Radiation Effects on Breast Reconstruction:

A Review

Nicole E. Rogers, B.A.,1 and
Robert J. Allen, M.D., F.A.C.S.2

ABSTRACT
Breast cancer patients must make important decisions regarding whether or not to undergo breast reconstruction as well as what kind of reconstruction is best for them. A number of options for reconstruction are available, including saline or silicone prostheses, autologous transverse rectus abdominis muscle (TRAM) flaps, and autologous, muscle-sparing deep inferior epigastric perforator (DIEP) flaps. Even more difficult, however, is the decision if and when adjuvant radiation should be administered. The timing of radiation therapy can significantly affect the breast’s final cosmetic and structural outcome. This article summarizes existing studies on how outcome is affected, with the conclusion that no reconstructive techniques are impervious to the damaging effects of postoperative radiation. However, there are numerous psychologic and economic benefits associated with immediate reconstruction. Depriving patients of these benefits is unnecessary when the likelihood of cancer recurrence is low. Together, surgeons, oncologists, and patients must first decide whether radiation is appropriate. Then they must assess the proper timing for its administration to achieve an outcome that is not only free of disease but also cosmetically acceptable.

KEYWORDS:
Radiation, breast reconstruction, review

It is generally agreed that radiation therapy impairs wound healing, by causing tissue ischemia and hypoxia, by decreasing fibroblast proliferation and collagen production, and by destroying epithelial cells.1 It is also agreed that radiation is an important means of preventing the recurrence of breast cancer for many women.Where there is not yet consensus is how medicine can fully utilize the protective effects of radiation while minimizing its damage to tissues. The literature contains nearly 200 articles relating to radiation therapy and breast reconstruc- tion. Studies have examined both the timing of radiation as well as its relative success with different reconstructive techniques, including implants, transverse rectus abdominus (TRAM) flaps, and deep inferior epigastric artery perforator (DIEP) flaps. The evolution of thinking by both reconstructive surgeons and radiation oncologists demonstrates that there is still much to be understood about radiation and breast reconstruction. Radiation has traditionally been reserved for patients with locally advanced disease, that is, stage III or higher (T3N1, T0–3N2–3, and T4N0–3).2 It has been given as part of a multimodal therapy, in combination with chemotherapy and surgery. However, research published in the last few years suggests that adjuvant therapy may improve survival among all breast cancer patients. One study randomizing patients to treatment with chemotherapy and adjuvant radiation, or chemotherapy alone, found a significant improvement in local recurrence, disease-free survival, and total survival time in the adjuvantly radiated group.3 These results were significant and existed irrespective of tumor size, nodes, or histopathological grade. Another study demonstrated not only a decrease in the local recurrence rate but also a reduction in mortality with the use of adjuvant radiation.4 Together, these studies suggest that more and more patients will be undergoing radiotherapy postoperatively in the future.

RADIATING PRIOR TO RECONSTRUCTION
A number of studies have examined the connection between prior radiation and reconstruction with TRAM or latissimus dorsi flaps. As early as 1984, Bostwick et al. created a system for classifying the complications due to radiation to the breast.5 They numbered them I to VI, using I to describe a mild breast necrosis and VI to describe radiation-induced neoplasia. They illustrated the use of the TRAM and latissimus dorsi flaps to repair these complications. Their study was not so much an attempt to assess the ability to reconstruct breast tissue following radiation but rather a description of how reconstruction may ameliorate the complications created by radiation. Ten years later, Kroll et al. specifically addressed the question of whether prior radiation precluded successful reconstruction with TRAM and latissimus dorsi flaps.6 They compared the postoperative complication rates among previously irradiated and nonirradiated patients. The authors found significantly higher complication rates among the previously radiated patients (39 vs. 25%, p = 0.03). Esthetic outcome was also poorer in the previously irradiated group. The authors did not view these complications as a contraindication for surgery and continued to recommend reconstruction following radiation. A second study by Williams et al. repeated the work done by Kroll, comparing postoperative outcome for patients who had undergone preoperative radiation therapy with those who had not.Although overall complication rates were the same for both groups, the study demonstrated a significantly higher rate of fat necrosis (17 vs. 10%) in the group that had been radiated beforehand.7

TRANSITION TO IMMEDIATE RECONSTRUCTION
Based on these studies, one can see why surgeons would prefer to reconstruct patients before their breast tissue had been damaged by radiation. By the mid-1980s, reconstructive surgeons were teaming up with surgical oncologists to provide immediate reconstruction to patients undergoing mastectomy. Although it would seem that this was to avoid operating on irradiated tissue, the transition to immediate reconstruction more likely occurred as a result of the numerous benefits it provided to patients.Whether the mode of reconstruction was with implants,TRAM flaps, or DIEP flaps, immediate reconstruction provided patients with less scarring, decreased operative time, and ultimately less time in the hospital. Perhaps the most important benefit was the decreased psychological distress. Patients could avoid experiencing feelings of self-consciousness and low self-esteem, given the fact that their general appearance after surgery was the same as it was beforehand.8,9 This technique continues to be a popular option for patients undergoing mastectomy. Our experience has shown that patients who are diagnosed between the age of 30 and 50 find it particularly beneficial, given that they are young and particularly sensitive to any changes in body image. In addition, the quality of their remaining years is not diminished by uncomfortable prosthetic enhancements.

RADIATING AFTER RECONSTRUCTION
Despite the current popularity of immediate reconstruction among both patients and surgeons, the downside of this approach is that the newly reconstructed site must sometimes be radiated postoperatively. There is debate ongoing as to whether the occurrence of complications following radiation is significant enough to warrant delaying reconstruction. In 1995, Italian researchers used objective measures to compare the symmetry and cosmetic results of patients who were radiated following breast conservation therapy with those who were not.10 Their study failed to demonstrate any significant differences between the two groups. However, more recent literature has identified specific radiation-induced changes, including implant contracture and fibrosis among autologous flaps such as the TRAM and DIEP.

SALINE IMPLANTS
There appears to be consensus that patients with radiated saline implants fare worse than their nonradiated counterparts. One of the earliest studies by Halpern et al. in 1990 demonstrated that, in a group of 11 patients with breast prostheses who underwent radiation, only 3 of the patients presented with a cosmetically good result.11 One year later, Kuske et al. observed a minimum complication rate of 46% among implant recipients who were radiated postoperatively.12 Spear and Onyewu conducted a retrospective, controlled study of patients reconstructed between 1990 and 1997. The authors demonstrated poorer cosmetic results and a higher complication rate among radiated patients.13 Specifically, they found that 19 of 40 patients who were radiated after reconstruction required additional or replacement flap tissue, whereas only 4 members of the matched control group required additional flap tissue. The same study also found that 32.5% of the radiated patients experienced capsular contracture, whereas none of the control patients did. An investigation by Vandeweyer and Deraemaecker, based on implant reconstruction patients from the same time period, also indicated that implant recipients had a significantly increased rate of capsular contracture and breast asymmetry over the nonradiated group.14 Although the results of this study were based on a small group (n = 6) of radiated patients, compared with 118 nonradiated patients, the authors showed that 100% of the radiated patients experienced either grade III or grade IV capsular contraction, whereas only 4 of the nonradiated patients experienced even a grade III contraction. A very recent study by Kreuger et al. again confirmed the increased rate of complications among radiated versus nonradiated implant recipients. Complications occurred in 68% (13 of 19) of the radiated patients compared with 31% (19 of 62) in the nonradiated group (p = 0.006). The authors found that reconstruction failure was significantly associated with the use of radiotherapy (p = 0.005). The observed reconstruction failure rates were 37% (7 of 19) and 8% (5 of 62) for patients treated with and without radiotherapy, respectively. 15

TRAM FLAPS
Results from studies examining the effects of radiation on the TRAM flap are somewhat contradictory. Two noncontrolled studies suggest that postoperative radiation is tolerable and need not be a contraindication for immediate reconstruction. The first of these, in 1997, observed recurrence rates and cosmetic results among 19 TRAM recipients. 16 The authors found that 84% of patients rated their cosmetic result as excellent or good and that there were no flap losses in the study group. One year later, Zimmerman et al. examined 21 patients who were radiated after TRAM reconstruction and found that cosmetic result was rated as excellent by 60% of patients, good by 30%, and fair by 10% of the patients.17 Evidence from a third study in 2000 found no acute side effects from postoperative radiation therapy among 25 patients.

However, this study evaluated patients only for erythema and desquamation of the breast and did not evaluate patients for more structural changes in the breast.18 More recent evidence indicates that TRAM flap recipients have poor outcomes following radiation. Tran et al., of MD Anderson, performed a retrospective review of 41 patients who were irradiated postoperatively and compared their outcomes with those of 1443 controls.19 Ten of 41 flaps demonstrated such severe contracture that they required secondary flap reconstruction. Fourteen of 41 displayed fat necrosis (34%), and 56% of the irradiated flaps were firm. In contrast, only 7 of 41 flaps maintained symmetrical reconstruction following radiation. Statistical comparison with controls indicated a significantly higher rate of fat necrosis, firmness, and flap contracture among radiated patients (p < 0.0001). The discrepancy of findings among different studies may be explained by the measures used for evaluation of outcome. Tran used objective measures, based on complication rates and the necessity of secondary flap reconstruction.

Hunt and Zimmerman employed more subjective means of evaluation, grading patients as excellent, good, etc., and thereby leaving room for bias. Hanks’ study is limited to a radiologist/oncologist perspective, which in this case only evaluated long-term skin changes from radiation. DIEP FLAPS Our experience with the DIEP flap has also demonstrated an increased frequency of complications among patients radiated after immediate reconstruction. Our series of 30 radiated DIEP flap recipients was matched with 30 nonradiated patients to observe differences in complication rates.20 In addition, our study enlisted 8 blinded judges to compare before and after photographs of 20 immediately reconstruction patients (10 who underwent radiation with 10 who did not).

The system used for esthetic analysis was a modified version of the method used by Netscher et al.21 in the evaluation of outcomes following breast implant removal. Frontal views of the patients were evaluated based on symmetry, the position of the superior pole, and overall esthetic proportion. Seventeen of 30 (56.7%) radiated patients experienced fibrotic change to the breast, 7 of 30 (23.3%) demonstrated fat necrosis, and 5 of 30 (16.7%) experienced flap contracture requiring secondary reconstruction. In the control group, none of the patients experienced these complications. Thus, statistical analysis demonstrated significantly increased rates of fibrosis/shrinkage (p = 0.000), fat necrosis (p = 0.006), and flap contracture (requiring an additional flap; p = 0.023) among the patients radiated postoperatively.

The matched cosmetic analysis of 10 radiated patients’ before and after photographs demonstrated significantly less desirable subjective outcomes than their nonradiated counterparts. Seven of the 10 radiated patients had lower scores following treatment than before treatment. In comparison, patients who did not receive radiation postoperatively saw a mean score improvement of one-half point. Other studies describing the effects of radiation on the DIEP flap are not yet available. Our experience at LSU is unique in that we have been able to observe a fairly large subset of patients who underwent both reconstruction with the DIEP flap and postoperative radiation therapy. As the use of this flap continues to grow in popularity, we hope that more research will examine its ability to withstand radiation effects. Our experience so far suggests that the likelihood of complications is high enough to warrant delaying reconstruction until after radiation is complete.

RADIATING BEFORE RECONSTRUCTION VS. RADIATING AFTER RECONSTRUCTION
The conclusion that logically arises from these studies is the following. If radiation effects are deleterious both before and after breast reconstruction, we should implement the sequence with the lowest complication rate and best cosmetic outcome. Two studies have attempted to answer this question of which sequence provides patients with the best outcome. Williams et al. compared the outcome among patients irradiated before TRAM reconstruction with those irradiated afterward.22 Although the difference was not significant, the authors found that patients radiated afterward experienced a higher complication rate (31%) than those radiated prior to reconstruction (25%). In addition, they found that the nature of the complication changed, from fat necrosis only (in previously irradiated patients) to fat necrosis plus fibrosis (seen in 31.6% of patients who underwent postoperative radiation). Another very recent study from MD Anderson indicates similar, and significant, findings. A second study by Tran et al. compared radiation effects in both immediate and delayed reconstruction cases.23 The authors found that the incidence of late complications was significantly higher in the immediate reconstruction group than in the delayed reconstruction group. (87.5 vs. 8.6%, p = 0.000) They also found that 28% of the patients who underwent immediate reconstruction required an additional flap to correct the shrinkage brought about by radiation. These results correspond with our own observations of radiation effects to the DIEP flap. Although our control group did not comprise patients radiated prior to reconstruction, our postoperatively radiated group uniquely experienced the same fibrosis and shrinkage that was observed in these studies.

CONCLUSION
Together, the results of these studies suggest that immediate reconstruction may not be appropriate for all patients with invasive breast cancer. In par- ticular, patients who undergo radiation therapy following mastectomy appear to be at an increased risk for experiencing complications such as fibrosis, fat necrosis, and flap contracture. In some cases, patients may even require secondary reconstruction to address the complications created by radiation. Nonetheless, there are many benefits from immediate reconstruction.Much progress has been made to reach the current standard of care, and it would be unfortunate to make women once again endure the psychological distress of an unnatural body habitus while completing adjuvant radiotherapy. For patients whose malignancy has been fully resected, and who will probably not require radiation, it seems unnecessary to prolong the reconstructive process. The difficulty occurs in not knowing whether the patient will require additional radiation until the mastectomy is finished and the pathology specimen has been examined. By this time it is too late to reconstruct. Therefore, both patient and surgeon must together decide how conservative the approach should be. Two main challenges exist in determining the proper sequence of radiation and reconstruction. As illustrated previously, it is first necessary to know which patients will require postoperative radiation. Second, it is helpful to know which patients among those receiving radiation are at greatest risk for complications. For instance, our experience has shown that patients who smoke, are obese, or have poor hygiene are at greater risk of experiencing complications. Further research in this area may help identify and confirm these observations. Then, recommendations for delayed or immediate reconstruction could be based on the presence of certain risk factors. As mentioned previously, one must choose between the lesser of two imperfect solutions: radiating and then reconstructing or reconstructing immediately and incurring the risk of fibrosis following radiation. Although the apparent solution is to delay reconstruction for all patients with invasive carcinoma, this option deprives patients, who are otherwise at low risk for complications, of immediate reconstruction. Further research in this area will be necessary to elucidate the most appropriate treatment plan for each type of patient.

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