Side effects of systemic oncological therapies in dermatology

Authors


Prof. Dr. Dirk Schadendorf Department of Dermatology University Hospital of Essen Hufelandstraße 55 D-45122 Essen, Germany Tel.: +49–201-723–4342 Fax: +49–201-723–5935 E-Mail: dirk.schadendorf@uk-essen.de

Summary

The discovery of specific gene mutations, termed “driver mutations”, in different tumors has brought personalized medicine into the focus of cancer treatment. Targeted treatment agents generally are administered orally and have a tolerable adverse event profile; they have become widely used in both inpatient and outpatient settings. The approval of the selective BRAF inhibitor vemurafenib (Zelboraf®) as first-line therapy of metastatic melanoma in Europe in February 2012 as well as the increasing use of MEK inhibitors within clinical trials confronts dermatologists and oncologists with a new spectrum of side effects. Knowledge of these possible adverse events and their management will be crucial for optimized patient care. This article offers an overview of the most important adverse events of currently employed dermato-oncologic therapeutic agents.

Introduction

In the age of personalized medicine in oncology, “targeted therapies” characterized by high specificity for a molecular target structure are being employed increasingly. They act by interrupting or greatly reducing a molecular signaling pathway of essential importance to the tumor. Due to their targeted mechanism of attack, they have in comparison to conventional chemotherapy agents the advantage of optimal therapeutic success with significantly less toxic side effects on healthy cells (Table 1). Nevertheless, specific cutaneous side effects are quite frequent, so that a new spectrum of side effects and new therapeutic challenges result for the dermatologist.

Table 1.  Study overview of vemurafenib, ipilimumab and DTIC [1–5].
SubstanceBest overall response rateMedian survival [in months]Progression-free survival (PFS) [in months]Tolerability after dose modification or above grade 3Cost in Euro (approx.)
  1. 1Tolerability after dose modification; 2Tolerability above grade 3 of autoimmune-induced side effects; 3With respect to PFS; With respect to induction with 4 cycles; With respect to 3 cycles.

Vemurafenib48 % (BRIM 3) [1] 53 %13.8 (BRIM 3) [1]6.8 (BRIM 2) [2]38 %1 (BRIM 3) [1]54,4003
 (BRIM 2) [2]15.9 (BRIM 2) [2] 64 %1 (BRIM 2) [2] 
Ipilimumab (3 mg/kg) [3]10.9 %10.12.8615 %2104,0004
DTIC (1,000 mg/m2 body surface)5–12 %[4, 5]6.4 [5]–9.1 [4]1.6 (BRIM 3) [1]16 %1 (BRIM 3) [1]1,1005

With the approval of the immunomodulatory CTLA-4 antibody ipilimumab (Yervoy®) as second-line therapy of metastatic melanoma in 2011 in Europe, the dermatologist as well as the internist is confronted with an entirely new spectrum of in part severe autoimmune side effects. Knowledge and management of these side effects are indispensable in order not to endanger the treatment of the patient.

Classical chemotherapy continues to play an important role in the treatment of malignant tumors, as only a portion profit from immunotherapy. In the following the side effects of the newer targeted and immunomodulatory therapeutic agents as well as cutaneous side effects of conventional therapeutic agents used in dermato-oncology and their management will be reviewed.

Kinase inhibitors of the mitogenactivated protein kinase (MAPK) signaling pathway

Binding of ligands to the membrane-bound receptor kinases leads to activation of subsequent signal transduction pathways such as MAPK signaling and the phosphatidyl-insoitorl-3-kinase (PI3K/AKT) signaling pathway that results in increased cell growth and resistance to apoptosis. In addition to endogenous receptor-ligand interactions, the MAPK signaling pathway can also be activated by RAS (rat sarcoma) or BRAF (v-raf murine sarcoma viral oncogene homolog B1) mutations that have been identified in various tumors [6, 7]. Among BRAF inhibitors selective class I RAF (rat fibrosarcoma) inhibitors such as vemurafenib and dabrafenib and non-selective class II RAF inhibitors such as sorafenib, which are associated with different side effects are differentiated [6]. In the following only the new class I RAF inhibitors will be considered more closely.

BRAF inhibitors

Class I RAF inhibitors (selective BRAF inhibitors)

They include the selective oral BRAF inhibitors such as vemurafenib (Zelboraf®) and dabrafenib (GSK2118436) [6]. Vemurafenib was licensed by the Food and Drug Administration Agency (FDA) in the USA in August 2011 and by the European Medicines Agency (EMA) in Europe in February 2012 on the basis of a phase III study [1]. For vemurafenib general side effects such as arthralgias [8], fatigue, nausea, diarrhea and particularly cutaneous side effects stand in the forefront (Table 2). Arthralgias are frequent during treatment with selective BRAF inhibitors. Unfortunately, many nonsteroidal anti-inflammatory drugs are metabolized via the cytochrome (CYP)-P450 isoenzyme 2C9. Thus, the bioavailability of selective BRAF inhibitors can be markedly affected. A possible way out is etoricoxib, which is only partly metabolized via CYP3A4 and which in our experience is effective and well-tolerated in a dose of 30 mg daily [8]. With severe arthralgias that predominantly affect finger, hand, elbow, knee and ankle joints, a dose reduction or therapy interruption may be necessary.

Table 2.  Most common toxicities (grade 2, 3 CTCAE 4.0) of vemurafenib in the BRIM-3 trial [1].
Adverse eventsFrequency in %
Dermatological adverse events
• RashGrade 2: 10 %, grade 3: 8 %
• PhotosensitivityGrade 2/3: 12 %
• Squamous cell carcinomasGrade 3: 12 %
• KeratoacanthomasGrade 2: 2 %, grade 3: 6 %
• AlopeciaGrade 2: 8 %
• PruritusGrade 2: 6 %, grade 3: 1 %
• HyperkeratosisGrade 2: 5 %, grade 3: 1 %
Gastrointestinal adverse events
• NauseaGrade 2: 7 %, grade 3: 1 %
• VomitingGrade 2: 3 %, grade 3: 1 %
• DiarrheaGrade 2: 5 %, grade 3: < 1 %
Other
• ArthralgiaGrade 2: 18 %, grade 3: 3 %
• FatigueGrade 2: 11 %, grade 3: 2 %

Typical cutaneous side effects are follicular hyperkeratotic rash over the ventral and dorsal midline as well as on the legs (Figure 1a), verrucous hyperkeratotic lesions, and squamous cell carcinomas or keratoacanthomas as well as UVA-induced phototoxic reactions [9] (Figure 2a). Further, hyperkeratosis of the areola (Figure 2b), keratosis pilaris at typical sites such as the extensor or lateral aspects of the upper and lower limbs (Figure 2c), Grover disease, palmoplantar erythrodysesthesia, alopecia and alterations of hair structure, as well as cystic/ milia-like lesions especially of the face can occur [10, 11]. Various treatment options are available for the specific cutaneous reactions (Table 3).

Figure 1.

Cutaneous adverse events in patients undergoing treatment with class I RAF inhibitors: (a) rash with follicular papules; (b) verrucous, hyperkeratotic lesion; (c) squamous cell carcinoma (SCC), tumor thickness 4.0 mm, 24 weeks after treatment initiation.

Figure 2.

Cutaneous adverse events in patients undergoing treatment with class I RAF inhibitors: (a) phototoxic reaction of the hands after sunlight exposure; (b) hyperkeratosis of the areola mammae; (c) keratosis pilaris of the thighs.

Table 3.  Treatment options of cutaneous toxicities in BRAF and MEK inhibitor treatment [25, 26].
BRAF inhibitor
UVA-photosensitivityNo sun exposure; information of patient that UVA penetrates window glass; broad-spectrum sun protection with SPF 50+; UV-protective clothing; in case of dermatitis solaris: symptomatic with topical corticosteroids, NSAID, when indicated
Rash, follicular hyperkeratoticSkin care with emollients with 10 % urea, topical corticosteroids (class II–III), when needed oral antihistamines, when indicated prednisolone 0.5 mg/kg orally
Squamous cell carcinomas/keratoacanthomasInformation of patient about development of secondary tumors, regular skin cancer screening, excision
Alterations of nevi, melanomasInformation of patient, instruction in self-examination, regular skin cancer screening with dermatoscopic controls, excision (with adequate safety margins, when indicated)
Verruciform hyperkeratosisExcision when malignancy is suspected, in part self-limiting course, skin care with 10 % urea
Palmoplantar erythrodysesthesia (synonyms: acral erythemas, hand-foot skin reaction)Avoidance of pressure and friction on feet and hands; soft, broad shoes with insoles; regular removal of hyperkeratoses by chiropodist, topical preparations containing 20–40 % urea, salicylic acid in petrolatum, topical preparations with tanning agents, topical corticosteroids (class III–IV); depending on severity: dose reduction or interruption of therapy
Hair alterations (alopecia or alterations of hair structure)No need for action; if therapy is urgently requested perhaps trial with Trichosense® or Regaine®
Hyperkeratosis of the areola mammaeSelf-limiting course; no need for therapeutic measures; in case of suspicious, non-hea-ling lesions: biopsy to exclude malignancy
Keratosis pilarisTopical preparations containing urea (e.g. with 10 % urea), topical corticosteroids (class II), when indicated
Cystic/ milia-like lesionsNo need for action
MEK inhibitor
 Grade 1: antibiotic cream b.i.d. (e.g. with metronidazole or nadifloxacin or erythromy-cin, as an alternative azelaic acid)
 Grade 2: metronidazole once daily in alternation with methylprednisolone aceponate; oral: minocycline 50 mg b.i.d. or doxycycline 100 mg b.i.d. (preferred in the case of renal insufficiency)
Papulopustular rashGrade 3: as grade 2, in addition: dose reduction/ therapy interruption of the MEK inhibitor; in case of lack of improvement: perhaps systemic prednisolone 0.5 mg/kg or systemic antibiotics according to antibiogram; when bacterial superinfection is suspected: fusidic acid + betamethasone valerate b.i.d.
 Grade 4: as grade 3; targeted antibiotic therapy according to antibiogram
ParonychiaHand and foot baths with antiseptic additives; in case of infection combination prepa-rations such as fusidic acid + betamethasone valerate and, when indicated, systemic doxycycline or in the event of pathogen identification systemic antibiosis according to antibiogram; for lesions resembling pyogenic granuloma silver nitrate solution
Fissures/ rhagadesTopical preparations containing 10–40 % urea, 10 salicylic acid in petrolatum; hand and foot baths with antiseptic additives; short-term use of combination preparations such as fusidic acid + betamethasone valerate under occlusion; liquid film dressing with e.g. Urgo direct®
Xerosis cutis/ pruritusTopical preparations with 10 % urea b.i.d.; short-term (1–2 weeks) topical corticoster-oids (class II–III); oral antihistamines when indicated for severe pruritus
TelangiectasesNo treatment option known to date, symptomatic treatment possible (laser, make-up, self-tanning agent)
Hair alterationsTrichomegaly: shorten eyelashes; hypertrichosis facialis: laser epilation, eflornithine (Vaniqa®)

Skin tumors such as squamous cell carcinomas and keratoacanthomas develop in 15–26 % of patients treated with class I RAF inhibitors within 2–36 weeks after initiation of therapy, especially on sun-exposed skin [1, 2, 10–13]. These are well-differentiated squamous cell carcinomas that require no further therapy other than complete excision. In none of the studies performed to date did therapy with class I RAF inhibitors have to be interrupted due to squamous cell carcinomas/ keratoacanthomas. The pathogenesis is not yet fully understood but molecular genetic studies of squamous cell carcinomas that occurred during therapy showed an increasing number of RAS mutations, particularly of H-RAS (harvey rat sarcoma) mutations [12, 13]. This suggests that there is a paradoxical activation of the MAPK signaling pathway via activating RAS mutations in analogy to the paradoxical activation of BRAF wild-type cells [14, 15]. Through inhibition of a kinase below RAS-RAF in the signaling cascade, e.g. by a MEK (MAPK kinase) inhibitor, it should therefore be possible to prevent the development of squamous cell carcinomas. This suspicion is supported by the results of a phase I/II combination study with the oral MEK1/2 inhibitor trametinib (GSK1120212) and the oral BRAF inhibitor dabrafenib (GSK2118436) [16]. In this combination study, no patient treated developed a squamous cell carcinoma. In addition therapy-associated rash and hyperkeratosis were distinctly reduced.

It must be taken into consideration that RAS mutations also play a role in the development of other tumors such as lung, colon and pancreas carcinomas. In view of the use of class I RAF inhibitors in the adjuvant setting, particular attention should be paid to the occurrence of secondary malignancies [6, 13, 17]. In the event of suspicious findings in internal organs, one should have a low threshold for performing a biopsy. Dalle et al. [18] reported the appearance of 5 primary melanomas and a dysplastic nevus in 4 patients during therapy with vemurafenib. In the mutation analysis all patients demonstrated a BRAF wild-type. This observation was confirmed by Zimmer et al. [19] who reported 12 primary melanomas and 9 dysplastic nevi in 19 patients undergoing therapy with class I RAF inhibitors. Once again, all melanomas and dysplastic nevi displayed a BRAF wild-type in the mutation analysis. Further, in one patient with melanoma and two patients with dysplastic nevi a NRAS mutation also was found. Twenty-two nevi of 21 healthy patients served as control group. In 8 of the 22 nevi a BRAF mutation but no NRAS mutation could be detected. The paradoxical activation of the MAPK signaling pathway appears to play a significant role here also. In patients undergoing therapy with class I RAF inhibitors skin cancer screening with dermatoscopic controls [18, 19] as well as excision of suspicious lesions is recommendable.

MEK inhibitors

Besides blockade of RAF, currently inhibitors of molecules further downstream in the signaling pathway such as MEK are being tested also in clinical studies on melanoma and other solid tumors. These include, among others, the selective MEK1/2 inhibitors selumetinib (AZD6244), trametinib (GSK1120212), MEK162 and RO4987655. The most common side effects are papulopustular rash (74–85 %), diarrhea (48–56 %), peripheral edema, fatigue, nausea and vomiting [20, 21]. We have also repeatedly observed asymptomatic elevations of creatinine kinase. Further, ocular toxicities such as blurred vision, macula edemas, retinal detachment, retinal vein occlusion, central serous retinopathy, glaucoma and elevated intraocular pressure can occur. Therefore before initiation of and during therapy, regular ophthalmological consultations are necessary [20, 21]. Most ocular alterations are reversible on discontinuation of therapy. Loperamide can be administered successfully for therapy of diarrhea; an interruption of therapy may be indicated [21]. The papulopustular rash usually appears in the first 3 weeks after initiation of therapy in the seborrheic areas such as face and trunk. After discontinuation of therapy it is usually completely reversible within 4–6 weeks (Figure 3a) [22, 23]. During the course bacterial superinfection with Staphylococcus aureus may occur (Figure 4a) [22]. Further cutaneous lesions that are usually observed after more than 6 weeks of therapy are paronychia, xerosis cutis, pruritus, fissures of the finger tips and heels, cheilitis angularis, alopecia, telangiectases and hyperpigmentation [22, 23]. The clinical spectrum of cutaneous lesions observed resembles the known cutaneous toxicities that can occur during therapy with EGFR (epidermal growth factor receptor) inhibitors (Figures 3a, b; 4 a, b). Schad et al. [23] additionally reported depigmentation of scalp hair as has already been observed in therapy with c-Kit inhibitors [24]. After interruption of therapy, repigmentation occurred regularly. Pathophysiologically, inhibition of the MAPK signaling pathway in keratinocytes appears to result in similar cutaneous side effects either by blockade of the EGF receptor or the MEK kinase [23]. Therefore, the same recommendations as for EGFR-induced cutaneous lesions apply to the prevention and therapy of cutaneous side effects during MEK inhibitor therapy (Table 3).

Figure 3.

Papulopustular rash of: (a) the face in patients undergoing MEK inhibitor treatment; (b) the scalp during treatment with cetuximab.

Figure 4.

Superinfected papulopustular rash: (a) in patient undergoing MEK inhibitor treatment; (b) in patient undergoing treatment with erlotinib.

Immunomodulatory agents

Ipilimumab

The new development of the antibody ipilimumab against the cytotoxic T-lymphocyte antigen 4 (CTLA-4) first demonstrated an advantage with respect to survival in melanoma patients with advanced disease who were first treated with chemotherapy [3]. These results led to approval in Europe in 2011. CTLA-4 is a type I membrane protein expressed on activated T cells and monocytes [27]. Physiologically it mediates a local, temporary down-regulation of the immune response. The blockade of CTLA-4 with specific humanized monoclonal CTLA-4 antibodies can abolish the inhibition of the T-cell immune response, producing a sustained and prolonged anti-tumoral T-cell response [28]. The plasma half-life of ipilimumab is 14 days. This must be taken into consideration in the management of side effects. Because the heightened immune response also acts on the body's own cells, therapy is associated with autoimmune adverse events. A majority of patients develop these adverse events. Autoimmune-related adverse events were observed in a total of 60 % of the patients in the licensing study [3]. In 10–15 % of the patients these adverse events were classified as grade 3 or 4 according to NCI-CTCAE v3.0 (National Cancer Institute – Common Terminology Criteria for Adverse Events) [3]. Seven of the total of 14 deaths were attributed to immunological adverse events [3]. In principle any organ can be affected, but some organ-specific adverse events are more frequent (Table 4) and can limit therapeutic use [3].

Table 4.  Ipilimumab – organ-specific autoimmune-related adverse events (irAE) and recommended treatment measures (modified according to [29]).
Common irAE (with respect to grades according to CTCAE v3.0)Reported frequency[%]Recommended therapeutic measures (severity classification according to CTCAE v3.0)
  1. Uveitis, iritis, conjunctivitis, blepharitis, (epi-)scleritis, eosinophilia, hemolytic anemia, elevated lipase levels, elevated amylase levels, pancreatitis, glomerulonephritis, pneumonitis, myo-/ pericarditis, meningitis

  2. Abbreviations: ULN, upper limit of normal; irAE, autoimmune-related adverse events (irAE)

irColitis/ diarrhea∼30 %Grade 1: symptomatic (loperamide), further ipilimumab administration possible Grade 2: Prednisone 1 mg/kg/d orally, interrupt ipilimumab until < grade 1 Grade 3/4: initially methylprednisolone 2 mg/kg/d, discontinue therapy with ipilimumab permanently For all grades substitute fluids and/or electrolytes if indicated
irHepatotoxicity<5 %GOT/GPT < 5x ULN + total bilirubin < 3x ULN: close monitoring of liver function tests, further ipilimumab administration possible GOT/GPT > 5–^ 8x ULN + total bilirubin > 3–< 5x ULN: close monito-ring of liver function tests, ipilimumab therapy interruption until GOT/GPT < 5x ULN + total bilirubin < 3x ULN GOT/GPT > 8x ULN + total bilirubin > 5x ULN: initially methylprednisolone 2 mg/kg/d i.v, discontinue therapy with ipilimumab permanently
irEndocrinopathy (hypo-physitis, hypopituitarism, adrenal insufficiency, hypothyroidism)∼8 %Depending on symptoms and laboratory values: hormone substitution, systemic mineral corticosteroids, when indicated; if needed ipilimumab interruption until endocrinopathy under control through hormone substitution therapy
irNeuropathies<5 %Grade 1: symptomatic treatment according to neurologist's recommendation, if indicated oral prednisone, further ipilimumab administration possible Grade 2: symptomatic treatment according to neurologist's recommendation, if indicated oral prednisone; ipilimumab therapy interruption until < grade 1 Grade 3/4: initially methylprednisolone 2 mg/kg/d i.v, discontinue therapy with ipilimumab permanently
irDermatitis (pruritus, rash, vitiligo)∼40 %With respect to ir-rash:Grade 1, 2: topical corticosteroid therapy, e.g. betamethasone 0.1 % cream or prednisone 1 mg/kg/, further ipilimumab administration possible Grade 3: as grade 2 + prednisone 1 mg/kg/d, if needed, ipilimumab therapy interruption until < grade 1 Grade 4: initially methylprednisolone 2 mg/kg/d, discontinue therapy with ipilimumab permanently
  It fundamentally applies that skipped ipilimumab administration due to irAE may not be made up
Rare irAE<1 % 

The appearance of autoimmune-related cutaneous adverse events about 3–6 weeks after the initiation of therapy was documented in about 40 % of patients in the licensing study. Both pruritus, usually mild, and maculo-papulo-pustular rash were seen in about 17 % of patients [3]. Review of study data from further clinical studies before licensing demonstrated that 27 % of patients each developed pruritus or a rash. Further, vitiligo developed in about 3 % of patients [3]. Severe cutaneous adverse events (grade 3 or above) were seen rarely in the licensing study or in further clinical studies on the use of ipilimumab [3, 4, 29].

Early recognition and treatment of these antibody-associated adverse events (Table 4) is of particular importance in order to care for patients in accordance with present treatment algorithms and not endanger them [30]. Experience to date demonstrates that the learning process with respect to diagnostics and therapy is in its early stages for dermatologists but also for internists.

Classical cytostatic therapy

In comparison to targeted agents, classical cytostatic drugs act on all rapidly dividing cells. Correspondingly, side effects on hair, skin, nails and mucous membranes are common. Further important side effects are leukopenia, nausea and emesis as well as the risk of extravasation in intravenous administration (for prevention and therapy of extravasation see review article by Kähler et al. [31]). Table 5 provides an overview of the most important side effects and their management; special dermatological side effects are presented more in depth in the text.

Table 5.  Spectrum of adverse events of conventional chemotherapeutics in dermato-oncology.
Cytostatic agentSubstance groupLicensed forNon-dermatological major side effectsEmetogenic potentialParavasationAlopeciaHypersensitivity reactionsSpecial cutaneous lesions
  1. Abbreviations: CA, carcinoma; SCR, single case reports; NSCLC, non-small cell lung cancer

DTIC (dacarbazine)Alkylating agentsMelanoma Hodgkin disease and soft tissue sarcomasNausea, emesis, myelosuppression BEWARE: liver necrosis due to hepatic vein occlusion possibleHighTissue irritantRareIn up to 20 %Phototoxicity, SCR: inflammation of actinic keratoses, radiation recall dermatitis
TemozolomideAlkylating agentsMelanoma, brain tumorsNausea, emesis, myelosuppression, headaches, obstipationModerateNot applicable55 %RareRash, pruritus SCR: xerosis cutis, erythemas, erythema multiforme, Stevens-Johnson syndrome
PaclitaxelTaxanesOvarian CA, NSCLC, breast CA, AIDS- associated Kaposi sarcomaNeutropenia, peripheral neuropathy, arrhythmiaLowTissue irritant, questionable cause of tissue necrosisFrequentFrequentMucositis, especially in leukemi patients, radiation recall dermat tis, erythema multiforme, ony-cholysis, SCR: hand-foot syndrome, AGE-like generalizec pustular dermatosis, multiple fi xed drug eruptions, Stevens-Johnson syndrome, photosensi tivity, subacute cutaneous lupus erythematosus, multiple cutaneous ulcerations, pseudoscleroderma, hyperpigmentation
CarboplatinPlatinum compoundsOvarian CA, NSCLCMyelosuppression, nausea, emesis, electrolyte disturbances, nephrotoxicity, neuroto-xicity, ototoxicityModerateNot toxic to tissueVery frequentAbout 2 %Hyperpigmentation (also nails) rash, radiation recall dermatitis
Liposomal doxorubicinAnthracyclinesBreast CA, ovarian CA, multiple myeloma, AIDS-as-sociated Kaposi sarcomaMyelosuppression, cardiotoxicity nauseaLowTissue irritantMild3-25 %Stomatitis, hand-foot syndrom SCR: rash, radiation and UV recall dermatitis, hyperpigmentation especially palmoplantar and mucosal

DTIC and temozolomide

DTIC (dacarbazine) is highly emetogenic; adapted antiemetic therapy (Table 6) adapted to individual risk factors is important. As the most severe, acute non-dermatological side effect in rare cases (> 1/10,000, < 1/1,000) liver vein occlusion can result in liver necrosis (veno-occlusive syndrome). Sun exposure after administration of DTIC can lead to pruritic, maculo-urticarial erythemas accompanied by burning pain especially in light-exposed areas. These most probably phototoxic reactions usually manifest after the third infusion and are possibly caused by the metabolite 2-azahypoxanthine [32, 33]. Patients should be instructed to avoid direct sun exposure after administration. To avoid photodegradation of DTIC, the infusion bags and lines must be protected from light [32]. The erythemas can be treated with topical corticosteroids as needed. In severe phototoxic reactions, therapy must be discontinued, as skin lesions may be intolerable for the patient and it is suspected that the phototoxic metabolite 2-azahypoxanthine has no antitumor activity [32]. A switch to the sister substance temozolomide (Temodal®) is possible; here no phototoxic reactions have been seen to date [32].

Table 6.  Antiemetic dosing by chemotherapy risk categorya, recommendations of the American Society of Clinical Oncology [54].
Risk groupDose on the day of chemotherapyDose on the following days
  1. In patients receiving chemotherapy over several days the treating physician must first determine the emetogenic potential of all substances of the protocol. The substances with the highest therapeutic index should be administered to the patient daily on the days of chemotherapy as well as up to 2 days thereafter. Transdermal granisetron patches that act therapeutically over several days can be offered to the patient instead of daily administration of serotonin antagonists. Abbreviations: 5-HT3, hydroxytryptamine; NK1, neurokinin 1. aEmetogenic potential: high > 90 %, moderate 30–90 %, low 10–30 %, minimal < 10 %. bIncludes combination of anthracyclines and cyclophosphamide. cThe dexamethasone dosage applies to patients receiving the recommended 3-day regimen for highly emetogenic chemotherapy. When patients do not receive aprepitant, the dexamethasone dose should be 20 mg on day 1 and 16 mg on day 2 and 4. dPhysicians who have selected an NK1 antagonist should follow the dosage scheme for highly emetogenic therapy. Important: The corticosteroid is administered only on day 1 at a dosage of 12 mg dexamethasone

High emetogenic potentialb
NK1antagonist
• Aprepitant125 nig orally80 mg orally; day 2 and 3
• Fosaprepitant150 mg i.v. 
5-HT3 antagonists
• Granisetron2 mg orally; 1 mg or 0.01 mg/kg i.v. 
• Ondansetron8 mg orally 2x/d or 0.15 mg/kg i.v. 
• Palonosetron0.50 mg orally; 0.25 mg i.v. 
• Dolasetron100 mg orally 
• Tropisetron5 mg orally; 5 mg i.v. 
• Ramosetron0.3 mg i.v. 
Corticosteroidc
Dexamethasone12 mg orally or i.v.8 mg orally or i.v; day 2—3 or day 2—4
Moderate emetogenic potentiald
5-HT3 antagonists
• Palonosetron0.50 mg orally; 0.25 mg i.v. 
Corticosteroid
• Dexamethasone8 mg orally or i.v.8 mg; day 2 and 3
Low emetogenic potential
Corticosteroid
• Dexamethasone8 mg orally or i.v. 

Hypersensitivity reactions that are usually seen after the first or second administration are observed in up to 20 % of patients treated [34]. Dependence on dose has not been detected. In individual patients a severe form of hypersensitivity with fever, hypereosinophilia, disturbed hepatic function (cytolysis and cholestasis) and delayed bone marrow aplasia has been seen [34]. In mild hypersensitivity, DTIC therapy can be continued under administration of antihistamines and corticosteroids.

Radiation recall dermatitis in fields formerly treated by radiation therapy has been reported in one woman [35]. Acute radiation recall dermatitis can be treated with topical and when needed oral corticosteroids and possibly be prevented in subsequent cycles by pre-treatment with corticosteroids [35].

In contrast to DTIC orally administered temozolomide undergoes degradation spontaneously ubiquitously in the body and not only in the liver to 3-methyl-(triazen-1-yl) imidazole-4-carboxamide (MTIC). Dermatological side effects are rare; rash and pruritus (8 %) as well as hypersensitivity reactions have occasionally been reported. Alopecia, which develops frequently (55 %) in comparison to DTIC, must be viewed in consideration of the patient group that has often undergone previous total brain irradiation.

Paclitaxel

Hypersensitivity reactions with dyspnea, hypotension, bronchospasm, urticaria and erythemas regularly occur during paclitaxel therapy [36], which is why premedication with dexamethasone, diphenhydramine and/or an H2-blocker has become routine. The vehicle Cremophor® EL is held responsible, as it is known to induce mast cell degranulation [37]. Further dermatological side effects of paclitaxel include radiation recall dermatitis [38], erythema multiforme [39] and onycholysis [40]. Now a nanoparticle formulation of paclitaxel (nab-paclitaxel) for which no solvents are needed is available. In a phase III study without premedication only 4 % of patients developed hypersensitivity reactions; the rate of peripheral neuropathies was significantly higher in contrast to non-encapsulated paclitaxel [41]. Phase II studies demonstrated good antitumor activity of nab-paclitaxel even in melanoma [42, 43], which must still be confirmed in phase III studies (NCT00864253).

Carboplatin

Hypersensitivity reactions during carboplatin treatment occur in only about 2 % of patients usually after longer therapy duration [44]; the spectrum of side effects ranges from severe reactions with erythroderma, tachycardia, tightness in the chest, facial edema, dyspnea and hypo-/hypertension [45] to mild symptoms such as pruritus and erythema especially of the palms and soles or facial flushing [46]. In contrast to paclitaxel it is probably the substance itself and not the vehicle that is the triggering agent. In mild reactions the administration of antihistamines suffices, in the event of severe reactions therapy should be discontinued.

Pegylated liposomal doxorubicin (PLD)

By means of liposomal encapsulation the side effect potential is distinctly reduced on the whole in comparison to non-encapsulated doxorubicin. Cutaneous and mucosal side effects are the major side effects of this substance.

The hand-foot syndrome (HFS) is observed in up to 50 % of patients at a higher dosage (50 mg/m2 every 4 weeks) [47] and up to 4 % at a lower dosage (20 mg/m2 every 3 weeks) [48]; it usually manifests after 2–3 infusions and is often the dose-limiting side effect. The patients first report palmar-plantar dysesthesia, in the further course burning pain and sharply demarcated erythema and edema (Figure 5a) that can progress to blistering and desquamation [49]. In contrast to the hand-foot skin reactions (HFSR) during multi-tyrosine kinase inhibitor (MTKi) therapy, involvement of the back of the hands and feet and intertriginous areas (Figure 5b) and under tightly fitting clothing (Figure 5c) has been reported in some cases. Further, the lesions are less hyperkeratotic [49]. The pathogenetic mechanism is likely excretion of the chemotherapeutic agent via sweat glands, which would explain the distribution of the cutaneous lesions at sites with a rich supply of sweat glands. PLD therapy should be adapted according to the CTCAE side effect grade as described in the prescribing information.

Figure 5.

HFS in women receiving treatment with PLD for metastatic breast cancer: (a) well-demarcated, edematous erythema of the soles extending to the back of the foot; affected areas can include the intertriginous areas, e. g. (b) the axilla as well as (c) areas of tightly fitting clothing contact such as the right thigh as depicted here.

Measures for prevention and symptomatic therapy are the same as in the therapy of HFSR under MTKi (Table 3). Cooling of hands and feet during the infusion as well as washing the hands repeatedly with lukewarm water can serve as prevention [50], even though the data are not yet definitive [51]. Preclinical data [52] as well as case reports support the prophylactic efficacy of systemic therapy with pyridoxine (vitamin B6) during PLD therapy. In a double-blind, randomized, placebo-controlled study the administration of 100 mg vitamin B6 (pyridoxine) twice daily was nonetheless not able to prevent the occurrence of HFS in women undergoing PLD therapy for breast cancer [53]. On the basis of current data use outside of clinical studies cannot be recommended [51]. The topical use of radical quenchers such as dimethyl sulfoxide (DMSO) or Mapisal® may also be effective; sufficient data are not currently available to make a general recommendation [51]. As with MTKi and EGFRi, comprehensive patient information with preventive behavioral measures has priority.

Stomatitis can also be dose-limiting. Due to the risk of superinfection, culture is obligatory. When infection is detected, specific therapy is indicated; otherwise only symptomatic treatment is possible. Topical care measures (such as camomile tea or dexpanthenol) also in combination with corticosteroids and local anesthetics for topical application can provide relief. Before and during the intravenous administration, local cooling of the oral cavity is possible, and attention should be paid to good oral hygiene and avoidance of irritating foods.

Conclusions

The goal of personalized, effective cancer therapy low in side effects is continually coming closer through the detection of therapeutically relevant molecular alterations and new understanding at the immunological level. The licensing of new targeted and immunomodulatory therapeutic agents where especially cutaneous autoimmune-induced side effects besides the general well-known side effects such as nausea, vomiting, diarrhea and fatigue stand in the forefront, present oncologists as well as dermatologists with new therapeutic challenges. Due to the increasing number of oncologic patients treated with these substances, in part in combination with chemotherapeutic agents, knowledge of the specific side effects is of key importance to the oncologist as well as dermatologist. Thereby unnecessary discontinuation of therapy or severe side effects can be avoided. The success of these new oncologic therapies will to a great extent depend on the quality of pre-treatment patient information. A sound knowledge of expected side effects will increase patient compliance and optimize management of these side effects, should they occur.<<<

Conflicts of interest

LZ: honoraria from Bristol-Myers Squibb and Roche; JV: honoraria from Amgen, Boehringer Ingelheim Pharma, Essex, Roche, Bristol-Myers Squibb, GlaxoSmithKline; EL: honoraria from Bristol-Myers Squibb; DS: honoraria from and advisory boards of Roche, Bristol-Myers Squibb und GlaxoSmithKline.

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