Topical chemotherapy of advanced cutaneous malignancy with 5-fluorouracil creme

Journal of Secrgical Oncology 3(3): 351-365 (1971)

Topical Chemotherapy of Advanced Cutaneous Malignancy with 5 -Fluorouracil Creme

Martin S. Litwin, M.D.,’35 Robert F. Ryan, M.D.,~~:

Richard J. Reed, M.D.,335 and Edward T. Ihementz, M.D.4,’

Klein et al. have demonstrated that basal cell carcinoma responds favorably to topical applications of 5-fluorouracil in an aquaphor creme base. In the present study 53 patients with advanced cutaneous basal cell and epidermoid carcinoma were treated with 5,10, or 20 percent 5-fluorouracil(5-FU) in an aquaphor creme base to determine whether this mode of therapy might be superior to surgical excision or irradiation therapy. Patients included in the study fulfilled a t least one of the following criteria on which the diagnosis of advanced cutaneous malignancy was made: (1) Primary epidermoid or basal cell carcinoma of the skin-(a) 2.0 cm in diameter or larger, or (b) involving deeper structures such as cartilage on the ear or bone on the top of the head, or (c) occurring in an area that would require a major surgical procedure to cure, or (d) requiring extensive irradiation therapy to cure. (2) Recurrent lesion at a site where a previous malignant lesion had been adequately treated. (3) Repeated solitary lesions occurring at different anatomic sites. (4) Multiple lesions, a t least one of which was malignant, occurring simultaneously over a wide cutaneous area. The appropriate concentration of 5-FU creme was applied once daily for a minimum of 6 weeks and an average period of 9 weeks. One patient with a Marjolin’s ulcer was treated in the hospital, and the remainder were treated on an outpatient basis. Pathologic diagnosis were as follows: basal cell, 35; epidermoid, 9; carcinoma in situ, 4; basal cell and epidermoid in the same patient, 3; and basosquamous, 2. In 50 patients progressive inflammation, gradual regression, disappearance, and healing were noted. Only malignant and premalignant tissue and its stroma appeared to be affected, while normal

This paper was presented at a symposium entitled ‘Recent Advances in the Management of Skin Neoplasms’ held April 11-12,1969, New York, New York.

Supported by Tulane Skin Cancer Reseach Fund and Grants 5-P-02-CA-05837, 5-T01-CA-05108, and 5-T12-CA-08087 from the National Cancer Institute. M.S.L. holds Public Health Service Research Career Award 1-K3-HE-38, 601-01, from the National Heart Institute.

Associate Professor of Surgery. Professor of Surgery and Chief, Plastic Surgical Division.

Professor of Surgery and Director, Clinical Cancer Research Center.

24 351

3 Formerly Professor of Pathology and Chief, Dermatopathology Division.

5 Departments of Surgery and Pathology, Tulane University School of Medicine, New Orleans, Louisiana.

352 Litwin, Ryan, Reed, and Krementz

skin was affected only slightly or not a t all. Healing occurred primarily with minimal or no scar formation. No local or invasive sepsis occurred. In three patients an apparently adequate inflammatory response was achieved, but the primary disease process was not eradicated; two of these patients had epidermoid carcinoma and one had basal cell carcinoma. Except for one patient who has been followed for 2 months since completing chemotherapy, the post-treatment follow-up period has ranged from 4 months t o 2 years. The average follow-up period is 9 mouths. These preliminary results seem to indicate that daily topical application of an appropriate concentration of 5-fluorouracil in an aquaphor creme base for a t least 6 weeks to advanced cutaneous basal cell or epiderrnoid Carcinoma is the treatment of choice when the diseaseis diffuse, there are no obvious metastases, and the procedure necessary to totally remove the involved area would be unusually mutilating.

INTRODUCTION Basal cell epidermoid carcinoma of the skin occurs commonly in fair-skinned patients who are chronically exposed to actinic radiation. In the basal cell nevoid syndrome, chromosomal abnormalities have been noted, and diffuse cutaneous basal cell carcinomas occur in great numbers. When these diseases recur chronically in multicentric fashion, conventional surgical or irradiation therapy is not only impractical but usually impossible, and less than optimal cosmetic results may be achieved. Klein et al. (1962, 1965, 1966) have studied the effects of topical applications of various cancer chemotherapeutic agents in the treatment of cutaneous malignancies. They have demonstrated tha t basal cell carcinoma responds favorably t o topical applications of 5-fluorouracil in an aquaphor creme base. As a result of their outstanding work, the usefulness of this therapeutic method has been clearly established, and results of its clinical application by others have recently been reported (Litwin etal. , 1969).

In the present study patients with advanced cutaneous basal cell and epidermoid carcinoma were treated with 5, 10, or 20 percent 5-fluorouracil (5-FU) in . an aquaphor creme base6 t o determine whether this mode of therapy might be superior t o surgical excision or irradiation therapy.

METHODS AND RESULTS Advanced cutaneous basal cell and epidermoid carcinomas were treated with

topical 5-FU creme in 53 patients. Patients included in the study fulfilled a t least one of the following criteria on which the diagnosis of advanced cutaneous malignancy was made : 1. Primary epidermoid or basal cell carcinoma of the skin.

a. 2.0 cm in diameter or larger, or b. involving deeper structures such as cartilage on the ear or bone on the top of the head, or

5-Fluorouracil creme used in these studies was prepared by Mr. Robert W. Case, Director of Pharmacy Services, Roswell Park Memorial Institute, from 5-FU powder supplied by Dr. Edward Miller, Director of Clinical Oncology, Hoffmann-LaRoche, Inc. Adequate quantities of the medication were made available to us through the generous cooperation of Mr. Case and Dr. Edmund Klein, Chief of Dermatology, Roswell ParkMemorial Institute, Buffalo, N.Y.

Topical Chemotherapy of Advanced Cutaneous Malignancy with 5-Fluorouracil Creme 353

TABLE I Pathologic Diagnoses in 53 Patients with Advanced Cutaneous Carcinoma Treated

with 5,10, or 20 Percent 5-Fluorouracil Creme

Basal cell 35

Carcinoma in situ 4 3

Epidermoid 9

Basal cell and epidermoid in same patient Basosquamous 2

Total patients treated 53

2.

3. 4.

c. occurring in an area that would require a major surgical procedure to cure, or d. requiring extensive irradiation therapy to cure. Recurrent lesion a t a site where a previous malignant lesion had been adequately treated. Repeated solitary lesions occurring a t different anatomic sites. Multiple lesions, a t least one of which was malignant, occurring simultaneously over a wide cutaneous area.

Therapy consisted of once-daily application of the appropriate concentration of 5-FU creme for periods ranging from 6 through 14 weeks. The average treatment period was 9 weeks. One patient with epidermoid carcinoma in a varicose ulcer (Marjolin’s ulcer) was treated in the hospital; all others were treated on an outpatient basis. After the diagnosis was established by biopsy, therapy was begun with 5-FU creme. Pathologic diagnoses are listed in Table I. The course of the disease was followed on photographic records, and serial biopsies were taken during the therapeutic course. All patients were followed and all biopsy specimens were interpreted personally by the authors.

Six patients, two with epidermoid carcinomas, one with basosquamous carcinoma, and three with basal cell carcinomas, failed to respond to the drug concentration used initially; response became optimal when the medication concentration was increased from 5 to 20 percent in five cases and from 10 t o 20 percent in the other. Three patients, including two with basal cell carcinomas and one with basal cell nevoid syndrome, initially over-responded to either 10 or 20 percent concentration; response became optimal when the concentration of their medication was de- creased to 5 percent 5-FU.

In 50 patients progressive inflammation, gradual regression, disappearance, and healing were noted. Only malignant and premalignant tissue and its stroma appeared t o be affected, while normal skin was affected only slightly or not a t all. Healing occurred primarily with minimal or no scar formation. No local or invasive sepsis occurred. In three patients an apparently adequate inflammatory response was achieved, but the primary disease process was not eradicated; two of these patients had epidermoid carcinoma and one had basal cell carcinoma.

Except for one patient who has been followed for 2 months since completing chemotherapy, the post-treatment follow-up period has ranged from 4 months to 2 years. The average post-treatment follow-up period is 9 months.


Fig. la. Case No. 1. This infiltrating progressively enlarging lesion had been present for 1 year.

Fig, lb . Case No. 1. Biopsy showed nests of atypical basophilic cells taking origin from the epidermis and infiltrating the dermis (100 x ; reduced 50% for reproduction).

Fig. lc. Case No. 1. Daily topical chemotherapy with 5 percent 5-FU creme begun on 15 August 1968 was discontinued on 26 September 1968 after a biopsy showed that no tumor remained. Healing was complete by 14 November 1968, and there has been no recurrence.


The response to treatment observed in most patients could be divided into four definite stages :

Early Inflammatory Response Phase During the first 7-10 days, in patients who were being treated for the first

time, little reaction could be seen grossly. Microscopically, moderate mononuclear cell infiltration is usually noted in cutaneous malignancies, but when 5-FU applications were begun the rapid further increase noted was striking. This phase was shortened to 3-5 days if other lesions had been treated previously.

Severe Inflammatory Response Phase During the second stage of response, between the second and the fourth weeks

of treatment, lesions became progressively reddened, somewhat tender, and painful on exposure t o sunlight, and a superficial crust of exuded serum appeared. Microscopically, there was a marked heavy infiltration of lymphocytes, monocytes, and plasma cells into the area. Malignant cells began t o swell and progressively disintegrate.

Tumor Disintegration Phase In the next stage, toward the end of the sixth to eighth weeks of treatment,

even the cells located in the deepest levels of the lesions showed signs of cell death, and viable malignant cells could usually no longer be found in the lesion. The surface was covered with a thickened eschar which was occasionally blackened. Healing pink skin could be seen invading the surrounding margins. Microscopically, necrosis of vessels was a prominent feature. Heavy mononuclear cell infiltration persisted, but polymorphonuclear leukocytes began t o replace them. If biopsies at this time were negative, 5-FU applications were discontinued.

Healing Phase After completion of therapy, the fourth response phase, which took place during

the next 2-4 weeks, was characterized by completion of healing from the edges and depths of the treated area with complete slough of the eschar. Polymorpho- nuclear cells persistedfor 8-12 weeks more.

CASE REPORTS

Case No. 1 Mr. L. L., an 86-year-old retired actor, had a large infiltrating lesion over the

bridge of his nose that had been present for 1 year and was progressively enlarging (Fig. la). Over the past 30 years he had had several extensive plastic surgical operations for removal of similar lesions, but because his present cardiopulmonary condition was so precarious, another operation was felt t o be contraindicated.

A biopsy of the involved area showed ‘nests of atypical basophilic cells taking origin from the epidermis and infiltrating the dermis’ (Fig. lb) . Daily topical


applications of 5 percent 5-FU creme were begun on 15 August 1968 and continued for 6 weeks until a repeat biopsy showed ‘no evidence of viable tumor on sections examined.’

The area healed rapidly and uneventfully after chemotherapy (Fig. 1c) ; there has been no evidence of recurrence.

Comment Flat superficial infiltrative basal cell and epidermoid carcinomas usually

respond optimally to 5 or 10 percent 5-FU creme. The inflammatory response achieved after chemotherapy with 20 percent 5-FU creme is more severe than is necessary to cure the disease. When this type of flat infiltrative lesion is being treated, it is important t o include a wide margin of apparently normal tissue in the treatment area so that adjacent nests of premalignant or malignant cells that may lead to disease recurrence are destroyed. Normal skin appears t o be affected only slightly or not a t all.

Case No. 2 Mr. J. A. Y., a salesman of beautician’s supplies who is a habitual fisherman,

had noted a progressively enlarging mass over his left eye for 3 years (Fig. 2a). He had had several other cutaneous carcinomas previously excised and had been told that the plastic surgical procedure necessary to ensure complete removal of this lesion would be rather extensive. He desired topical chemotherapy as an alternative therapeutic method.

Multiple biopsies of the lesion showed ‘atypical basophilic cells infiltrating the dermis’ (Fig. 2b). Daily topical applications of 20 percent 5-FU creme were begun on 2 February 1968. A biopsy performed on 18 April 1968 showed ‘no evidence of carcinoma on multiple sections examined.’ Applications were therefore discontinued (Fig. 2c).

Fig. 2a. Case No. 2. This bulky exophytic tumor had been progressively enlarging for 3 years.


Fig. 2b. Case No. 2. Multiple biopsies showed nests of atypical basophilic cells infiltrating the dermis (110 x ; reduced 5006 for reproduction).

Fig. 2c. Case No. 2. Daily topical applications of 20 percent 5-FU creme were begun on 2 February 1968. A biopsy performed on 18 April 1968 showed shrinkage, pyknosis, and fragmentation of the nuclei of the basophilic tumor cells, and therapy was discontinued.

The area healed uneventfully after chemotherapy (Fig. 2d), and there has been no recurrence. Biopsies taken after healing have shown dermal fibrosis compatible with scar. There has been ‘no evidence of carcinoma on multiple sections examined’ from multiple biopsies.

Subsequently, several other basal cell carcinomas over this patient’s face and ears have been treated with topical 5-FU creme with equally good success.

,Comment Bulky exophytic basal cell tumors respond best to 20 percent 5-FU creme.

I n this kind of lesion, the inflammatory response to 5 percent 5-FU creme is so


Fig. 2d. Case No. 2. Healing occurred rapidly after completion of chemotherapy. There has been no recurrence. Multiple biopsies taken from the healed area seen in this figure have shown no evidence of carcinoma on multiple sections.

mild that tissue slough either occurs very slowly or not at all. The response to 10 percent 5-FU creme is usually better than tha t t o 5 percent but is nevertheless inconsistent. There have been no therapeutic failures when 20 percent 5-FU creme has been used for topical chemotherapy of this type of basal cell carcinoma.

Case No. 3 Mr. E. L., a 57-year-old man, had noted a progressively enlarging ulcerated

lesion on his left ear for 3 years (Fig. 3a). He gave no history of having had previous skin lesions removed.

A biopsy of the area showed ‘nests of atypical basophilic cells taking origin from the epidermis and infiltrating the dermis’ (Fig. 3b). Daily topical applications of 20 percent 5-FU creme were begun on 16 May 1968. A biopsy done on 20 June 1968 no longer contained malignant cells. Topical chemotherapy was discontinued on 16 July 1968.

The lesion healed rapidly and uneventfully after chemotherapy (Fig. 3c), and there has been no recurrence to date.

Comment This patient’s carcinoma was bulky and ulcerated. As in Case No. 2,20 percent

5-FU creme has been found to be the optimal concentration for chemotherapy of this type of lesion. The cosmetic result achieved was very gratifying.

Case No. 4 Mr. W. J. B., a retired 77-year-old man, had three ulcerated lesions over his

head and a friable fungating lesion 2.5 cm in diameter just in front of his right ear (Fig. 4a). Because he had severe cardiorenal disease and was Eelt t o be a very poor operative risk, he was considered for topical chemotherapy.


Fig. 3a. Case No. 3. This ulcerated lesion had been progressively enlarging for 3 years.

Fig. 3c. Case No. 3. After daily topical chemotherapy with 20 percent 5-FU creme from 16 May through 20 June 1968, there was no evidence of carcinoma in multiple sections examined. Chemotherapy was discontinued on 16 July 1968, and the lesion healed rapidly. There has been no recurrence. The cosmetic result achieved was excellent.

Fig. 3b. Case No. 3. A biopsy taken from the edge of the lesion showed nests of atypical basophilic cells taking origin from the epidermis and infiltrating the dermis. The epidermis was part- ially ulcerated (83 x ; reduced 50% for reproduction).

A biopsy of the lesion in front of his ear showed ‘nests of atypical keratinizing squamous cells taking origin from the epidermis and infiltrating a stroma composed of edematous inflamed granulation tissue’ (Fig. 4b). Daily topical chemotherapy was begun with 20 percent 5-FU creme on 18 April 1968. By 6 June 1968, approxi- mately 7 weeks later, no carcinoma was evident on multiple sections (Fig. 4c). Because the lesion was a squamous cell carcinoma, 5-FU applications were continued through 20 June.1968.


Fig. 4a. Case No. 4. Daily topical chemotherapy with 20 percent 5-FU creme was begun to this preauricular friable fungating lesion on 18 April 1968.

Fig. 4b. Case No. 4. A prctreat- ment biopsy showed nests of atypical keratinizing squamous cells taking origin from the epidermis and infiltrating a stroma composed of edematous inflamed granulation tissue (39 x ; reduced 5096 for reproduction).

Fig. 4c. Case No. 4. There was no evidence of carcinoma in a biopsy performed on 6 June 1968, but because the lesion was an epidermoid carcinoma therapy was continued until 20 June 1968. Three other ulcerated lesions on the patient’s head, one of which was on the right forehead, as shown in this photograph, were treated in the same way as and simultaneously with the squamous cell carcinoma. Pretreat- ment biopsies from these areas showed atypical epithelial hyperplasia but no evidence of carcinoma. These areas have all healed.


Fig. 4d. Case No. 4. On 26 September Fig. 4e. Case No. 4. By 31 October 1968 1968 a firm nodular area was noted at the the scar had become flat, soft, and pliable. site where the previous carcinoma had There has been no recurrence of disease, becn treated. Biopsy showed dermal and no palpable regional lymph nodes or fibrosis compatible with scar. other evidence o f metastases have been

found.

Following chemotherapy, healing was rapid and uneventful. On 26 September 1968 a firm nodule in the treated area was biopsied with a No. 1 cutaneous punch (Fig. 4d). The biopsy showed ‘dermal fibrosis compatible with scar.’ The scar has since become soft and flat, and there has been no local recurrence of carcinoma t o date (Fig. 4e). No palpable regional lymph nodes or other evidence of metastases have been found.

Biopsies taken from the other three ulcerated lesions on this patient’s head were interpreted as showing ‘atypical epithelial hyperplasia.’ These areas were treated simultaneously with the squamous cell carcinoma on his right cheek and also healed.

Comment When the tumor being treated is a bulky fungating locally invasive squamous

cell carcinoma, of those concentrations used, 20 percent 5-FU creme was found to be the best. Complete response of this type of squamous cell carcinoma t o 10 percent 5-FU creme is inconsistent and t o the 5 percent concentration only slight.

Case No. 5 Mrs. J. D., a 59-year-old housewife, was admitted to the hospital on 2 January

1968 with a persistent varicose ulcer on her lower lateral left leg tha t had been present for 3 years (Fig. 5a). In spite of constant bed rest with elevation and repeated Unna boot applications, the lesion had stubbornly refused to heal. A biopsy


Fig. 5a. Case No. 5. This velvety epidermoid carcinoma in a varicoseulcer (Marjolin’s ulcer) was biopsied on 2 January 1968.

Fig. 5b. Case No. 5. Pathologic interpretation of the biopsy was as follows : ‘The epidermis shows acanthosis, atypical epithelial liyperplasia and marked intra- and intercellular edema. There are nests of atypical squamous cells taking origin from the epidermis and infiltrating the dermis. The dermis shows marked edema, hyalination, and chronic inflammation. (42 x ; reduced 50% for reproduction).

done on 2 January 1968 showed ‘epidermoid carcinoma’ (Fig. 5b). The patient asked that radical surgical therapy be postponed and that she be treated with topical 5-FU creme.

Daily topical applications were begun on 7 January 1968 with 10 percent 5-FU creme. Multiple circumferential biopsies taken on 7 February 1968 showed no tumor t o be present. Chemotherapy was discontinued on 16 February 1968.


Fig. 5c. Case No. 5. After topical chemotherapy with 10 percent 5-FU creme from 7 January 1968 through 7 Feh- ruary 1968, there was no evidence of carcinoma on multiple sections examined from multiple biopsies, but chemotherapy was continued until 16 February 1968. A large eschar then formed locally.

Fig. 5d. Case No. 5. The local eschar progressively sloughed and was replaced by healthy granulation tissue. After this photograph was taken on 3 May 1969, one-half strength Dakin’s sol- tion soaks to the ulcer were begun twice daily.

Fig. 5e. Case No. 5. A split- thickness skin graft applied on 13 May 1968 was firmly established by 13 June 1968, the date this photograph was taken. The patient has been ambulatory since then. To date, there has been no local recurrence. No regional lymph nodes are palpable nor is there other evidence of metastases.


A large eschar which formed locally (Fig. 5c) progressively sloughed and was replaced by healthy granulation tissue (Fig. 5d). A split-thickness skin graft was applied on 13 May 1968. By 13 June 1968 the graft was firmly established (Fig. 5e), and the patient was ambulatory. To date there has been no local recurrence, and no regional lymph nodes are palpable nor is there other evidence of metastases.

Comment Because this patient’s lesion presented a large ulcerated surface, absorption

of 5-FU t o toxic levels was feared. Therefore, chemotherapy was carried out with 10 percent 5-FU creme rather than the 20 percent concentration. Therapeutic response was complete, but there is no doubt in the authors’ minds that when drug absorption is not a problem an ulcerated or fungating squamous cell carcinoma responds better t o 20 percent 5-FU creme than t o 10 percent.

DISCUSSION Advanced cutaneous basal cell and epidermoid carcinomas have been thera-

peutic enigmas. While Klein et al. demonstrated that basal cell carcinoma responds favorably to topical applications of 5-FU, the use of this therapeutic method in the treatment of advanced cutaneous malignancy has been limited.

In other series, significant recurrence rates have been reported following topical application of 5-FU for treatment periods of up to 4 weeks. In the present study the inflammatory response appeared to be a t its maximum a t that time. The preparation of 5-FU in a creme base rather than a liquid vehicle allowed the precise localization of topical applications of the drug for prolonged periods of a t least 6 weeks. The tumoricidal phenomenon could thereby persist until all malignant cells were destroyed. Since the creme used was water soluble, all of the suspended medication appeared to be available for release into the area desired. Preparation of the creme t o contain varyingly high concentrations of 5-FU allowed the treatment to be varied so that the drug concentration used was optimal for the disease being treated.

Significantly, there have been no recurrences in those patients in whom biopsies of lesions being treated reverted to negative. It should be noted, however, that in two patients with epidermoid carcinoma and one with basal cell carcinoma, their diseases were not eradicated in spite of what appeared to be adequate therapy. While the possibility does exist that the medication was improperly applied, other patients with the same diseases did respond; therefore, the authors have assumed tha t lack of response in these patients was due to some basic difference in the bio- logic nature of the tumor being treated.

CONCLUSIONS Patients with advanced cutaneous basal cell or epidermoid carcinoma are

usually doomed t o frequent recurrences when surgical excision or irradiation of isolated lesions is done. When the disease is multicentric, mutilating procedures must often be performed. Even then the incidence of recurrence is very high.


Topical application of 5-FU creme allows treatment of malignant and adjacent premalignant lesions over wide areas a t the same time. The method is simple and inexpensive. In most cases, the patient may perform his own therapy outside the hospital. Scar formation has been negligible and healing rapid. Normal skin is affected only slightly or not a t all.

These preliminary results seem to indicate tha t daily topical applications of an appropriate concentration of 5-fluorouracil in an aquaphor creme base for a t least 6 weeks to advanced cutaneous basal cell or epidermoid carcinoma is the treatment of choice when the disease is diffuse, there are no obvious metastases, and the procedure necessary to totally remove the involved area would be unusually mutilating.

NOTE ADDED IN PROOF

Since these data were originally presented in April 1969, further follow-up of patients presented has continued. None has had recurrences in the treated areas even though new lesions have cropped up elsewhere.

Of the cases shown, case No. 1 (Mr. L. L.) was free of disease when last seen on 1 May 1970; he died on 14 January 1970 from heart disease. Case No, 2 (Mr. J. A. V.) and case No. 3 (Mr. E. L.) were free of disease when last seen on 4 June 1970 and 24 September 1970, respectively. Case No. 4 (Mr. W. J. B.) was free of disease when last seen on 7 August 1969; he died on 10 December 1969 from a myocardial infarct. Case No. 5 (Mrs. J. D.) was also free of disease when last seen on 24 April 1970. The grafted area on her leg remains in good condition, but repeated ulceration has occurred around its margins due to her underlying venous disease; biopsies of these areas have been negative and metastases have not occurred.

REFERENCE§ Klein, E., Helm, F., Milgrom, H., Stoll, H. L., and Traenkle, H. L. (1962). Tumors of the skin. 11.

Keratoacanthoma: Local effect of 5-fluorouracil. Skin 1 : 153. Klein, E., Stoll, H. L., Milgrom, H., Case, R. W., Traenkle, H. L., Graham, S., Laor, Y., and Helm, F.

(1965). Tumors of the skin. IV. Double-blind study on effects of local administration of antitumor agents in basal cell carcinoma. J. Invest. Dermatol. 44: 351.

Iclein, E., Stoll, H. L., Milgrom, H., Traenkle, H. L., Graham, S., and Helm, F. (1966). Tumors of the skin. VI. Study on effects of local administration of 5-fluorouracil in basal cell carcinoma. J. Invest. Dermatol.47: 22.

Iitwin, M. S., Ryan, R. F., Reed, R. J., and Krementz, E. T. (1969). Topical chemotherapy of cutaneous malignancy of the head and neck. Southern 1Med.J. 62: 556.

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Topical chemotherapy of advanced cutaneous malignancy with 5-fluorouracil creme