By Ruth Carol, contributing writer

As the number of cancer treatments grow and people with the disease live longer, so do the number of patients who have cutaneous side effects. Although dermatologic adverse events are some of the most common side effects of cancer treatments, they vary by severity as well as type of therapy and dose. Dermatologists are in a unique position to be a part of the health care team that cares for these patients because many of these side effects are common diseases they routinely encounter.

“There are so many more lines of therapy that have become available,” said Sharon Hymes, MD, associate medical director of the Melanoma and Non-Melanoma Skin Cancer Center at MD Anderson. “We still have the old standards, such as traditional chemotherapy, but immunotherapies and targeted therapies have opened the door to a whole new world of treatment.”

These new treatments have also introduced more and different types of cutaneous side effects that, if severe enough, can affect the patient’s quality of life, and cause dose changes and treatment delays. “Our goal is to support our patients so that the dermatologic side effects can be identified and minimized, enabling them to complete their cancer therapy.”

Radiation therapy

When it comes to radiation therapy for internal tumors, the goal, certainly, is to target that treatment toward that tumor. However, the patients’ skin stands between the radiation source and the tumor and as a result radiation dermatitis is the most common dermatologic adverse event resulting from radiation therapy. “For radiation dermatitis, we know to look where the radiation comes in, but also where it goes out,” Dr. Hymes said. “Even when the skin is not the primary target, it may be injured as an innocent bystander.”

Acute radiation dermatitis typically occurs within 90 days following exposure, whereas chronic radiation dermatitis may not develop for years after treatment. A mild case of radiation dermatitis is characterized by blanchable erythema and dry desquamation, she said. Other symptoms may include pruritus, epilation, scaling, and dyspigmentation. The area can be washed using plain water or water with a mild, low pH-cleanser that does not irritate the existing dermatitis. Mild cases are treated mostly with emollients, with or without hydrogel dressings, Dr. Hymes added. The goal is to minimize water loss, reduce pain, and prevent the dry desquamation from turning moist.

Severe radiation dermatitis is characterized by skin necrosis or ulceration that is painful and may be prone to bleeding. Typically, it is treated with wound and dressing care to improve the integrity of the epidermis, she said. “We watch for infection in patients who lose epidermal integrity,” Dr. Hymes added. She monitors those patients over time, so they don’t get chronic radiation changes characterized by non-healing wounds or radiation-induced fibrosis or morphea. Chronic radiation changes are particularly difficult to treat because of the impaired healing and increased risk of infection.

There is some evidence, although it is not strong, to suggest that topical corticosteroids can be used to prevent or treat radiation dermatitis, Dr. Hymes said. It’s more likely that topical steroids can minimize radiation dermatitis, but not prevent it. However, their use remains controversial.
Radiation dermatitis has become much less of a problem thanks to technologic advances in radiation doses and delivery, she noted. For example, proton therapy delivers a higher, targeted dose of radiation to the tumor, while minimizing exposure of normal tissue, so it causes far fewer radiation-induced changes to the skin. Intensity-modulated radiotherapy focuses multiple beams coming from all different directions, so the skin doesn’t get one concentrated dose.

Chemotherapy

Common dermatologic side effects associated with chemotherapy are hair loss; itchy and/or dry skin; and nail damage in the form of loss or infection, stated Mario Lacouture, MD, director of the Oncodermatology Program at Memorial Sloan Kettering Cancer Center. These side effects occur because chemotherapy blocks rapidly growing cells to treat the cancer, but it also blocks the skin, hair, and nails as they are rapidly growing tissue, he explained.

Dr. Hymes also sees patients with numerous non-specific drug rashes, maculopapular rashes, toxic epidermal necrolysis, and drug reaction with eosinophilia and systematic symptom, or DRESS, syndrome. In some cases, the toxic reagents can concentrate in sweat and eccrine glands causing these side effects, she said. Some patients have infusion reactions characterized by blistering and skin necrosis that occur when the chemotherapy drug infiltrates a peripheral line. Infusion reactions occur because the chemotherapy can be toxic when it comes in direct contact with the skin.

Hand and foot syndrome is on Dr. Hymes’ list of unique cutaneous side effects of chemotherapy. “However, it’s a little different than the hand and foot syndrome you see with targeted therapies,” she said, “because it tends to appear profusely across the hands and is dose dependent.” Leg ulcers are associated with hydroxyurea-type chemotherapy, whereas neutrophilic eccrine hidradenitis is associated with cytarabine. Generalized pigment darkening is sometimes referred to as “busulfan tan.”

There are many side effects of chemotherapy. However, hair loss is often one of the most devasting side effects for patients, and one that many will turn to their dermatologists for help addressing. Hair loss may be prevented by using a scalp cooling system that is approved by the FDA, Dr. Lacouture said. Scalp cooling technology has come a long way in recent years. According to a recent study, 85.7% of breast cancer patients who were treated with a scalp-cooling device saw an increase in hair volume of more than 50% within 12 weeks after chemotherapy — with no serious adverse events. Additionally, 27% of patients had no alopecia at the end of chemotherapy in the scalp-cooling group compared to 0% of patients in the control group (Front Oncol. 2019; 9:733). In addition to scalp cooling for hair loss, medications, such as pregabalin, are very effective for treating itching, said Dr. Lacouture. Topical steroids or oral antibiotics are helpful for treating rashes. Oral antibiotics can be used to treat nail damage.

Treatment options depend on how severe the side effects are, their impact on the patient’s quality of life, and how important it is for the patient to receive that particular chemotherapy, Dr. Hymes said. “You have to consider each patient individually,” she added. Topical steroids can be used to treat many of these immunologic reactions, but if they are severe, they may require systemic steroids. Many of these patients tend to be profoundly immunosuppressed, keeping physicians ever vigilant about recognizing any cutaneous infections. These patients are also prone to having flares of their psoriasis or eczema, for example, which might merit a prescription for immunomodulators. “However, we’re very careful about what we give already immunomodulated patients. We don’t want to add insult to injury,” Dr. Hymes said.

“We do everything we can to mitigate whatever symptoms the patient is having or treat whatever infections they get, so they can get to the end of the treatment cycle,” she said. However, if a patient is in so much pain from leg ulcers that they can’t walk or their hands are so swollen and painful they can’t do simple tasks, a medication vacation or dose reduction may be warranted. Sometimes the oncologist can be a little flexible regarding the number of chemotherapy cycles to provide the patient. “We can help determine if the patient can reach the end of the cycle or it should be stopped a little short,” Dr. Hymes said.

Fortunately, supportive care for profoundly immunocompromised patients has improved significantly in the past few years, she noted. For example, physicians can provide platelet infusions for patients with a bleeding disorder, prescribe growth factors to support their white blood cell counts, and help treat their infectious diseases.

The cutaneous side effects may not always be eliminated, Dr. Lacouture said, but they can be reduced significantly, allowing the patient to continue with the cancer therapy.

Stem cell transplants

The increased use of hematopoietic stem cell transplants over time has resulted in an increased need for dermatologic care, noted Jennifer Huang, MD, a pediatric dermatologist at Boston Children’s Hospital and associate professor of dermatology at Harvard Medical School.
One of the most serious dermatologic side effects remains graft versus host disease (GVHD). Symptoms include thickening of the skin, rashes, blistering, scarring, and hair loss. GVHD is the result of the donor cells attacking the patient’s cells because the role of the immune system is to attack “foreign” entities in the body, she explained. The skin is the most common organ that is attacked.

Transplant patients also often get rashes from their conditioning regimen to prepare for the bone marrow transplant, Dr. Huang noted. Shortly following transplantation, they can develop acute GVHD. Patients can also develop chronic GVHD. The most severe form is known as sclerotic GVHD characterized by thickening, hardening, and tightness of the skin. The patients’ mobility could be affected long term because their skin tightens around the joints. Sclerotic GVHD is the hardest to treat, she said, and it could take years for the condition to resolve. These patients are at a higher risk of developing skin cancers, most commonly squamous cell carcinoma. They also have to be monitored very closely for melanoma because they tend to get more moles.

Systemic steroids are the first line therapy for GVHD. There is no consensus on a second line agent as no one option has proven to work better than the others, Dr. Huang said. Extracorporeal photophoresis and mycophenolate mofetil have been used with some success. Recently, Janus kinase, or JAK, inhibitors and interleukin-2, or IL-2, inhibitors are being used to treat GVHD. All of these therapies work by dampening the immune response, Dr. Huang said.

Using immunosuppressive drugs after a transplant is not ideal as they can cause skin cancer and other secondary malignancies. These patients also need to be monitored very carefully for relapse of the primary malignancy, she said.

Some patients respond well to treatment and the GVHD can resolve, Dr. Huang said. For others, the symptoms improve, but patients have residual limitations in mobility or scarring. A primary goal in managing these patients is to treat side effects of transplant without causing relapse of their primary disease.

Immunotherapy

The most common skin-related adverse events of immunotherapy are itching and various types of rashes, said Edward Cowen, MD, MHSc, senior clinician in the Dermatology Branch of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and head of the Dermatology Consultation Service at the National Institutes of Health. The rashes can be maculopapular or resemble eczema, psoriasis, or lichen planus. They typically occur within the first month of treatment.

The most interesting cutaneous side effects are the true autoimmune reactions, he said. Among them are vitiligo, alopecia areata, and bullous pemphigoid. Autoimmune adverse events can occur many months after treatment has been initiated, requiring dermatologists to be suspicious of any skin-related symptom that shows up during any part of treatment, not just at the start, Dr. Cowen noted.

The likelihood of the patient having skin-related side effects increases when two different immunotherapies are used in combination, he added. Two-thirds of these patients will have those reactions.

Immunotherapies stimulate the immune system to fight the cancer cells, but in doing so, they may also attack healthy cells, Dr. Cowen explained.

Common treatments for immunotherapy-related reactions are topical steroids, topical emollients, anti-histamines, and non-immunosuppressive steroid-sparing systemic agents, he noted. The goal is to avoid using systemic steroids, when possible, so as not to compromise the effects of cancer therapy, added Milan J. Anadkat, MD, professor of medicine in the division of dermatology at the Washington University School of Medicine. However, that has to be balanced with the patient’s discomfort, which can be significant, particularly for patients with severe itch.
If the side effects are severe — grade 2 or higher on the CTCAE — the oncologist may stop the immunotherapy, at least temporarily, to mitigate the toxicity and agree to a short course of systemic steroids, he said. Overall, treatment is stopped in less than 5% of these patients, Dr. Anadkat added.

In many instances, the treatments are sufficient to eliminate the side effects. In other cases, they minimize them. “So, the rash that was all over the patient’s hands and feet is now just affecting the toes,” he said. “The goal is to minimize discomfort and improve the patient’s quality of life.”
Patients who get severe reactions tend to have better tumor response, Dr. Cowen noted, so treating with systemic steroids could potentially affect that response. “We need to be careful and do our best to find other alternatives when possible.”

Targeted therapy

Dermatologic adverse events are among the most frequent side effects across targeted therapies. The most common ones are inflammatory eruptions that can resemble lichen planus, psoriasis, and eczema, stated James B. Macdonald, MD, director of dermatopathology at Revere Health. They can be on the face, chest, or back, but also on the arms, legs, and trunk. These reactions can be very painful and itchy. Other general side effects related to the skin are eczema, hair loss, a sudden eruption of moles, and photosensitivity.

Each targeted therapy, however, has its own unique set of cutaneous side effects, he said. As an example, skin-related side effects of epidermal growth factor receptor (EGFR) inhibitors include papulopustular eruption, hair and nail changes, mucositis, and photosensitivity whereas RAF inhibitors trigger cutaneous eruptions, keratotic squamo-proliferative lesions, and photosensitivity. BRAF inhibitors cause hand foot syndrome and squamous cell carcinomas to develop. “It takes a dedicated dermatologist who knows what kind of reactions are associated with each treatment to counsel patients even before they get treatments, so they know what to expect,” Dr. Macdonald said.

These cutaneous adverse events occur because the targeted therapies activate the immune pathways to target the cancer cells, but these pathways are also present within the skin cells, he explained. In addition, sometimes the target is on the skin as in the case of melanoma.
Treatments for the follicular reactions are topical anti-inflammatory drugs, topical steroids, and oral antibiotics. Gentle soaps and moisturizers are a must. “We are starting to recommend diluted bleach baths to help calm the reactions,” Dr. Macdonald said. Acne treatments are prescribed for acneiform eruptions. Supportive care is provided to manage the blisters and avoid trauma to the skin that could incite blistering. Bandaging and topical emollients help hydrate the skin and prevent shearing. Topical steroids help enhance the skin barrier.

If side effects interfere with the patients’ activities of daily living, options include taking a medication holiday, cutting the dose, or considering another type of targeted therapy. “For the most part, the cutaneous side effects are manageable, so the patients can continue on their treatment,” he said. The emerging data that show some of these toxicities are positive indicators of tumor response are usually strong encouragement for patients to keep going, Dr. Macdonald added.

An integral part of the team

The introduction of EGFR inhibitors increased awareness about the value of working with dermatologists when treating cancer patients because skin reactions are the number one side effect of this class of drugs, Dr. Anadkat noted. About 90% of patients who are treated with EGFR inhibitors have a rash that starts within the first two weeks of therapy. The subsequent introduction of checkpoint inhibitors reinforced this notion.

“Before dermatologists got involved in the care of cancer patients, up to half of patients would have to stop therapies because of toxicity,” he said. “Once dermatologists got involved, we developed regimens to help the patients through the toxicity without necessitating dose reduction or interruption in anti-cancer therapy.”

Now that cancer patients are living longer than ever thanks to the remarkable contribution of oncologists, quality of life considerations have taken on greater importance, Dr. Lacouture said. “Dermatologists are uniquely positioned to allow patients to receive live-saving or life-prolonging therapies by mitigating their cutaneous side effects,” he said. “Dermatologists are also able to enhance patients’ lives by maintaining their appearance and sense of well-being.”

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