Palliative treatment of skin metastases in dermato-oncology

Authors

  • Katharina C. Kähler,

    Corresponding author
    1. Schleswig-Holstein University Hospital, Campus Kiel, Department of Dermatology, Venereology, and Allergology, Kiel, Germany
    • Correspondence to

      Dr. med. Katharina C. Kähler

      Universitätsklinikum Schleswig-

      Holstein, Campus Kiel

      Klinik für Dermatologie, Venerologie und Allergologie

      Schittenhelmstraße 7

      24105 Kiel

      E-mail: kckaehler@yahoo.de

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  • Friederike Egberts,

    1. Schleswig-Holstein University Hospital, Campus Kiel, Department of Dermatology, Venereology, and Allergology, Kiel, Germany
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  • Ralf Gutzmer

    1. Medical University Hanover, Department of Dermatology, Allergology, and Venereology, Hannover, Germany
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  • Section Editor Prof. Dr. Jan C. Simon, Leipzig

  • Conflicts of interest None.

  • Visible skin metastases are often very distressful for the patient. Excision is the first-line therapy for solitary skin metastases.

  • A main indication for palliative radiotherapy is not so much to reduce the size of the tumor (i.e., debulking) but rather to alleviate the symptoms as quickly as possible.

  • Radiotherapy already has an analgesic effect at low dosages of 8 Gy or more; it reaches its maximum two to four weeks after stopping radiation therapy.

  • Electrochemotherapy consists of combination therapy using electroporation along with administration of systemic cytostatic agents (bleomycin, cisplatin) for local treatment of cutaneous and subcutaneous skin tumors and metastases.

  • For bleomycin, the response rate ranges between 77–87%, depending on the tumor entity.

  • In patients with severe skin metastases, limb perfusion is an effective treatment option.

  • One option is intratumoral administration of interleukin-2, which is a highly effective local therapy for skin metastases in patients with melanoma.

  • If there is heavier bleeding, topical application of an astringent nasal spray may be effective.

  • A paste consisting of pulverized metronidazole tablets, or 2% chlorophyll solution, when applied directly to foul-smelling lesions, can also minimize the odor.

Summary

Patients with metastatic melanoma, but also other solid tumors (e.g., lung or breast cancer), may develop cutaneous metastases in advanced stages. The goal of treatment is to alleviate symptoms such as pain, fetor, secretions, or bleeding. Current treatment modalities are based on a multimodal treatment approach. Beside surgery, treatment options such as electrochemotherapy, isolated limb perfusion, radiotherapy, and local administration of cytokines or chemotherapy agents are available. In case of concomitant visceral metastases, this local treatment approach may not affect overall survival, but the palliation of these tumor-associated symptoms very often improves the quality of life for the patient.

Introduction

Along with primary skin tumors, which are usually still treatable at the time of diagnosis with curative surgery, palliative treatment of cutaneous metastases from solid tumors (such as carcinomas of the breast, kidney, prostate gland, lungs and other organs) seen in everyday dermatological practice require -individually-tailored, multimodal treatment. About 10% of patients with solid tumors develop cutaneous or subcutaneous metastases over the course of their disease [1].

Typical problems

Skin metastases from solid tumors behave in a similar fashion, irrespective of the tumor entity. The lesions may be distressing for the patient, due to their visibility or symptoms such as weeping, bleeding, pain, and fetor (Figure 1) [1]. Intense fetor, in particular, can significantly impair the patient's quality of life and lead to social isolation. Given the often very distressful symptoms, even in patients with visceral metastases, the treatment of the skin metastases may take precedent.

Figure 1.

Symptomatic skin metastases of melanoma on the chest wall.

Palliative therapy options in skin metastases

Ablative techniques

Visible skin metastases are often very distressful for the patient. Excision is the first-line therapy for solitary skin metastases [2]. Other alternatives include -cryotherapy as well as laser therapy for flatter lesions. Doctors should discuss the advantages and disadvantages with the patient. One may also consider combining resection of a large lesion with topical treatment of multiple smaller metastases.

Radiotherapy

Indications

Pain related to skin metastases primarily occurs with space-occupying masses; weeping, bleeding, fetor may occur due to tumor disintegration. Palliative -radiotherapy is mainly indicated to alleviate the symptoms as quickly as possible rather than to achieve a reduction in tumor size (i.e., debulking) [3]. In palliative radiotherapy, fractionation is based on an individual treatment decision, taking into account the personal needs of the patient. Long-term toxic effects should be avoided. The treatment should be brief, and thus higher individual doses (3.0–4.0–8.0 Gy), or hypofractionation, may be advisable. The length of treatment is significantly minimized, depending on the individual dose (one day, one week, two weeks). A prerequisite is adequate relative biological effectiveness which brings about rapid, lasting, and certain pain relief.

Adequate pain relief does not necessarily require complete healing of the tumor. Radiotherapy already has an analgesic effect at low dosages of 8 Gy or more; it reaches its maximum two to four weeks after stopping radiation therapy [3].

The use of palliative radiotherapy for ulcerated skin metastases leads to rapid reduction in the size of the ulcerous lesion; over the following weeks, the lesions often heal. For superficial tumors, treatment with high-energy electrons is suitable. With the aid of CT-supported 3D planning, deeper tumors may be reached with photon radiation. The dosage is based on the prognosis and histology, and may be 5 × 4 Gy, 10 × 3 Gy, or 20–25 × 2 Gy. For radiosensitive tumors, a lower individual dosage is preferred. At the beginning of radiotherapy, ulceration may occur due to tumor disintegration. Careful wound management is essential to avoid the risk of a superinfection.

Electrochemotherapy

Electrochemotherapy consists of combination therapy using electroporation along with administration of systemic cytostatic agents (bleomycin, cisplatin) for local treatment of cutaneous and subcutaneous skin tumors and metastases. The electrical impulses increase permeation of cell membrane, allowing for increased uptake of the cytostatic drug. Studies have underscored its ease of use and favorable risk-to-benefit profile [4].

Electrochemotherapy may be given as a one-time treatment or as repeated, palliative treatment for cutaneous metastases of varying origin. The favorable side-effect profile and the short treatment duration make it suitable for use on an outpatient basis. Electrochemotherapy is used in accordance with standard operating procedures (SOP) and is standardized for clinical use. The delivery of electrical pulses causes painful muscle contractions during treatment. Patients should thus be given local anesthesia, or preferably a general anesthesia. The cytostatic drugs may also cause side effects. These include pulmonary fibrosis in patients taking bleomycin. Short-term treatment has a high response rate; for bleomycin it ranges between 77–87%, depending on the tumor entity [4].

An advantage is that with this treatment method, symptoms such as bleeding, weeping, and fetor begin to resolve soon after the first session (Figures 2, 3). Over the course of a few weeks, the tumor tissue transforms into a flat necrotic lesion, the removal of which aids further healing.

Figure 2.

Bleeding and secreting skin metastases of melanoma before electrochemotherapy.

Figure 3.

Remission of skin metastases after electrochemotherapy.

Extremity perfusion

Isolated extremity perfusion (isolated limb perfusion; ILP) is generally used for treating malignant melanoma or sarcoma of the limbs, although it may be used for other tumor entities as well.

Extremity perfusion involves isolating the limb from the systemic circulation. Using a heart-lung bypass machine, targeted perfusion with the chemotherapy agent melphalan is performed, sometimes in combination with TNF α. Cytostatic drugs may also be given at higher concentrations (up to 100 times more than intravenous administration) or together with hyperthermia techniques -(tissue temperature to about 40 °C), which can enhance the effects of the cytostatic agent. After the 90-minute perfusion phase, the metabolic products are washed out before reconnecting the extremity to the circulation; this avoids leakage of the cytostatic drug and tissue toxins into the rest of the body.

Postoperative complications include redness, excessive warmth, blistering, and desquamation of the skin. There have also been reports of rhabdomyolysis, or even compartment syndrome, as well as cardiac complications related to administration of TNF-α.

In a systematic review of 22 studies with 2,018 patients [5], the median complete remission rate (CR) was 58%, and the response rate (PR + CR) was 90%; the response rate for melphalan, given as monotherapy, was 46% and thus lower than when it is used in combination with TNF-α (69%). Treatment success depends on factors such as tumor stage, the number of in-transit metastases (< 10), and a maximum tumor diameter of < 4 cm [6].

In patients with severe skin metastases, limb perfusion is an effective treatment option. Yet one must take into account the significant technical costs as well as effort for the patient, since it is not available everywhere. Treatment-related morbidity is also an issue, especially in patients whose overall health is diminished or who have other serious diseases.

Local immunotherapy

One option is intratumoral administration of interleukin-2, which is a highly effective local therapy for skin metastases in patients with melanoma. A response rate of more than 80% has been reported for administration of the drug 2–3 times per week for 2–57 weeks (3–18 MIU per session). In one clinical study, which included 51 patients with a total of 917 in-transit metastases, local, complete remission occurred in 69% of patients; 79% of the treated metastases went into complete remission, and 1% went into partial remission [7]. Similar to electrochemotherapy, this treatment is more effective with smaller metastases. Another treatment option is the use of imiquimod which works through the toll-like receptor 7. In a clinical study, the sequential use of imiquimod, given daily for 4 weeks, followed by intralesional administration of IL-2, given 1–3 times weekly, led to a response rate of about 50% [8].

Topical therapy with cytostatic agents

The option of stimulating an immune response by triggering a contact allergy, using dinitrochlorobenzene (DNCB) or diphenylcyclopropenone (DCP), has declined in popularity. Combining local administration of DNCB 2% with subsequent chemotherapy (DTIC) has been shown to lead to a local response rate of 62% of patients with stage III non-resectable disease [9].

In patients with breast cancer, local 6% miltefosine solution may be used to treat skin metastases. One placebo-controlled study showed that its use can lead to a response rate of about 30% [10].

Supportive measures in patients with symptomatic skin tumors

Bleeding

In patients with symptomatic skin tumors, wound care is especially important. Bleeding skin metastases tend toward adhesions so that the use of non-adherent gauze (e.g., Adaptic®), as well as moistening the dressing prior to changing it, are helpful. If there is heavier bleeding, topical application of an astringent nasal spray may be effective.

Fetor

Foul-smelling tumors on the skin present a significant impairment, because they severely limit the affected patients’ participation in social life. As a result of tumor cell disintegration and subsequent superinfection with various organisms, the odor worsens over the course of disease. Cleansing with antiseptic preparations (such as octenidine solution), as well as the use of wound dressings containing silver, can help reduce the odor.

A paste consisting of pulverized metronidazole tablets, or 2% chlorophyll solution, when applied directly to foul-smelling lesions, can also minimize the odor [11]. Activated charcoal [11] is also well suited for binding odors. Commercially available products, sometimes in combination with silver, may be used (Actisorb® silver 220).

Summary

Various options are available for the treatment of skin tumors and skin metastases from solid tumors of another origin. Resecting solitary lesions is the preferred method of treatment. In patients with multiple lesions, or symptomatic metastases, with bleeding, weeping, fetor, or pain, the use of a multimodal treatment concept is advisable. Along with systemic therapy, which should also have a locoregional effect, other local treatment options, such as electrochemotherapy, limb perfusion, radiotherapy, or local use of cytokines may be considered. In patients with cancer, maintaining the patient's quality of life is very important. The additional use of supportive measures is thus an important component in any multimodal treatment concept.

Fragen zur Zertifizierung durch die DDA

  1. Zur palliativen Behandlung von Hautmetastasen eignet sich nicht?
    1. Chirurgie
    2. Strahlentherapie
    3. Elektrochemotherapie
    4. Ozontherapie
    5. Extremitätenperfusion
  2. Eine palliative Bestrahlung von Hautmetastasen…
    1. ist nur bei einer Lebenserwartung von mindestens 6 Monaten sinnvoll.
    2. ist für multimorbide Patienten ungeeignet.
    3. führt erst ab einer Gesamtdosis von 40 Gy zu einer Schmerzlinderung.
    4. führt meistens rasch zu einer Symptomlinderung.
    5. dauert mindestens 4 Wochen.
  3. Das Verfahren der Elektrochemotherapie…
    1. kombiniert Gleichstromimpulse mit einer Immuntherapie.
    2. eignet sich ausschließlich für Melanompatienten.
    3. kann mit Bleomycin oder Carboplatin erfolgen.
    4. bewirkt eine Zunahme der intrazellulären Konzentration des Zytostatikums.
    5. birgt nicht das Risiko einer Lungenfibrose.
  4. Die Extremitätenperfusion bei Hautmetastasen…
    1. wird nur beim Melanom eingesetzt.
    2. führt zu Rötung, Überwärmung, Blasenbildung des Behandlungsareals.
    3. erfolgt mit dem Zytostatikum Bleomycin.
    4. wirkt unabhängig von der Größe der Mestastasen gleichermaßen gut.
    5. birgt nicht das Risiko einer Rhabdomyolyse.
  5. Die supportive Therapie von Hautmetastasen…
    1. ist bei einer wirksamen Lokaltherapie unnötig.
    2. ist nur Mittel der letzten Wahl.
    3. umfasst eine angemessene Wundversorgung.
    4. ist nicht Bestandteil der dermatoonkologischen Therapie.
    5. erfordert immer die Zusammenar-beit mit einem Palliativmediziner.
  6. Welche Aussage trifft nicht zu? Hautmetastasen stellen für Patienten eine Belastung dar, weil…
    1. eine Geruchsbelästigung auftreten kann.
    2. Schmerzen bestehen.
    3. diese eine starke Sekretbildung aufweisen können.
    4. immer ein starker Juckreiz beschrieben wird.
    5. der Anblick an die bestehende Tumorerkrankung erinnert.
  7. Eine palliative Bestrahlung von Hautmetastasen…
    1. kann nur durch eine Dermopan-Bestrahlung sinnvoll durchgeführt werden.
    2. ist bei oberflächlicher Ausdehnung durch schnelle Elektronen gut zu behandeln.
    3. führt erst ab einer Gesamtdosis von 20 Gy zu einer Schmerzlinderung.
    4. hat vor allem eine Symptomlinderung zum Ziel.
    5. ist in erster Linie durch das Resultat eines Debulkings indiziert.
  8. Das Verfahren der Elektrochemotherapie…
    1. wirkt prinzipiell bei Metastasen eines jeden soliden Tumors.
    2. ist nur in Vollnarkose durchführbar.
    3. ist nur einmal durchführbar.
    4. kann zu Muskelzuckungen führen.
    5. führt erst nach mehrmaliger Anwen-dung zu einer Symptomlinderung.
  9. Die Extremitätenperfusion bei Hautmetastasen…
    1. ist ein technisch unaufwendiges Ver f ahren.
    2. erfolgt nach Isolierung der Extremität vom Körperkreislauf.
    3. erfolgt immer kombiniert mit Melphalan und TNF-a.
    4. wirkt unabhängig vom Tumorstadium gleichermaßen gut.
    5. kann auch bei multimorbiden Patienten problemlos eingesetzt werden.
  10. Die Geruchsbelästigung durch nässende Hautmetastasen…
    1. ist therapeutisch schwer beeinflussbar.
    2. ist durch den Einsatz von Puder zu lindern.
    3. kann durch eine Paste aus gemörserten Metronidazol-Tabletten minimiert werden.
    4. wird durch eine bakterielle Besied-lung unwesentlich beeinflusst.
    5. stellt für die meisten Patienten keine relevante Beeinträchtigung dar.

Liebe Leserinnen und Leser,

der Einsendeschluss an die DDA für diese Ausgabe ist der 17. Dezember 2013. Die richtige Lösung zum Thema „Das allergische Kontaktekzem“ in Heft 7 (Juli 2013) ist: 1d, 2a, 3e, 4b, 5c, 6c, 7e, 8a, 9d, 10b.

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