Radiation-Induced Tissue Damage: Clinical Consequences and Current Treatment Options

Abstract

Radiation therapy is a valuable tool in the treatment of numerous malignancies but, in certain cases, can also causes significant acute and chronic damage to noncancerous neighboring tissues. This review focuses on the pathophysiology of radiation-induced damage and the clinical implications it has for plastic surgeons across breast reconstruction, osteoradionecrosis, radiation-induced skin cancers, and wound healing. The current understanding of treatment modalities presented here include hyperbaric oxygen therapy, autologous fat grafting and stem cells, and pharmaceutical agents.

Nearly 20 million new cases of cancer are diagnosed each year. ¹ Radiation therapy (RT) is one of the most significant evidence-based advancements of modern cancer care, decreasing local tumor recurrence and increasing overall survival rates for a variety of malignancies. It is estimated that around 50% of cancer patients receive RT. ^{1 2}

Despite the efficacy of RT from an oncological perspective, RT also comes with negative consequences. A major area of concern is the damaging effect of RT on normal neighboring tissues. RT causes acute and chronic tissue damage in noncancerous tissues with subsequent long-term clinical consequences that range from mild to life-threatening. As cancer survival rates continue to improve, increasing numbers of patients will live with the long-term effects of RT. ³ Understanding the pathophysiology of radiation-induced tissue damage, the long-term clinical consequences and current treatments are essential. The aim of this paper is to review the literature on radiation-induced tissue damage and its clinical implications.

Radiation

RT uses ionizing radiation energy which detaches electrons from other atoms to destroy cancer cells. RT can be administered in different ways. External beam radiation (EBT) delivers radiation from outside the patient's body and will be the main focus of the current review. ^{4 5} Once RT is administered, powerful energy is deposited within cells, damaging DNA, and ultimately causing cancer cell death. ⁵ DNA damage can occur directly or indirectly through generation of reactive oxygen species (ROS). Direct and indirect DNA damages cause single- and double-strand breaks in DNA, the latter accounting for the majority of cell death. ⁵

The goal is to maximize the radiation dose to cancer cells and minimize the dose to surrounding normal healthy cells. Compared with normal cells, cancer cells are more sensitive to radiation and cannot repair as efficiently, allowing for specificity in cancer cell targeting. ⁶ Still, radiation inevitably damages healthy cells.

Pathophysiology of Tissue Injury

Radiation evokes a dynamic and complex series of events characterized by (1) ROS production, (2) vascular injury and chronic hypoxia, (3) chronic inflammatory response, and 4) myofibroblast activation and fibrosis. ⁷

Reactive Oxygen Species Production

ROS production is attributed with mediating a major component of the cell and tissue damage induced by radiation. ^{8 9 10} ROS are highly unstable and reactive molecules that are formed when radiation interacts with intracellular water molecules. ROS react with cellular components including lipids, proteins and DNA, and cause severe intracellular damage. ¹¹ A key feature of ROS-induced damage is that, it amplifies the damage from radiation and can continue for a long period of time. ⁸

Vascular Injury and Hypoxia

Vascular injury is intimately involved in the pathogenesis of radiation injury on both micro- and macroscopic levels. ⁹ Macroscopically, radiation induces coagulation pathways within vessels triggering vascular occlusion, tissue ischemia, and ultimately chronic hypoxia. ¹⁰ A low oxygen state perpetuates the production of ROS, leading to further cellular damage. Microscopically, the endothelial barrier is disrupted, increasing vascular permeability and allowing for release of proinflammatory chemokines and cytokines and immune cell migration. ⁷

Inflammation

Damaged cells release endogenous danger signals known as damage-associated molecular patterns (DAMPs) which attract innate and adaptive immune cells. ⁷ Neutrophils arrive in the acute phase of inflammation and secrete proinflammatory cytokines including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-α, further triggering ROS. Lymphocytes and monocytes arrive during the chronic inflammatory phase and interact to promote monocyte differentiation into two subtypes of macrophages. M1 macrophages secrete further inflammatory factors, while M2 macrophages attract fibroblasts, stimulate fibroblast differentiation into myofibroblasts, and release transforming growth factor β (TGF-β), a potent profibrotic factor. ¹¹

Myofibroblasts and Fibrosis

Fibrosis is a dose-limiting complication of radiation, driven by inflammation and largely mediated by TGF-β. TGF-β works through multiple signaling pathways, resulting in activation of a profibrotic genetic program. TGF-β converts fibroblasts and other cell types into myofibroblasts. Myofibroblasts have contractile proprieties and are the main source of extracellular matrix (ECM) proteins responsible for fibrosis. The overall result is excess accumulation of collagen and ECM proteins ¹² which underlies the pathology of radiation-induced tissue damage.

Tissues that were not exposed to radiation are likewise affected by signals from nearby radiated cells by a phenomenon known as the bystander effect. ¹³ These mechanisms persist for many years after the initial radiation exposure driving profound changes at the cellular and molecular level. The overall result of radiation damage to tissue is the profound alteration tissue structure and function.

Radiodermatitis- and Chronic Radiation-Induced Fibrosis

Acute radiation damage, also known as radiodermatitis, occurs within 90 days of treatment. Signs include erythema, edema, desquamation, and ulceration. These acute symptoms can often improve with conservative treatment. ¹⁴

Chronic damage, known as chronic radiation-induced fibrosis (RIF), presents 4 to 6 months after RT and continues to develop for years. Skin becomes thin, dry, and semitranslucent. Hair follicles and sebaceous glands are often lost. Subcutaneous tissue is replaced by dense fibrous tissue that causes induration and limited range of motion. Ischemia caused by vessel occlusion and changes in vasculature, including telangiectasia, deprive tissue of oxygen and nutrients, predisposing skin to breakdown, and ulcer formation. Skin is injured from light trauma and ulcers persist for years due to impaired healing capabilities and increased susceptibility to infection. For patients, chronic RIF can be extremely painful and for the most part, is irreversible. ^{8 15} Current areas in which RIF presents challenging clinical problems and patient morbidity includes breast reconstruction, osteoradionecrosis (ORN) of the jaw, secondary skin malignancies, and wound healing issues.

Clinical Challenges of Chronic Radiation-Induced Fibrosis

Breast Reconstruction

RT significantly reduces local recurrence and mortality of breast cancer. ¹⁶ Postoperative radiation is required for almost all breast-conserving therapy and is used postmastectomy in a variety of clinical situations. ¹⁷ The structural and functional changes in irradiated breasts include skin retraction, discoloration, induration, and pain and tightness in the surrounding chest, shoulders, and neck. ¹⁸ RIF significantly impacts both implant-based and autologous reconstructive outcomes.

Implant-Based Reconstruction

Implant-based reconstruction is currently the most popular reconstruction technique. ¹⁹ However, implant-based reconstructions in irradiated patients have higher complication rates compared with nonirradiated patients, including capsular contracture (CC), infection, implant loss, and reconstructive failure. ^{20 21 22 23 24 25 26 27} Patient-reported outcomes also tend to be inferior among radiated patients including for aesthetic outcomes, satisfaction, and quality of life. ^{28 29}

Two-Stage Implant-Based Reconstruction

A recent meta-analysis estimates overall implant-based reconstructive failure in irradiated breasts is 17.6%. ³⁰ In this study, tissue expander (TE) reconstruction was associated with higher reconstructive failure rates compared with single-stage direct-to-implant (DTI) reconstruction. Similarly, Naoum et al found that TE reconstruction had significantly increased complication rates compared with DTI, including infection, skin necrosis, implant exposure, CC, and failure. ³¹ Higher rates of complications and failures in TE reconstruction compared with DTI have been further supported by other recent data. ³² Lin et al ³³ retrospectively reviewed 256 radiated patients and found the TE patients had more complications, skin necrosis, wound breakdown, infections, and explantations compared with DTI. ³⁴ These results are in line with previous literature. ^{32 34 35}

Inferior surgical outcomes associated with two-stage TE reconstruction may be related to the fact that the second operation is performed on radiated tissue, given the diminished capacity for tissue healing. This is supported by evidence that 75% of complications within TE patients occur following exchange surgery. ³¹ While radiation is a risk factor for complications and reconstructive failure in TE-based reconstruction, ³⁶ it allows for a second-stage surgery to correct some of the structural changes that occurred with Post-Mastectomy Radiation therapy (PMRT).

Single-Stage Implant-Based Reconstruction

DTI reconstruction has advantages of immediate psychological and physical benefits from immediate restoration of breast volume and shape, shorter procedure time, hospital stay, and recovery. ^{37 38} There is also the benefit of a single surgery. Nonetheless, RT increases the risk of developing minor and major complications including cellulitis, delayed wound healing, and dehiscence. ³⁹ Another potential issue is that any early complications following DTI surgery can delay the initiation of adjuvant RT. A recent analysis determined that while there is an increased risk of delay, the time period is not long enough to impact survival outcomes. ⁴⁰

The prepectoral surgical plane has gained popularity in recent years for DTI reconstruction. ^{39 41} A benefit of the prepectoral plane is that it avoids pectoralis muscle fibrosis and shortening caused by radiation. In the irradiated submuscular plane, the implant can be disrupted by these muscle tissue changes. ⁴² The prepectoral plane is associated with reduced pain, elimination of animation deformity, and high patient satisfaction. ^{43 44} Avoiding irradiation of the pectoralis muscle minimizes associated issues. ⁴⁵

Capsular Contracture

Considering the capacity of radiation to induce fibrosis, it is unsurprising that radiation is also a risk factor for developing CC. The same TGF-β pathways that underlie RIF may also be associated with the pathogenesis of CC. ⁴⁶ It is estimated that CC effects 10% of patients and 40 to 50% of patients with history of radiation. ^{30 47} CC causes significant patient morbidity including pain, poor aesthetic outcomes and has been attributed with being a primary cause of failure in implant-based reconstruction of radiated patients. ⁴⁸

Research on acellular dermal matrix (ADM) has shown growing evidence that it may reduce the risk of radiation-induced CC. ^{49 50} While initially intended to provide support and cover the lower breast pole, there is also increasing scientific evidence in support of the reduced clinical risk of CC. ^{51 52} This effect may be related to decreased inflammation, fibroblast activity, and collagen deposition that can be seen with capsule samples from patients that have been reconstructed with ADM. ⁵³

Secondary procedures for managing radiation associated CC can be successful. A recent study demonstrated that implant exchange with capsule release successfully treated over 70% of cases, while fat grafting elevated success rates up to 86%. ⁴⁸ While fat grafting shows promise in the treatment of RIF, it has not demonstrated the ability to influence the occurrence or severity of CC alone. ⁵⁴

Autologous Reconstruction

Autologous flaps still represent the gold standard of reconstruction in irradiated fields, as it allows for the transfer of health nonirradiated tissue to be brought into the radiation field. Compared with implant-based reconstruction, autologous reconstruction is associated with decreased complications and failures, greater patient satisfaction, and improved quality of life. ^{52 53 55} However, radiation of an autologous breast reconstruction is still prone to complications, particularly RIF, contracture, fat necrosis, volume loss, and distortion of breast shape. ^{56 57}

Similar to implant-based reconstruction, the optimal timing of reconstruction in relation to radiation is an active area of discussion. The options are to perform autologous tissue transfer at the time of mastectomy, before radiation is administered or to perform tissue transfer in a delayed fashion after radiation treatment has been completed. Emerging evidence tends to be in support of delayed autologous reconstruction; however, the ideal time period is still unknown. Delayed reconstruction avoids the exposure of flap tissue to radiation. Many studies show decreased complications, wound contracture, volume loss, fat necrosis, and need for revision surgery, ^{58 59 60 61} although delayed reconstruction comes with the disadvantage of requiring the patient to have an unreconstructed mastectomy defect for some time. Several studies support safe and acceptable outcomes for immediate autologous reconstruction, and it should be considered an optimal option for selected patients. ^{62 63 64}

Osteoradionecrosis

Radiation damage also has implications for head and neck cancer (HNC) patients. ORN is a significant and morbid complication associated with poor cosmetic and functional outcomes that affects 7% of radiated HNC patients. ⁶⁵ By definition, ORN is a necrotic process of the bone resulting from RT that persists for greater than 3 months and is unrelated to neoplastic disease or recurrence. ⁶⁶ The mandible is most often the site of pathology and symptoms usually present within the first year of RT. ⁶⁷ ORN typically presents as painful denuded bone and can include purulent drainage and fistula formation. In advanced stages, necrosis can progress through the full thickness of bone and lead to pathologic fractures. ^{68 69}

Treatment of ORN correlates with severity of disease, ranging from conservative management to surgical resection and free flap reconstruction. Basic management approaches involve optimization of oral health. Poor periodontal health hygiene is not only a significant risk factor for ORN, but dental extractions are the most common initiating factor. ^{68 70} Other risk factors include a high radiation dose (>60 Gy), as well as alcohol and tobacco abuse. ⁷⁰ Management of risk factors, local irrigation, and antibiotic therapy for acute infections results in resolution in up to one-third of cases for patients with mild disease. ^{70 71 72}

Surgical treatment options include wound debridement, sequestrectomy (removal of isolated islands of necrotic bone), and mandibulectomy for advanced disease. Advanced ORN includes those with fractures and fistulas. Risk of flap failure and postoperative complications are significantly higher compared with in nonradiated HNC patients. ⁷³ The fibular free flap remains the gold standard for advanced ORN reconstruction. ⁷⁴

Radiation-Induced Skin Malignancy

Nonmelanoma Skin Cancer

RT increases life-time risk of developing precancerous lesions and nonmelanoma skin cancer (NMSC) within the radiation field. ^{14 75} The mechanism may be linked to the reduction of tumor suppressor genes and activation of oncogenes induced by RT. ⁸ Most cases of radiation-induced NMSC are connected with head and neck radiation. ⁷⁶ There is an established association between RT and basal cell carcinoma (BCC), with an estimated incidence of 2%. ⁷⁶ Evidence for squamous cell carcinoma (SCC) and melanoma are weaker. ^{77 78}

Merkel's Cell Carcinoma

Merkel's cell carcinoma (MCC) is another rare and aggressive cancer that may be induced by RT. MCC is a cutaneous neuroendocrine tumor that usually presents in the elderly and is linked to immunosuppression, chronic ultraviolet radiation exposure, and Merkel's cell polyomavirus. ⁷⁹

Wound Healing

The damage induced by radiation fundamentally impairs normal skin function and wound healing processes. ^{15 80 81} Normal wound healing relies on inflammation, proliferation, and remodeling phases. Inflammation is hindered from disrupted cytokine and chemokines involved in normal wound healing. Proliferation is impacted by endothelial damage, the resulting vasculopathy, and impaired neovascularization. Lastly, damaged fibroblasts produce dysfunctional collagen and impaired wound strength. Together, the effects manifest as poorly healing skin. ⁸²

However, performing surgery on irradiated tissues is sometimes unavoidable. Soft tissue sarcoma's resection often presents this clinical situation. Sarcomas are relatively rare malignant tumors that affect 1% of the population, often presenting on the extremities. ⁸³ Historically, sarcomas were treated with limb amputation. Similar to breast-conserving therapy, limb-preserving therapy is reliant on RT and surgical tumor resection. ^{84 85} Major wound complications following sarcoma resection and radiation treatment are estimated at 30 to 46%. ^{86 87}

Timing of radiation significantly affects wound healing. Patients who receive radiation prior to surgery experience more wound healing difficulties, infection, seroma, hematoma, and dehiscence. ^{86 88} Other risk factors for wound complications in irradiated sarcoma patients are diabetes, older age, obesity, smoking, acute radiation dermatitis, and tumor size >10 cm. ^{86 89}

Radiation-Induced Fibrosis Treatment Options

Hyperbaric Oxygen Therapy

Hyperbaric oxygen (HBO) therapy involves inhalation of pure oxygen in a closed chamber. HBO was used for decades as adjuvant treatment of ORN and has been applied to radiation-induced tissue complications of the head, neck, and breast. ⁹⁰ HBO creates an oxygen gradient across hypoxic tissue, stimulates anigiogenesis, and reduces necrosis. ⁹¹ Other benefits include decreased production of inflammatory cytokines and inhibition of fibroblast activity. ^{92 93} HBO is used for postradiation soft tissue necrosis both pre- and postoperatively. ⁹⁴ Recently, debate of the efficacy of HBO therapy for ORN has grown after studies provided underwhelming evidence of clear benefits. ^{91 95 96} However, more robust prospective multicenter randomized controlled trials are underway. ⁹⁷ A recent case series of breast cancer patients showed promising results of HBO treatment for radiation tissue injury including decrease in pain, fibrosis, edema, and increased shoulder movement. ⁹⁸

Autologous Fat Grafting and Adipose-Derived Stem Cells

Autologous fat grafting (AFG) is a promising, minimally invasive therapeutic approach for improving side effects of radiation. AFG was originally used to restore volume deficits but is gaining attention in its ability to restore damaged tissue. ⁹⁹ AFG has been shown to reduce pathologic dermal thickness, collagen production, and increase healthy vascularity in irradiated tissue, ¹⁰⁰ and the clinical result is improved symptoms in RIF patients. ⁹⁸ In breast cancer patients, AFG has been used to treat radiation-induced wounds ¹⁰¹ and has been shown to improve esthetic outcomes, such as skin quality in reconstructed patients. ^{102 103 104}

The mechanism in which AFG induces tissue regeneration is debated. It is believed that adipose-derived stem cells (ADSC) are responsible; however, this has not yet been definitively proven. ¹⁰⁵ Adipose tissue contains ADSC, which produce angiogenic and antiapoptotic paracrine signaling factors, ¹⁰⁶ and have the ability to differentiate into multiple mesenchymal cell lineages, ¹⁰⁷ including endothelial cells that incorporate into vessels and promote new vessel growth. ¹⁰⁸ However, the quantity of ADSC in lipoaspirate is thought to be insufficient to be responsible for the regenerative affects. ADSCs can be concentrated through cell-assisted lipotransfer which involves enzymatically digesting the lipoaspirate with collagenase and subsequently centrifuging it to extract the stromal vascular fraction. ^{109 110} However, cell-assisted lipotransfer is considered stem-cell therapy by the U.S. Food and Drug Administration and use is currently limited to clinical trials overseen by the organization. One of the reasons for strict regulation is that the concern over the ability of stem cells to promote malignancy and metastases, especially in cancer patients. ^{111 112} In contrast, traditional fat grafting indicated for breast reconstruction and esthetics is considered safe in breast cancer patients from an oncological perspective. ^{113 114 115}

Pharmaceutical Agents

Anti-inflammatory and Antioxidant Treatment

A common pharmaceutical therapy for radiation fibrosis is combined treatment with pentoxifylline and α-tocopherol (vitamin E). ⁴⁰ Pentoxifylline is a methylxanthine derivative that induces vasodilation, increases erythrocyte membrane flexibility, and decreases platelet aggregation to enhance blood flow. Vitamin E has antioxidant properties that can limit free radical damage and is also proposed to inhibit TGF-β, collagen, and fibronectin production. ¹¹⁶ The combination of both agents' works through multiple mechanisms to reduce subcutaneous fibrosis. It is commonly used in HNC patients and has recently been introduced to breast cancer patients. ^{117 118 119 120 121} Currently, data are limited but small clinical studies suggest pentoxifylline and vitamin E therapy can treat and prevent RIF with low rates of side effects. ¹²²

Fibrosis Inhibitors

Due to its crucial role in the pathogenesis of fibrosis, TGF-β and its associated signaling molecules have been examined as therapeutic targets. For example, the small molecule inhibitor, LY2109761, and a natural derivative (halofuginone) have all been used to target various components of the TGF-β pathway to mitigate inflammation, matrix deposition, and fibrosis. These agents are currently in animal model stages ^{123 124 125} but preclinical data are promising. Efficacy in humans has not yet been shown. ¹²⁶

Deferoxime

Deferoxime (DFO) is a well-studied iron chelator drug commonly used to treat iron overload. ¹²⁷ Over the past years, attention has shifted to the therapeutic ability of DFO in the treatment of wounds by reducing iron-catalyzed ROS production and improving tissue vascularization through the activation of proangiogenic genes. ¹²⁸ Previous animal models demonstrated the ability of DFO to improve tissue hypoxia in skin flaps and irradiated bone and to prevent diabetic ulcer formation. ^{129 130 131} The potential role of DFO in the treatment of RIF was demonstrated recently with evidence that radiated mice treated with transdermal DFO had significantly improved skin perfusion and reduced dermal thickness akin to nonirradiated tissue. ¹³²

Conclusion

In conclusion, RT has tremendous implications on wound healing and surgical outcomes. As surgeons, it is important to understand the pathophysiology of this changes, as well as the surgical scenarios most effected by RIF. Future studies will help hopefully elicit and demonstrate the effectiveness of new therapeutics in the fight against radiation-induced tissue changes.