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 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 21  |  Issue : 1  |  Page : 24-31

Radiation dermatitis: An overview


Department of Radiation Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India

Date of Web Publication22-Nov-2013

Correspondence Address:
Nehal R Khanna
Department of Radiation Oncology, Tata Memorial Hospital, Dr. E. Borges Lane, Parel, Mumbai - 400 012
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-653X.121877

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  Abstract 

Radiation dermatitis is the commonest side effect encountered during definitive radiotherapy. Radiation depletes the basal cell layer of skin and initiates a complex sequence of events leading to dose-dependent acute or late sequelae. The incidence and severity of radiation dermatitis depends upon multiple patient and treatment related factors. With the use of megavoltage radiation and implementation of conformal radiotherapy, the incidence of severe radiation dermatitis has reduced significantly. Treatment interruptions due to severe reactions may affect outcome. Prevention and management of radiation dermatitis requires a multidisciplinary approach. For acute radiation dermatitis, maintaining hydration which will eventually promote epithelialization is the key; while for moist desquamation, prevention of infection and facilitation of epithelialization are important. Barrier dressings like human amniotic membrane and hydrocolloid dressing are useful as they prevent trauma and infection, trap moisture, and thus facilitate healing. Late radiation dermatitis presenting as a difficult to treat long standing chronic radionecrotic ulcer is seen rarely in the current practice. Radionecrosis refractory to hyperbaric oxygen therapy (HBOT) may require surgical intervention to restore function and alleviate pain. Although there is lack of robust data to define strict policies for management of radiation dermatitis, the current practices are based on institutional protocols and personal experiences.

Keywords: Management, radiation dermatitis, radionecrosis


How to cite this article:
Khanna NR, Kumar DP, Laskar SG, Laskar S. Radiation dermatitis: An overview. Indian J Burns 2013;21:24-31

How to cite this URL:
Khanna NR, Kumar DP, Laskar SG, Laskar S. Radiation dermatitis: An overview. Indian J Burns [serial online] 2013 [cited 2019 Sep 15];21:24-31. Available from: http://www.ijburns.com/text.asp?2013/21/1/24/121877


  Introduction Top


Radiation therapy (RT) forms an integral component of management in oncology and approximately three-fourth of patients diagnosed with cancer receive RT during the course of their treatment. The aim of RT is to maximize the therapeutic ratio by optimizing the dose to the target tissue, while minimizing the dose to the surrounding critical structures. The deoxyribonucleic acid (DNA) damage due to radiotherapy impairs cell growth and eventually leads to cell death. Normal cells exhibit repair capacity, but repetitive radiation exposure leads to imbalance in cell damage and repair. [1] Acute and late radiation induced damage is seen as a result of the cumulative radiation damage caused to the germinal cells. Skin reactions are the commonest RT related acute toxicity seen in patients undergoing RT. In the early days of radiotherapy, acute skin reaction was the dose limiting factor, and the concept of Haut-Erythema Dosis (HED) was used for dose prescription. With the use of megavoltage radiation which characteristically spares the skin and the use of techniques which conforms the radiation to the target volume, severe radiation dermatitis is not commonly seen. [2] Radiodermatitis may be acute or chronic and can be painful, thus affecting quality of life. Severe skin reactions may often require interruption in treatment and thus may be detrimental in terms of outcome. Hence, prevention and management of radiation induced skin reactions is of utmost importance and requires dedicated efforts from not only radiation oncologists but also their surgical/medical team members as well as the nursing staff.

Incidence of radiation dermatitis

The overall incidence of acute erythematous reactions is 80-90%, while moist desquamation is seen in around 10-15% of the patients undergoing RT to radical doses. [3]

Moist desquamation or ulceration of the irradiated chest wall/breast skin (grade 3-4) toxicity has been reported in 20-25% of patients receiving radiotherapy to breast. [4] Majority of patients undergoing radiotherapy for head and neck cancers experience mild to moderate (grade 1-2) radiation dermatitis, while about 25% patients experience severe toxicity (grade 3). [5] RT induced late toxicities in the form of altered skin pigmentation, subcutaneous fibrosis, and edema is seen in approximately 25% (mild to moderate) and <5% (severe) of patients. [6] Incidence of radionecrosis presenting as a difficult to treat long standing chronic ulcerative lesion and requiring a plastic surgical intervention/reconstruction is a rare phenomenon in the current practice.

Pathophysiology of radiation dermatitis

The functional subunit (FSU) of skin is a single microvessel with associated epidermis and dermis. The pathophysiology of radiation dermatitis has been explained on the basis of radiation effects on these functional subunits. [7]

Radiation exposure causes depletion of basal epithelial layers of skin. It also induces an inflammatory and a vascular response with extracapillary cell injury and capillary dilation. Erythema occurs as a result of capillary dilatation and resultant increased vascularity in the dermis. [7],[8] Pigmentary changes are caused by increased melanin production by melanocytes and the migration of melanin to the more superficial layers of the epidermis. [8] The exposure of the subdermal lymphatics as a result of loss of the superficial epithelium leads to moist desquamation, or after higher doses, skin necrosis. Similar damage caused to the epithelial lining of hair follicles, causes epilation. Telangiectasia result from excessive loss of microvascular endothelium, causing capillary loops to contract and fuse into dilated channels beneath an atrophied epidermis. [9]

Radiation dermatitis is not a radiation burn

Burns wound occur immediately after the trauma. Radiation dermatitis which essentially occurs due to an imbalance between the normal production and destruction of basal cells can occur during or even months or years after the insult. In contrast to physical trauma which leads to instantaneous structural damage, radiation not only leads to cell kill due to DNA damage, but also alters complex molecules and cellular pathways. Radiation inflicts a series of fractionated insults leading to perturbation of reparative process compromising the integrity of repair. [9] In radiation dermatitis the damage is initiated at the basal layer of skin and progresses in severity as the dose increases, while in thermal burns the damage starts in the superficial layers and progresses deeper with severity of the injury. However, both types of wounds may range from superficial to full thickness involving the deeper tissues like muscles and bone. The adjacent 'healthy looking' irradiated tissue also suffers from anatomical and physiological change leading to impaired graft uptake. [9]

Clinical syndromes

Clinical syndromes of skin irradiation are dose dependent manifestations of continuous remodeling of the epidermis, dermis, and microvasculature. [7],[9] Radiation induced skin syndromes are classified into early and late changes depending upon the time of onset following RT.

Early effects

Early changes occur during the first 10 weeks following irradiation or during the course of fractionated radiotherapy. Skin erythema is the first sign of radiation dermatitis and its intensity varies with the radiation dose. Transient erythema may be seen even after a single fraction of radiation (2 Gy). Hyperpigmentation, epilation, and desquamation appear as radiation dose increases Figure 1. Epilation occurs at approximate dose of 20 Gy at the rate of 1.8-2.0 Gy per fraction. Hyperpigmentation and dry desquamation occur after 45 Gy. Higher doses of fractionated radiation above 50-60 Gy may lead to moist desquamation. Radiation doses above 60 Gy may lead to further damage leading to radionecrosis. [1] A landmark publication by Emami, et al., compiled the normal tissue tolerance doses (TDs) for various critical structures including the skin in terms of TD5/5 and TD50/5 and is widely used by radiation oncologists for dose prescription all over the world. [10] Recently, a new set of recommendations known as the Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) has been published based on evidence-based guidelines. [11]

Late changes

These changes occur after 10 weeks following irradiation. There may be a variable latent period following acute/early changes during which skin may appear normal and late effects like xerosis, atrophy, telangiectasia, subcutaneous fibrosis, and necrosis that may develop after years. Telangiectasia can appear as early as 6 months after therapy, and continue to evolve beyond that. [12] Fibrosis may develop, with progressive induration, edema, and thickening of the dermis and subcutaneous tissues.

Fibrosis and endothelial damage, lead to impaired vascular and lymphatic flow. The inability of hypovascular tissue to maintain normal tissue turnover may result in tissue necrosis, infection, and ulceration. These ulcers may develop spontaneously many years post radiotherapy. [13] The total radiation dose is critical in determining the severity of acute skin reactions, while the late effects are more influenced by the dose per fraction. Hypofractionated schedules that employ larger daily doses (2.5-3.0 Gy or higher) can result in greater late effects. [14]

Healing of radiation dermatitis

A regular wound healing occurs in a phased manner involving hemostasis and inflammation, followed by proliferation and maturation. This requires a complex interplay (highly organized sequence of events) of cytokines and growth factors and their receptors, which gets disrupted with repetitive radiation injury. [15] The cytokines (tumor growth factor TGF-β and TNF-a with TNF-α, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-a, interleukins (ILs), etc.) are overexpressed leading to uncontrolled matrix accumulation, abnormal keratin expression by keratinocytes, disorganized collagen deposition, and inadequate soft tissue remodeling by fibroblasts, irregular angiogenesis, leading to fibrosis, and delayed and poor wound healing. The adjacent normal looking irradiated tissue also harbors similar molecular and cellular insults. Impaired postoperative wound healing is frequently seen due to similar events. [15]

Consequential late effects

In intensive fractionation protocols the stem cell population is depleted below the levels needed for tissue restoration, due to which an early reaction in a rapidly proliferating tissue may persist as a chronic injury. This is called a consequential late effect, for example, fibrosis or necrosis of skin consequent to desquamation and acute ulceration. Bentzen evaluated 229 patients and reported a relation between acute moist dermatitis and late telangiectasias as a result of consequential reactions. [16] Most of the studies however deny correlation between acute and late toxicities.

Radiation recall reaction

Radiation recall reaction is a poorly understood, uncommon, and unpredictable phenomenon that is characterized by an acute inflammatory reaction confined to previously irradiated areas and triggered by the administration of precipitating systemic agents (e.g., alkylating agents as well as docetaxel, dacarbazine, etoposide, 5-fluorouracil, taxanes, interferon, transtuzumab, etc.) after the radiation treatment. [17] The precise mechanism is unknown, and various hypotheses have been proposed: 1) Cytotoxic treatment induces a remembered reaction in the remaining surviving cells, 2) mutation caused by the radiotherapy yields more vulnerable cells that cannot tolerate cytotoxic treatment, and 3) a vascular reaction that occurs after radiotherapy. [17] The reported time interval between the end of radiation and the recall reaction ranges from a few days to 15 years. [18] These are managed as per the severity of the dermatitis with frequent use of topical and oral steroids in conjunction with the removal of the causative agent.

Factors affecting radiation dermatitis

The incidence and severity of radiation dermatitis is dependent upon multiple patient and treatment related prognostic and predictive parameters. [19] The common ones relevant in day to day clinical practice are enlisted in [Table 1] [19],[20] . Irrespective of these parameters a patient to patient variability has been reported which makes prediction of the incidence and severity of radiation dermatitis difficult. [20]
Table 1: Factors affecting the incidence and severity of radiation dermatitis

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Scoring/grading of radiation dermatitis

Uniform grading of radiation dermatitis is essential for effective documentation, interventions, and appropriate supportive measures. The management of radiation dermatitis is based on the severity of symptoms as determined by grading systems. Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC), Common Toxicity Criteria (CTC), and Late Effects in Normal Tissues/Subjective, Objective, Management, and Analytic Scales (LENT/SOMA) are some of the grading systems used for reporting of acute and late dermatologic adverse events detailed in [Table 2]. [21],[22] The RTOG radiation morbidity score is an objective criteria-based scale that assesses toxicities in tissues and organs and is followed most commonly by radiation oncologists worldwide for reporting of radiation related acute and late effects. [22]
Table 2: Radiation dermatitis grading systems[21,22]

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Management

The key in managing skin reactions [Figure 1] is to prevent the development of severe dermatitis (Grade 3-4). Different modalities have been recommended depending upon the severity of dermatitis. It is of utmost importance to maintain skin hydration as it improves epithelialization and hence, moisturizers, barrier creams, aloe vera, lanolin, and steroid creams are used extensively. [23] Moist desquamation may require dressings to maintain hydration as well as to prevent infection. However, once infected its use is contraindicated. Jennings, et al. in a review reported recommendations for skin care during radiotherapy which include: 1) Keeping area clean and dry, 2) gentle washing with water and use of a mild soap, 3) no rubbing of skin, 4) no irritants (deodorants, perfumes, creams), 5) no starch-based products (risk of infection), 6) wear and use natural fibers next to the skin, and 7) avoid extremes of temperature. [23],[24]
Figure 1: Radiation dermatitis seen in a case of head and neck cancer treated with conventional external beam radiotherapy. (a) Area depicting hyperpigmentation, (b) dry desquamation, and (c) confluent moist desquamation

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Management of mild to moderate radiation dermatitis

Aloe vera

Aloe vera known for its hydrating, anti-infective, and sun protective properties is commonly used to treat a number of skin complaints, such as dry skin and irritant contact dermatitis, burns, and is one of the most commonly used agent for the treatment of radiation induced dermatitis; and has been reported in the literature as early as 1935. [25] Williams, et al., reported a Phase III double blind randomized clinical trial (RCT) in 1996 which failed to demonstrate the efficacy of aloe vera. [26] A systematic review of literature emphasized that there is no evidence from clinical trials to suggest that topical aloe vera is effective in preventing or minimizing radiation induced skin reactions. [27] Though used extensively by oncologists, aloe vera lacks evidence to support its use. In the study by Olsen, et al, patients treated with higher doses of RT reported benefit with aloe vera. More importantly it delayed the appearance of reactions and the reactions that occurred were less severe when aloe vera was used. As aloe vera is free from adverse side effects, the authors recommend its use as a part of normal skin care for all points on RT. [28]

Steroid ointment

Steroid ointments have also been tried commonly owing to its anti-inflammatory properties. Studies have shown that topical steroid application may reduce symptoms of burning, itchiness, and clinical erythema as well as delays the progression of skin reactions. Schmuth, et al., in a RCT reported no benefit in terms of severity of dermatitis with the use of 1% methyprednisolone cream. [29] However, it was useful in ameliorating dermatitis related symptoms in the patients. Topical mometasone used in another prospective RCT study reported significant benefit in terms of reducing the severity of reactions. The authors recommend its use from the 1 st day of radiotherapy until 3 weeks after its completion as a prophylaxis against acute severe dermatitis. [30] The fairly limited use of steroid application may be due to the apprehension of infections and delayed healing as well as late side effects owing to prolonged steroid use like development of skin atrophy and telangiectasias.

Other agents used

Hyaluronic acid gel is known to play a role in the process of healing. Liguori, et al., reported benefit in terms of delay in the onset of reactions as well as severity and duration of symptoms. [31] Kirova, et al., reported no significant benefit as compared to a simple emollient in the treatment of acute dermatitis but showed a trend towards an improvement in both pain and skin colorimetry. [32] Another prospective study by Pinnix, et al., was prematurely closed as patients using hyaluronic acid gel reported higher rates of grade II dermatitis. [33] In view of paucity of evidence supporting the use of Hyaluronic acid gel in prevention or repair of radiation dermatitis, its use is not routine in clinical practice. Wells, et al., randomized 357 patients with head and neck, breast, or anorectal cancer to receive either aqueous cream, sucralfate cream, or no cream from the start of treatment. Outcome measures included the measurement of grade of skin reaction, erythema readings using reflectance spectrophotometry, a quality of life (QOL) score, and symptoms including pain, itching, burning, and sleep disturbance. No significant differences were found between the treatment arms. The researchers concluded that there was no benefit from a prophylactic application of a cream to the treatment area. [34]

Emollient creams containing agents like sucralfate, chamomile (Kamillosan), trolamine, almond oil, azelastine, soya extracts, prostaglandin E1, honey, placentrex, essential fatty acids, vitamin C and E, etc., have been commonly used. Bolderston, et al. in a meta-analysis of 28 trials supports the use of steroid ointment, but does not recommend the use of sucralfate, biafine, ascorbic acid, aloe vera, chamomile cream, almond ointment, or polymer adhesive skin sealant. [35]

Management of severe radiation dermatitis

The principles of managing moist desquamation are to prevent infection, facilitate epithelialization, and reduce pain.

Topical application

Topical application of Gentian violet 1% (GV) has been used conventionally to treat radiation induced moist wounds because of its antifungal and antiseptic effects. However, it dries the dermis and may interfere with wound healing. Other disadvantages include masking of wound and staining of the clothes making it a cosmetically unappealing option for moist wounds. However, its low cost and ease of application makes it one of the preferred choices for treatment of moist desquamation. [36]

Barrier creams and dressings

Barrier creams containing sucralfate have also been reported. Evensen, et al., assessed skin reactions in patients with head and neck cancer randomized to receive either sucralfate or a placebo. These authors reported no difference in erythema, but the placebo group had less moist desquamation. [37] Maiche, et al., randomized women with breast cancer to apply sucralfate cream or a base cream twice daily during 5 weeks of RT and reported a significant reduction in the development as well as rapid healing with the sucralfate cream. [38] The conflicting results between these two trials may be related to the different patient groups and treatment doses and the different formulations of the sucralfate cream used. Due to lack of evidence its use too has been limited.

Barrier dressings for moist desquamation is based on the premise that it prevents trauma, traps moisture, and ensures healing with epithelialization as well as prevents infection. Barrier dressings may be adherent or nonadherent and permeable/semipermeable. Cryopreserved human amniotic membrane has been used successfully for management of moist desquamations. [39] It can conform to the area of moist desquamation and provide an effective barrier to trauma and microbial penetration. It also helps in retaining physiologically moist microenvironment which promotes healing. Amniotic membrane promotes epithelialization and hence decreases the need of multiple dressings. Its use is limited due to lack of availability and is contraindicated in presence of infection. [39]

Margolin reported the use of hydrocolloid occlusive dressing (duoderm) to be effective in terms of healing time, repeated dressings, comfort, and lack of infection. [40] Shell, et al., reported the superiority of moisture vapor permeable hydrocolloid dressing (MVP, Tegaderm 3M) over lanolin in terms of rate of healing (19 vs 24 days) and patient comfort. [41] Vuong, et al., evaluated the role of antibacterial silver leaf nylon dressings. They reported significantly improved grade 3-4 score of radiation dermatitis. This study highlighted the role and benefit of using an antibacterial dressing in patients receiving radiation for anal canal and gynecologic cancers. [42] Mak, et al., compared GV with a nonadherent dressing and found no difference in the outcome. The dressing was associated with poor pain score as it was mandatory to remove the dressing during the radiotherapy treatment. GV was found to be more cost effective and comfortable to the patient. [36] Hydrocolloid dressings are adherent and can be left in place for a longer time and are best used after completion of radiotherapy. Transparent films allow close observation of the wound; but, because they do not absorb exudates, they are more practical in protecting the fragile epidermis or covering early erosions. Heavily exudative wounds are best treated with burn pads or with the use of alginate or foam dressings, which are highly absorptive. [43] Postradiotherapy persistent eschars should be removed/debrided and dressing should be applied. [43] Gauze dressing (wet/dry) is contraindicated during radiotherapy as it pulls up the radiation dose towards the skin leading (bolus effect) to further aggravation of radiation dermatitis. A systematic review also determined that there is insufficient evidence to recommend a particular type of dressing for the management of moist desquamation. [35]

Other agents used in preclinical and clinical studies are injectable autologous fibroblasts and multipotent stem cells. These active cells are presumed to alter the local milieu by promoting synthesis of healing factors and angiogenesis. [44],[45] Topical application of active agents like bioflavanoids, histone deacetylase inhibitors, ascorbic acid, copper tripeptide, thrombin receptor activating peptide, etc., have been analyzed in several cell culture and animal studies. These active agents accelerate wound healing by stimulating endothelial cells and fibroblasts. [15] Different growth factors have also been analyzed for their potential role in wound healing. Important factors that may be suitable for this therapy include recombinant human granulocyte colony-stimulating factor (rhG-CSF), recombinant human macrophage CSF (rhM-CSF), basic fibroblast growth factor, TGF- β1, and an inhibitor of TGF-β 1 receptor kinase. [46],[47] These interventions may become possible therapeutic strategies in the near future for severe RT dermatitis.

Management of radionecrosis

Unlike thermal burns, radiation induced skin reactions depict a chronological dose-dependent clinical scenario which ranges from mild erythema to rare cases of radionecrosis. Radionecrosis can be acute as well as delayed and is essentially due to the damage to epidermis as well as dermis and deep subcutaneous tissue such as muscle, vessels, and at times even bone. The pathophysiology which involves intense inflammatory cascades and endothelial and fibroblastic response also leads to poor vascularity and subsequently poor healing. Such sequelae are a rare occurrence in current radiotherapy practice. Rarely, such reactions may progress to a nonhealing phase for a prolonged duration extending from months to years.

Hyperbaric oxygen therapy (HBOT) is often utilized for chronic nonhealing radiation dermatitis without a strong evidence to support it. It uses 100% oxygen at pressures more than atmospheric pressure, each session lasts 60-90 min and the number of sessions may range from five to up to 50 in refractory cases. Due to the occlusive endarteritis radiation wounds are hypocellular, hypovascular, and hypoxic. HBOT promotes angiogenesis and hyperoxygenation of the irradiated tissues, thereby initiating slow healing of radionecrotic wounds. Typically, radiation induced wounds are chronic and nonhealing and show poor skin graft uptake. In mandibular reconstruction of an irradiated field, HBOT has been shown to markedly improve the outcomes after composite reconstruction. It has been shown to be specifically beneficial for osteoradionecrosis and complications of pelvis irradiation (cystitis and proctitis). In a systematic review by Eskes, et al., HBOT was found to be an effective solution for 'difficult to heal' wounds. [48] A Cochrane review based on 11 randomized trials also found HBOT to have improved healing outcomes in late radiation induced injury to irradiated tissues of head, neck, and pelvis. [49]

Surgical intervention

Surgical intervention may be crucial for few chronic, painful, and nonhealing full thickness ulcers. These are wounds which have been resistant to the conventional measures like dressings and HBOT. Surgical intervention is often sought when the ulcer exposes the underlying tissues like muscles, neurovascular structures, and bone. The principle of surgical management of the irradiated field involves generous debridement and coverage of the defect with well-vascularized nonirradiated tissue. [50] For large established post-radiation ulcers, total excision of the ulcer, including the surrounding irradiated tissue beyond the area of the telangiectasia has been advocated. Radionecrotic ulcers are painful and are prone to get infected. [51] Early plastic intervention and reconstruction restores function, prevents further damage, and alleviates pain. [52] The choice of reconstructive procedure depends on the site of the lesion, the size of the defect, age, general condition of the patient, and the local condition of the lesion. [53] The reconstructive options usually include skin grafts, local flaps, regional flaps, or free flaps. [54] Skin grafts remain an inferior choice due to the hypovascularity of recipient bed. [50] Arnlod, et al. report inferior the inferior outcomes with local flaps as they are rotated hypovascular irradiated tissues. [55] Compared to skin grafts and local flaps, regional flaps or free flaps with uninvolved tissue derived from outside the irradiated field are possibly a good choice. [54],[56] Although reconstructive surgery of wounds irradiated with high-dose radiation (>60 Gy) is difficult, most irradiated wounds are ultimately closed. [57]

Systemic treatment

Amifostine is a thiol derivative that has demonstrated radioprotective effects in multiple studies against radiation dermatitis. [58] Two RCTs examined the efficacy of oral hydrolytic enzymes and reported that the maximum extent of skin reaction was lower in the enzyme-treated group. [59],[60] Pentoxifylline, zinc supplements, and multivitamin combinations have also been tried. Antibacterials and anti-inflammatory may be used when required.


  Conclusion Top


Radiation dermatitis is a commonly encountered adverse effect of definitive radiation therapy. Severity of radiation dermatitis is influenced by multiple patient and treatment related factors. Although severe radiation dermatitis is a rarity in current practice, there are occasions which necessitate active intervention by a multidisciplinary group to manage both acute and late effects of radiation therapy on skin and the subcutaneous tissues. Management policies vary as per institutional guidelines and personal preferences and are mostly based on individual experiences and reviews.

 
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