1 Baseline screening of skin and mucous membranes

1.1 History of drug allergies

For patients allergic to sulfonamides, clinical cross reactivity should be considered when using drugs with sulfonamide groups such as vemurafenib and dabrafenib. It was reported that patients allergic to sulfonamides developed toxic epidermal necrolysis after using vemurafenib, and patient sera were confirmed to be cross-reactive to vemurafenib and dabrafenib via lymphocyte tests in vitro [1].

Some chemotherapeutic drugs and monoclonal antibody drugs may induce immediate hypersensitivity reactions, such as rapid rash and even anaphylactic shock [2]. Cetuximab was reported to induce type I hypersensitivity reactions and even death from anaphylactic shock. Drug sensitization to platinum-based drugs occurs after multiple chemotherapy cycles. Hypersensitivity reactions to taxanes are usually seen within the first or second dose. For these patients, drug desensitization should be performed before reintroduction. In addition, hypersensitivity to these drugs can be assessed by skin tests, including skin prick tests [3].

1.2 Previous history of skin diseases

The mechanisms of many chronic skin diseases are closely related to autoimmunity, inflammatory factors, and vascular function. For cancer patients that also have skin diseases, cancer treatment may imbalance the internal environment or target blood vessels, leading to progression of the original skin disease, while drugs administered for the original skin disease may also impact cancer treatment. It has been confirmed that a baseline hormone dose ≥ 10 mg prednisone (or equivalent) can weaken the effect of PD-1 monoclonal antibodies in non-small cell lung cancer patients. Therefore, it is necessary to dynamically monitor chronic skin disease conditions before and during cancer treatment. Common chronic skin conditions susceptible to cancer treatments are as follows:

  • (1) Connective tissue disease

Collective evidence indicates that various cancer treatments may induce or aggravate connective tissue diseases [4, 5], including systemic lupus erythematosus, dermatomyositis, and scleroderma. Moreover, surgery may aggravate interstitial pneumonia in patients with connective tissue diseases. In addition, radiotherapy may aggravate vascular damage and promote fibroblast proliferation, thus aggravating connective tissue diseases. Chemotherapy drugs such as taxanes and gemcitabine can induce scleroderma-like changes. Autoimmune diseases such as dermatomyositis induced or exacerbated by ICIs have been reported [6,7,8].

The National Comprehensive Cancer Network (NCCN) recommends prohibition of ICI drugs for patients with autoimmune neurologic or neuromuscular diseases, life-threatening autoimmune diseases, poorly controlled diseases or autoimmune diseases controlled by high-dose immunosuppressive agents [9].

For patients with cancer and connective tissue disease, a detailed medical history is necessary, and analyses of blood and urine contents, liver and kidney function, autoantibodies, complement factors, and rheumatism markers should be routinely performed prior to treatment. It is recommended that rheumatologists and dermatologists together make a personalized cancer treatment plan. For connective tissue disease patients who also need tumor therapy, the disease activity score can be used to monitor certain diseases, such as the systemic lupus erythematosus disease activity index (SLEDAI). Patients with dermatomyositis can be assessed via muscle strength, creatine kinase levels, creatine kinase isoenzyme levels and other indicators.

  • (2) Erythematosquamous skin disease

Psoriasis is the most common erythematosquamous skin disease. VEGF antagonist drugs such as sorafenib can aggravate existing psoriatic rashes. ICIs can cause psoriatic rash and psoriatic arthritis relapse [10]. The psoriasis area and severity index (PASI) is recommended to monitor dynamic changes in psoriasis rash due to its convenience. The ACR20 scale is suitable for dynamic monitoring of psoriatic arthritis patients. A multicenter retrospective study in 2021 [11] found that among cancer patients (including melanoma, lung cancer, head and neck cancer, etc.) with previous psoriasis, 57% of patients had recurrence of psoriasis after using ICIs. Among them, 53% received only local therapy, 21% required systemic medication, and 7% of patients discontinued antitumor immunotherapy due to psoriasis. The progression-free survival (PFS) of patients with psoriasis recurrence was significantly longer than that of recurrence-free patients (39 vs. 8.7 months, P = 0.049). Upon ICI initiation, the deterioration of clinically active psoriasis occurred sooner than that of nonactive psoriasis at baseline (p < 0.05).

Despite the recurrence or aggravation of psoriasis rash upon using antineoplastic drugs, most rashes can be effectively controlled by topical medication (glucocorticoids, vitamin D3 derivatives, calcineurin inhibitors) and narrow-band ultraviolet light therapy. Antineoplastic drug discontinuation is not commonly seen.

  • (3) Vitiligo

Vitiligo is one of the most common skin adverse reactions in cancer patients using ICI drugs, especially in melanoma patients, and presents as rapid progression of bilateral, symmetrical hypopigmentation spots after several months of anticancer treatment. The presence of vitiligo in advanced melanoma patients is associated with a better treatment response and longer survival [12, 13]. A rough estimate of hypopigmented areas can help evaluate the degree of vitiligo, but this method is limited as the time span is relatively large. The VASI score is a more objective and convenient monitoring method and is based on the proportion of hypopigmented area to the total body area. As the area of a patient's palm is approximately 1% of the body surface area, it is convenient to record dynamic changes in the hypopigmented area.

Vitiligo induced by ICI drugs often occurs on exposed sites such as the face and back of the hands. A timely reminder of sun protection prior to taking ICI drugs for patients at risk of developing vitiligo is needed.

  • (4) Bullous skin disease

Anti-PD-1/PD-L1 or anti-CTLA-4 therapy may exacerbate preexisting bullous pemphigoid in cancer patients, while several reports have stated that the appearance of bullous pemphigoid during tumor therapy may indicate a promising patient prognosis. To date, pemphigus vulgaris induced by tumor therapy has not yet been reported.

  • (5) Diseases of the skin appendages

Mild folliculitis at baseline screening may progress into suppurative folliculitis after using EGFR inhibitors (e.g., cetuximab) and MEK inhibitors (e.g., selumetinib and trametinib), which may be associated with neutrophil infiltration of the pilosebaceous unit and local hyperproliferation caused by Staphylococcus epidermidis [14]

For cancer patients with preexisting rosacea, especially facial papulopustular rosacea, the rash may be aggravated during immunotherapy, which can be alleviated by topical metronidazole and oral doxycycline [15].

  • (6) Photosensitive skin disease

Vemurafenib may cause photosensitivity, which manifests as burning erythema after short-term exposure to UVA for 10-15 min and can last for several days [16]. This condition may be related to the decrease in the protoporphyrin levels and the significant increase in porphyrin levels after vemurafenib treatment in the blood. Such photosensitivity can be prevented by broad-spectrum sunscreen and clothing [17]. Notably, if a female patient of childbearing age has photosensitivity prior to cancer treatment, an inquiry and screening laboratory tests of lupus erythematosus are needed [18].

  • (7) Urticarial skin disease

Cold urticaria may worsen during ICI therapy [19].

  • (8) Sarcoidosis

Sarcoidosis at baseline may be exacerbated during tumor therapy. It was reported that ICI tumor therapy may induce sarcoidosis [20]. Systemic corticosteroids usually improve rash, after which immunotherapy can be restarted [21]. For isolated sarcoidosis rashes, topical corticosteroids or synthetic antimalarials can be adopted [22, 23].

2 Treatment of skin lesions associated with tumors

2.1 Treatment of cutaneous and mucosal lesions by immunotherapy drugs

2.1.1 Treatment of Stevense-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN)

Mild cases. Topical drugs: it may consider calamine lotion for the treatment of acute redness and swelling, erosion and exudation can be treated with 3% boric acid solution or 0.01% benzalkonium chloride wet compress for several times a day, 15 ~ 30 min each time for 1 to 3 consecutive days, until the exudation is controlled. Topical glucocorticoid preparations can be used other than erosive skin lesions. Systemic medication: it is prefer to consider the second-generation H1 receptor antihistamines; For patients with sleep disorders, first-generation H1 receptor antihistamines can be considered; An oral 0.5 mg/kg.d prednisone can be prescribed for 3-5 days.

Severe cases. Daily wound care should be strengthened and aseptic operation should be paid attention to avoid a secondary infection. At present, domestic and foreign guidelines do not recommend the routine use of systemic antibiotics for preventive treatments. It is recommended to complete the sampling and testing of bacteria in the broken skin area and consider systemic antibiotic treatment when the number of a single strain increases significantly from the results of bacteria culture, high fever and inflammatory indicators increase for more than 5 days, or high fever and inflammatory indicators increase significantly or increase a second time during the course of the disease, and the body temperature of patients drops suddenly or the patient's condition deteriorates. Before completion of susceptibility testing, broad-spectrum, less susceptible and less resistant antibiotics should be considered. When the results of drug susceptibility test are present, the corresponding antibiotics that are difficult to sensitize can be selected based on the results. When the efficacy of antibiotics is poor, the possibility of infection with drug-resistant bacteria or complicated with other infections (e.g. viral and fungal infections) should be considered, and the treatment plan should be adjusted in a timely manner. Hypoproteinemia and water-electrolyte disorders should be corrected in time, and blood volume should be maintained. If necessary, blood, plasma or protein could be transfused to maintain a colloid osmotic pressure. Patients with other organ system disorders should also be treated accordingly, and the relevant department physicians should be consulted. A 1 ~ 2 mg/kg.d intravenous glucocorticoid, prednisone can be prescribed for 7 ~ 10 days, and the dose can be reduced rapidly after the control of the disease. A 400 mg/kg.d intravenous immunoglobulin can be infused for 3 to 5 days when necessary. Immunosuppressants such as cyclosporine can be considered to treat SJS/TEN, with a recommended dose of 3 mg/kg.d. Other available immunosuppressants and biologics include cyclophosphamide, mycophenolate mofetil, TNF-α inhibitors, etc. [24].

2.1.2 Treatment of autoimmune bullous dermatosis

For localized (rash confined to a single anatomical area) or mild lesions, it is preferable to consider topical high/ulter-potency corticosteroids. For example, a 15 g/day dose should be divided into 1 ~ 2 external use, with a continuation of 3 weeks if the disease is not controlled, and the dosage can be increased to 30 g (pay attention to avoid the facial area, weight < 45 kg no more than 20 g). Emollients should be used to protect the skin barrier during both treatment and maintenance.

For moderate to severe lesions, the recommend prednisone dose of initial use of systemic glucocorticoids is 0.5 ~ 1 mg/kg.d; if the condition is not significantly controlled after 1 ~ 3 weeks (with more than 5 new blisters and bullae per day, and the itching condition not being reduced), the combination of immunosuppressants can be considered. When the disease is controlled (< 5 new blisters per day, the original erosive surface is basically covered by new epithelium), it should reduce the dosage of glucocorticoid. For the first 3 to 4 weeks, reduce the total dosage by 10% every 7 to 10 days, and then reduce the same every 2 to 4 weeks; slow down the later reduction speed, and gradually transit to the maintenance stage of daily medicine taking, that is, taking 5 to 20 mg every other day in the morning, and the medication often require to be taken for more than 1 year [25,26,27].

2.1.3 Drug eruptions with maculopapular rash as the main form

Treatment of drug eruptions with maculopapular rash as the main form is shown in Table 1.

Table 1 Treatment of drug eruptions with maculopapular rash as the main form
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2.1.4 Treatment of eczematous eruptions

In this case, it may consider a medium/high potency topical steroid (face and skin folds), topical calcineurin inhibitors, systemic antihistamines, and topical emollients. Narrowband UVB or UVA1 phototherapy also can be considered when possible [29].

2.1.5 Treatment of lichenoid eruptions

The high-potency topical steroids are recommended, while oral corticosteroids can be given in refractory cases. Moreover, narrowband ultraviolet B light phototherapy therapy, acitretin, and cyclosporine are also proved effective [30, 31].

2.1.6 Treatment of psoriasis

Topical high-potency glucocorticoid preparations and vitamin D3 derivatives are proved helpful. Systemic treatments, such as acitretin, methotrexate, and apremilast, can be also used to treat psoriasis. Biologics, particularly tumor necrosis factor inhibitors, are not recommended [32, 33].

2.1.7 Treatment of vitiligo

To strengthen sun protection, and high-potency topical steroids, calcineurin inhibitors and sunscreen can be used. Systemic immunosuppressants such as glucocorticoids or cyclosporine are not recommended.

It should be noted that currently, immunotherapy-based combination drug regimens are gradually increasing in anti-tumor therapy regimens. For drugs that enhance immune response, such as PD-1 monoclonal antibody, combined with other immunotherapy drugs, such as CTLA-4 monoclonal antibody and interferon alpha, the incidence of adverse reactions of various systems increases significantly, and the damage of cutaneous and mucosal system is no exception. According to recent experience in the diagnosis and treatment of associated adverse reactions in dermatology, compared with monotherapy, the occurrence time of adverse reactions in skin and mucosa caused by combined immunotherapy is significantly advanced, with higher severity and greater difficulty in treatment. Taking melanoma as an example, the most common cutaneous and mucosal adverse reactions in the combination regimen of PD-1 monoclonal antibody plus high-dose interferon α1b include lichenoid drug eruptions, vitiligo and oral mucosal degradation and ulcers, with a significantly higher incidence than that of PD-1 monoclonal antibody or interferon alone, which can appear within 2 weeks after one combination therapy at the earliest. In addition, the incidence of severe drug eruptions also increased and progressed rapidly. In terms of treatment, compared with SJS/TEN caused by other common drugs (such as antibiotics, antipyretic and analgesic drugs, traditional Chinese medicine, etc.), cases caused by immunotherapy drugs have a poor response to conventional TNF-α monoclonal antibody or systemic hormone therapy, so the combination of the two drugs and strengthening local care are often needed to achieve better control [34, 35].

2.2 Treatment of cutaneous lesions by targeted drugs

Prevention and early treatment of skin lesions caused by targeted drugs can largely avoid tapering or discontinuation of medications.

2.2.1 Treatment of papulopustular eruptions (acneiform eruptions)

Such adverse reaction may be caused by medications such as epidermal growth factor receptor (EGFR) inhibitors, the occurrence and severity of these eruptions are positively associated with tumor response to EGFR blockade and overall survival. The patient should be advised of the possibility of such condition before treatment. Local and/or systemic treatment can be given based on the severity of the rash and the discomfort degree of patient's. Antihistamines may be used for pruritus caused by skin lesions, and doxepin when pruritus is severe at night. It should avoid to use hot water for lesions cleaning. Specific treatment programs are shown in Table 2.

Table 2 Treatment of papulopustular eruptions
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2.2.2 Treatment of exanthematous drug eruptions

Treatment of exanthematous drug eruptions exanthematous is shown in Table 3.

Table 3 Treatment of exanthematous drug eruptions exanthematous
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2.2.3 Treatment of photosensitive skin eruptions

Such condition may be caused by drugs such as epidermal growth factor receptor inhibitors. The hyperpigmentation may gradually fade over months after the discontinuation of treatment; During the treatment, effective sun protection measures should be taken, such as wearing sunscreen clothing when going out, using broad-spectrum sunscreen (SPF ≥ 30 and PA ≥ ++ to prevent UVB and UVA respectively), and try to avoid long-term outdoor activities during the noon period (10:00 ~ 15:00); Pulsed dye laser or intense pulsed light therapy may be useful to telangiectasia disappearance [41].

2.2.4 Treatment of dry and itchy skin

Such adverse reaction may be caused by medications such as EGFR inhibitors. Patients should be advised to avoid harsh toiletries and skin care products, and use emollients for moisture enhancement. For topical use, excipients are often given as creams or ointments. Topical drugs with excipients of cream or ointment are commonly considered. Pruritus caused by dryness or papular pustular rash can be treated with topical glucocorticoid ointment (e.g. 0.1% mometasone furoate cream) or first/second generation antihistamines (e.g. ebastine, loratadine, etc.). If refractory pruritus still cannot be relieved, gabapentin or pregabalin can be considered to improve intractable pruritus after excluding other diseases that induce pruritus (e.g. diabetes, abnormal liver and kidney function, and hematological tumors).

2.2.5 Treatment of hyperkeratotic Hand-Foot Skin Reaction (HFSR) and Hand-Foot Syndrome (HFS, also called Palmar-Plantar Erythrodysesthesia Syndrome, PPES)

Such adverse reaction may be caused by medications such as multikinase inhibitors. Patients should be advised of such dose-dependent cutaneous adverse reaction prior to treatment. Patients should avoid pressure and friction, prolonged walking and lifting, and be prevented by wearing loose elastic footwear and gloves. Treatment should be given according to the severity of lesions. Specific treatment programs are shown in Table 4.

Table 4 Treatment of HFSR and HFS
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2.2.6 Treatment of epidermal neoplasms

Lesion features that may suggest squamous cell carcinoma (ie, rapid growth, pain, etc.) should be monitored closely. Early cryotherapy, surgical curettage or excision, electrocoagulation, CO2 laser, and photodynamic therapy are available for treatment; Topical drugs including keratolytic, imiquimod, 5-fluorouracil, etc. may be considered. For SCCs that occur during treatment with vemurafenib or dabrafenib, surgical excision is proved effective without dose adjustment [40, 42].

2.2.7 Treatment of keratosis pilaris-like reaction

Topical retinoids, urea, alpha-hydroxy acids, or salicylic acid can be considered to relieve pains. If the lesion is significantly pruritic, topical glucocorticoid and oral antihistamines may be used. The eruptions usually clear within a few weeks [43].

2.3 Treatment of cutaneous lesions by chemotherapy drugs

2.3.1 Treatment of SJS and TEN

Same as above.

2.3.2 Treatment of papulopustular eruptions (acneiform eruptions)

Same as above.

2.3.3 Treatment of HFS

Same as above.

2.3.4 Treatment of photosensitive skin eruptions

Same as above.

2.3.5 Treatment of autoimmune skin disorders

It should complete a skin biopsy and autoantibody examination.Enhanced sun protection during treatment is helpful to prevent lupus photosensitivity reactions. For lesions that have occurred, topical or oral corticosteroids may be considered. Scleroderma-like dermal fibrotic changes in the skin can be significantly reversed after stopping alkylating drugs such as taxanes [44].

2.3.6 Treatment of drug extravasation

Early detection of this condition can be achieved by more frequent rounds during treatment, and it requires the discontinuation of drug infusion, indwelling catheter and attempted aspiration. Apply a local cold application for the first 24-72 h, followed by warm compresses and, if appropriate, antidotes. Consider early surgical consultation for local debridement if necessary [45].

2.3.7 Treatment of seborrheic keratosis and actinic keratoses

Continue treatment. When local inflammation is severe, topical calcineurin inhibitors can be prescribed. Surgical resection and skin histopathological biopsy can be considered if necessary.

2.3.8 Treatment of intertrigo

Keep lesions dry and clean. For obvious exudation, a compress of normal saline can be applied topically, and a low/medium potency glucocorticoid or calcineurin inhibitor can be for dry eruptions. In cases where candidal infection is not considered, topical azole antifungal preparations such as fluconazole or econazole may be used. If treatment is ineffective, a histopathological biopsy of skin histology should be performed [46].

2.3.9 Treatment of radiation recall

Patients should be advised of potential photosensitivity, and should avoid excessive exposure to sunlight, and should be provided with adequate sun protection. Such risk of toxicity may disappear after discontinuing chemotherapy [47].

2.3.10 Treatment of ulceration and vascular diseases

For gemcitabine-induced vasculitis, it may subside after discontinuation of the drugs, or a three times daily use of prednisone 1 mg/kg and colchicine 0.5 mg is also proved effective. Hydroxyurea-induced chronic ulcers are difficult to treat and the condition may improve after discontinuation. The topical wound care should be enhanced and topical fibroblast growth factor, pentoxifylline, and prostaglandin E1 (alprostadil) are proved effective [48].

2.4 Treatment of cutaneous lesions cause by radiation therapy

2.4.1 Treatment of autoimmune bullous dermatosis

Same as above.

2.4.2 Treatment of acute radiation dermatitis

Topically strengthen moisturizing and topical glucocorticoid, silver nylon dressings and silver sulfadiazine cream can be considered. For more serious erosions and ulcers, vitamin B12 powder or human granulocyte macrophage stimulating factor can be applied to the wound healing, and the wound should be covered with oily gauze after regular washing [49, 50].

2.4.3 Treatment of chronic radiation dermatitis

It can be treat systematically with pentoxifylline, topical superoxide dismutase, statins and other medications, as well as physical therapy such as pulsed laser dye laser therapy, low-energy helium laser therapy, etc. For patients with chronic radiation dermatitis whose recurrent breakouts seriously affect their quality of life and for whom drug therapy is not effective, surgery treatment should be considered, but it should be noted that repair surgery should not be performed within 3 months after radical radiotherapy [51].

2.4.4 Treatment of chronic ulceration

For skin lesions without clear infection and exudation, it can be treated with topical glucocorticoid, long-term synthetic dressings, topical negative pressure dressings, and hyperbaric oxygen, etc. The growth factor of platelet promotes the growth of local granulations. In addition, topical or systemic antibiotics may be prescribed to combat infection. Along with increased healing of soft tissue necrosis, reversal of fibrosis can be achieved with pentoxifylline alone or in combination with vitamin E. Other treatment options include amifostine, and 5% sildenafil citrate topical hydrogel [52].

2.4.5 Treatment of lymphedema

For early treatment options, local massage can be considered to help with lymphatic drainage, compression dressing, and wearing a protective gear. In case of the development of advanced lymphedema, surgical intervention such as liposuction may be considered [53].

2.4.6 Treatment of secondary cutaneous malignancies

If there is a clear secondary cutaneous malignancy, Mohs microsurgical surgery can be performed. For squamous epithelial carcinoma tumor or basal cell carcinoma, it can be treated with standard excision with a wider surgical margin (> 4 mm). For in situ tumor or less aggressive malignancy, curettage and topical therapy (topical 5-fluorouracil) may be considered [54].

2.4.7 Treatment of radiation-associated angiosarcoma

For localized angiosarcoma, a complete surgical resection can be performed. Chemotherapy, anti-angiogenic therapy and immunotherapy such as doxorubicin, gemcitabine, bevacizumab and pablizumab are available for advanced angiosarcoma [55].

2.4.8 Treatment of radiation-induced morphea (RIM)

For mild cases, topical calcineurin inhibitors, high-potency glucocorticoid preparations, or UVA1 phototherapy are considered for treatment, and it may also consider systemic therapy (e.g., methotrexate and oral corticosteroids) in refractory cases [56].

3 Treatment of tumor-related mucosal injury

3.1 Common clinical manifestations of cancer treatment-related mucosal injury

In addition to traditional radiotherapy and chemotherapy, various new targeted drugs and immunotherapy drugs have increased the incidence of treatment-related mucosal injury [57]. The clinical manifestations of mucosal damage caused by anti-tumor drugs are diverse. Early identification of mucosal damage is conducive to standardized management and timely adjustment of treatment plans. The specific mucosal damage is discussed above.

3.2 Classification of mucosal injury severity

In the process of cancer treatment, mucosal injury manifests only as mild dry mouth in some patients, while in severe cases, mucosal tissue necrosis, spontaneous bleeding, severe abdominal pain, high-frequency diarrhea, gastrointestinal mucosal tissue necrosis perforation, and other life-threatening situations may occur [58,59,60]. The severity of mucosal damage is classified according to the patient's symptoms and signs of mucosal involvement. Clinically, the severity of mucosal damage can be used to assess whether the administration of tumor targeted drugs needs to be reduced or discontinued [58, 61].

3.3 Stratification management strategies for mucosal damage prevention

3.3.1 General preventive measures

General therapeutic measures include patient education, oral hygiene, professional oral care plans [58], and maintaining the moisture of the mucosal surface.

  1. 1)

    Patient education: Help patients understand the importance of mucosal care, maintain oral hygiene throughout the anticancer treatment period, choose a soft-bristled toothbrush with fluoride toothpaste for oral cleaning, 2-3 times a day [58];

  2. 2)

    Clean the mouth immediately after meals and at bedtime with gentle salt water or sodium bicarbonate solution to remove food residue [58, 61].

  3. 3)

    When mucosal damage occurs, trying to eat soft and liquid diets, eating less but more often, avoiding cold, hot, spicy, and other irritant foods and oral administration of probiotics such as Bifidobacterium that regulate the gut microbiome [59].

If patients experience abdominal pain, diarrhea, nausea, and other digestive symptoms, a thorough stool examination should be carried out promptly to exclude infectious diarrhea [59]. In addition to the patient's subjective symptoms, endoscopy can more accurately assess the degree of damage to the gastrointestinal mucosa and can be used in combination with other analyses to evaluate the degree of damage to the patient's mucosa [59].

3.3.2 Treatment

Principles of graded management

The choice of medication must be based on the location and severity of the damage. The principle of drug treatment involves actively symptomatic patients and graded management, with local symptomatic treatment as the main focus and systemic whole-body treatment as a supplement. For patients with grade I mucosal damage, local symptomatic treatment is the main focus, with proper basic oral care and changes in dietary habits as supplementary treatments. There is no need to discontinue related antitumor drugs. For patients with grade II mucosal injury, low- to medium-dose glucocorticoids (0.5–1.0 mg/kg/d) are administered locally [59]. If the symptoms of mucosal injury are mild, the tumor-targeting drugs do not need to be adjusted. If the symptoms are obvious and unbearable, it is necessary to discontinue the tumor-targeting drugs until the damage recovers to grade I and then the cancer treatment can restart at the same dose. For patients with grade III mucosal injury, symptomatic treatment is combined with glucocorticoids and tumor-targeting drugs are suspended until recovery to grade I, and antitumor therapy was restarted at a low dose. If grade III or above mucosal damage recurs, it should be managed according to grade IV mucosal damage. For grade IV mucosal damage, in addition to grade III treatment measures, tumor-targeting drugs should be permanently discontinued, and supportive treatment should be given [59, 61].

Local therapy

① Mucosal protectant

Mucosal protectants mainly include oral gel, oral ulcer protective agents, free radical scavengers, essential amino acids and supersaturated calcium phosphate [62, 63]. There is evidence supporting the role of oral gel (Peroxyl), oral ulcer protective agent (limepin), and amifostine in protecting oral mucosa and alleviating pain [61, 63]. These drugs can form a protective film on the mucous membrane with ulceration and erosion and help palliate mucosal pain and attenuate irritation [57].

② Anti-inflammatory agents

Local use of glucocorticoids and nonsteroidal anti-inflammatory drugs is recommended. Mucosal edema, inflammatory responses of the skin and mucosa, and clinical symptoms can be alleviated by glucocorticoids, different preparations of which are available for local administration at the sites of occurrence. For example, 0.1% triamcinolone acetonide oral ointment and other gel or oral ointment preparations can be used for oral or mucosal administration, dexamethasone eye drops can be used for ocular mucosal adminstration, and different types of intranasal steroid sprays can be used for nasal mucosal adminstration [61]. Nevertheless, the course of treatment is suggested to be shortened, as appropriate, due to the increased risk of oral fungal infection, atrophoderma, folliculitis and other hormone-related adverse skin reactions caused by long-term medication.

As a nonsteroidal anti-inflammatory drug, bendamine hydrochloride can inhibit the production of TNF-α, interleukin-1 β and other proinflammatory cytokines [64]. The use of bendamine mouthwash can prevent oral mucositis in patients with head and neck cancer who receive medium-dose radiotherapy [57, 64, 65].

③ Growth factor

Palifermin (keratinocyte growth factor-1) is the only oral mucositis drug approved by the United States Food and Drug Administration and the European Drug Administration. Other growth factors with insufficient evidence include fibroblast growth factor-20, keratinocyte growth factor-2, granulocyte-colony stimulating factor, transforming growth factor- β, and recombinant human EGF [57, 60, 65].

④ Analgesic solutions

Patients with mucous membrane involvement often experience local pain, which impairs nutritional intake and quality of life, and 2% lidocaine solution, procaine solution, lidocaine gel and other topical analgesic drugs can be used externally on the wound surface [66]. Some mucosal protective agents with potent pain relief are also therapeutic approaches [60].

⑤ Antibiotic therapy

Depending on the evaluation of the presence of infection (including bacteria, fungi and viruses) in lesion sites, local or systematic anti-infection therapy can be carried out when necessary [66]. Local anti-infective interventions include various lotions or mouthwashes containing anti-infective ingredients, such as nystatin tablets dissolved in sodium bicarbonate solution for gargling [62].

⑥ Laser and other phototherapy

It is recommended to use low-level laser therapy (LLLT) to prevent oral mucositis in patients with hematopoietic stem cell transplants who have undergone high-dose chemotherapy pretreatment and in those who have received radiotherapy for oropharyngeal cancer without chemotherapy [60]. A previous study showed that the progression of oral mucositis was slower in the low-dose nitrogen neon laser group [61].

⑦ Other local treatments

Traditional Chinese medicine preparations, such as Kangfuxin Liquid, can have a pain-relieving effect by means of local wet compresses, rinses or gargles. Nasal irrigation with sodium and chloride plasma can promote the integrity and improve the function of epithelial cells [66].

Systematic treatment

In regard to patients in severe condition, a better solution to control the disease is systemic hormone therapy at the proper dosage, prior to which it is recommended to weigh the benefits of drugs against the potential risks based on the patient's basic condition. In the case of grade II mucosal damage without obvious improvement after local treatment, glucocorticoids can be administered at a dose of 0.5–1 mg/kg/d. They can be used in combination with other drugs for a short time [59]. In the case of grade III/IV mucosal damage, glucocorticoids are administered at a dose of 1–2 mg/kg/d [59]. Glucocorticoids remain the first-line treatment, but close attention should be given to protecting the gastric mucosa.

Nutritional support therapy

Radiotherapy, chemotherapy, molecular targeted drug therapy or ICI therapy may lead to decreased salivary gland secretion and damage to the gastrointestinal mucosa [60]. Optimal nutritional support helps to resist local infection in the oral cavity, maintains the integrity of the mucosa and is essential for enhancing mucosal tissue repair and reducing the exacerbation of existing mucositis [67]. Therefore, in addition to the nutritional support provided to cancer patients, the nutritional risk caused by mucosal damage should be taken into account.

Doctors, nutritionists and nurses should implement dynamic nutritional risk screening for cancer patients, provide scientific nutrition education to patients and their families, assess problems that may affect nutrition, such as taste disorders, loss of appetite, and difficulty in opening mouse and swallowing, and actively improve nutrition as appropriate [60]. Early nutritional intervention can reduce the incidence and severity of severe oral mucositis.

  • ① Diet requirements should be evaluated. Patients should eat less dregs and smooth food, avoid inappropriate food (sour, hot, and spicy food), and quit smoking and drinking alcohol to prevent and reduce irritation to the oral mucosa [64].

  • ② Swallowing problems, malnutrition and weight loss should be monitored and patients should be provided with support and advice. Food consistency should be assessed, and food fortification and intake methods should be adjusted. Oral nutritional supplements should be considered when diet intake is inadequate [68]. For patients with grade III and above oral mucositis, a clinical nutritionist should be asked to assist in formulating a personalized diet, and patients should be intaking liquid or semiliquid food to prevent coughing. If patients with pain in the oral cavity that significantly affects eating cannot eat for more than 7 days or eat less than 60% of their daily requirements, parenteral nutrition support is needed [69].

  • ③ Nutritional screening and regular follow-up should be offered to patients during anticancer treatment [70]. Commonly used clinical validation tools include but are not limited to the Malnutrition Universal Screening Tool (MUST), Malnutrition Screening Tool (MST), Patient Subjective Global Assessment (PG-SGA), Nutritional Risk Screening (NRS 2002) and Micronutrition Assessment (MNA) [71]. Once mucosal damage occurs, early recognition and nutritional intervention are needed [70].

  • ④ The best application route of nutritional intervention is oral intake. Oral nutrition is preferred in patients who can eat. If not, the main nutritional interventions are enteral and parenteral intravenous nutrition. Intravenous nutrition has many complications, and enteral nutrition, is recommended clinically.

4 Treatment of tumor-related damage of skin appendages

Skin appendages refer to hair, nails, eccrine sweat glands and apocrine sweat glands, which may suffer from the same damage and changes as skin and mucous membranes during the treatment of the tumor. For example, traditional radiotherapy and chemotherapy can cause not only acute but also subacute and chronic skin and appendage damage, such as alopecia and pigmentation. In recent years, molecular targeted therapy and immunotherapy have improved the effect of cancer treatment, but damage to skin appendages is still a common adverse reaction that not only affects the patient’s appearance, causes psychological stress, and reduces the quality of life but also reduces treatment compliance [72].

4.1 Damage of skin appendages caused by molecular targeted drugs

Molecular targeted antitumor drugs mainly include EGFR inhibitors, TK inhibitors, ICIs, and BRAF inhibitors. The skin appendages affected by molecular targeted antitumor drugs mainly include hair follicles, hair, and nails.

4.1.1 Treatment of skin appendage damage caused by anti-EGFR monoclonal antibody therapy

The EGFR pathway in the skin regulates the growth and differentiation of the cells in the epidermis and promotes wound healing, which is closely related to the maintenance of immune homeostasis and barrier function. Local and international studies have shown that more than 80% of patients who receive anti-EGFR monoclonal antibody treatment will experience typical adverse skin reactions, among which the main symptoms in the skin appendages are acneiform papulopustular rash, paronychia, and hair abnormalities.

The papulopustular rash caused by anti-EGFR antibody therapy can be treated with tropical external treatment or oral antibiotics according to the severity of the symptoms and the impact on the patient’s psychology and life. When there are pustules in the rash, external antibiotic ointment including clindamycin, erythromycin, fusidic acid, and compound polymyxin are preferred, while when there is only erythema papules with no obvious pustules, glucocorticoid and calmodulin inhibitors are preferred. For the face, calmodulin inhibitors, such as 1% pimecrolimus and 0.03%-0.1% tacrolimus, are preferred; for the torso and limbs, calmodulin inhibitors are preferred, and the concentration can be increased from weak to medium or even strong based on the severity of the symptoms. Tetracyclines, such as minocycline and doxycycline, are the first choice among oral antibiotics. Tetracycline antibiotics have nonspecific anti-inflammatory effects, including reducing the activity of matrix metalloproteinase, inhibiting leukocyte chemotaxis, and reducing the production of proinflammatory cytokines. The dose of minocycline is 100 mg/day and the dose of doxycycline is 100 mg/twice a day and treatment with either drug lasts 4–6 weeks. Meta-analysis showed that patients with colorectal cancer who experience a papulopustular rash after treatment with an anti-EGFR monoclonal antibody have a longer survival time and higher remission rate than those without a papulopustular rash, suggesting that papulopustular rash is a clinical indicator of the efficacy of anti-EGFR monoclonal antibody treatment in colorectal cancer. Therefore, it is currently believed that the cancer treatment drugs need to be discontinued only in patients with papules/pustules involving more than 30% BSA with moderate to severe symptoms [73].

The prevention of paronychia caused by anti-EGFR antibody treatment is more important than the treatment. At the beginning of treatment, the correct method for tending to the skin and nails of the hand and foot should be taught, including (1) avoiding wearing tight shoes and socks, reducing the wear and trauma of the nail edge, and avoiding work or sports that may cause damage to hands and feet; (2) applying moisturizer daily after cleaning to avoid dryness and cracking of the skin and prevent secondary infection; and (3) trimming the nails of the hand and foot correctly to keep the nail edge round and blunt and to avoid ingrown nails. In the case of paronychia, external medication should be selected based on the results of etiological examination: for bacterial infection, fusidic acid cream, clindamycin gel, and mupirocin ointment can be selected; for fungal infection, antifungal drugs, such as ketoconazole cream and terbinafine cream, can be selected; for conditions that cannot be determined or examined, external drugs that are effective for both bacterial and fungal infections can be selected, such as clioquinol ointment. Antibiotics, such as first-generation cephalosporins or tetracyclines, can be used orally or intravenously if necessary. Severe or repetitive paronychia may require surgical intervention. If there is tissue similar to granuloma pyogenicum around the nail, fulgerized or external silver nitrate can be used to remove the excessive granular tissue. A recent study found that β-blockers can be used to treat granuloma pyogenesum around nails as a noninvasive measure [72].

4.1.2 Treatment of skin appendage damage caused by TK inhibitors

Damage to skin appendages induced by first generation TK inhibitors such as imatinib may include alopecia, acneform eruptions, and hyperhidrosis. The incidence of imatinib-induced pigmentation is high and may not only occur on the skin but also on the palatal mucosa, nails, teeth, hair, and gingiva. The skin appendage damage induced by second generation TK inhibitors (nilotinib and dasatinib) and the third generation TK inhibitors (ponatinib) is mainly hyperkeratosis. Moreover, second generation TK inhibitors can also cause noncicatricial/cicatricial alopecia, which also affects the eyebrow hair, and scarring.

Pigmentation cannot be treated or is treated only with brightening agent or camouflage cream since it does not affect the treatment of the disease and external decolorant and photoelectricity have a poor effect. Effective drugs for the treatment of follicular pustular, hyperkeratosis, and noncicatricial alopecia mainly include glucocorticoids, keratolytics (such as retinoic acid), and antihistamines. Retinoic acid can be administered orally if necessary. If the itching is serious and the treatment is ineffective, the dose of TK inhibitors should be reduced or administration should be temporarily suspended. Local hyperhidrosis usually does not affect quality of life or cancer treatment, but local injection of Clostridium botulinum can be administered if the condition becomes life-threatening [74].

4.1.3 Treatment of skin appendage damage caused by other molecular targeted antitumor drugs

mTOR inhibitors include rapamycin and its derivatives, such as sirolimus, everolimus, and temsirolimus. The damage to skin appendages caused by mTOR inhibitors usually includes nail abnormalities (onycholysis and split nails at the distal end), alopecia, and facial hair. Hedgehog signaling may be abnormally activated in many malignant tumors. The most common adverse reaction to Hedgehog signal pathway inhibitors is alopecia, which occurs in 10-14% of patients. The pathological changes suggest an abnormal cornification of hair follicles, leading to the absence of hair shafts in hair follicles. Generally, this kind of alopecia can be reversed, but it seriously affects the quality of life, especially for female patients. External use of minoxidil can improve the symptoms of alopecia, but no drug can prevent alopecia caused by Hedgehog signal pathway inhibitors. Vemurafenib and dabrafenib are mutant BRAF-targeting drugs, and the changes in skin appendages caused by these drugs include alopecia, alopecia, and paronychia, which can be treated according to the treatment principles for alopecia and paronychia caused by molecular targeted antitumor drugs.

In general, the impact of molecular targeted therapy on skin appendages is not serious, and most of them do not affect immunotherapy itself. Skin appendage adverse reactions are graded according to the involved area and the impact in the clinic. Mild or moderate (grade 1-2) adverse reactions can be treated symptomatically according to the above principles without stopping cancer treatment; if the adverse reactions are severe (grade 3-4), cancer treatment needs to be stopped and glucocorticoids can be administered if necessary. Dermatologists need to learn about the adverse skin reactions of related drugs, which will help to make accurate clinical diagnoses, develop reasonable treatment regimens, avoid unnecessary interruption of immunotherapy, prolong the overall survival time of patients, and improve the quality of life of patients.

4.2 Treatment of skin appendage damage caused by ICIs

Vitiligo, a hypopigmented skin lesion, may occur during the treatment of melanoma with PD-1 and PD-L1 inhibitors. Vitiligo usually occurs several months after the start of immunotherapy for melanoma, and is generally unrelated to the dose of the drug. The skin lesions are white spots that are symmetrically distributed on both sides of the torso and limbs. Vitiligo not only affects the skin but also the appendages, and includes the decolorization of the pelage (eyelash and eyebrow hair). Studies have found that the occurrence of vitiligo skin lesions is positively correlated with the prognosis of melanoma patients after cancer treatment. The loss of the skin pigment mainly affects the appearance, so the patient is advised maintain sun protection strategies and immunotherapy. Depigmented macules can be treated with glucocorticoids or calcineurin inhibitors or combination treatment with phototherapy to prevent further loss of pigment and help the skin return to its original color. The use of ICIs can also cause alopecia and nail changes. Since the alopecia caused by targeted drugs is mostly noncicatricial alopecia, an external minoxidil solution can be used to improve local circulation and promote hair growth. Nail changes do not need to be treated [75].

4.3 Treatment of skin appendage damage caused by radiotherapy and chemotherapy

The skin damage caused by radiotherapy may be acute, subacute or chronic, with alopecia in the early stage and permanent alopecia, hypohidrosis, adiapneustia, and abnormal skin temperature in the late stage. The systemic and local application of chemotherapy drugs may lead to a variety of lesions of the skin, mucous membrane, hair and finger/toenails. The skin appendage damage mainly includes alopecia, pigmentation, hair discoloration and finger/toenail discoloration or detachment. There is only a small amount of hair loss in patients with mild alopecia, while in patients with serious alopecia, there is a large amount of hair loss. However, the hair regrows after stopping chemotherapy for a certain period of time. Moderate alopecia is between the above two alopecia grades. For most patients, the hair can regrow after stopping chemotherapy, but sometimes it cannot regrow. To prevent alopecia, some patients will wear ice caps when injecting chemotherapy drugs to cool the scalp and constrict the local blood vessels, which reduces the amount of drug that reaches the hair follicle, thus reducing alopecia. Since the effect is not obvious, some patients choose to shave or wear a cap before chemotherapy to reduce the impact on appearance. Changes in pigment can occur in the skin, nails, gingiva, and mucosal membrane, which can be relieved with drug withdrawal but can also exist for a long time. Pigmentation, color changes, transverse depression (Beau line) of the nail plate, onycholysis, and paronychia caused by chemotherapy drugs have been reported. The appearance of the Beau line reflects the decrease in the mitotic activity of the proximal nail matrix. The Beau line moves to the far end as the nail grows at a speed of approximately 0.1 mm per day, so the application time of chemotherapy drugs can be deduced according to the changes in color or distance of the Beau line. Pigmentation and nail changes generally do not require treatment. The treatment of paronychia caused by EGFR inhibitors can be evaluated based on the severity of the condition.

5 Treatment of skin damage related to surgery and local treatments

Skin and mucosa damage is one of the common complications in the process of cancer treatment, which not only reduces the quality of life of patients but also affects the implementation of cancer treatment plans in serious cases.

5.1 Treatment of skin and mucosa damage related to surgery

The skin and mucous membrane damage caused by tumor surgery is mostly seen directly in the area of skin and other percutaneous tumor resection.

5.1.1 Poor wound healing

Poor wound healing is a common complication after surgery. The high-risk factors that cause poor wound healing after surgery include infection, incision hematoma, fat liquefaction, suture reaction, operation type selection, blood supply, advanced age, anemia, malnutrition, and diabetes. Moreover, cachexia in patients with malignant tumors can reduce wound healing. Accurate evaluation and effective correction during the perioperative period, improved methods during the operation, symptomatic treatment after the operation, and local treatment with high-energy red light, semiconductor laser and other technologies can promote wound healing. For patients with large wounds and poor healing after surgery, the nutrition risk score (NRS) scale is used to assess the pain of the wound. If the NRS score is more than 3 points, the appropriate medication is given to relieve pain. If the NRS score is 0 to 3 points, the patient is instructed to relax to relieve pain. Moreover, the NRS tool is used to assess the nutritional status of patients, and a nutritional care plan is formulated according to the score.

5.1.2 Skin and soft tissue infection

Infection is the main cause of poor wound healing after surgery. In the case of infection symptoms, the general condition and local wound should be evaluated over time. The treatment of wound infection includes timely removal of the suture, cleaning of the wound, removal of necrotic tissue, incision and drainage, and administration of antibacterial drugs according to bacterial culture and drug sensitivity results of the wound secretion. If new granulation tissue is found, oil gauze or iodophor gauze can be used for local pressure bandages. If the skin lesion area is small, dressing can be used to heal the wound. If the skin lesion are is large, skin flap or skin graft repair can be used for healing. In addition, lifestyle guidance should be provided: maintaining healthy living habits, paying attention to personal hygiene, avoiding smoking and eating spicy food, and improving nutrition. Moreover, keeping the skin clean and dry, avoiding overly tight clothes and trousers, avoiding carrying heavy objects with the upper limb on the side of the surgical site, and properly raising the lower limb to promote blood circulation and facilitate recovery are also suggested.

5.1.3 Bleeding and subcutaneous hematoma

The common causes of bleeding are incomplete hemostasis, loss of the ligation line and blood coagulation disorder during surgery. Therefore, the blood coagulation function of the patient should be tested before the operation, and the wound should be bandaged or hemostatic drugs should be used after the operation to reduce the amount of bleeding. The treatment of subcutaneous hematoma mainly depends on prevention. Drainage strips or negative pressure drainage tubes can be placed during the operation to compress and bind the wound. If there is a small blood clot under the wound, it is compressed and bandaged for absorption when changing the dressing; if there are many blood clots and they cannot be drained using negative pressure drainage tubes, the blood clots are removed, the dressings are changed and sutured, and pressure bandage is applied again.

5.1.4 Scar

Any operation can leave a scar. The degree of scarring is related to the individual, selection of surgical incision and postoperative treatment. When too much skin is removed during surgery, the local tension will increase in some patients, resulting in the widening and obvious hyperplasia of the scar tissue. The patient can be instructed to use medical seam-free adhesive tape for 3–6 months after surgery and minimize intense activities to reduce skin tension. Moreover, anti-scar treatments should be used to prevent or diffuse scars.

5.1.5 Skin metastasis/implantation

Metastasis/implantation of tumors at the surgical incision is rare, and the overall incidence rate is reported to be < 5%. It can occur after any tumor operation. Generally, it is considered skin metastasis. If it is found in time, it can be treated effectively. Most skin metastases/implants occur at the tumor surgical incision and puncture biopsy site and manifest as multiple skin nodules and ulcers [76, 77]. The occurrence of skin tumor metastasis usually indicates poor patient prognosis. It is necessary to distinguish natural tumor metastasis to the skin from skin implantation metastasis caused by surgery as soon as possible for early treatment. In clinical practice, the indications for invasive examination should be strictly understood, the puncture technology should be improved, the puncture site should be more carefully wiped and disinfected and incision protection film should be used to effectively protect the incision and reduce the chance of implant transfer.

5.2 Treatment of skin and mucosa damage caused by local nonsurgical treatment

5.2.1 Skin and mucosa damage caused by tumor hyperthermia

Skin pricking

When pain is severe, tumor hyperthermia must be stopped immediately, and cold water should be applied regularly to prevent the skin from heat damage caused by local high temperature. After taking measures to alleviate the pain, treatment can be continued or completely terminated depending on the situation.

Skin redness

Symptomatic treatment, such as cold milk or physiological saline cold compress, is recommended.

Skin burn

Most of the adverse reactions of local and regional hyperthermia are mild burns, such as erythema and blisters. Systemic hyperthermia mainly manifests as a low-heat skin burn, which is related to the hyperthermia temperature and heat application time [78]. This kind of burn has the following characteristics: ① It is prone to hemiplegia, anesthesia, diabetes, local hypoesthesia, and can be present in elderly individuals and children; ② The injury temperature is relatively low, but the application time is long; ③ The wound surface is deep, mostly Grade III, and difficult to heal; ④ The blister on the third-degree burn wound is easily mistaken for the second-degree burn. Skin heat injury caused by hyperthermia should be treated according to the principle of burn treatment. When blisters occurred, the wound and surrounding skin is sterilized with 75% alcohol, a syringe is used to drain the exudate in the blisters under strict aseptic operation, physiological saline or chlorhexidine is used to externally clean the wound, and scald ointment is externally applied to keep the wound dry and avoid infection. If the burn occurs at the distal end of the limb, especially at the back of both feet, with local swelling as the main manifestation, the affected limb should be properly raised to facilitate venous return and promote local detumescence, and the functionality of the limb should be carefully monitored. In the case of local continuous swelling, fever, pain, increased exudation or purulent secretion, the secretion should be collected for bacterial and fungal culture combined with drug sensitivity testing in a timely manner, and effective antibacterial drugs should be selected according to the drug sensitivity results. Moreover, attention should be given to diet education, and a diet rich in protein, calories and vitamins should be consumed to increase the body's resistance to infection and facilitate tissue repair.

Subcutaneous fat induration

Subcutaneous fat induration

5.2.2 Chemical ablation (interventional) treatment of skin and mucosa damage

This section mainly introduces vascular interventional therapy, including transcatheter arterial infusion chemotherapy and transcatheter arterial chemoembolization.

1) Transcatheter arterial infusion chemotherapy (TAI)

Chemotherapy drugs are directly injected into the tumor blood supply artery through the catheter to increase the local drug concentration in the tumor, kill the tumor and reduce the occurrence of systemic toxicity and side effects [79]. Due to the continuous local infusion of large doses of chemotherapy drugs, a series of adverse reactions can occur, mainly oral mucositis and venous thrombosis in the skin (mostly in the left lower limb). Oral mucositis should be treated with Kangfuxin solution gargle and tacrolimus ointment. Thrombosis risk assessments are conducted according to the Caprini risk assessment model after admission [80]. A score of 0 to 1 points indicates low risk, 2 points indicates medium risk, 3 to 4 points indicates high risk, and ≥ 5 points indicates high risk. Precautionary anticoagulation therapy should be carried out during the perioperative period. Postoperative sandbag compression for 6 to 8 h, immobilization for 24 h and then moving around, the use of compression elastic socks, and the appropriate use of rivaroxaban tablets and nadroparin calcium injections can effectively prevent thrombosis. In the case of venous thrombosis, vascular surgical intervention should be performed.

2) Arterial embolization (TAE) and arterial chemoembolization (TACE): TAE and TACE are common treatment options for unresectable advanced tumors that can be used alone or in combination with intravenous chemotherapy and targeted drugs. The treatment of adverse skin reactions is the same as that of arterial infusion chemotherapy. Moreover, high-quality physiological treatment, appropriate body positions, medication and pain nursing can effectively reduce the occurrence of complications.

5.2.3 Skin and mucosa damage related to local injection

Common skin and mucous membrane damage after local injection includes pain, swelling, subcutaneous hematoma, ulcers and necrosis at the injection site.

  1. 1)

    Swelling and pain at the injection site: Swelling and pain are common at the injection site and a 25% magnesium sulfate wet compress or polysulfonate mucopolysaccharide cream can be used for external treatment.

  2. 2)

    Subcutaneous hematoma: Subcutaneous hematoma is often seen deep into the injection site, and results in the rupture of blood vessels under the tumor tissue. Attention should be given to selecting the appropriate syringe needle, reasonably controlling the injection depth and angle, and applying pressure while withdrawing the needle. Small hematomas can be pressed locally for 30 min and can be absorbed after local ice compression. Large hematomas can be aspirated by syringe or cut and cleaned and then wrapped with sterile dressing.

  3. 3)

    Ulcers and necrosis: These conditions are mainly caused by drug irritation, repeated puncture at the injection site and infection. It should be noted that the site should be injected from different angles and repeated puncture at one point should be avoided. Moreover, aseptic technique should be precisely performed, tumor rupture should be avoided, the local reaction of patients after medication adminstration should be observed in a timely manner, and infection should be avoided.

5.2.4 Skin and mucosa damage caused by photodynamic therapy

Photodynamic therapy (PDT) uses photosensitive drugs and laser activation methods. Photosensitive drugs can be selectively absorbed and accumulated by tumor tissue and converted into photosensitizers. A series of photochemical reactions after specific wavelength light irradiation produce reactive oxygen species, leading to necrosis or apoptosis of tumor tissue. At present, photodynamic therapy is mainly used in the treatment of skin cancer but also in the treatment of lung cancer and cancers of the nervous, digestive and urinary systems.

Skin and mucosa damage related to photodynamic therapy are discussed below.

Local reaction

Pain, burning sensation, redness, erosion, bleeding, ulcers, erythema, and pigmentation may occur in the target and adjacent tissues.

① Erythema

There may be light erythema in the photodynamic irradiation area, which generally subsides after a few days.

② Exfoliation

Some patients have brown thin scabs on the target area after treatment, which can fall off naturally after approximately one week.

Pain

PDT-related pain management principles: The methods used to control PDT-related pain mainly include local cooling, surface anesthesia, injection anesthesia, and inhalation anesthesia [81]. At present, the commonly used local cooling methods include cold air analgesia equipment and water spray, but these treatments may reduce the clinical efficacy. Injection anesthesia, including local infiltration anesthesia, swelling anesthesia and nerve block, is currently the most effective PDT pain control method, especially nerve block. Although it controls pain, this method can potentially cause hematoma and even direct nerve damage.

Infection

The risk of infection is very small, which may be caused by the inherent antibacterial activity of PDT. However, it can manifest as cellulitis (mainly caused by Staphylococcus aureus). After analyzing the tissue culture combined with the drug sensitivity test, penicillin antibiotics can be given prophylactically. Herpes simplex infection is rare, and preventive antiviral treatment is not recommended at this time.

Scar

The probability of scar formation from PDT treatment is less than 1%. The treatment of scars includes chemical stripping, surgery, and laser treatment.

Pigmentation

Since PDT treatment can lead to inflammatory reactions in the treatment area, the incidence of pigmentation after inflammation in patients with skin cancer stages IV-VI is relatively high and usually naturally fades over time.

Mucosal injury

Mucosal injury is often seen after the PDT treatment of respiratory tract and digestive tract tumors using endoscopic examination. It is mainly caused by the burning of mucosa by the laser beam. Budesonide spray and Kangfuxin liquid can effectively promote mucosal repair.

Phototoxicity

Phototoxicity is a common side effect of PDT treatment, and mainly manifests as erythema, edema and urticaria. Erythema peaks approximately 1-2 h after irradiation and usually subsided within 1-2 weeks. Occasionally, erythema lasts more than 3 months. Urticaria can be prevented with antihistamine drugs.

5.2.5 Treatment of skin and mucosa damage caused by cryoablation

Cryoablation causes cells to form ice crystals with the help of low-temperature freezing. The cell membrane ruptures and tissue necrosis occurs. In recent years, argon-helium cryoablation has mainly been used [82]. The adverse skin reactions were mainly subcutaneous hemorrhage and infection at the puncture site, and the treatment was the same as previously stated. During freezing, continuous humidification of the skin at the puncture point with 50 °C warm saline can effectively prevent frostbite of the surrounding skin.