RT (irradiated group: OR =3.346, 95% CI: 0.327–34.195, P=0.308; and non-irradiated groups: OR =0.665, 95% CI: 0.372–1.191, P=0.170).

Prosthetic reconstruction failure was associated with RT in univariate analysis (OR =2.375; 95% CI: 1.061–5.315; P=0.035) (Table 3). Multivariate analysis showed RT (OR =2.442; 95% CI: 1.009–5.908; P=0.048) and HT (OR =8.222; 95% CI: 1.056–64.034; P=0.044) were independent risk factors associated with prosthetic reconstruction failure (Table 4).

Prosthetic reconstruction complications and radiation dose distribution

The differences between different RT techniques, CTV, whether the CTV included the posterior wall of implants, location of hot spots, and dose distribution between subgroups with and without complications were analyzed (Table 5). Patients with complications had significantly higher D5cc (108.26% vs. 107.12%, P=0.045), D10cc (108.04% vs. 106.61%, P=0.034), V%105% (30.95% vs. 19.29%, P=0.019), V107% (51.06 vs. 5.94 mL, P=0.027), and V%107% (8.90% vs. 1.12%, P=0.042) compared to patients without complications. Dmax and “near Dmax”, such as doses to the hottest 0.03, 1, and 2 cc of PTV did not differ significantly between the two subgroups. In addition, there were no significant differences between the two subgroups in terms of RT techniques (IMRT vs. 3DCRT), whether the CTV included the bottom of the implant, the target volume (chest wall vs. chest wall + supraclavicular lymph nodes vs. chest wall + supraclavicular lymph nodes + internal mammary lymph nodes), location of the hot spot (proximal chest wall vs. proximal chest wall vs. proximal sternum vs. near mid-axillary side vs. implant surface vs. implant), nor whether surgical scars were irradiated with high-dose radiation. Therefore, the ROC curve was drawn to explore the relationship between radiation dosimetry and overall complications (Figure 2). Neither “hot spot” volumes nor their ratio to the CTV volume, such as D5cc [area under the curve (AUC) =0.631, P=0.094], D10cc [AUC =0.641, P=0.071], V107% [AUC =0.651, P=0.053], V%105% [AUC =0.659, P=0.042] and V%107% (AUC =0.659, P=0.042) was predictive of the development of complications (Table 6). No positive relationship between the severity of radiation dermatitis and complication rate was detected [dermatitis G0 7/11 (63.6%), G1 17/40 (42.5%), G2 1/2 (50%), and G3 5/6 (83.3%), P=0.200].

Figure 2 The ROC curve for the development of implant reconstruction complication. ROC, receiver operating characteristic.

Discussion

With the development of the economy, the number of breast reconstructions after mastectomy for breast cancer has gradually increased in China in the past decade (30). Two studies published in 1997 identified the necessity of PMRT for patients with positive lymph nodes (5,6), and in 2013, this was further confirmed for patients with 1–3 positive lymph nodes (7,8). However, RT can increase the incidence of reconstruction complications, as well as prosthesis failure caused by severe complications, whether the implant is an expander or a permanent prosthesis (10,31). RT can also damage blood vessel cells, reduce blood supply, and cause tissue hypoxia. Additionally, it increases myofibroblast transformation and fibrosis, leading to capsular contracture (32).

The current study showed that the incidence of breast prosthesis reconstruction complications could be increased with RT, which is consistent with the conclusions of previous studies (10,31,33). The incidence of some specific complications were also increased in patient with RT, such as wound dehiscence (15.3 vs. 6.8%, P=0.039), infections (22.0% vs. 9.5%, P=0.009), and implant reconstruction failure (18.6% vs. 8.6%, P=0.027). Compared with the prosthesis loss rate reported in the study by Cordeiro et al. (9.1% vs. 0.5% in patients with and without RT) (9) and Nava et al. (7.1% vs. 2.3% in patients with and without RT) (11), the reconstruction failure rate was higher in patients without RT in our study, but RT increased the reconstruction failure rate by 1.16 folds. Therefore, the effect of RT on the failure rate of prosthesis reconstruction is acceptable.

The most common reason for implant reconstruction failure was infection (63.6% in irradiated implants and 47.4% in non-irradiated implants), consistent with previous studies (34,35). Thus, efforts to actively treat or prevent infections during the perioperative period should be made to reduce the risk of implant reconstruction failure.

In addition to infection, the sequence of RT and expander-implant replacement may be another reason for the higher failure rate. All patients in the study by Cordeiro et al. underwent expander-implant replacement before PMRT (9). This sequence was also used in two-thirds of RT patients in Nava et al.’s study. It reported that the incidence of reconstruction failure was 40% and 6.4% in patients treated with RT before and after expander-prosthesis replacement, respectively (P<0.0001) (11). Two meta-analyses also confirmed that expander-implant replacement before RT may be beneficial for reducing failure rates, but this sequence will inevitably delay the start of PMRT and may affect the anti-tumor efficacy (36,37). Therefore, delayed autologous reconstruction can be suggested for eligible patients when it is challenging to balance RT efficacy and the risk of complications (38).

Univariate and multivariate analyses suggested that RT and chemotherapy are independent risk factors for reconstruction complications. It is believed that chemotherapy inhibits cell proliferation by affecting DNA replication and mitosis, thereby affecting wound healing (39). Lam et al. demonstrated that postoperative prosthesis loss was 5.3% for patients undergoing adjuvant chemotherapy, and 11.3% for patients receiving chemoradiotherapy, suggesting that both RT and chemotherapy increased the risk of prosthesis loss (10). A previous study has also confirmed that RT and chemotherapy are related to reconstruction complications (15).

In our study, BMI, HT, diabetes mellitus (DM), and smoking history are not risk factors for overall complications, and this was inconsistent with the results of previous studies showing that age greater than 50 years, BMI higher than 25 kg/m², smoking history, and DM are risk factors (13,14,40). Chinese breast cancer patients are characterized by a younger age of onset and less willingness for breast reconstruction in older patients. Therefore, the average age is younger and the BMI is lower in this study, which suggests that the results of this study are mainly aimed at the relatively young patients with average weight. In addition, the small number of patients with a history of smoking and DM may affect the reliability of the univariate analyses, and a history of DM and smoking was not included in the multivariate analysis.

The meta-analysis concluded that immediate prosthesis reconstruction might be associated with a higher complication rate than immediate-delayed reconstruction, primarily increased flap necrosis, reoperation, and implant loss (41). Some scholars also believe that immediate prosthesis reconstruction is more likely to over expand the flap and increase its tension, leading to flap necrosis, infection, prosthesis exposure, and implant reconstruction failure (42,43). However, the results in this investigation showed that the reconstruction method was not associated with overall complications. The reason might be that surgeons tended to recommend 2-step breast implant reconstruction for patients with thinner subcutaneous fat layer, larger tumor size, and smaller breast that required PMRT, creating a selection bias.

Multivariate analysis also showed a higher risk of reconstruction failure in hypertensive patients, consistent with previous findings (17). HT can cause changes in microcirculatory function and structure, thereby affecting the perfusion of skin flaps (18). Therefore, a patient’s blood pressure should be actively monitored and controlled during the perioperative period.

The association between RT and complications has been well-established, but the relationship between radiation dose distribution and complications remains to be fully elucidated. The results herein demonstrated that D5cc, D10cc, V%105%, V107%, and V%107% in patients with complications were significantly higher than that in patients without complications after treatment with PMRT (Table 5). However, there was no significant difference in Dmax, D0.03cc, D1cc, nor D2cc between the two subgroups. In contrast to our results, Muresan et al.’s study reported that reconstruction complications were associated with higher Dmax and D1cc (26), but there was no significant difference among patients with and without complications. Chang et al. and Chung et al. found that near Dmax parameters (D0.03cc, D2cc) were able to predict the risk of reconstruction complications (27,28). Muresan et al.’s study reported that patients with complications had higher mean Dmax and lower D10cc than those in our study (26). The other two studies reported by Korean scholars included hypofractionated RT, resulting in significantly higher D2cc (27,28). Thus, the radiation dose distributions were quite different and not comparable among previous and current studies. We therefore hypothesized that complications were not only related to excessive spot doses but also related to a larger volume with high radiation doses (specifically, V105% and V107% in this study).

ROC analysis involving 5 factors was conducted to determine the clinically relevant predictors of reconstruction complications in patients with PMRT in clinical practice (Table 6). Although the AUCs of V%105% and V%107% (AUC =0.659, P=0.042) for predicting the risk of complications was relatively low, it still indicated that the volume of the hot spot should be reduced while minimizing the maximum dose level.

The development of IMRT can deliver a more homogeneous dose of radiation throughout the breast and efficiently removes radiation hot spots. A previous study has demonstrated a higher rate of radiodermatitis with 3DCRT compared to treatment with IMRT in breast cancer patients, but no significant differences in terms of late toxicities, such as atrophy, telangiectasia, fibrosis, lymphoedema, or breast edema, were detected (44). We found no evidence that RT techniques (3DCRT vs. IMRT) were associated with complications, consistent with the findings before. Indeed, Muresan reported that different RT techniques (IMRT, 3DCRT, field-in-field irradiation, and hybrid RT techniques) do not affect the occurrence of complications. Chang et al.’s study showed that there was no difference in Dmax between patients undergoing different RT techniques (IMRT vs. 3DCRT) (27).

For the first time, the relationship between complication rates and surgical scars exposed to high-dose radiation was analyzed. The results demonstrated that complication rates were likely higher in patients with surgical scars exposed to high-dose radiation, even though there was no statistical significance (P=0.054), suggesting that we should take care to avoid high-dose radiation from surgical scars for patients in clinical practice. These results should be validated in future studies.

There were some limitations to this study. First, as this was a retrospective study, it has inherent biases in patient selection and treatment assignment. Second, this study excluded patients due to tumor recurrence, metastasis, death, and loss to follow-up. The lack of this data may affect the conclusions herein. Third, we only analyzed breast reconstruction complications from a physician’s perspective and did not investigate the patients’ perceptions.

Conclusions

RT is associated with overall implant reconstruction complications and can lead to an increased risk of implant reconstruction failure, but its effect on reconstruction outcomes is acceptable in a multidisciplinary setting. In addition to RT, chemotherapy is a risk factor for overall complications of breast reconstruction, and a history of HT increases the risk factor for reconstruction failure. For patients requiring PMRT, complication rates were likely higher in these patients with surgical scars received from high-dose radiation. The maximum dose in the PTV was not associated with the occurrence of reconstruction complications, while D5cc, D10cc, V105%, V%105%, V107%, and V%107% were significantly higher in patients with reconstruction complications. Controlling the hot spot volume, reducing the hot spot dose level, and keeping hot spots away from the scar may improve reconstruction outcomes.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-22-633/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-22-633/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-22-633/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the First Affiliated Hospital of Chongqing Medical University Ethics Committee (No. 2021-377) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: J. Teoh)