Opinion statement
Malignant fungating wounds (MFW) are severe skin conditions generating tremendous distress in oncological patients with advanced cancer stages because of pain, malodor, exudation, pruritus, inflammation, edema, and bleeding. The classical therapeutic approaches such as surgery, opioids, antimicrobials, and application of different wound dressings are failing in handling pain, odor, and infection control, thus urgently requiring the development of alternative strategies. The aim of this review was to provide an update on the current therapeutic strategies and the perspectives on developing novel alternatives for better malignant wound management. The last decade screened literature evidenced an increasing interest in developing natural treatment alternatives based on beehive, plant extracts, pure vegetal compounds, and bacteriocins. Promising therapeutics can also be envisaged by involving nanotechnology due to either intrinsic biological activities or drug delivery properties of nanomaterials. Despite recent progress in the field of malignant wound care, the literature is still mainly based on in vitro and in vivo studies on small animal models, while the case reports and clinical trials (less than 10 and only one providing public results) remain scarce. Some innovative treatment approaches are used in clinical practice without prior extensive testing in fungating wound patients. Extensive research is urgently needed to fill this knowledge gap and translate the identified promising therapeutic approaches to more advanced testing stages toward creating multidimensional wound care strategies.
Introduction
Cancer-related skin conditions are very common and diverse, including numerous issues, such as sores, pressure ulcers, burnings, rashes, xerosis, pruritus, peeling, pain, and malignant wounds. These skin problems range from temporary, uncomfortable to serious, adverse reactions, occurring as side effects of oncologic treatments (e.g., chemotherapy, targeted therapy, immunotherapy, radiation, and bone marrow transplants) or as manifestations of different types of cancer (e.g., breast cancer, head and neck, primary skin, anal-rectal, groin, genitals, gastrointestinal cancer, and lymphoma) [1, 2].
Malignant wounds are directly related to the infiltration of primary cancer or metastasis into superficial structures (i.e., skin and afferent blood and lymph vessels) [3, 4]. These wounds are found in the literature under the following interchangeable terms: “fungating wound,” “malignant wound,” “ulcerating malignant wound,” or “malignant cutaneous wound.” Such skin conditions can proliferate in the form of a cauliflower-like nodule, resulting in their association with the terms “fungating” or “crater-like ulcer.” Fungating wounds may be caused by malignant tumors that interfere with local tissue oxygenation, lymphatic drainage, and hemostasis, hindering wound healing and provoking secondary bacterial infection and subsequential tissue necrosis [5, 6•].
All malignant wounds share one similarity: they do not heal under standard chronic wound treatment [7]. In addition, cancer wounds are associated with a series of physical complaints, including pain, malodor, exudation, pruritus, inflammation, edema, and bleeding, that further affect the quality of life of the patients [8,9,10]. Patients with malignant wounds may experience body image changes, diminished self-esteem, lack of concentration, impaired interpersonal relationships, anxiety, and depression, feeling overwhelmed as the wound progresses [8, 11•].
In the context of advanced cancer, malignant fungating wounds are considered unhealable, severe, and debilitating conditions that strongly affect patients’ quality of life in the last months of their lives. Thus, the proper management of malignant wounds is shifted from healing to palliation, being focused on minimizing wound-related pain and suffering through physical and psychological approaches [4, 9, 10].
Therefore, this review proposes a comprehensive approach to malignant wounds, starting by defining these lesions and describing their burden in terms of pathology and incidence; further, there are presented the common management strategies for dealing with these skin conditions, followed by a series of newly proposed alternatives for better wound management. In this regard, there have been reviewed English language publications from the last decade from ScienceDirect, PubMed, and Google Scholar databases retrieved through various combinations of the following keywords: “malignant wounds,” “chronic wounds,” “fungating wounds,” “cancer,” “metastasis,” “bad odor,” “inflammation,” “wound healing,” “antimicrobial,” “therapeutic management,” and “wound care.”
The burden of malignant wounds (definition, pathology, incidence)
Malignant or fungating wounds have been reported to affect up to 15% of cancer patients in advanced disease stages (during the last 6–12 months of life), either as the result of primary skin cancer, local extension, and epithelial erosion from primary tumors or as metastasis to the skin. Such wounds occur when cancer becomes uncontrollable and tumor cells break into the epidermis, invading the epithelium and its blood and lymph vessels, further progressing to tissue death and necrosis, inflammation, infection, bleeding, odor, and draining [6•, 12, 13••, 14]. In what concerns cancer types, the most likely to lead to malignant wounds are breast, head and neck, primary skin, gastrointestinal, and lung cancer [4], with breast and head and neck regions being the most prevalent sites for such severe skin conditions [15] (Fig. 1). Nonetheless, it is difficult to accurately assess malignant wound prevalence, given that there is no register to monitor their incidence. Besides, the negative feelings associated with this type of wound may result in an under-reported prevalence. It can also be assumed that, as new medicines are available and the population ages, the incidence of fungating wounds will increase due to the more people living with cancer [16].
Malignant wound incidence by location. Created based on information from [15].
If cancer cells are not under control via chemotherapy, radiotherapy, or hormone therapy, fungation may locally extend, causing escalating damage by loss of vascularity, proliferative growth, and ulceration [3]. These aspects negatively impact patients’ quality of life, as they face tissue deformity and putrefaction, pain, exudate, strong malodor, bleeding, pruritus, impaired mobility, infection, nausea, and anorexia. All these features add up to cancer symptoms, given that oncological patients already suffer from the side effects of chemotherapy and palliative radiation. Moreover, the physically detrimental outcomes are also reflected in the social and psychological distress experienced by these patients [4, 13••, 14, 17,18,19, 20•, 21]. Seeing the wounds on their bodies forces cancer patients to confront the disease, further leading to depression, denial, shame, fear, disgust, lack of self-respect, and poor confidence. Furthermore, malodorous wounds cause a visceral response in patients, caregivers, and staff, leaving the patients with the mental pressure of feeling inadequate, stigmatized, socially isolated, and deprived of the therapeutic effects of physical touch and intimacy [4, 13••, 21].
The unpleasant odor of malignant wounds is caused by the combination of bacteria, high levels of exudate and poorly vascularized tissues, that creates a mixture of foul-smelling volatile agents. In more detail, the loss of vascularity from the affected tissues allows aerobic and anaerobic bacteria to rapidly proliferate and decompose serum proteins present in the wound fluids. Thus, bad-smelling compounds are generated, including short-chain organic acids produced by the action of anaerobic bacteria (e.g., n-butyric, n-valeric, n-caproic, n-heptanoic, and n-caprylic acid), dimethyl trisulfide produced by aerobic microorganisms, and amines resulted from the metabolic processes of other proteolytic bacteria (e.g., putrescine and cadaverine) [20•, 21, 22]. In what concerns the involved microorganisms, Staphylococcus was found to be the predominant genus. Nevertheless, malignant fungating wounds are polymicrobial; various studies identified up to 20 different species of aerobes and 14 species of anaerobes [20•]. Among them, several bacterial species, including Bacteroids, Clostridium spp., Enterobacteriaceae, Pseudomonas aeruginosa, Proteus mirabilis, and Fusobacterium necrophorum, were particularly associated with offensive wound odor [20•, 21, 22, 23•].
Besides malodor, colonizing bacteria are responsible for peri-wound skin damage, gagging and vomiting, and loss of appetite. Moreover, bacterial charges larger than 105/g bacteria were correlated with increased pain and exudate. It was also noted that the diverse microbiome of malignant wounds produces an imbalance in maintaining an optimal skin barrier and leads to biofilm development [20•]. These aspects are associated with slowing the healing process as they prevent re-epithelization of the physical barrier, induce chronic inflammation, and impede the activity of antibiotics. In addition, the biofilm-mediated activation of the innate immune system delays the proliferative healing phase [24, 25]. Nonetheless, the roles of microbiota in developing or increasing the severity of malignant fungating wound symptoms have not yet been elucidated, as is the case with chronic ulcers or acute wounds, posing challenges in developing more precise and effective topical interventions [20•]. Furthermore, there is scarce information regarding the host immune response triggered by infection and colonization in malignant wounds.
Current therapeutic management of malignant wounds
According to the experiences of both patients and clinicians, malignant wounds are some of the most challenging cases of skin conditions, requiring a multidisciplinary and holistic approach for managing severe physical symptomatology and acknowledging distress [4, 5]. The main goal of fungating wound treatment is to keep the wound comfortable, clean, and infection-free [26]. Given their unhealable nature, malignant wounds are treated in relation to their symptoms; thus, the core principles of palliative care include stopping wound progression, eliminating malodor, reducing pain, and managing exudate [27,28,29,30,31,32].
The primary treatment option for localized malignant wounds is micrographic surgery. This procedure is aimed at reducing the risk of tumor recurrence. In general, it can be performed as classic Mohs surgery with histologic control of the entire excision margin in frozen sections. However, for larger tumors, when Mohs surgery is not available, paraffin sections can be used for histologic margin control, and defect closure is delayed by several days. Even though surgical removal of malignant wounds is considered beneficial in the short term, it is associated with postoperative complications, the most common being surgical site infection. This is a frequent issue because bacteria and fungus easily infect pre-operative exposed wounds. Depending on the entity and tumor stage, alternative antitumor progression strategies can be used for malignant lesions, such as radiotherapy, electrochemotherapy, topical chemotherapy, intralesional interferon, cryotherapy, and photodynamic therapy [7, 33, 34].
Concerning pain management, the systemic or topical administration of opioids remains the mainstay treatment in malignant wounds. Nonetheless, systemic agents are associated with side effects, and topical opioids are preferred due to their minimal systemic absorption (unless used on large wounds) [4, 5]. For pain caused by dressing changes, short-acting analgesics can be used, including entinox or fentanyl. Instead, for constant wound pain, the application of a hydrogel, ibuprofen foam dressing, or lidocaine patches may prove a better care alternative. Another option for persistent wound pain is the topical application of diamorphine injectable 6.25–15 mg (usually 10 mg) mixed with 8 g of an amorphous gel, a solution that was found the most effective when the nerve receptors have not been damaged (given that the mechanism of action involves binding to nerve receptors). Alternatively, transcutaneous electric nerve stimulation can be employed in alleviating pain, along with complementary therapy, distraction, and relaxation techniques [16, 35].
In the case of bleeding fungating wounds, the usual treatment involves the application of natural hemostats, sclerosing agents, coagulants, or other topical agents [5]. Several examples of products effective in bleeding control include calcium alginate, surgical hemostats, and silver nitrate [31]. One more agent suitable for palliating bleeding malignant wounds is the Mohs paste (controlled-release zinc chloride), as an increasing number of case series reported excellent results following its topical application [4]. Because of the poor prognosis of malignant wounds with minor or hemorrhagic bleeding, care settings should provide patients with solutions as early as possible [36•].
For highly exudative malignant wounds, specialized dressings should be applied. Proper materials, such as alginates, hydrofiber dressings, foams, and highly absorbent pads based on diaper technology, should be used to cope with the exudate while avoiding provoking additional trauma and pain [5, 29]. In addition, using dressings that keep the wound well hydrated may also aid in cooling the skin, thus preventing pruritus. Other pruritus-relieving options include garments and bed linen proven effective in eczema-like conditions, menthol creams, and bath additives with oils applied on intact skin and tepid baths and cool compresses for easing the itch [16].
As malodor is one of the most pressing issues associated with malignant wounds, multiple treatment options have been attempted for preventing, suppressing, or controlling bad odors [37]. One possibility is to eliminate necrotic tissues from fungating wounds through wound debridement. Nonetheless, if performed mechanically, debridement may cause bleeding and pain. Alternatively, autolytic and biological debridement are preferred as topical treatments. However, their use is limited to intense, pulsating bleeding caused by the rupture of larger blood vessels [13••]. In some cases, depending on the patient’s prognosis, it may be better not to intervene, leaving intact the hard necrotic tissue and simply protecting the area [16].
Given the correlation of disagreeable smells with the presence of wound microbiome, most odor-controlling therapeutic strategies focus on the administration of antimicrobial agents toward reducing bacterial bioburden [4, 37]. To date, topical metronidazole is the most extensively studied antibacterial treatment. When administered as 0.75–1% w/v concentrated gel, this nitroimidazole antibiotic aids in odor reduction in malignant or necrotic wounds. However, it is not approved by the Food and Drug Administration for the management of wound odor, being used off-label due to its ability to reduce odor-producing anaerobic pathogens [4, 5, 26, 37, 38]. Another promising topical agent is represented by miltefosine 6% (Miltex; Asta Medica, Frankfurt, Germany), which can be applied as a fluid to small malignant fungating ulcers. This formulation was noted to have both antimicrobial (i.e., antifungal and antiprotozoal) and cytostatic effects, being effective in slowing wound progression [26].
In the context of ever-increasing antibiotic resistance, attention has also been drawn to antibiotic-free approaches [39]. One particularly appealing strategy is the use of silver nanoparticles, which can indirectly reduce odor through their antimicrobial activity. Specifically, they can bind to bacterial cell walls, increase membrane permeability, stimulate reactive oxygen species (ROS) production, and eventually conduct to bacterial cell death. Moreover, silver dressings can be applied for chronic fungating wounds with the concept of “TIME” (T-Tissue management, I-Inflammation and infection control, M-Moisture balance, E-Epithelial advancement), due to the special properties of this nano-metal (e.g., excellent antimicrobial activity, limited anti-pathogenic resistance, efficiency against multidrug-resistant microorganisms, intrinsic anticancer effects, and anti-inflammatory action) [4, 37, 40, 41]. Another possibility for wound odor management assumes the use of biocompatible materials with large active surfaces that can absorb or trap volatile organic compounds. In this respect, charcoal and its derivative activated carbon can be effective in eliminating malodor. Charcoal-based products can be used as a secondary dressing or within a bandage system matched to the level of exudate [4, 37, 38].
Honey represents another useful agent in dealing with malignant wounds. Its bioactive constituents have been recognized for reducing inflammation, edema, and pain, being also correlated with a debridement effect and accelerated granulation and epithelialization. Moreover, honey’s low pH leads to an increase in the release of bactericidal ROS and deactivates harmful proteases that would otherwise hinder wound healing. In addition, its high osmolarity results in a hygroscopic effect, dehydrating bacteria and increasing lymph transit through the wound base. Honey used in wound healing applications was reported to produce more aesthetic outcomes than other therapeutics in terms of wound healing consequences while also decreasing hospital stay duration and providing cost efficiency [4, 42, 43]. Regarding antibacterial properties, they are attributed to several active compounds, such as dicarbonyl methylglyoxal, hydrogen peroxide, and other complex peptides able to disturb bacterial cell morphology, interfere with biofilm, and prevent its formation [4]. However, the pharmacological activity and potential of honey, including antimicrobial effects, may fluctuate depending on regional climate, harvesting, processing, storage, and flower sources [43]. Among all honey types, Manuka honey is well recognized for its composition rich in phenolic compounds and for the presence of methylglyoxal recommended for wound healing. Manuka honey was reported to reduce malodor in two ways: through its inherent antimicrobial properties (i.e., inhibits the growth of Gram-negative bacteria and destroys the cell wall of Gram-positive bacteria) and by providing an alternative nutrient source for the bacteria within the malignant wounds leading to the production of lactic acid as a bacterial waste product instead of bad-smelling sulfur-containing compounds [37, 44].
Novel strategies for an improved management of malignant wounds
Even though certain strategies have been implemented with different degrees of success in treating malignant wounds, patients and caregivers have reported low efficacy of many therapeutic agents. Moreover, there is no consensus concerning the optimal care of these complex wounds, and the evidence base to support current practices is limited. Thus, given the literature gaps regarding handling pain, odor, and infection control in malignant wounds, urgent research is imperative for developing effective and efficient novel alternative approaches for improved wound management [5, 22, 45].
Natural therapeutic alternatives
In this respect, increasing interest has been recently registered in developing plant-based treatment alternatives, especially as malignant wounds associated microbiome revealed the presence of opportunistic pathogens known for their multiple drug resistance (MDR) phenotypes (e.g., Staphylococcus, Enterococcus, Pseudomonas, and Acinetobacter genera) [46,47,48,49]. Plant-derived compounds serve as an inexhaustible source of bioactive agents with various properties of interest for malignant wound healing, counting broad-spectrum antimicrobial, antioxidant, anti-inflammatory, chemopreventive, and chemotherapeutic activities [50, 51, 52•]. Thus, selected bioactive compounds from various plants can be used to develop multifunctional bioactive topical formulations that can reduce the bioburden of aerobic and anaerobic bacteria, contributing to malodor and exudate control, promoting tissue regeneration, managing the pain, and simultaneously preventing cancer recurrence and wound infections.
For example, isoquinoline alkaloids from Chelidonium majus present various biological activities of interest for malignant wound management, counting significant antimicrobial potential, anti-inflammatory properties, and cytotoxic effect [53]. Moreover, the ethanolic extract of C. majus was demonstrated to have indirect antitumor effects against several human tumor cell lines (i.e., A549, H460, HCT 116, SW480, MDA-MB 231, and MCF-7), promoting cell cycle arrest, inducing apoptosis, inhibiting migration effect, and working in synergy with doxorubicin [54].
Various species of Tamarix can also be considered useful and promising in the field of malignant wounds [55]. Their leaves and flowers are rich in polyphenolic compounds and bioactive constituents recognized for their significant antioxidant, anti-inflammatory, antineoplastic, and immunomodulatory effects [56]. Specifically, extracts from different parts of T. gallica plant exhibit high antioxidant activity and excellent antibacterial properties against human pathogen strains; extract of T. indica roots demonstrates exceptional antinociceptive and anti-inflammatory activities; bark and leaf extracts of T. ramosissima display satisfying antioxidant properties and notable antimicrobial effects [55].
Potent active compounds can also be found in Acacia nilotica. Different A. nilotica extracts present antibacterial, antioxidant, anti-inflammatory, and anticancer activities owing to their high polyphenolic content. Acetone and methanol extracts were reported as particularly effective against Gram-positive bacteria, also showing significant MDA-MB-231 and HEp-2 cell death while sparing normal Vero cells [57, 58].
The root extracts of Scutellaria baicalensis have also attracted interest for various therapeutic purposes. In particular, baicalin, the most important compound derived from the roots of S. baicalensis, is endowed with antimicrobial, anti-biofilm, antioxidant, anticancer, anti-apoptotic, and anti-inflammatory properties, also displaying enhanced antibacterial activity when used in combination with antibiotics [59, 60].
One more promising source of bioactive compounds is represented by pomegranate (Punica granatum L.). Being rich in anthocyanins, ellagitannins, and hydrolysable tannins, pomegranate-based formulations have shown anti-inflammatory, anti-proliferative, and anti-tumorigenic activities, recommending its application as a promising chemopreventive/chemotherapeutic agent [61]. Moreover, pomegranate peel contains high concentrations of polyphenols with a broad-spectrum antimicrobial activity (including both Gram-positive and Gram-negative bacterial strains and fungi) [62], thus providing an alternative to antibiotics for treating malignant wound-associated infections.
Other plant sources of interest for therapeutic management of fungating wounds include but are not limited to citrus fruits rich in limonene (antimicrobial, anti-biofilm, and antitumor properties; ability to increase permeation of other drugs) [63, 64], cinnamon (antibacterial, antifungal, anti-inflammatory, anti-ulcerogenic, antioxidant, anticancer, and anesthetic activities) [65, 66], lemongrass (antibacterial, antifungal, antioxidant, and anticancer potential) [67], curcumin isolated from Curcuma longa (antimicrobial, anti-biofilm, antioxidant, anti-inflammatory, anticancer, and immunomodulatory properties; promising application as photosensitizer in photodynamic therapy) [68, 69], Prunus cornuta (antibacterial and anticancer effects) [70••], Berberis aristata (antimicrobial, antioxidant, anti-inflammatory, anti-hemorrhagic, and anticancer potential) [71,72,73], Thevetia peruviana latex (antimicrobial, antioxidant, anti-inflammatory, and anticancer activities) [74••], and Quercus semecarpifolia (antibacterial and anticancer properties; bleeding treatment and wound healing applications) [70••].
In addition to plant-derived compounds, beehive products have been well recognized for their biological attributes. Besides the useful characteristics of honey, recent studies unraveled properties of interest for pollen, propolis, royal jelly, and bee venom. These bee products have anticancer potential, being also efficient alternative therapies in treating various conditions that might occur in patients undergoing oncological treatments, such as radiotherapy and radio-chemotherapy-induced oral mucositis, radiotherapy-induced skin toxicity, and radiotherapy-induced xerostomia [75, 76]. Moreover, the bioactive constituents from propolis endow it with antimicrobial, antioxidant, anti-inflammatory, immune-modulatory, biofilm inhibitory, antitumoral, cytostatic, and wound healing properties [77,78,79]. Important therapeutic properties have also been reported for bee pollen, counting antibacterial, antifungal, antioxidant, chemopreventive, and immune-enhancing activities [80]. Additionally, various chemical components from royal jelly exhibit pharmacological activities, such as antimicrobial, antioxidant, anti-inflammatory, antitumor, and immunoregulatory effects [81]. Despite being less investigated in relation to cancer than the other mentioned beehive products, bee venom also holds promise in malignant wound healing management through its antibacterial, antioxidant, anti-inflammatory, antinociceptive, analgesic, immunomodulatory, and anti-apoptotic effects [76, 82].
In recent years, bacteriocins have also received attention as antimicrobial compounds. These ribosomal-synthesized cationic bacterial peptides secreted by Gram-positive bacteria display antibacterial properties with narrow to broad-spectrum activities, being a promising solution against antibiotic-resistant strains and biofilm infections [83, 84]. Seven anti-biofilm bacteriocins are registered on the antimicrobial peptide (AMP) database, out of which nisin is the most important due to its dual anti-biofilm and wound healing effect. Therefore, these bacteriocins could be a suitable option for managing infected wounds [85, 86••]. Moreover, they act as signaling peptides, being able to signal other bacteria through bacterial cross-talk and quorum sensing within microbial communities or send signals to cells of the host immune system, denoting immunomodulatory potential [49, 84]. In addition, cytotoxic bacteriocins can be involved in designing antitumoral formulations, given their high affinity towards the negatively charged membranes of cancer cells [49, 83]. Having the necessary attributes to deal with several problematic aspects of malignant wounds, bacteriocin-based therapeutic approaches should be considered for further research works in the field.
Nanotechnology-based approaches
As numerous nanomaterials have been recently fabricated and studied in relation to their antimicrobial [87,88,89,90] and antitumoral activities [91,92,93,94,95], promising therapeutics can be envisaged by involving nanotechnology in the treatment of malignant wounds. Nanomaterials with either intrinsic biological activities or capable of carrying synthetic or natural therapeutic agents have been reported in the literature with encouraging results against bacterial infections and/or various cancers. Some of the nanoparticles (NPs) that have advantageous properties and may bring positive outcomes in the treatment of fungating wounds include but are not limited to silver NPs [96,97,98, 99•], gold NPs [97], ZnO NPs [100], ZnS NPs [101•], ZrO2 NPs [101•], graphene oxide NPs [101•], and CeO2 NPs [102] (Table 1).
The use of biocompatible and biodegradable nanomaterials for designing novel drug delivery systems holds promise for enhancing wound healing and ensuring the prolonged release of loaded therapeutic agents [103]. Particularly, the incorporation of nanoparticles into hydrogels allows easy delivery through the skin, providing efficient local treatments [104]. For instance, Ahmed et al. have synthesized CeO2 nanoparticles using the Abelmoschus esculentus extract and further embedded them in a chitosan hydrogel membrane. This nanoformulation was reported as cytotoxic against cervical cancerous cells and bactericidal against S. aureus and K. pneumoniae. Moreover, it exhibited resilient antioxidant activity and displayed wound healing properties, inducing collagen deposition and increasing skin tensile strength [102]. Alternatively, Zhou and colleagues developed a multifunctional system of CuS nanoparticle complex hydrogel with self-healing and injectable abilities, good biocompatibility, extraordinary photothermal/photodynamic performance under near-infrared laser irradiation, anticancer potential, and wound healing acceleration capacity, recommending its use for bacterial infection treating, skin wound healing, and skin-tumor therapy [105]. Therefore, this formulation might produce favorable outcomes in managing complex malignant wounds.
Similarly, nanoparticles can be loaded into various wound dressings or scaffolds, enhancing the wound healing properties of these devices [90, 106]. For instance, Yahyaei et al. [107] fabricated an electrospun polyvinyl alcohol scaffold loaded with microbial-synthesized silver nanoparticles. The in vitro tests revealed acceptable antibacterial properties against four bacterial strains (i.e., Staphylococcus aureus ATCC 29213, Bacillus subtilis ATCC 6051, Escherichia coli ATCC 25922, and Pseudomonas aeruginosa ATCC 27853) and good anticancer activity against the human melanoma cell line COLO 792, indicating the potential of this scaffold in treating fungating wounds [107]. Various nanoparticulate components were also embedded into different composite wound dressings based on chitosan [101•, 102], leading to optimistic results (Table 1).
Performant wound dressings
Wound dressing application is a convenient strategy in wound management, as it can prevent microbial contamination, support affected areas, ameliorate pain and inflammation, absorb excessive extracellular fluid, and enhance wound healing, re-epithelialization, and collagen formation [103, 112, 113]. However, products designed for classic wounds of other etiology may not be effective in fungating wounds. Numerous factors have to be considered when choosing the best suiting dressing options, including size, thickness, adhesive capacity, healing time, changing frequency, and requirements for other products (e.g., secondary dressings, antibiotics and analgesics) [6•, 38]. Nevertheless, specialized dressings should be developed and utilized in malignant wounds to address the complex needs of the patients.
An ideal wound dressing for fungating wound care should be antimicrobial, non-adhesive, absorbent, soft, comfortable, easy to apply/remove, and large enough to cover the entire area without causing trauma. Moreover, it should overcome the malodor specific to ulcerating malignant wounds and ensure fluid evaporation [16, 114] (Fig. 2). Nevertheless, unfortunately, no such dressing is currently clinically available.
However, several materials hold promise for fabricating performant wound dressings. One particularly attractive possibility is the use of a collagen-based dressing. Collagen is advantageous due to its natural origin and similarity to the extracellular matrix, presenting high biocompatibility and low immunogenicity [118]. In addition, given that collagen is a major component of the extracellular matrix involved in the cellular and molecular mechanisms of wound healing, its topical application on the affected area can improve tissue regeneration [90, 119,120,121]. Moreover, collagen can be combined with other natural and synthetic polymers to generate composite materials that integrate wound healing and exudate-absorbing activities [113].
Another material that has attracted interest in fabricating efficient wound dressing is chitosan [101•, 102, 111]. Chitosan utilization for such biomedical applications is recommended by its excellent biological properties, including antitumor, antioxidant, antimicrobial, and wound healing activities [122]. In addition, its structure is also suitable for therapeutics delivery allowing the incorporation of anticancer drugs and antibiotic agents toward creating dressing with superior efficacy [123].
In recent years, several other materials have been investigated as well. For instance, Wojcik et al. have created wound dressings based on mixtures of curdlan and agarose and curdlan and chitosan. The authors reported that these wound care products are non-toxic, non-adherent, and superabsorbent and support wound healing, being suitable for the management of chronic wounds with moderate to high exudate [111]. Alternatively, Firmino et al. have incorporated regenerated oxidized cellulose hemostatic into calcium alginate dressings, recommending them for bleeding control of malignant wounds in patients with breast cancer [124]. On a different note, Zmejkoski and colleagues designed a composite dressing made of bacterial cellulose and lignin, further loading it with a dehydrogenative polymer of coniferyl alcohol. This formulation was observed to ensure prolonged release of antibacterial compounds, inhibit the growth of clinically isolated bacteria, and exhibit high swelling properties, rendering it appropriate for chronic wound healing [110].
Overview of emerging strategies
The newly proposed strategies that have been tested in vitro and in vivo have been summarized in Table 1 to provide a clearer overall image of the mentioned studies. Unfortunately, not many new treatment options have reached the clinical testing stage. Searching the term “malignant wound” on the ClinicalTrials.gov platform resulted in retrieving 37 studies. Restricting the search to “interventional studies,” only 25 clinical trials were tabulated. From this point further, the list was manually refined to exclude unrelated results (i.e., studies concerning surgical wounds of cancer patients), and the remaining eight relevant clinical studies were included in Table 2.
Only one of the tabulated clinical studies, i.e., NCT02431741, has publicly available results. This study proposes the use of Mepilex® Transfer Ag, a thin and conformable antimicrobial exudate transfer layer that maintains a moist environment in association with an appropriate secondary dressing. This silver-containing dressing reduces the bioburden from malignant wounds, as it has been demonstrated to inactivate wound-relevant pathogens within 30 min up to 14 days. In addition to its rapid and sustained antimicrobial activity, Mepilex® Transfer Ag aids in reducing malodor, allows for less painful dressing changes, is easy to use for difficult-to-dress wounds, and can be cut to suit different shapes [130•].
Further, it can be expected that already completed studies (i.e., NCT00435474, NCT00813631, NCT02408835, NCT02373722) may soon bring updates concerning obtained therapeutic results. Thus, the knowledge in the field of fungating wounds would be extended with clarifications regarding the long-term outcomes of proposed interventions (e.g., silver-releasing dressings, PICOTM device, Mohs surgery, petrolatum-mineral oil-lanolin-ceresin ointment, relaxation therapy, and psycho-social support). Moreover, the existence of a few undergoing clinical trials (i.e., NCT05685628, NCT05457309, NCT05800834) represents a hopeful perspective that soon will be confirmed several new therapeutic formulations with improved efficacy in treating malignant wounds.
In addition, several innovative treatment approaches have been introduced into practice by clinicians without prior extensive testing in fungating wound patients (Table 3). Facing challenging malignant wounds, carers have decided to try new management methods, including the use of ostomy bags [11•], administration of medical cannabis (MC) [10], utilization of negative pressure wound therapy (NPWT) [125,126,127], extensive tissue resection followed by layered reconstructive structures [128], and synergic combination of cryopreserved umbilical cord graft and injection of particulate amniotic membrane umbilical cord [129]. However, despite their promising results regarding positive effects in wound healing and reduction of upsetting symptoms, these studies are case-specific and may not represent a suitable solution for all fungating wounds. Another identified limitation concerns short follow-up times, imposing the need for longer monitoring periods of treated patients. Unfortunately, this cannot be done in some cases, given that despite all care efforts, treated patients have died because of cancer progression.
Conclusion
To summarize, malignant fungating wounds are severe skin conditions that fail to heal under classically prescribed wound treatments. The appalling associated symptomatology creates tremendous distress in oncological patients in advanced cancer stages. Several therapeutic strategies are approached in clinical practice, including surgery, administration of opioids, and application of different wound dressings and topical agents. However, none of these options exhibits satisfactory efficiency on its own. Thus, recent research investigated new possibilities, such as natural therapeutics, nanoformulations, and multifunctional dressings.
Increasing interest has been recently registered in developing natural treatment alternatives based on beehive, plant extracts (e.g., Chelidonium majus, Tamarix sp., Acacia nilotica, Scutellaria baicalensis, Punica granatum, Citrus sp., Curcuma longa, Prunus cornuta, Berberis aristata, Thevetia peruviana, Quercus semecarpifolia), pure vegetal compounds (isoquinoline alkaloids, polyphenolic compounds, anthocyanins, ellagitannins, hydrolysable tannins, latex), or bacteriocins. These alternatives are targeting the malignant wound-associated microbiome and contributing to malodor, exudate, and bleeding control, decreasing inflammation, promoting tissue regeneration, managing the pain, and simultaneously preventing cancer recurrence and wound infections.
Promising therapeutics can also be envisaged by involving nanotechnology due to either intrinsic biological activities or drug delivery properties of nanomaterials. Silver NPs, ZnO NPs, ZnS NPs, ZrO2 NPs, graphene oxide NPs, and CeO2 NPs have been used to control the wound microbial burden and biocompatible and biodegradable nanomaterials for designing novel drug delivery systems (e.g., hydrogels, electrospun polyvinyl alcohol scaffolds, or composite dressings based on chitosan, collagen, cellulose, lignin, curdlan, agarose).
Unfortunately, not many new treatment options have reached the clinical testing stage, with less than 10 relevant clinical trials and only one made publicly available the obtained results, reporting on the efficiency of a silver-containing dressing in reducing the bioburden of malignant wounds, the malodor, and the pain associated with dressing changes.
Other innovative treatment approaches are used in the clinical practice without prior extensive testing in fungating wound patients (ostomy bags, medical cannabis, negative pressure wound therapy, tissue reconstructive methods).
Nonetheless, future research should provide interdisciplinary solutions to this burdensome health condition, exploiting the advancements in medicine, biology, chemistry, material science, and nanotechnology toward creating multidimensional wound care strategies (Fig. 3). In addition, increased attention should be given to correctly and timely diagnosing malignant wounds to allow therapeutic start as soon as possible. Thus, clinicians should consider the possibility of a malignant wound when facing patients with chronic ulcers with atypical clinical aspects or in unusual locations and provide an early diagnosis before the onset of wound complications.
Current approaches and perspectives in multidimensional wound care (created with biorender.com).
In conclusion, recent contributions have been reported in the field of malignant wound care, yet the literature in this domain is still mainly based on in vitro and in vivo studies on small animal models, disparate case reports, and a few clinical trials. Therefore, extensive research is urgently needed to fill this knowledge gap and translate the identified promising therapeutic approaches to more advanced testing stages toward promptly improving the quality of life of malignant wound patients.
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Funding
This work was supported by a grant of the Romanian National Authority for Scientific Research, CNCS–UEFISCDI, project PN-III-P2-2.1-PED-2021-2193 (594PED/2022).
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Conceptualization: M.C.C., A.N.; Investigation and writing – original draft preparation: A.N., M.G., C.B.U.; G.B., and M.A.; Writing – review and editing: M.C.C., I.C.M., and S.S.M.; Methodology and supervision: M.C.C., A.N. and M.P.; Data curation and visualization: M.G. and A.N.; Funding: M.G.
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Niculescu, AG., Georgescu, M., Marinas, I.C. et al. Therapeutic Management of Malignant Wounds: An Update. Curr. Treat. Options in Oncol. 25, 97–126 (2024). https://doi.org/10.1007/s11864-023-01172-2
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DOI: https://doi.org/10.1007/s11864-023-01172-2