Skin Cutaneous Toxicities

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Contents

22.1 Alopecia . . . 355

22.1.1 Incidence . . . 355

22.1.2 Etiology . . . 355

22.1.3 Treatment . . . 356

22.1.4 Prognosis . . . 356

22.2 Altered Skin Integrity Associated with Radiation Therapy . . . 357

22.2.1 Incidence . . . 357

22.2.2 Etiology . . . 357

22.2.3 Prevention . . . 357

22.2.4 Treatment . . . 358

22.2.5 Prognosis . . . 358

22.3 Radiation Sensitivity and Recall . . . 358

22.3.1 Incidence . . . 358

22.3.2 Etiology . . . 358

22.3.3 Treatment . . . 359

22.3.4 Prognosis . . . 359

22.4 Photosensitivity . . . 359

22.5 Cutaneous Reactions Associated with High-dose Cytosine Arabinoside . . . 359

22.5.1 Incidence . . . 359

22.5.2 Etiology . . . 359

22.5.3 Prevention and Treatment . . . 359

22.6 Nail Dystrophies . . . 360

22.7 Graft Versus Host Disease . . . 360

22.7.1 Incidence and Etiology . . . 360

22.7.2 Treatment . . . 361

22.7.3 Prevention . . . 362

22.7.4 Treatment . . . 362

22.7.5 Prognosis . . . 362

References . . . 363

22.1 Alopecia 22.1.1 Incidence

Alopecia is one of the most common dermatological side effects of cancer therapy. It can vary in degree from sporadic thinning to complete baldness (Batch- elor, 2001). The majority of chemotherapy protocols, particularly those with mitotic inhibitors, and any radiation involving the scalp (including total body irradiation) will affect the rapidly dividing cells in the hair follicles. Chou et al. (1996) reported that approximately 50% of children receiving total body irradiation for bone marrow transplant displayed alopecia.

The degree of hair loss was not described, though; the description of hair loss is frequently under-reported in the literature (Batchelor, 2001).

Table 22.1 describes cytotoxic drugs associated with alopecia in children. The severity of hair loss also depends on the route, dose, and schedule of the drugs and on the hair condition.

22.1.2 Etiology

The proliferating hair follicles are targeted by the treatment, which results in thin, weak hair or complete loss of the hair shaft formation (Alley et al., 2002). Up to 90% of all hair follicles are in a phase of rapid growth. The hair follicles of skin areas with the most rapid growth, such as the scalp, are affected more than the slower-growing eyebrows, eyelashes, and other body hair. However, repeated treatments with mitotic inhibitor agents can eventually lead to thinning and loss of hair in these areas as well (Alley et al., 2002). Alopecia of this nature is reversible, but the hair that grows back may be different in color or

Skin

Cutaneous Toxicities

Deborah Tomlinson · Nan D. McIntosh

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texture. The pathobiology of the response of hair follicles to cytotoxic treatment is largely unknown (Botchkarev 2003). Research by Botchkarev and colleagues (2000) has indicated an essential role of the p53 gene in the process of chemotherapy-induced hair loss.

22.1.3 Treatment

Methods to reduce the incidence of chemotherapy- induced alopecia have been studied since the 1970s, with varying evidence for the efﬁcacy of the measures taken. Recent devices have included gel cool caps (Macduff et al., 2003), digitized scalp-cooling systems (Ridderheim et al., 2003), and Penguin Cold Cap systems (Katsimbri et al., 2000). Marginal beneﬁts in preventing alopecia in adult cancer patients were reported; these devices are time-consuming and usually present some discomfort.

Patient reactions to hair loss vary and may be related to the individual’s perception of the importance of hair. Hair can have religious connotations; reﬂect trends of personal expression; and characterize beauty, age, and one’s gender (Batchelor, 2001). In the pediatric population, adolescents (particularly girls) are generally more likely to be affected by the resulting change in body image caused by hair loss (Wu and Chin, 2003). In a study on quality of life among childhood leukemia patients, Hicks et al. (2003) found that hair loss was one of ﬁve emergent themes.

Ten of the 13 children (5–9 years old) in this study

mentioned hair loss; however, only one was distressed when it occurred (Hicks et al., 2003). Parents may be more distressed than their child about the hair loss, as it conﬁrms the harsh reality of initial treatment (McGrath, 2002).

Nurses can play an important role in assisting children, adolescents, and parents to cope with alopecia.

Nurses can help prepare for alopecia by providing in- formation on the process and strategies for protecting the skin and eyes following hair loss (Batchelor, 2001). Adolescents may warrant more attention related to how they perceive their appearance and how to help them develop a positive body image (Wu and Chin, 2003). Shaving the head once hair loss becomes apparent is relatively common and can help with scalp irritation as well as avoiding prolonged hair loss, which may be uncomfortable for the patient.

Wearing caps, scarves, and wigs can help the individual cope with alopecia (Alley et al., 2002).

22.1.4 Prognosis

Alopecia does not present a medical threat to children or adolescents with cancer; however, it may be psychologically devastating, particularly to the ado- lescent.

Table 22.1. Cytotoxic agents that cause hair loss in children (adapted from Batchelor 2001)

Mild hair loss Moderate hair loss Severe hair loss

Bleomycin Busulphan Cyclophosphamide

5-Flurouracil Methotrexate Daunorubicin

Hydroxyurea Mitomycin Doxorubicin (Adriamycin)

Melphalan Teniposide Ifosfamide

Cisplatin Actinomycin Etoposide

Cytarabine arabinoside Vincristine High-dose vincristine

Thioguanine Vinblastine

Chlorambucil L-asparaginase Thiotepa

Mercaptopurine (6-mp)

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22.2 Altered Skin Integrity Associated with Radiation Therapy

22.2.1 Incidence

It has been reported that 95% of patients treated with radiation therapy experience a skin reaction (Porock et al., 1999). It is unclear whether this incidence in- cludes children, and the severity of the reaction is unreported, but it does include radiation-recall skin reactions.

Advanced planning and delivery techniques of radiotherapy help decrease its effect on the skin, but the radiation invariably affects some of the skin cells.

22.2.2 Etiology

The radiotherapy acts on the proliferating cells of the epidermis at the point of entry (or exit) of the radiation. Cells in the epidermis have a life cycle of 2–3 weeks, and skin reactions often begin around this time.

Table 22.2 lists four recognized stages of radiation skin reaction.

22.2.3 Prevention

Preventative measures must be instigated from the day radiotherapy begins. The skin condition of children receiving radiotherapy should be assessed daily.

Table 22.2. Stages of radiation skin damage (Boot-Vickers and Eaton, 1999; Hopkins et al., 1999)

Stage Reaction Cause Treatment

Erythema Reddening of skin Dilation of capillaries Water-based moisturizing cream/aqueous within 1 week of in response to the cream.

beginning therapy. damage A topical steroid (usually 1 % hydrocortisone) Hot, irritable rash to reduce irritation, itching and soreness.

This treatment should be prescribed and used sparingly as it can inhibit healing due to its anti-inﬂammatory properties

Dry desqua- Dry, ﬂaky skin usually Cell death in the upper As for erythema.

mation 2–4 weeks after onset layers of skin. If damage is due to friction, a self-adhesive, of therapy. Decreased ability of thin, aerated dressing may be applied and left Peeling skin epidermal basal cells intact until treatment is complete. If used, Irritation to replace surface cells. this dressing needs to be kept dry Often occurring Sweat and sebaceous

in skin folds glands are damaged.

Friction increases damage

Moist desqua- Skin peeling or Damage to the epidermis Wound-healing principles (institutions may mation denuding with exudate; that exposes the dermis vary in treatment policies).

often white or yellow and allows leakage of Hydrogel dressing covered with gauze in color serous ﬂuid from the and secured without the use of adhesive tape.

tissues. Area is at risk from Dressing must be removed during radiotherapy infection and ﬂuid loss. treatment as it could alter the dimensions for the A break in therapy may penetration of the radiation

be necessary to allow repair of tissue

Necrosis Darkened tissue that Therapy has exceeded Surgery with debridement ± grafting eventually turns black the tolerance dose and

causes basal cell death, leading to ulceration and necrosis

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Radiation skin reactions may not be preventable, but general principles of skin care included in skin-care policies may help decrease the severity of reactions (Campbell and Lane, 1996; Boot-Vickers and Eaton, 1999). Principles include the following:

1. Ensuring good skin hygiene to prevent increased irritation of the epithelium and to prevent bacteria build-up. Advice should include the need to use mild soap and warm water, pat skin dry, and pre- serve treatment marks

2. Washing hair gently, if the head area is treated, avoiding scrubbing; drying hair on a low setting if a hair dryer if necessary

3. Avoiding deodorants and perfumes at the radiation site

4. Preventing dehydration of the skin by applying moisturizing cream or aqueous cream, which helps to retain water and lubricates to reduce friction

5. Protecting skin from the sun during treatment and for 8 weeks following treatment. High-factor sunscreen should be used for at least 1 year post-treatment (and preferably for life)

6. Avoiding hot water bottles and ice packs

7. Swimming may be allowed, but the irradiated area should be showered gently afterwards and an aqueous cream applied

8. Choosing loose-ﬁtting clothing that will not cause friction or trauma to the treatment site

Treatment options are included in Table 22.2.

Good assessment and proper skin care should prevent permanent skin damage from radiation therapy.

Nurses have a role to instigate skin assessment and deal with concerns about altered skin integrity for these children and adolescents

22.3 Radiation Sensitivity and Recall 22.3.1 Incidence

Some cytotoxic drugs can sensitize the skin to radiation (Alley, 2002). Radiation recall dermatitis is the occurrence of an acute inﬂammatory toxicity in a previously radiated ﬁeld following subsequent administration of cytotoxic therapy (Yeo and Johnson, 2000). The incidence in the pediatric population is unreported, but drugs that are particularly associated with radiation sensitization and recall are listed in Table 22.3. The radiation dermatitis develops days to weeks (and sometimes years) after radiation therapy with subsequent administration of chemotherapy.

Ataxia telangiectasia gene mutation and protein kinase deﬁciency have been associated with an increased susceptibility to severe radiation-induced skin toxicity (Yeo and Johnson, 2000).

22.3.2 Etiology

The mechanisms of radiation-recall sensitivity are undeﬁned. Possibilities include the following:

▬Depletion in tissue stem cells within the irradiated ﬁeld caused by the radiation therapy and subsequent chemotherapy exposure causes a “remem- bered” reaction by the remaining cells (Yeo and Johnson, 2000).

Table 22.3. Cytotoxic drugs commonly associated with radiation interactions (adapted from Alley et al., 2002)

Radiation interaction Drug Radiation sensitization and recall Bleomycin

Dactinomycin Daunorubicin Etoposide 5-Fluorouracil Hydroxyurea Melphalan Methotrexate Vinblastine

Photosensitivity 5-Fluorouracil

Methotrexate Vinblastine

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▬Radiation induces heritable mutations within sur- viving cells, producing a group of defective stem cells that are unable to tolerate a second insult with systemic chemotherapy (Indinnimeo et al., 2003).

Skin reactions can range from a mild rash to severe skin necrosis with manifestations that include maculopapular eruptions with erythema, vesicle formation, and desquamation of the affected skin areas (Al- ley et al., 2002).

There is no speciﬁc treatment for this dermatitis, but topical steroids are often used. Other anti-inﬂamma- tory agents may also be prescribed, and supportive therapy is necessary. On rare occasions the cytotoxic therapy may be discontinued.

Most of the lesions will heal with supportive therapy.

A decision to continue with the chemotherapeutic agent is usually determined by the severity of the reaction and the chemoresponsiveness of the tumor to that particular drug (Yeo and Johnson, 2000).

22.4 Photosensitivity

There is no reported incidence of photosensitivity in children; however, it is established that ultraviolet radiation (sunlight) can produce effects on the skin of patients previously treated with cytotoxic therapy similar to those seen in radiation-recall. Table 22.3 lists the main drugs used in pediatrics that are likely to cause photosensitivity.

It has also been reported that children previously treated for malignancy have an increased number of benign melanocytic nevi (moles), which may increase their risk of developing melanoma (Hughes et al., 1989).

Children and caregivers should be educated on the need for adequate sun protection: using sunscreen, seeking shade, wearing sun hats. Interestingly, studies show that the use of sunscreen can often increase the

number of sunburn incidences (Davis et al., 2002;

Horsley et al., 2003). This ﬁnding emphasizes a need for education regarding the proper use of these prod- ucts and an increased need for protective measures for the entire population.

22.5 Cutaneous Reactions Associated with High-dose Cytosine Arabinoside 22.5.1 Incidence

The incidence of cutaneous toxicity associated with high-dose cytosine arabinoside (HDAC) has been stated to range from 3% to 72% (Richards and Wujick, 1992). A study by Cetkovska et al. (2002) reported the overall incidence of cutaneous reaction to be 53% in 172 patients aged 16–71 treated with HDAC. Whitlock and colleagues (1997) found that 22% (4 of 18) of children developed cutaneous reactions with HDAC.

22.5.2 Etiology

The etiology of toxicity associated with HDAC is unclear. This toxicity can range from erythema to painful swelling, bullae formation, and desquamation. The severity of the reaction appears to be related to the dose and the number of consecutive doses.

Erythema of this nature that begins on the palms and soles is known as hand-foot syndrome, or palmar- plantar erythrodysesthesia, and was originally described in patients receiving HDAC (Alley et al., 2002). However, other drugs have been associated with this toxicity, including 5-ﬂuorouracil, doxorubicin, and methotrexate (Alley et al., 2002).

22.5.3 Prevention and Treatment

No therapy has been shown to prevent this condition, but most skin changes clear spontaneously (Cetkovs- ka et al., 2002). Although this side effect is considered manageable, nurses must explore measures that could minimize these complications and reduce their impact on the patient’s quality of life.

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22.6 Nail Dystrophies

Although nail changes in patients receiving chemotherapy are reportedly fairly common (Alley et al., 2002), they are unreported as a problem for children.

However, transverse ridges may occur, reﬂecting cyclic damage to the nail matrix. Nurses should be aware that nail changes are a possibility.

22.7 Graft Versus Host Disease 22.7.1 Incidence and Etiology

Graft versus host disease (GvHD) occurs when trans- planted donor cells recognize and react to recipient histoincompatible cells, causing tissue damage (Fig. 1). It remains a major complication after allogeneic hematopoietic stem cell transplantation, espe- cially with the increased use of stem cells from unrelated and mismatched donors. GvHD is classiﬁed as acute and chronic, although the distinction between them is not simply chronological. They both result from activation of donor T-cells against host antigens, but they have a different pathogenesis.

The acute form of GvHD usually develops up to 100 days after allogeneic SCT and is graded according to severity (Table 22.4).

Clinically relevant grades II to IV occur in approximately 20–50% of patients who receive stem cells from a human leukocyte antigen (HLA) identical sibling donor and in 50–80% whose donor is an HLA-

mismatched sibling or HLA-identical unrelated donor (Tabbara et al., 2002).

The classically recognized target organs affected by acute GvHD are the skin, liver, and gastrointestinal tract, but other organs may be affected.

Chronic GvHD is a result of a later phase of allore- activity. It occurs in approximately 30% of patients, usually after the ﬁrst 100 days but up to years after transplantation. It can follow acute GvHD (progres- sive); can occur after the resolution of acute GvHD

Figure 22.1

Mechanisms involved in phase 1 of GvHD

Total body irradiation/high dose chemotherapy Extensive damage

Activation in host tissues

Release of inﬂammatory cytokines

Recipient major histiocompatibility complex (MHC) antigens enhanced

Table 22.4. Clinical grading of acute GvHD

Grade Skin Liver Gastrointestinal

0 No rash Bilirubin <2 mg/dl <500 ml diarrhea/24 hours

I Rash on <25 % of body surface Bilirubin 2–3 mg/d >500 ml diarrhea/24 hours II Rash on 25–50 % of body surface Bilirubin 3–6 mg/d >1,000 ml diarrhea/24 hours III Generalized erythroderma Bilirubin 6–15 mg/dl >1,500 ml diarrhea/24 hours IV Desquamation and bullae Bilirubin >15 mg/dl Severe abdominal pain ± ileus

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(quiescent); or be de novo, in which case there was no acute GvHD. Clinical manifestations of chronic GvHD are similar to autoimmune collagen vascular diseases. It appears to be a syndrome of immune dys- regulation resulting in autoimmunity and immunod- eficiency (Shere and Shoenfield, 1998). It may involve various organs including the skin, liver, mouth, and eyes. Chronic GvHD is classified as either limited or extensive (Table 22.5) in an attempt to determine which patients need treatment.

Patients who receive an allogeneic bone marrow transplant fulﬁll the criteria necessary for the development of GvHD (Billingham, 1966):

▬Administration of adequate numbers of immuno- competent cells

▬Donor and recipient histocompatibility

▬Inability of the recipient to destroy the donor cells

Table 22.6 shows a three-phase model that elucidates the major processes that lead to GvHD (Ferrara et al., 1999).

The skin is the most commonly affected system of acute GvHD. It is typically characterized by the following signs and symptoms, but these may also be a consequence of chemotherapy, radiation, or other drugs and are therefore not diagnostic of acute GvHD (Goker et al., 2001).

▬A pruritic maculopapular rash involving the face, trunk, palms, and soles of the feet usually marks the onset (see Fig. 22.2)

▬The rash usually occurs at or near the time of en- graftment

▬The rash may look like a sunburn

▬In severe cases, the rash develops into generalized erythroderma, bullous lesions, and desquamation, and may progress to epidermal necrosis

GvHD may also affect the liver, with derangement of hepatic function resulting in increased bilirubin, al- kaline phosphatase, and aminotransferase levels. In the post-transplant setting, these abnormalities may occur secondary to drug-induced liver toxicity, veno- occlusive disease, or hepatitis. Abdominal cramping and profuse diarrhea are characteristic manifestations of acute GvHD of the gastrointestinal tract.

Other symptoms may include anorexia and weight loss.

Table 22.5. Classiﬁcation of chronic GvHD

Limited Extensive chronic GvHD chronic GvHD

Either or both: Either generalized skin involvement or localized skin involvement Localized skin with or without hepatic

involvement dysfunction

Hepatic dysfunction or eye involvement or oral mucosa involvement or any other target organ involvement

Table 22.6. Processes leading to GvHD (Goker et al., 2001)

Phase Processes

Phase 1 (conditioning) Recipient conditioning resulting in damage to the tissues that starts before the infusion of the graft; see Fig. 22.1

Afferent phase

Phase 2 (induction and expansion) Recognition of the foreign host antigens by donor T-cells and activation, stimulation, and proliferation of T-cells

Afferent phase

Phase 3 Direct and indirect damage to host cells

Effector phase (the cytokine storm)

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For diagnostic purposes, skin, rectal, and colonic biopsies may be performed. Liver biopsies are usually only performed when isolated GvHD is suspected.

Histologically, the diagnosis is conﬁrmed by lympho- cyte inﬁltration characterized by Woodruff “satellite cell necrosis.”

22.7.3 Prevention

The ﬁrst approach for GvHD prevention is to reduce the risk factors if possible. The incidence of GvHD without prophylaxis can reach 100% (Sullivan et al., 1986).

The most effective approaches to GvHD prevention involve removing T-cells from the graft by lym- phocyte depletion. However, these methods increase the risk of graft failure or rejection and relapse as a consequence of a loss of the graft-versus-leukemia (GvL) effect, which is the attack of immunocompe- tent cells in the graft against any remaining disease cells in the patient after transplantation. Pharmaco- logic GvHD prophylaxis using immunosuppressive drugs is the preferred approach to disrupt the three phases of the GvHD cascade and prevent GvHD. It is aimed at removing or attenuating the activity of donor T-lymphocytes, reducing the risk of graft failure and attempts to maximize the GvL effect (Peters

et al., 2000). Immunosuppression with combined drugs is more effective (Sullivan et al., 1986); the most commonly used drugs are cyclosporin and methotrexate.

There are no pharmacologic drugs to prevent chronic GvHD.

Acute GvHD (grades II–IV) is treated by continuing immunosuppression and adding methylpredniso- lone at 2–2.5 mg/kg/day, with starting doses ranging from 1 to >20 mg/kg/day (Jacobsohn and Vogelsang, 2002). Steroids are tapered based on the patient’s response rather than a ﬁxed schedule. Bacterial, fungal, and viral infections may complicate acute GvHD and are the most common cause of death in these patients.

Immunosuppressive drugs such as steroids, cyclosporin, and tacrolimus are used to treat patients classiﬁed as having extensive chronic GvHD. Chronic GvHD may cause signiﬁcant morbidity, and when mortality occurs it is most often due to infection.

Clinical trials have evaluated various monoclonal antibodies as treatment for GvHD in various settings, with different reported success rates. Future studies will aim to develop agents that will use stem cell transplantation with GvL effect devoid of GvHD.

Although signiﬁcant improvements have been made in allogeneic stem cell transplantation, GvHD remains a major complication that can lead to signiﬁ- cant morbidity and mortality. The more recent and less damaging approaches to allogeneic stem cell transplantation may help to reduce GvHD by de- creasing the intense conditioning regimen, which 1. reduces early transplant-related mortality 2. plays an important role in the development of GvHD Supportive measures such as symptomatic control, parenteral nutrition, infection prophylaxis, skin care, psychological support, and physical rehabilitation are equally important to minimize further complications and improve quality of life.

Figure 22.2

GvHD of the skin in a 13-year-old boy 3 weeks after an allogeneic bone marrow transplant. Image courtesy of

„ B. Cohen & Dermatlas, http://www.dermatlas.org

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