Systemic Anticancer Agents: Dermatologic Indications and Adverse Events

Sorafenib

Sorafenib currently has FDA-approved use in the treatment of thyroid carcinoma, hepatocellular carcinoma, and renal cell carcinoma. It is an oral multikinase inhibitor that targets receptor tyrosine kinases, including c-Kit, RET, platelet-derived growth factor receptor (PDGFR), and vascular endothelial growth factor receptor (VEGFR) 1, 2 and 3, in addition to inhibiting the serine/threonine kinase RAF pathway. In addition to its FDA-approved use in the treatment of various carcinomas, sorafenib has demonstrated encouraging results for patients with angiosarcoma. In a phase II trial of sorafenib (800 mg/day), 4 of 37 patients with vascular sarcomas experienced a partial response and one experienced a complete response, although many patients developed dermatologic toxicities that required dose modifications.

The most frequently observed dermatologic AE with sorafenib include rash/desquamation, hand–foot skin reaction (HFSR), alopecia, facial erythema, nail changes, and pruritus. Q37.1 Other less commonly reported cutaneous AE are stomatitis, mucositis, eruptive benign nevi, and keratoacanthomas/SCC. HFSR is characterized by tender blisters with an erythematous halo localized to areas of increased pressure on the hands and feet ( Fig. 37.2 ). Painful hyperkeratosis and desquamation may occur later on, which significantly affect patients’ quality of life and limit activities of daily living. Symptoms typically occur within the first 2 to 4 weeks of sorafenib treatment. Q37.6 Results of a recent meta-analysis showed the incidence of all-grade and high-grade HFSR with sorafenib to be 34% and 9%, respectively. HFSR differs from palmar–plantar erythrodysesthesia (PPE) or hand–foot syndrome (HFS) associated with conventional cytotoxic agents, which is characterized by diffuse and symmetric erythema and edema of the palms and soles. Pre-emptive management of HFSR includes removing calluses, wearing cotton or wool socks and padded orthotic shoes, avoiding friction to the palms and soles, and application of urea 10% cream. Symptomatic treatment depends on the severity of the cutaneous findings. Different treatments, such as clobetasol 0.05% and topical urea 40%, have shown anecdotal benefit. If patients develop intolerable grade 2 or grade 3 skin changes with an impact on activities of daily living, dose modification may be necessary. Pain management is the most important aspect to control during this toxicity.

Imatinib Mesylate

Imatinib mesylate has been approved as a single agent for the treatment of DFSP, systemic mastocytosis, and chronic myelogenous leukemia (CML). It is a potent and specific inhibitor of several protein kinases, including BCR-ABL, c-Kit, and PDGFR. Imatinib is additionally under investigation for treatment of melanoma, desmoid tumors, and KS. In KS there is an upregulation of both c-Kit and PDGFR, which leads to KS proliferation. As imatinib inhibits the aforementioned receptors, it has been used in a phase II study in the treatment of acquired immune deficiency syndrome (AIDS)-related KS. In the study, imatinib demonstrated significant activity against AIDS-related KS.

A small subgroup of melanomas arising from acral and mucosal surfaces and chronically sun-damaged skin have been found to harbor KIT gene alterations. Two recent phase II studies have demonstrated that imatinib has significant clinical activity against metastatic melanoma in patients with proven genetic c-Kit aberrations.

Cutaneous AE to imatinib are common and have been reported in 9.5% to 69% of patients. One of the most common dermatologic toxicities is edema that involves the periorbital region in up to 70% of patients. A wide variety of additional skin toxicities have been reported, including urticaria, maculopapular exanthem, pityriasis rosea-like eruption, skin hypopigmentation, Sweet syndrome, acute generalized exanthematous pustulosis, exacerbation of psoriasis, pseudoporphyria, mycosis fungoides (MF)-like reaction, and oral and cutaneous lichenoid eruption. In one study, the most common AE was a nonspecific skin rash, which developed in 33.9% of patients. The skin eruptions appear to be dose dependent, with mild reactions to doses of 200 to 600 mg daily, and more severe reactions to high doses of 800 to 1000 mg daily. Generally, most cutaneous AE secondary to imatinib therapy do not require cessation of the drug and are rather self-limited in nature. If cutaneous AE occur, oral or topical corticosteroids (CS) may be prescribed to help alleviate symptoms.

Nilotinib

Nilotinib is currently approved for patients with newly diagnosed or previously treated CML. Nilotinib functions as a tyrosine kinase inhibitor of BCR-ABL, c-Kit, and PDGF. It has similar efficacy to imatinib mesylate but a better tolerated AE profile. Additionally, it has greater selectivity and potency than imatinib and was developed following resistance to imatinib. One phase II trial of nilotinib in patients with metastatic melanoma harboring the Kit gene mutation demonstrated a 26.2% response rate (all partial response) in patients receiving nilotinib therapy. Of patients enrolled in the trial, 47.6% showed stable disease. Clinical trials assessing the efficacy of nilotinib in DFSP have yet to be conducted.

Several dermatologic AE have been reported in patients treated with nilotinib. A phase II study of nilotinib in patients with CML reported the incidence of all-grade rash to be 28%, of which 3% were high grade. Pruritus occurred in 24% of treated patients. Xerosis, eczema, flushing, urticaria, and edema have also been reported with varying incidences. Additionally, up to 10% of patients experience alopecia with nilotinib. Patients who experience AE can receive a trial of topical or oral CS, which has been shown to be effective in alleviating symptoms.

Carboplatin

Carboplatin is FDA approved for the treatment of advanced ovarian cancer. The most common cutaneous AE to carboplatin is alopecia. It is more severe after cycles of treatment or if carboplatin is administered concomitantly with other chemotherapeutic drugs. The incidence of a hypersensitivity reaction is about 2%, and management depends on the severity, but may include premedication with antihistamines, desensitization protocols, or discontinuation of the drug.

Cisplatin

Cisplatin is approved for the treatment of HNSCC that is locally advanced and cannot be treated with surgery. It is additionally used alone or in conjunction with carboplatin in the treatment of MCC. One of the most frequent cutaneous AE of cisplatin is permanent, localized, patchy hyperpigmentation which affects up to 70% of treated patients. Q37.7 It can involve the dorsal surfaces of extremities, the nails, elbows, knees, neck, or sites of pressure. It may also cause oral hyperpigmentation, hair color changes, hypersensitivity reactions, exfoliative dermatitis, flushing, inflammation of actinic keratoses, and Raynaud phenomenon, which occurs when cisplatin is administered with other chemotherapeutic agents. Nail changes include leukonychia, Beau lines, and diffuse nail hyperpigmentation. A case of porphyria after treatment with cisplatin has also been reported.

Dacarbazine

Dacarbazine is FDA approved in the treatment of metastatic melanoma and Hodgkin lymphoma. As monotherapy for melanoma, this drug has been associated with a response rate of 7% to 12% but does not increase survival. Higher response rates have been seen in combination chemotherapy regimens. This is exemplified by a recent phase III study in which patients with metastatic melanoma treated with ipilimumab plus dacarbazine versus dacarbazine alone experienced significant improvement in overall survival (11.2 vs. 9.1 months). In another phase III trial, patients with metastatic melanoma receiving fotemustine monotherapy had superior overall response rates compared with patients receiving dacarbazine monotherapy. Cutaneous toxicities of dacarbazine include erythematous, macular, papular, and/or urticarial rash, alopecia, nail hyperpigmentation, phototoxicity reactions, flushing, and fixed drug eruptions.

Etoposide

Q37.8 Etoposide has FDA approval for use in small cell lung cancer as well as testicular cancer. Etoposide functions by inhibiting topoisomerase II, an enzyme involved in DNA unwinding, and thus causing breakage of DNA strands. Etoposide has also been used off-label in the treatment of MCC. Etoposide in combination with a platinum agent (cisplatin or carboplatin) is the most common chemotherapy for MCC. Although the potential benefit of adjuvant chemotherapy in MCC is unclear, several studies have proposed the addition of carboplatin and etoposide to radiotherapy for the management of MCC. However, when MCC patients treated with adjuvant radiation, carboplatin, and etoposide were compared with MCC patients who had been treated with surgery and radiation therapy alone, there was no significant improvement in any clinical endpoints.

Etoposide has also demonstrated some benefit as monotherapy and in combined regimens for the treatment of advanced cutaneous T-cell lymphoma (CTCL). There are several ongoing studies evaluating etoposide in combination chemotherapy regimens for the treatment of relapsed or refractory CTCL and previously untreated disease. One study has shown etoposide monotherapy as effective in the treatment of MF with a 69% patient response rate.

Q37.1 Many cutaneous AE to etoposide have been described, including alopecia, leukocytoclastic vasculitis, pigmentation of nail beds and fingers, onycholysis, Beau lines, PPE, mucositis, radiation recall dermatitis, and flushing. Q37.7 When etoposide is administered in combination with other chemotherapeutic agents, several additional reactions have been observed, including Raynaud phenomenon, skin hyperpigmentation, and hypersensitivity reactions.

Paclitaxel

Paclitaxel is currently FDA approved for the treatment of AIDS-related KS. It functions by stabilizing microtubules and inhibiting their disassembly, thereby inhibiting cellular replication. It is currently being evaluated in combination chemotherapy regimens for its efficacy in metastatic melanoma. One phase III trial examined the efficacy of nanoparticle albumin-bound (nab)-paclitaxel versus dacarbazine in patients with metastatic melanoma. Nab-paclitaxel differs from paclitaxel in that it is albumin-bound and solvent free, which is meant to decrease AE associated with solvent and increase drug delivery through its binding to albumin. Median progression-free survival was 4.8 months in the nab-paclitaxel group versus 2.5 months in the dacarbazine group. The overall response rate was 15% and 11% (nab-paclitaxel and dacarbazine, respectively). Taxane-based chemotherapy has also demonstrated promising antitumor activity for patients with metastatic angiosarcoma.

A wide range of skin toxicities to paclitaxel treatment have been reported, including hypersensitivity reactions, radiation recall dermatitis, erythema multiforme, and reversible alopecia involving the eyebrows, eyelashes, scalp, and axillary and pubic regions. Nail changes are also prevalent and commonly reported to be painful. In a clinical trial of weekly paclitaxel in patients with metastatic breast cancer, nail toxicity, which included discoloration, paronychia, onycholysis, exudation, and subungual hemorrhages, occurred in 27.6% (16/58) of patients. Additional nail changes caused by paclitaxel may include nail ridging and hyperpigmentation of the hyponychia. Q37.9 Routine premedication with dexamethasone, diphenhydramine, and an H ₂ antihistamine is recommended before paclitaxel infusion owing to its vehicle, Chremophor EL, inducing immediate hypersensitivity reactions.

Docetaxel

Docetaxel is FDA approved for use in combination with cisplatin and fluorouracil for the induction treatment of patients with inoperable, locally advanced HNSCC. Docetaxel shares a similar mechanism of action to paclitaxel, but it may also inhibit VEGF and it displays immunomodulatory properties. Docetaxel has demonstrated efficacy in advanced-stage AIDS-related KS, including several cases of patients pretreated with anthracyclines, paclitaxel, or other systemic chemotherapy. Like paclitaxel, docetaxel also demonstrated antitumor activity and a favorable prognosis for patients with metastatic angiosarcoma. Additionally, docetaxel has been investigated for its efficacy in patients with metastatic melanoma.

Q37.1 Dermatologic toxicities associated with docetaxel include PPE, mucositis, alopecia, erythema, pruritus, macular eruption, and desquamation. PPE associated with taxanes, and particularly docetaxel, has more accurately been described as periarticular thenar erythema with onycholysis (PATEO) syndrome, which is clinically different from the PPE caused by MKI, capecitabine or 5-fluorouracil (5-FU)/doxorubicin. PATEO syndrome involves tender or pruritic erythema on the dorsum of the hands, along with subungual hemorrhages leading to nail separation and infection in up to 30% of treated patients. Nail changes can also occur independently of PATEO syndrome and are seen in up to 58% of patients. Specifically, the nail changes include onycholysis, Beau lines, onychomelanosis, onychomadesis, subungual erythema, and subungual hemorrhages. High-potency TCS and gel-containing frozen gloves and socks used during docetaxel infusion have led to reduce nail toxicities. Q37.9 Oral dexamethasone therapy is recommended for the treatment of grade ≥2 PPE. If drug extravasation occurs, docetaxel acts as an irritant causing local pain, erythema, bullae, or phlebitis to the affected area. These manifestations resolve over weeks but can leave residual hyperpigmentation.