Management of Dermatologic Toxicities

Dermatologic toxicities related to cancer therapies have become even more common with the use of targeted treatments. A proactive approach is necessary to reduce the pain and suffering these patients experience. The oncologist should become comfortable in preventing and managing these complications to keep patients on optimal drugs and doses. At the NCCN 20th Annual Conference, Dr. Mario E. Lacouture advised clinicians on appropriate strategies to manage rash, paronychia, alopecia, and other dermatologic conditions frequently seen in patients with cancer.

Abstract

Dermatologic toxicities related to cancer therapies have become even more common with the use of targeted treatments. A proactive approach is necessary to reduce the pain and suffering these patients experience. The oncologist should become comfortable in preventing and managing these complications to keep patients on optimal drugs and doses. At the NCCN 20th Annual Conference, Dr. Mario E. Lacouture advised clinicians on appropriate strategies to manage rash, paronychia, alopecia, and other dermatologic conditions frequently seen in patients with cancer.

Oncology providers should take an early, proactive approach in managing dermatologic toxicities associated with cancer treatment, Mario E. Lacouture, MD, emphasized at the NCCN 20th Annual Conference.

These toxicities—which affect the skin, hair, nails, and mucous membranes—strongly impact patients' quality of life, sense of privacy, and physical, psychosocial, and financial well-being. Importantly, serious adverse events often result in treatment modification, which can compromise clinical outcomes, said Dr. Lacouture, Associate Professor of Dermatology at Cornell University and Associate Member of Memorial Sloan Kettering Cancer Center.

It is important for oncology providers to learn how to prevent and manage these toxicities themselves. Although referral to dermatologists is ideal, timely appointments are not always possible.

At Memorial Sloan Kettering Cancer Center, Dr. Lacouture said, “We have tried to mitigate this delay through a referral system in which the oncology provider contacts the dermatologist, who sees the patient within a day or 2 and then communicates the treatment plan to the oncologist.”

Skin Rash

Most FDA-approved targeted agents are associated with a wide spectrum of dermatologic toxicities.. Dr. Lacouture made several key points about skin rash produced by different cancer therapies:

  • Most patients taking EGFR inhibitors develop an acneiform rash on the face, scalp, and upper body, often within the first 4 weeks. This is associated with pruritus, tenderness, and even spontaneous bleeding. When EGFR inhibitors are combined with cytotoxic chemotherapy, the incidence of severe rash almost doubles.

  • dMEK inhibitors produce acneiform rash in more than 50% of patients.

  • BRAF inhibitors can produce a maculopapular rash that is “explosive,” occurring early and spreading quickly.

  • mTOR inhibitors can produce an acneiform rash that is extremely pruritic, rarely affects the face, and mostly affects the trunk.

  • Immunotherapies such as ipilimumab and PD-1 inhibitors produce a nonspecific maculopapular rash in about 20% of patients. This rash is usually pruritic.

  • Cytotoxic chemotherapy may also be associated with skin toxicities. Gemcitabine, usually in combination with other agents, can produce a macular rash associated with edema in the extremities. Pemetrexed as a single agent produces rash in 17% of patients. Liposomal doxorubicin can produce intertriginous rash in 20%, with pain in the skin folds.

The mainstay of treatment for most macro-papular rashes is medium- or high-potency topical steroids. In grade 3 rash, oral corticosteroids and antihistamines may be warranted. Oral aprepitant can address resistant pruritus. Oral corticosteroids and compression therapy can be useful for gemcitabine-associated peripheral edema. Maculopapular rash that is intertriginous (ie, in body folds) may not itch but can be painful and become infected; it is treated with topical corticosteroids and topical antibiotics.

Prophylactics for EGFR Inhibitor-Associated Rash

“The impact of an acneiform rash associated with EGFR inhibitors cannot be understated,” he said. Ironically, however, severity of rash corresponds to better response to treatment, according to several trials of metastatic colorectal cancer, with longer survival times among patients with grade 3 rash.1 Acne-like rash emerges first, followed by postinflammatory effects such as dry skin, fissures in palms and soles, and paronychia (nail changes).

Unfortunately, surveys have shown a high rate of discontinuation or reduction of EGFR inhibitors due to rash, Dr. Lacouture noted, “which underscores the notion that this rash should be prevented or treated very early.”

Dr. Lacouture cited a large body of data supporting prophylactic antibiotics to prevent this rash. Minocycline 100 mg per day was shown to reduce lesions by more than 50% and rash severity within the first 4 weeks of treatment with cetuximab.2 Similarly, 150 mg of minocycline twice per day on day 1 of treatment with erlotinib reduced rash by 40% compared with the reactive use of topical clindamycin plus hydrocortisone with and without minocycline.3 And prophylactic use of doxycycline 100 mg twice per day plus a low-potency topical steroid reduced grade 2 or higher skin toxicity by 70%, versus reactive treatment, and also reduced pruritus, secondary infections, and paronychia as well as non-dermatologic toxicities grade 3 or greater (diarrhea, neutropenia, etc).4

“Importantly, prophylaxis does not negate the beneficial anti-tumor effects of EGFR inhibitors,” he added.

Secondary infections often accompany this rash. He suggested having “a low threshold” for culturing any lesions with discharge, because almost 40% of patients taking EGFR inhibitors with skin toxicities develop secondary bacterial, viral, or fungal infections.

More than 6 months of EGFR inhibition is also likely to produce dry skin. Moisturizing is best accomplished with creams that contain ammonium lactate, salicylic acid, or urea, which provide good moisture retention along with easy application.

Severe pruritus associated with biologic agents often responds to the NK-1 receptor inhibitor aprepitant, as shown in a pilot study of patients with resistance to first-line oral antihistamines and corticosteroids. Of these patients, 91% had more than 50% reduction in intensity of pruritus, and itching recurred in only 13%.5

Paronychia

Some 15% to 25% of patients on EGFR and mTOR inhibitors can develop paronychia as a result of nail plate thinning, ingrowth of particles, and secondary infection. Treatment depends on severity. Nail avulsion sounds extreme, but patients are often relieved by it and return for additional procedures as needed, he said.

A different type of nail change is induced by taxanes, especially docetaxel, with which 30% of patients may demonstrate grade 3 toxicity. This involves elevation of the nail plate, inflammation, and sometimes subungual bleeding and pain. These adverse events can be prevented by cold therapy with ice packs for 15 minutes before infusion, during infusion, and 15 minutes after infusion.

Brittle nails are also a consequence of EGFR inhibition. Brittle nails are also often seen in patients with breast cancer receiving everolimus or trastuzumab/pertuzumab. For repairing splitting, ridges, and fragility, Dr. Lacouture recommended a hydro-soluble nail lacquer or the prescription product polyureaurethane 16%, which produce a rigid barrier to the nail plate. The dietary supplement biotin (2.5

Figure 1
Figure 1

Panels A through D show common dermatologic adverse events.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 13, 5S; 10.6004/jnccn.2015.0204

mg) may also be beneficial.

Hand-Foot Syndrome

Hand-foot syndrome (HFS) can be seen with a variety of cancer drugs, and its manifestations can differ by drug class. With taxanes, lesions are erythematous and maculopapular; with anthracyclines and anti-metabolites, erythema, fissuring, and edema may be seen. With multikinase inhibitors, blisters may form with erythematous halo, followed by hyperkeratosis, which can be painful (seen in 60% of patients treated with regorafenib). Due to peripheral vasoconstriction, patients can develop skin fragility and blisters in other areas subject to trauma, such as the elbow.

The only randomized study of HFS prevention, conducted in patients receiving capecitabine, showed that prophylactic celecoxib 200 mg/day reduced HFS grade 2 or greater by more than 50%.6 Oral corticosteroids can be beneficial when HFS is due to liposomal doxorubicin.

Anecdotally, several agents may ameliorate HFS induced by multikinase inhibitors: clobetasol foam, salicylic acid 6% cream, and lidocaine creams and patches. Topical urea 10% was only mildly effective in a recent randomized study of 871 patients treated with sorafenib.7 “There's lots of room for improvement in treating HFS,” Dr. Lacouture acknowledged.

Radiation-Related Toxicities

When patients receive a targeted agent in addition to radiation therapy, the risk of dermatitis and mucositis essentially doubles over that seen with radiotherapy alone. Interestingly, the best treatment appears to be washing with soap and water, which is shown to almost halve the risk of radiation dermatitis.8 The medium-strength topical corticosteroid mometasone was shown in randomized placebo-controlled trials to significantly reduce discomfort, itching, and redness.9

Conversely, interventions not shown to be effective include topical nonsteroidal agents, trolamine, petrolatum, and topical moisturizers.

Mucositis is being seen more with the use of the mTOR inhibitor everolimus. Although “magic mouthwashes” are often prescribed for chemotherapy- and radiation-induced mucositis, canker sores, and mouth pain, in reality “there's no magic in them,” according to Dr. Lacouture, who said there is no evidence supporting their efficacy and recommended a topical corticosteroid instead.

Alopecia

Alopecia has long been a side effect of treatment that greatly concerns patients. In addition to alopecia related to cytotoxics, hair thinning can also occur with inhibitors of BRAF, MEK, EGFR, and hedgehog signaling pathway. Dr. Lacouture made the following recommendations to prevent or manage hair loss:

  • Correcting thyroid, iron, and vitamin abnormalities, in addition to minoxidil 5% twice daily, are mainstays of therapy for alopecia.

  • For eyelash alopecia, bimatoprost has been shown to increase the length of eyelashes in patients undergoing chemotherapy almost three-fold and to more than double eyelash thickness.10

  • The use of scalp cooling, ie, a “cold cap,” during chemotherapy has been shown to prevent hair loss. In a study involving 1400 patients, 50% of patients who used scalp-cooling did not wear a head covering during their last chemotherapy session.11 In another study of 57 patients, protection from severe hair loss was seen in 36% to 92%, depending on chemotherapy regimen.12

  • Topical minoxidil reduces the duration of complete hair loss by approximately 2 months.13

Dr. Lacouture concluded by emphasizing that dermatologic toxicities matter even more to patients now as they are “surviving longer, and therefore have more opportunity to worry about their appearance and quality of life issues. In the majority of patients, dermatologic events can be well managed.”14,15

Dr. Lacouture has disclosed that he has received consultant fees/honoraria from Amgen Inc., Brikell Biotech, Foamix, Galderma, GlaxoSmithKline, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novocure, Pfizer Inc., Pierre Fabre, Reata Pharmaceuticals, and Threshold Pharmaceuticals; has received grants or research support from Berg, Bristol-Myers Squibb Company, and Genentech, Inc.; and other financial benefits from Physicians' Education Resource.

References

  • 1.

    BooneSLRademakerALiuD. Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology2007;72:152159.

    • Search Google Scholar
    • Export Citation
  • 2.

    ScopeAAgeroALDuszaSW. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol2007;25:53905396.

    • Search Google Scholar
    • Export Citation
  • 3.

    MeloskyBLHandersonHBurkesRL. Pan-Canadian rash trial with EGFR inhibitors [abstract]. J Clin Oncol2014;32(Suppl 5):Abstract 8013.

  • 4.

    LacoutureMEMitchellEPPiperdiB. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol2010;28:13511357.

    • Search Google Scholar
    • Export Citation
  • 5.

    SantiniDVincenziBGuidaFM. Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study. Lancet Oncol2012;13:10201024.

    • Search Google Scholar
    • Export Citation
  • 6.

    ZhangRXWuXJLuSX. The effect of COX-2 inhibitor on capecitabine-induced hand-foot syndrome in patients with stage II/III colorectal cancer: a phase II randomized prospective study. J Cancer Res Clin Oncol2011;137:953957.

    • Search Google Scholar
    • Export Citation
  • 7.

    RenZZhuKKangH. Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin Oncol2015;33:894900.

    • Search Google Scholar
    • Export Citation
  • 8.

    RoyIFortinALarochelleM. The impact of skin washing with water and soap during breast irradiation: a randomized study. Radiother Oncol2001;58:333339.

    • Search Google Scholar
    • Export Citation
  • 9.

    MillerRCSchwartzDJSloanJA. Mometasone furoate effect on acute skin toxicity in breast cancer patients receiving radiotherapy: a phase III double-blind, randomized trial from the North Central Cancer Treatment Group N06C4. Int J Radiat Oncol Biol Phys2011;79:14601466.

    • Search Google Scholar
    • Export Citation
  • 10.

    MorrisCLStinnettSWoodwardJ. The role of bimatoprost eyelash gel in chemotherapy-induced madarosis: an analysis of efficacy and safety. Int J Trichology2011;3:8491.

    • Search Google Scholar
    • Export Citation
  • 11.

    van den HurkCJPeerboomsMvan de Poll-FranseLV. Scalp cooling for hair preservation and associated characteristics in 1411 chemotherapy patients: results of the Dutch Scalp Cooling Registry. Acta Oncol2012;51:497504.

    • Search Google Scholar
    • Export Citation
  • 12.

    KatsimbriPBamiasAPavlidisN. Prevention of chemotherapy-induced alopecia using an effective scalp cooling system. Eur J Cancer2000;36:766771.

    • Search Google Scholar
    • Export Citation
  • 13.

    DuvicMLemakNAValeroV. A randomized trial of minoxidil in chemotherapy-induced alopecia. J Am Acad Dermatol1996;35:7478

  • 14.

    LacoutureME. Dr Lacouture's Skin Care Guide for People Living With Cancer. Cold Spring Harbor, NY: Harborside Press; 2012.

  • 15.

    LacoutureME. Dermatologic Principles and Practice in Oncology. Hoboken, NJ: Wiley-Blackwell; 2014.

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Correspondence: Mario E. Lacouture, MD, Memorial Sloan Kettering Cancer Center, 16 E 60th Street, Dermatology Service, Department of Medicine, MSK 60th Street Outpatient Center, Suite 302, New York, NY 10022. E-mail: lacoutum@mskcc.org

Article Sections

Figures

  • View in gallery

    Panels A through D show common dermatologic adverse events.

References

  • 1.

    BooneSLRademakerALiuD. Impact and management of skin toxicity associated with anti-epidermal growth factor receptor therapy: survey results. Oncology2007;72:152159.

    • Search Google Scholar
    • Export Citation
  • 2.

    ScopeAAgeroALDuszaSW. Randomized double-blind trial of prophylactic oral minocycline and topical tazarotene for cetuximab-associated acne-like eruption. J Clin Oncol2007;25:53905396.

    • Search Google Scholar
    • Export Citation
  • 3.

    MeloskyBLHandersonHBurkesRL. Pan-Canadian rash trial with EGFR inhibitors [abstract]. J Clin Oncol2014;32(Suppl 5):Abstract 8013.

  • 4.

    LacoutureMEMitchellEPPiperdiB. Skin toxicity evaluation protocol with panitumumab (STEPP), a phase II, open-label, randomized trial evaluating the impact of a pre-Emptive Skin treatment regimen on skin toxicities and quality of life in patients with metastatic colorectal cancer. J Clin Oncol2010;28:13511357.

    • Search Google Scholar
    • Export Citation
  • 5.

    SantiniDVincenziBGuidaFM. Aprepitant for management of severe pruritus related to biological cancer treatments: a pilot study. Lancet Oncol2012;13:10201024.

    • Search Google Scholar
    • Export Citation
  • 6.

    ZhangRXWuXJLuSX. The effect of COX-2 inhibitor on capecitabine-induced hand-foot syndrome in patients with stage II/III colorectal cancer: a phase II randomized prospective study. J Cancer Res Clin Oncol2011;137:953957.

    • Search Google Scholar
    • Export Citation
  • 7.

    RenZZhuKKangH. Randomized controlled trial of the prophylactic effect of urea-based cream on sorafenib-associated hand-foot skin reactions in patients with advanced hepatocellular carcinoma. J Clin Oncol2015;33:894900.

    • Search Google Scholar
    • Export Citation
  • 8.

    RoyIFortinALarochelleM. The impact of skin washing with water and soap during breast irradiation: a randomized study. Radiother Oncol2001;58:333339.

    • Search Google Scholar
    • Export Citation
  • 9.

    MillerRCSchwartzDJSloanJA. Mometasone furoate effect on acute skin toxicity in breast cancer patients receiving radiotherapy: a phase III double-blind, randomized trial from the North Central Cancer Treatment Group N06C4. Int J Radiat Oncol Biol Phys2011;79:14601466.

    • Search Google Scholar
    • Export Citation
  • 10.

    MorrisCLStinnettSWoodwardJ. The role of bimatoprost eyelash gel in chemotherapy-induced madarosis: an analysis of efficacy and safety. Int J Trichology2011;3:8491.

    • Search Google Scholar
    • Export Citation
  • 11.

    van den HurkCJPeerboomsMvan de Poll-FranseLV. Scalp cooling for hair preservation and associated characteristics in 1411 chemotherapy patients: results of the Dutch Scalp Cooling Registry. Acta Oncol2012;51:497504.

    • Search Google Scholar
    • Export Citation
  • 12.

    KatsimbriPBamiasAPavlidisN. Prevention of chemotherapy-induced alopecia using an effective scalp cooling system. Eur J Cancer2000;36:766771.

    • Search Google Scholar
    • Export Citation
  • 13.

    DuvicMLemakNAValeroV. A randomized trial of minoxidil in chemotherapy-induced alopecia. J Am Acad Dermatol1996;35:7478

  • 14.

    LacoutureME. Dr Lacouture's Skin Care Guide for People Living With Cancer. Cold Spring Harbor, NY: Harborside Press; 2012.

  • 15.

    LacoutureME. Dermatologic Principles and Practice in Oncology. Hoboken, NJ: Wiley-Blackwell; 2014.

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