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Topical and Intralesional Chemotherapeutic Agents


Questions

  • Q47.1 What is the evidence for the success of topical 5-fluorouracil (5-FU) in the treatment of actinic keratoses? (Pg. 543)

  • Q47.2 How should topical 5-FU be used to treat nonmelanoma skin cancer? (Pg. 543)

  • Q47.3 Which inherited enzyme deficiency significantly increases the risk of toxicity with 5-FU therapy? (Pgs. 543, 544)

  • Q47.4 What commercial product(s) are suitable alternatives for compounded nitrogen mustard? (Pg. 544)

  • Q47.5 Concerning topical nitrogen mustard therapy, what is (1) the risk (and management) of allergic contact dermatitis, and (2) the risk of nonmelanoma skin cancer? (Pg. 545x2)

  • Q47.6 How is topical nitrogen mustard prepared in both aqueous and ointment forms? (Pg. 545)

  • Q47.7 For which of the topical chemotherapeutic agents discussed in this chapter is laboratory monitoring necessary? (Pg. 546x2)

  • Q47.8 What is the evidence for efficacy of intralesional (IL) vinblastine and vincristine in the treatment of Kaposi sarcoma lesions? (Pg. 547x2)

  • Q47.9 Which vascular anomalies have been effectively treated with IL bleomycin? (Pg. 547)

  • Q47.10 What local adverse effects are possible with IL bleomycin? (Pg. 547)

Abbreviations used in this chapter

5-FU

5-Fluorouracil

AE

Adverse effects (events)

AK

Actinic keratosis

BCC

Basal cell carcinoma

BCNU

Bischloronitrosourea (carmustine)

CR

Complete response (remission)

CTCL

Cutaneous T-cell lymphoma

DHFU

Dihydrofluorouracil

DPD

Dihydropyrimidine dehydrogenase

IL

Intralesional

KS

Kaposi sarcoma

LM

Lymphatic malformation

NM

Nitrogen mustard

PDT

Photodynamic therapy

RCT

Randomized controlled trial

SCC

Squamous cell carcinoma

Introduction

This chapter will discuss topical chemotherapeutic agents, including 5-fluorouracil (5-FU), mechlorethamine (nitrogen mustard [NM]), and carmustine (BCNU), commonly used in the treatment of different benign, premalignant, and malignant dermatosis. We also briefly discuss the intralesional (IL) chemotherapy regimens vinblastine and bleomycin and their roles in cutaneous vascular lesions ( Table 47.1 ).

Table 47.1
Topical and Intralesional Chemotherapeutic Agents
Generic Name Synonym Trade Name Manufacturer Standard Concentrations Tube or Vial Size
Topical Administration
5-Fluorouracil 5-FU Efudex-40 a Valeant 5% cream a 40 g
2%, 5% solutions a 10 mL
Fluoroplex a Allergan 1% cream a 30 g
1% solution a 30 mL
Carac a Dermik 0.5% cream a 30 g
Tolak Pierre-Fabre 4% cream a 40 g
Mechlorethamine Nitrogen mustard Mustargen Yaupon Therapeutics 10 mg% ointment b
10 mg in 60 mL water		 10 mg vials
Carmustine BCNU BiCNU Bristol-Myers Squibb 300 mg in 150 mL stock solution c 100 mg vial
Intralesional Administration
Vinblastine N/A Velban Lilly 0.5 mg/mL 10 mg vials
Vincristine N/A Oncovorin, Vincasar PFS Prizer 1 μg/mL 1 mg or 2 mg vials
Bleomycin N/A Blenoxane Bristol-Myers Squibb 1% solution
1 U/mL		 15 U or 30 U vials
N/A, Not applicable.

a Proprietary formulations exist—all other products in the above table must be compounded.

b Ointment compounded 10 mg Mustargen in 10 mL absolute alcohol; subsequently compounded in 100 g of petrolatum or Aquaphor (instructions for compounding 10- and 40-mg% concentration are in text).

c Stock solution adequate for 1 month—daily use takes 2.5–5.0 mL stock solution in 30 mL water (depending on the extent of lesions in a given patient).

Topical Chemotherapeutic Agents

5-Fluorouracil

The antitumor activity of 5-FU was first demonstrated in the 1950s. It has been widely used as an intravenous chemotherapeutic agent in the treatment of various systemic cancers, including colorectal and breast, as well as head and neck, carcinomas. Its use as a topical agent began after a case report in 1962 described resolution of actinic keratoses (AK) in a patient who received 5-FU systemically. In 1963, a hydrophilic ointment of 20% 5-FU was used to treat patients with extensive AK for 4 weeks. A follow-up investigation of different concentrations of 5-FU found that 5% ointment had comparable outcomes to that of 20% ointment. These studies provided the foundation for further research that resulted in US Food and Drug administration (FDA) approval of 5-FU. Today, 5-FU is widely used as field-directed treatment of AK and certain keratinocyte carcinomas. Its other off-label uses include treatment of keratoacanthomas, actinic cheilitis, verruca vulgaris, and porokeratosis.

Pharmacology

5-FU is a structural analog of uracil with a fluorine atom at the C-5 position in lieu of a hydrogen atom ( Fig. 47.1 ). Cutaneous absorption of 5-FU has been studied using radiolabeled 5-FU ointment. Dillaha and coworkers approximated that 6% of 5-FU is absorbed systemically when applied topically and measured this by the amount of radioactivity recovered in the urine over time. In the authors’ opinion, this amount was too small to produce any systemic adverse effects (AE). In a second study, application of radiolabeled 5-FU to healthy skin resulted in slightly over 1% total absorption. By contrast, topical application of the same ointment to diseased or ulcerated skin resulted in a 15 to 75 times greater degree of systemic absorption. The selective effect allows the use of topical 5-FU over a broad area of skin without concern for damaging normal skin. In an in vitro study, percutaneous absorption was measured using full-thickness cadaver skin samples mounted on a flow-through diffusion cell apparatus. Comparison of 5% 5-FU versus 0.5% 5-FU revealed that flux through the skin was 20 to 40 times greater with 5% 5-FU than with 0.5% 5-FU.

Fig. 47.1, Topical and intralesional chemotherapy agents. NM, Nitrogen mustard.

Information on the metabolism of 5-FU is based on studies from intravenous administration of 5-FU; there are no available data on the metabolism of 5-FU in the skin. After it enters a cell, 5-FU is converted to several active metabolites: fluorodeoxyuridine monophosphate, fluorodeoxyuridine triphosphate, and fluorouridine triphosphate. A key enzyme in the metabolic pathway is dihydropyrimidine dehydrogenase (DPD), which converts 5-FU to dihydrofluorouracil (DHFU). Over 80% of 5-FU is catabolized in the liver. After intravenous injection of 15 mg/kg of 5-FU in human studies, plasma levels fall rapidly and no intact drug is detected after 3 hours. Approximately 60% to 80% is catabolized to carbon dioxide and excreted by the lungs. About 15% of the intravenous dose is excreted in the urine within 6 hours as intact 5-FU, and over 90% of this is excreted in the first hour.

Mechanism of Action

5-FU is a structural analog of uracil that works by irreversibly inhibiting thymidylate synthetase, thereby disrupting deoxyribonucleic acid (DNA) synthesis. 5-FU and its metabolites are also misincorporated into ribonucleic acid (RNA) and interfere with RNA synthesis.

Clinical Use

Indications

Actinic Keratosis

Topical 5-FU is principally used for treatment of actinic keratosis (AK). The FDA-approved brands of topical 5-FU include Efudex, Fluoroplex, Carac, and Tolak. AK are premalignant lesions caused by excessive ultraviolet exposure and present as rough, scaly erythematous papules or patches. AK have the potential to progress to keratinocyte carcinomas, mainly squamous cell carcinoma (SCC), with an approximate rate of transformation of 0.075% to 0.096%. The risk of progression to invasive skin cancer warrants treatment of all AK. Localized treatments for individual AK include liquid nitrogen cryotherapy, curettage, and shave excision. More numerous or larger crops of AK justify the use topical field treatments such as 5-FU. In the 1960s, Dillaha and associates demonstrated that 5% 5-FU ointment applied topically twice daily to the face and neck was effective for treating patients with numerous AK. The effect of 5-FU is also more selective for AK than for normal skin; thus, 5-FU can be applied to a broad area of skin without concern that normal skin will be damaged. The 5% 5-FU cream formulation has been most widely studied; 1% and 0.5% cream formulations, and a 2% solution, are also available.

Q47.1 Numerous studies have validated the efficacy of topical 5-FU for the treatment AK. Efficacy rates for topical 1% and 5% 5-FU for the treatment of facial AK suggest an overall lesional response rate of approximately 88% and a complete response of approximately 63%. The 0.5% 5-FU formulation applied once daily for 1, 2, or 4 weeks was shown to be more effective than placebo; greater efficacy was found with longer duration of treatment. A meta-analysis of 83 randomized controlled trials (RCT) comparing various interventions for AK including topical 5-FU found that diclofenac, 5-FU, imiquimod, and ingenol mebutate have similar efficacies, but their associated AE and cosmetic outcomes are different. The corresponding comparative efficacy in terms of number of participants completely cleared per 1000 were as follows: 313 with 3% diclofenac compared with 127 with 2.5% hyaluronic acid; 136 with 0.5% 5-FU compared with 15 with placebo.

Results from the randomized controlled VAKCC trial demonstrated a significant decrease in number of new AK in those treated with topical 5-FU compared with placebo-control group. The 5-FU group had 62% fewer new AK per person at 6 months, 50% fewer AK at 12 months, and 41% fewer AK at 24 months. After this prospective follow-up, Walker and associates concluded that 5-FU prevents new AK for 24 to 36 months. Neugebauer and colleagues found that 5-FU appeared to be significantly more effective than imiquimod in the short-term (2 years), but not long-term (5 years) prevention of subsequent AK. Yoon and coworkers found similar findings that resulted in significant cost savings for patients treated with 5-FU.

More recent literature has demonstrated efficacy of topical calcipotriol in combination with 5-FU. In a randomized, double-blind clinical trial involving 131 patients, Cunningham and associates demonstrated the superiority of calcipotriol plus 5-FU in mean reduction in number of AK than Vaseline plus 5-FU: 87.8% versus 26.3%, respectively ( P < .0001).

Nonmelanoma Skin Cancer

Q47.2 Topical 5-FU is also used for the treatment of keratinocyte carcinomas. Specifically, 5-FU is approved for the treatment of superficial basal cell carcinomas (sBCC) or BCC that are not amenable to surgical removal. Nonsurgical management may be preferable in (1) patients with multiple lesions, (2) patients who cannot withstand invasive procedures, and (3) patients with lesions located in anatomically difficult sites for surgical treatment. Of the 5-FU brands, only Efudex 5% is currently approved for the removal of sBCC and the recommended regimen is application twice daily for 3 to 6 weeks. In one study of 31 patients with sBCC treated with 5% 5-FU twice daily for 11 weeks, a 90% clearance rate was observed. Although it is only FDA approved for the treatment of BCC, 5-FU has been efficacious for SCC in situ and SCC, thus it has been used as an off-label alternative for the treatment of these lesions. Two studies with a treatment regimen of once daily for 1 week then twice daily for 3 weeks showed clearance rates of 56% and 48%, respectively. One study with a treatment regimen of twice daily for 8 weeks reported an 85% clearance rate with 4.6 years of follow-up. Additional options for treating keratinocyte carcinomas include Mohs micrographic surgery, excision, electrodessication and curettage, cryotherapy, topical imiquimod, radiotherapy, photodynamic therapy, and laser.

Actinic Cheilitis

Actinic cheilitis is a premalignant lesion of the lips, classically the lower vermillion, and has the potential to transition to SCC. Although laser vermilionectomy remains the gold standard, other treatment modalities include topical 5-FU, cryosurgery, chemical peels, photodynamic therapy, electrosurgery, and surgical resection. Topical 5-FU is not FDA approved for mucocutaneous diseases, but has been successfully used for the treatment of actinic chelitis. Studies using 5% and 1% 5-FU have demonstrated efficacy, although one study showed residual disease in posttreatment biopsies.

Keratoacanthoma

Keratoacanthomas (KA) are sharply circumscribed, rapidly growing papules located on the sun-exposed skin. There is concern that KA represent a variant of SCC and for this reason these lesions are generally treated. In one study, 12 of 15 patients treated with topical 2% or 5% 5-FU had complete resolution of KA within 3 to 5 weeks. In another study, 14 patients were treated with 20% 5-FU ointment for 2 to 4 weeks and all lesions cleared in an average of 3.4 weeks. Most KA respond to 5-FU within 8 weeks; however, any lesion that does not respond should prompt a biopsy to rule out invasive SCC.

Porokeratosis

Porokeratosis classically presents as an annular, hyperkeratotic plaque with raised borders, and has six clinical variants. Development of SCC within the lesion of porokeratosis is possible but rare. Histologically, lesions demonstrated coronoid lamellae or a linear column of parakeratosis and absent to decreased granular cell layer. There are case reports that suggest 5-FU is helpful in porokeratosis lesion treatment. In 1973, six patients with classic porokeratosis of Mibelli on the lips were successfully treated using 5-FU ointment. Another report describes the complete response of a lesion on the dorsal thumb after application of 5-FU solution with occlusion using petrolatum and/or bandage twice daily. Topical 5-FU has also been shown to be effective as a once-daily application without occlusion in the treatment of multiple disseminated porokeratosis lesions. Complete clearance of a case of porokeratosis of Mibelli was reported with combined use of photodynamic therapy (PDT) and 5-FU.

Contraindications

Q47.3 Topical 5-FU should not be used in patients with known allergic reaction to 5-FU and in those with the inherited deficiency of DPD, which is the key enzyme involved in the metabolism of 5-FU. Patients lacking this enzyme are unable to degrade 5-FU, resulting in in toxic levels. Women who are pregnant or who may become pregnant should also not be prescribed 5-FU because of its teratogenicity. 5-FU was previously described as a category X drug.

Adverse Effects

The most common AE are localized to areas of treatment and include erythema, irritation, burning, pain, pruritus, hypopigmentation, and hyperpigmentation. The inflammatory AE typically begin within 5 to 10 days of the start of treatment. Also, allergic contact dermatitis has been reported. Systemic AE are extremely rare with topical application of 5-FU. Q47.3 Studies of systemic absorption indicate that the amount absorbed is far below the levels from typical doses of 5-FU used for cancer chemotherapy. However, there is a case report of life-threatening toxicity in a patient treated with topical 5% 5-FU who was found to have a deficiency of DPD.

Therapeutic Guidelines

5-FU is commercially available as 1%, 2%, and 5% solutions and 0.5%, 1%, 4%, and 5% creams. The 1%, 2%, 4%, and 5% formulations are applied once or twice daily and the 0.5% cream is applied once daily. For AK, treatment duration is 2 to 6 weeks, depending on the site treated and the sensitivity of the individual patient to treatment. The usual treatment period for the face is 2 weeks; lesions on the hands and arms may require 4 to 6 weeks’ treatment to achieve the desired reaction. For sBCC, the recommended regimen is twice daily for >11 weeks. For SCC in situ, the recommended regimen is twice daily for 8 weeks. Care should be taken to avoid excessive application to sensitive areas such as the eyelids, nasolabial folds, and lips. Hands should be washed after application. An inflammatory reaction is expected; this may include erythema, edema, oozing, and crusting. If a minimal reaction occurs, treatment can be continued for another 1 to 2 weeks, while increasing to twice daily therapy if the initial frequency was once daily application.

To control more severe inflammatory reactions, the frequency or strength of 5-FU can be reduced. Topical corticosteroids (TCS) may be used concomitantly with the topical 5-FU and for 1 to 2 weeks beyond cessation of topical 5-FU application to relieve the inflammatory reaction, without impacting topical 5-FU efficacy.

Mechlorethamine/Nitrogen Mustard

NM are a group of alkylating agents with broad application in anticancer treatment. Mechlorethamine, (methyl-bis[2-chloroethyl]amine) hydrochloride, more commonly known as nitrogen mustard (NM), is a member of this group and was the earliest to be used in clinical medicine. Other agents in this group include: melphalan, chlorambucil, cyclophosphamide, ifosfamide, and thiotepa. All of these chemicals are highly reactive with DNA, resulting in the donation of alkyl groups to DNA and thus disrupting normal cell function. The ultimate cause of cell death related to DNA damage is unknown, although is likely because of apoptosis. NM is used systemically for the treatment of Hodgkin disease, lymphosarcoma, chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides (MF), and bronchogenic carcinoma. For decades, topical NM has been recorded as a safe and effective treatment for MF, yet never achieved FDA approval.

Q47.4 In 2013, NM received marketing approval for the treatment of MF under the brand name Valchlor by Ceptaris Therapeutics, Inc. Marketing approval was based upon the results of a randomized, noninferiority trial comparing NM with pharmacy-compounded mechlorethamine preparation in patients with stage IA to IIA MF. The pivotal trial compared the gel formulation with a pharmacy-compounded preparation, and the endpoint was a confirmed complete remission (CR) at 6 months, defined as at least a 50% reduction in the Composite Assessment of Index Lesion Severity score. This was achieved by 58.5% of patients treated with the proprietary gel but by only 48% of those treated with the pharmacy-compounded product. Clinical response and duration of clinical response was not statistically significant; however, the average time to achieve greater than 50% improvement was shorter with the gel (24 weeks) than the ointment (42 weeks) ( P < .01).

Pharmacology

The structure of NM is listed in Fig. 47.1 . There is no known significant systemic absorption of topical NM. No systemic toxicities from cutaneous absorption have been observed in long-term topical NM use in MF.

Mechanism of Action

The mechanism of action of topically applied NM is unclear. Clinical studies using topical NM have not assessed levels of NM in the blood. When administered systemically, NM is a strong electrophile and is chemically unstable, resulting in the formation of covalent linkages by alkylation of nucleophilic moieties. The chemotherapeutic effect is based on its alkylation of DNA. However, the ultimate cause of cell death related to DNA damage is not known, although is likely because of apoptosis.

Clinical Use

Indications

The primary indication for topical NM is in the treatment of MF. MF is a non-Hodgkin lymphoma of T-cell origin, and is the most common cutaneous lymphoma. Topical NM for treatment of MF was first described in the English literature in 1959. Subsequent reports have confirmed its efficacy in MF, including its ability to induce CR. It has been the most widely used therapy for MF patients with early-stage disease, defined as either T1 (limited patches/plaques, <10% of total body surface area [BSA]) or T2 (generalized patches/plaques, >10% of total BSA) according to the revised tumor–node–metastasis (TNM) staging classification for MF. Topical NM can be applied with an aqueous solution, ointment, or gel base. The aqueous solution was first described in 1959, and the ointment preparation was later described in 1982. The newest proprietary formulation is available as a gel. The largest published patient series using NM therapy are from Stanford, New York University, and Temple University. Results from these series are reviewed below and summarized in Table 47.2 .

Table 47.2
Summary of Topical Nitrogen Mustard Studies—Patients with Patch and/or Plaque (T1–2) Mycosis Fungoides
Institution No. of pts (N) Preparation (%) Clinical Stage (%) CR n (%) 5-, 10-Yr Survival Maintenance (yrs) Comments
Temple University 201 Aqueous (100) IA (44) 71 (80) 94, 89 3 Many patients with other concurrent therapies
IB (33) 45 (68) 85, 83
IIA (23) 28 (61) 82, 67
New York University 107 Aqueous (100) I-IIA (100) 67 (63) 93, N/A 1.5 Patients with lymphadenopathy (IIA) not analyzed separately
Stanford University 195 Ointment (81)
Aqueous (14)
PEG (5)		 IA (53) 69 (67) 97, 88 0.5–2 No other concurrent therapies
IB (38) 26 (35) 70, 57
IIA (9) 5 (28) 89, 67
N/A, Not available; PEG, polyethylene glycol.

Mycosis Fungoides—the Stanford University Experience

From 1968 to 1980, MF patients at Stanford were treated with NM aqueous solution, and since 1980 primarily with NM ointment. Hope and colleagues documented 123 patients with MF treated with topical NM during the course of their disease, with the majority of the patients having T1 disease. CR and PR rates were 51% and 37%, respectively, in patients with T1 disease and 26% and 43%, respectively, in T2 disease. Kim and coworkers updated their colleague’s study with long-term results and found that of the 203 patients who underwent NM therapy (including patients who used either aqueous or ointment-based preparation), overall response rate for the 203 patients was 83%, with a complete response rate of 50%. The median time to achieve CR was 12 months. The efficacy results were similar in patients treated with aqueous versus ointment preparations.

Mycosis Fungoides—the New York University Experience

At New York University between 1970 and 1986, 107 MF patients with early-stage disease were treated with topical NM solution. The CR rate was 63%. A solution of 10 mg NM in 60 mL water was used and patients applied the solution daily to the total body surface, sparingly to intertriginous sites. The overall median time to CR was 10.9 months. The median time to achieve CR for T1 patients was 4.4 months, and for T2 patients was 20.4 months.

Mycosis Fungoides—the Temple University Experience

Between 1968 and 1982, 201 early-stage MF patients at Temple University were treated with topical NM solution. Patients were treated with an aqueous solution of 10 to 20 mg NM in 40 to 60 mL water applied once daily to the entire surface of the skin except for the genital area. Included in this study were patients who concurrently received other therapies, such as local radiotherapy, total skin electron beam radiation, ultraviolet light, or systemic chemotherapies. Patients with T1 class had CR rate of 80%; patients with T2 had CR rate of 62%.

Contraindications

Topical NM therapy should be avoided in patients with previous hypersensitivity to NM. In the same manner, Valchlor should not be used in patients known to be severely allergic to mechlorethamine. Although a previous history of multiple SCC is not a contraindication, clinicians may use caution in treating these patients with NM, particularly if patients have had other skin-damaging therapies, such as radiation. Patients should not be pregnant or breastfeeding.

Adverse Effects

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