RU2722396C2 - Method of treating palmar-plantar erythrodysesthesia - Google Patents

Abstract

FIELD: medicine.SUBSTANCE: invention refers to medicine, namely to dermatovenereology, and can be used in medical institutions for treating palmar-plantar skin reaction in oncological patients. That is ensured by administering an alpha-lipoic acid preparation 600 mg a day intravenously for 4 weeks and ointment containing 0.005 % calcipotriol externally to a patient suffering a palmar-plantar response to the background of antitumour target therapy and 0.05 % betamethasone dipropionate, 2 times a day on skin in palms and plantar surfaces of feet 4–6 weeks.EFFECT: invention enables to conduct a full course of antitumour therapy with the targeted therapy preparations without reducing the doses and pauses in the treatment and withdrawal of the preparation, which enables prolonged control of the disease, stabilization of tumor process and improvement of survival rates of oncological patients, and also considerably improves quality of life of this category of patients.1 cl, 2 ex

Description

The invention relates to medicine, namely to dermatovenerology and oncology, and can be used in medical institutions with a dermatovenereological and / or oncological department, skin and venereal dispensaries, and oncology dispensaries.

Improving the chemotherapeutic treatment of tumors is a serious medical and social problem, the significance of which, first of all, is determined by the incidence and spread of oncological pathologies and the insufficient effectiveness of existing methods of therapy. The advent of targeted biological therapy drugs has determined a fundamentally new approach to the treatment of tumors, based on the blocking of certain molecules - receptors that transmit signals and trigger the pathogenetic mechanisms of oncogenesis. New drugs, possessing specificity and tropism for rapidly dividing tumor cells, also have a number of specific side effects, while the skin, as a constantly renewing organ, often acts as the main organ exhibiting undesirable effects of targeted therapy.

Targeted drug treatment is often accompanied by dermatological adverse reactions - dry skin, spotty-papular rash, acne-like rashes of varying severity, but the reason for drug withdrawal is most often palmar-plantar skin reaction (LCRC, hand-foot skin reaction, HFSR), which differs from palmar-plantar syndrome (LPS, hand-foot syndrome, HFS), caused by drugs of traditional chemotherapy. The term palmar-plantar erythrodysesthesia (palmar-plantar erythrodisesthesia, PPE), which combines the concepts of LPS and LPRC, is also used. Palmar-plantar skin reaction begins with dry skin, the appearance of dysesthesia of the palms and feet, peeling, cracks, and in severe, rapidly developing forms - blisters and erosion. The reaction rate reaches 50%, and when combined with other antitumor drugs, 80% (Chu D., Fillos T., Wu S. Risk of handfoot skin reaction with sorafenib: A systematic review and meta-analysis. Acta Oncologica. 2008; 47; : 176-86), which may lead first to a limitation of daily activity, and with further development and lack of dermatological care, to a limitation of self-care. The expansion of indications for the use of new targeted therapy drugs and the success of their use in colorectal cancer, non-small cell lung cancer, breast cancer, hepatocellular cancer, renal cell cancer, thyroid cancer, etc. determine the relevance of the treatment of LCRC and methods of its prevention.

The pathogenetic mechanisms of LPCR, as well as other manifestations of dermatological adverse events, are currently being actively studied. There is an obvious connection with the suppression of the activity of growth factors (VEGF, TGF-β1, EGF, PDGF, FGF2), an inhibitory effect on the growth and differentiation of skin fibroblasts, which, accordingly, leads to a decrease in the production of collagen, fibronectin and other components of the extracellular matrix, disrupts the differentiation processes , cell proliferation and skin repair (Shatokhina E.A., Kruglova L.S. Immunopathogenetic mechanisms of skin toxic reactions of antitumor therapy with multikinase angiogenesis inhibitors (review). Saratov Journal of Medical Scientific Research. 2017; 13 (3): 605-611).

The toxic effect of drugs is determined by the mechanism of action, the metabolism of the drug, the dose and duration of its use. LPRC is manifested in areas of skin in places of increased friction or pressure, most often these are projections of protruding bone structures (calcaneus, area of projections of the heads of the metatarsal bones and pressure zone with shoes and clothes).

According to the latest version of the classification, which determines the type and severity of side effects of antitumor therapy, in the section of adverse events from the skin, the palmar-plantar skin reaction is considered as palmar-plantar erythrodysesthesia syndrome (a disorder characterized by redness, severe discomfort, swelling and anesthesia in the palms or soles of the feet) ) and 3 degrees of severity stand out:

I degree - minimal changes in the skin: erythema, edema, hyperkeratosis in the absence of pain;

II degree - more pronounced skin lesions: desquamation, erythema, edema, hyperkeratosis, hemorrhage with pain and limited daily activity;

Grade III - serious skin changes: desquamation, blisters, erythema, edema, hyperkeratosis, hemorrhages, causing severe pain and leading to a limitation of self-care.

Multikinase inhibitors have a different frequency of skin toxicity variants, but it can be noted that palmar-plantar skin reaction is the most common side effect, and, according to various sources, its frequency reaches 20% with sunitinib, 26% axinitib, 32% %, cabosatinib -42%, sorafenib - 76% (Rumyantsev P.O., Volkova M.I., Podvyaznikov CO, Romanov I.S., Shavarova E.K., Shatokhina E.A. Toxicity control of angiogenesis inhibitors: resolution Expert Council Endocrine Surgery. 2017; 11 (3): 157-163). A meta-analysis showed that the incidence of LPCR in patients treated with sorafenib was 33.8%, with 8.9% with a third degree of severity (Chu D, Lacouture M E et al. Risk of Hand-Foot Skin Reation with Sorafenib: A systematic Review and Meta-Analysis. Acta Oncologica 2008; 416-186). For sunitinib: the frequency of LPCR is 18.9%, the third degree of severity is 5.5%. (Chu D, Lacouture M E et al. Risk of Hand-Foot Skin Reation with the Multitargeted Kinase Inhibitor Sunitinib in patients with Renal Cell and Non-Renal Cell carcinoma: a Meta-analysis. Clinical Genitourinary Cancer 2009, no.l 11- nineteen).

Preventive measures recommended for patients taking targeted therapy are aimed at preventing dryness and skin irritation: using warm water, comfortable clothes, shower oil, moisturizing creams, refusing hard washcloths, and wearing comfortable shoes with silicone soft insoles. But, unfortunately, even with the active implementation of such preventive measures, the development of LPCR is often observed. It should be noted that at the same time, the development of skin toxic reactions is a favorable prognostic sign of the body's response to antitumor therapy. In this regard, the development of methods for the treatment and prevention of palmar-plantar skin reaction is a relevant interdisciplinary area of dermatology and oncology.

Treatment of LPRC is a rather difficult task, since the pathological process is supported by taking the drug. In severe cases, it may be necessary to prescribe systemic corticosteroids at a dose of 30-40 mg in prednisone equivalent, dimethyl sulfoxide externally to reduce the extravasation of the drug, vitamin B 6 (pyridoxine) and over-the-counter pain medications, such as acetaminophen, to relieve the pain symptom (Kruglova L.S. Zhukova OV Correction of side effects of antitumor therapy with sorafenib Clinical dermatology and venereology. 2015; 3: 94-98).

External treatment includes the use of drugs with antioxidant properties (Elima), lanolin and derivatives of oil with hydroxyquinoline sulfate as an antiseptic component, epithelizing agents (dexopanthenol, methyluracil, actovegin, silver preparations), moisturizers with urea, anti-inflammatory (topical glucocorticosteroids, under occlusion. Topical glucocorticosteroids are recommended in the form of composite preparations to prevent secondary infection. The following recommendations can be attributed to preventive measures and weakening the severity of the palmar-plantar syndrome: care procedures (cooling baths with a succession, collecting herbs Elikosol or Brusniver), the constant use of emollients with a high urea content (10-30%), protective mode (wearing comfortable shoes , soft cotton socks, limiting excessive loads on the arms and legs). In this regard, it may be effective to use special socks and dressings with soft silicone (designed for patients with bullous epidermolysis), due to which they maintain a moist environment, prevent skin trauma and promote healing of already formed vesicle elements (Kruglova L.S. Zhukova O.V. Correction of side effects of sorafenib anticancer therapy Clinical dermatology and venereology. 2015; 3: 94-98; Lademann J, Martschick A, Kluschke F. Efficient prevention strategy against the development of Palmar-Plantar Erythrodysesthesia during chemotherapy, Skin Pharmacol Physiol 2014; 27 : 66-70).

Palmar-plantar syndrome caused by chemotherapeutic drugs (5-FU, capecitabine, pegylated liposomal doxorubicin, etc.) both in the clinical picture and histologically differs from palmar-plantar skin reaction that appears while taking multikinase angiogenesis inhibitors (sorafenibin) Levantinib et al.). Both conditions have palmar-plantar localization, soreness, sensitivity disorders, rapid regression of skin lesions after stopping the drug. LPCR differs from LPS in typical manifestations of localized hyperkeratotic lesions in areas of increased friction with erythematous changes along the periphery of the foci, with symmetrical paresthesia, pain and swelling. LPCR when using targeted drugs can occur on the side surfaces of the feet, and in the folds between the fingers. Histological changes in LCRC caused by targeted drugs from the group of multikinase inhibitors are vacuolar degeneration of keratinocytes in a prickly layer and epidermal acanthosis; LPS on the background of chemotherapeutic drugs demonstrates inflammatory infiltrate at the border of the dermis and epidermis, as well as vacuole degeneration of the keratinocytes of the basal layer. The vast majority of epidermal cells are keratinocytes, in the area of the palms and feet they have a number of specific features that distinguish them from keratinocytes in other areas. They have thick suprabasal layers, are hypopigmented and produce keratin-9. The main histopathological signs observed in LCRC are considered to be a violation of cell maturation with changes in the differentiation of keratinocytes, a possible increase in apoptosis in this cell population and specific inflammation. At the same time, the rate of cell division of the epidermis is significantly increased in places of active lesions. Unique to this condition is keratinocyte damage, manifested in the form of intracellular eosinophilic bodies (Kogonia L.M., Mazurin V.S., Ilnitskaya O.V., Gukasyan E.A., Kuzmichev V.A., Sidorov M.A. plantar erythrodysesthesia serious complication with capecitabine (own experience), Clinical Medicine Almanac. 2013; 28); Lacouture M E et al. Evolving Strategies for the management of Hand-Foot Skin Reaction associated with the Multitargeted Kinase Inhibitors Sorafenib and Sunitinib. The Oncologist. 2008; 13 (9): 1001-1011; Wood L. et al. Practical Considerations in the Treatment of Hand-Foot Skin Reaction caused by Multikinase Inhibitors Community. Oncology. 2010; 7 (1): 23-29).

Given the data of clinical observations and histological studies, pathogenetically substantiated is the treatment of LPCR with a combined topical preparation containing calcipotriol and betamethasone dipropionate. Calcipotriol / Betamethasone Dipropionate (Calcipotriol 50 μg / g and Betamethasone 0.5 mg / g) is a fixed combination of vitamin D3 analog and external corticosteroid, intended for local topical application once a day to treat psoriasis. This combination demonstrates anti-inflammatory and immunoregulatory properties, reduces the excessive proliferation of keratinocytes and helps to normalize their differentiation, and also has low systemic absorption, which is the goal when stopping manifestations of the palmar-plantar skin reaction and is optimal for the complex treatment of cancer patients.

Calcipotriol is a synthetic analogue of calcitriol, the active metabolite of cholecalciferol (vitamin D3). By binding the vitamin D receptor, it takes part in the regulation of cell growth, differentiation and immune function, as well as in the regulation of calcium and phosphorus metabolism, has an anti-inflammatory and immunomodulating effect, specifically reducing the excessive proliferation of keratinocytes, normalizing the differentiation of keratinocytes and lowering the levels of pro-inflammatory cytokines (Fenton Plosker GL. Calcipotriol / betamethasone dipropionate: a review of its use in the treatment of psoriasis vulgaris. Am J Clin Dermatol 2004; 5 (6): 463-78; Lea AP, Goa KL. Calcipotriol: a review of its pharmacological properties and therapeutic efficacy in the management of psoriasis. Clin Immunother. 1996 Mar; 5 (3): 230-48).

Betamethasone dipropionate is a potent, topical corticosteroid. It acts by binding receptors to glucocorticoids in the cytoplasm of cells, thereby suppressing transcription of genes, including pro-inflammatory cytokines, which causes the development of anti-inflammatory and immunosuppressive effects. As a result, inflammatory infiltrate, the severity of erythema, and edema decrease, the excessive proliferation of keratinocytes normalizes and their differentiation improves (Fenton C, Plosker GL. Calcipotriol / betamethasone dipropionate: a review of its use in the treatment of psoriasis vulgaris. Am J Clin Dermatol 2004; 5; (6): 463-78).

In a study of the pharmacodynamic properties of calcipotriol / betamethasone dipropionate conducted among healthy volunteers, it was demonstrated that the combined ointment was equivalent in biological activity to that in a single-component ointment containing the same concentration of betamethasone dipropionate (Traulsen J. Bioavailability of betamethasone dipropotate combined. J Dermatol. 2004 Aug; 43 (8): 611-7).

A study of possible skin atrophy in healthy volunteers showed a decrease in skin thickness to 15.6% after 3 weeks of using calcipotriol / betamethasone dipropionate 2 times a day, however, no visually detectable atrophy, erythema, or telangiectasia was clinically detected. Two weeks after the drug was discontinued, the skin recovered: skin thinning decreased by 6.5%. In a separate group, a decrease in skin thickness after 4 weeks was 12.3%, and in a group of betamethasone monotherapy with dipropionate - 13.2%. (Traulsen J, Hughes-Formella BJ. The atrophogenic potential and dermal tolerance of calcipotriol / betamethasone dipropionate ointment compared with betamethasone di-propionate ointment. Dermatology. 2003; 207 (2): 166-72).

This combination has found the greatest clinical application in the treatment of psoriasis. A histochemical study after the use of calcipotriol / betamethasone dipropionate revealed a decrease in the number of proliferating keratinocytes (Ki-67 +), an increase in the number of differentiated (K-10 +) epidermal cells and a significant decrease in the number of T cells of all subgroups (Rosina P, Giovannini A, Gisondi P , et al. Microcirculatory modifications of psoriatic lesions during topical therapy. Skin Res Technol. 2009 May; 15 (2): 135-8).

An important point is the effectiveness of the use of calcipotriol / betamethasone dipropionate specifically in patients with palmar-plantar psoriasis, in which the overall therapeutic efficacy was 60.4%, with clinical remission observed in 42% of patients, a significant improvement in 18.4%, an improvement in 5.3%, a slight improvement in 18.4%. With palmar-plantar psoriasis, the dermatological index of quality of life improved by 66.7%: from 21.2 ± 2.4 to 7.3 ± 2.5 points (Kruglova L.S., Dvornikov S.K. Dayvobet - long-term control over psoriasis. Consilium Medicum. Dermatology. (App.). 2010; 03: 22-26).

Thus, the combination of calcipotriol / betamethasone dipropionate in the external treatment of psoriatic skin manifestations is a significant, effective tool for topical administration once a day for the symptomatic treatment of both ordinary psoriasis and palmar-plantar. Given the similar clinical picture of palmar-plantar manifestations of psoriasis and LPCR, histological studies, studied the mechanisms of action of this combination and its safety, the use of dipropionate externally is reasonable in the complex treatment of calcipotriol / betamethasone.

Practical recommendations for maintenance therapy and correction of LPCR provide a list of external drugs only, including emollients, antimicrobial, analgesic, glucocorticosteroid external drugs, vitamin D analogues, are not included in the recommendations (Koroleva I.A., Bolotina L.V., Gladkov O.A. , Gorbunova V.A., Kruglova L.S., Manzyuk L.V. et al. Practical recommendations for the medical treatment of dermatological complications of antitumor drug therapy. Chapter in Malignant tumors: Practical recommendations RUSSCO. 2017; 7: 514-523). As the indications for the use of targeted therapy with multicase inhibitors expand, new combined regimens appear, and control over the development of such a side effect as LCRC needs to be improved. Prevention methods that prevent the occurrence of LCRC and its treatment should help patients not only receive a full course of anticancer treatment without dose reduction, but also maintain a level of quality of life.

None of the currently proposed treatment methods can effectively treat or prevent LCRC. Obviously, it is necessary to create an effective treatment for LPCR in order to realize the full potential of multikinase inhibitors, various treatment regimens and combinations in which they can and will be used.

The closest in technical essence to the present invention is a method based on the use of allopurinol for the treatment of palmar-plantar erythrodysesthesia (Author Rodemer I. (DE). Owner: NOBERA PHARMA, SL. (ES), patent for the invention (RU 2438673)) . The preferred range is the concentration of allopurinol in the cream is from 2 to 5%, more preferably from 2 to 4% of the total weight of the composition. A concentration of approximately 3% gives good results and is the best.

Compositions according to the invention may also include conventional additives and adjuvants for external dermatological preparations, such as preservatives, especially para-aminobenzoic acid esters (methylparaben, ethylparaben, propylparaben, butylparaben), quaternary ammonium compounds (benzalkonium chloride), formaldehyde compounds (imidazonidinyl-urea) benzyl alcohol, phenoxyethanol), acids (benzoic acid, sorbic acid); acids or bases used as pH buffering agents; antioxidants, in particular phenolic antioxidants (hydroquinone, tocopherol and their derivatives), as well as flavonoids, or other antioxidants (ascorbic acid, ascorbyl palmitate); perfumes; fillers (kaolin, starch); pigments or dyes; UV shielding agents; moisturizing components (glycerin, butylene glycol, hexylene glycol, urea, hyaluronic acid or their derivatives); anti-free radical agents (vitamin E or its derivatives; penetration enhancers, especially propylene glycol; ethanol; isopropanol; dimethyl sulfoxide; N-methyl-2-pyrrolidone; fatty acids / alcohols such as oleic acid, oleyl alcohol; terpenes such as limonene, menthol , 1-8 cineole; alkyl esters such as ethyl acetate, butyl acetate; ion pairing agents such as salicylic acid Most preferably, at the suggestion of the authors, mix allopurinol with a commercial cream base such as Bag Balm or Basiscreme DAC (Deutsches Arzneimittel codex) .

Apply in the form of creams, emulsions, gels or gels once, twice or three times a day, and more often during the day. For example, it is possible to use from 5 to 10 times a day, provided that the symptoms of palmar-plantar erythrodysesthesia are eliminated. Dosage may vary depending on the severity of the symptoms, cycles, or dose of the chemotherapeutic agent.

The pharmaceutical composition of the invention is recommended for patients who already have symptoms of palmar-plantar erythrodysesthesia of various degrees of severity, or as a prophylactic when conducting or planning chemotherapy with drugs with a high risk of developing this side effect.

The disadvantages of this method are: the lack of recommendations for the use of this method in the treatment of targeted antitumor drugs, the lack of a clear formulation of the external agent, including the concentration of the drug substance, composition, form of the drug; there is no prescription scheme, difficulty in preparing an external preparation, determining the optimal composition and regimen depending on the severity of palmar-plantar erythrodysesthesia.

The technical result of the proposed method for the treatment of palmar-plantar skin reaction in cancer patients taking targeted therapy drugs is the possibility of using the method both at the initial stage of the development of LCRC and with severe manifestations, increasing the therapeutic effect of the main antitumor drug by maintaining the therapeutic dosage without reducing the dose , interruptions in treatment and drug withdrawal, improving the quality of life of patients, maintaining patients self-care and daily activity.

The specified technical result is achieved by the fact that the patient is prescribed a drug of alpha-lipoic (thioctic) acid 600 mg per day for 4 weeks inside and a topical ointment containing 0.005% synthetic analogue of the vitamin D metabolite - calcipotriol and 0.05% glucocorticosteroid - betamethasone dipropionate. The ointment was administered 2 times a day on the skin in the palms and plantar surfaces of the feet for 4-6 weeks.

The treatment effect is achieved through the targeted use of the properties of the external combined drug and antioxidant drug inside. Calcipotriol, which is part of the local drug, inhibits the proliferation of keratinocytes and accelerates their morphological differentiation. Betamethasone, also in the cream, has a local anti-inflammatory, antipruritic, vasoconstrictive and immunosuppressive effect. Alpha-lipoic acid is a universal antioxidant with the ability to absorb various reactive oxidized substances, which provides protection under oxidative stress and intracellular protection. A powerful antioxidant effect is associated with the ability to eliminate free radicals; the ability to regenerate endogenous antioxidants; ability to reduce the production of free radicals. Alpha lipoic acid is a natural antioxidant and is found in every cell of the human body, is formed naturally in the liver and other tissues, and is chemically defined as 1,2-dithiolan-3-pentanoic acid (C8H1402S2). But its synthesis decreases with age, as well as in individuals with chronic diseases and toxic effects of various factors. Alpha-lipoic acid is a universal antioxidant, as it is both a water and a fat-soluble substance, the effectiveness of which has been proven both in laboratory conditions and in the body. The main effect is the absorption of various reactive oxidized substances, which provides an advantage in the protection of various forms of oxidative stress, in particular, intracellular protection. A powerful antioxidant effect is associated with the following properties:

- the ability to directly eliminate free radicals;

- the ability to regenerate endogenous antioxidants (glutathione, vitamins E and C);

- the ability to reduce the production of free radicals due to metal chelating activity (Vorobyova OV, Thioctic (alpha-lipoic) acid - a spectrum of clinical applications. Journal of Neurology and Psychiatry. 2011; 111 (10): 86-90).

Alpha-lipoic (thioctic) acid is used in the treatment of diseases and pathological conditions, which are based on an imbalance of oxidative-antioxidant homeostasis (diabetic polyneuropathy, alcoholic neuropathy, neuropathy of viral and toxic genesis, and is also used as an ingredient in cosmetic anti-aging creams). Alpha-lipoic acid also has the property of potentiation of the anti-inflammatory action of glucocorticosteroids (Shavlovskaya O.A. Thioctic acid: antioxidant therapy of neurological diseases. Breast cancer. 2014; 22 (13): 960-965).

Method description

A patient taking multikinase inhibitors and having an undesirable phenomenon in the form of a palmar-plantar skin reaction of 1-3 severity is prescribed an alpha-lipoic acid (thioctic) acid 600 mg daily for 4 weeks inside and a topical ointment containing 0.005% synthetic an analogue of the vitamin D metabolite is calcipotriol and 0.05% glucocorticosteroid - betamethasone dipropionate, 2 times a day on the skin in the palms and plantar surfaces of the feet for 4-6 weeks.

Examples of the application of the method Example No. 1

Patient K., 57 years old. Diagnosis: papillary thyroid cancer. Operation performed: subtotal thyroidectomy. According to a histological study: unencapsulated papillary thyroid cancer of the papillary structure, growing in the surrounding thyroid tissue and beyond. In the postoperative period, suppressive therapy was carried out, took L-thyroxine as daily oral doses of 125-150 μg / day. The oncological process progressed, which was found during the next ultrasound examination, 4 courses of radioiodine therapy with a total activity of 11 GBq were carried out, but despite the therapy, metastases in the lungs were found. The patient was prescribed sorafenib 800 mg daily by mouth. Of the adverse events, the development of the palmar-plantar skin reaction was noted, represented by foci of hyperkeratosis with erythema from the area of the protruding areas of the foot with dysesthesia in the form of tingling and sensory disturbances in the palms and soles of the first degree, first degree (NCI CCAE v.4.03.) One month after administration of the preparation, then the skin process worsened, painful blisters appeared, leading to a restriction of activity in everyday life (II degree), and then skin cracks appeared, which made self-care more difficult (III degree). A dose reduction of sorafenib based on the severity of cutaneous toxicity was planned.

The patient was additionally assigned a treatment regimen for LPCR, including the preparation of alpha-lipoic acid 600 mg per day, orally for 4 weeks, and an external ointment containing 0.005% calcipotriol and 0.05% betamethasone dipropionate, 2 times a day on the skin in the palms and plantar surfaces of the feet 4 weeks. Rapid relief of the manifestations of LPCR was noted, which was reflected in a decrease in the IGA (Investigator's Global Assessment) index, where symptoms (erythema, infiltration, desquamation, cracks) were assessed from 0 to 6 in terms of severity. Evaluation was performed before treatment and every week.

The patient evaluated subjective sensations - paresthesia, burning, pain according to the VAS (Visual Analogue Scale) scale - a visual analogue 5-point symptom scale.

As a result of the dermatological treatment, a dose reduction of sorafenib was not required, and the patient continued the course of vital modern and effective antitumor therapy.

Example No. 2

Patient N., 65 years old, was diagnosed with a tumor of the left kidney, surgery was performed (left-sided nephroadrenalectomy, paraaortic lymphadenectomy), cancer metastases were detected in the wall of the pelvis, and tumor growth into the kidney capsule was noted. According to a histological study, renal cell and clear cell cancer of the left kidney. Diagnosed with cancer of the left kidney of the III stage (pT3aN0M0), condition after surgical treatment (nephroadrenalectomy on the left, paraaortic lymphadenectomy). After 5 months, at the next follow-up examination, metastatic lung damage, a decision was made to conduct targeted therapy with sorafenib according to the scheme of 400 mg (2 tablets) orally 2 times a day. Two weeks later, against the background of taking the patient, side effects appeared: the patient complained of burning and skin of the hands and feet, accompanied by pains of the plantar surfaces when walking. In connection with severe pain in the skin, the patient refused to take the drug. A consultation by a dermatologist was recommended, a diagnosis of sorafenib-induced LCRC of the II severity was made, a treatment regimen was prescribed, including the preparation of alpha-lipoic acid 600 mg per day, orally for 4 weeks, and an external ointment containing 0.005% calcipotriol and 0.05% betamethasone dipropionate, 2 times per day on the skin in the area of the palms and plantar surfaces of the feet for 4 weeks, it is recommended to exclude wearing tight shoes, hot showers, bathtubs, and use silicone insoles. Against the background of the therapy and the recommendations received, the side effects resolved within 14 days. The patient continued treatment with sorafenib without interruption and dose reduction.

Over the course of the year, the patient maintained stabilization of the tumor process, and other side effects appeared - increased blood pressure, fatigue, there were repeated episodes of LCR, quickly stopped by the above treatment method.

The proposed method of treatment was applied in 39 patients with LPCR of varying severity. Clinical manifestations in the form of erythema, infiltration and desquamation were completely stopped, the fastest regression was observed in the first week: a decrease in erythema by 53%, a decrease in manifestations of peeling by 33%, cracks by 54%. Analyzing the assessment of subjective sensations by patients, it can also be noted that a significant improvement occurs in the first week of treatment, this is especially noticeable in a decrease in paresthesia by 65%.

Claims (1)

A method for the treatment of palmar-plantar erythrodysesthesia by using the alpha-lipoic acid drug inside, in combination with a topical combination preparation, characterized in that the drug is alpha-lipoic acid 600 mg per day, taken orally for 4 weeks, an ointment containing 0.005% calcipotriol and 0 is applied topically , 05% betamethasone dipropionate, 2 times a day on the skin in the palms and plantar surfaces of the feet for 4-6 weeks.