524
Journal of the Royal Society of Medicine Volume 84 September 1991
Treatment of basal cell carcinoma with intralesional interferon alpha-2b
M F Healsmith MB BS' J Berth-Jones mRCP' A Fletcher FRCPath2 R A C Graham-Brown FRCP1 Departments of 'Dermatology and 2Histopathology, Leicester Royal Infirmary, Leicester LE1 5WW Keywords: basal cell carcinoma, interferon
Summary We report a series of 11 basal cell carcinomas of various types treated with nine intra-lesional injections of 1.5 million units of interferon alpha-2b. The diagnosis was confirmed histologically in each case. After 3 months' follow-up six tumours had resolved both clinically and histologically. In three cases the tumour size was reduced. One tumour grew larger. Side effects were well tolerated except by one subject who was withdrawn. Those cases which responded have now been followed-up for between 12 and 26 months with no clinical or histological evidence of tumour recurrence. This is the longest period of follow-up so far reported for this novel treatment. The results are encouraging and, if maintained in future series, may indicate a useful role for interferon alpha in the management of this common cutaneous malignancy. Introduction Basal cell carcinoma is usually treated by radiotherapy or surgical techniques which carry a risk of scarring. These tumours may occur at sites on the face where excision is technically difficult and the cosmetic result is often important. A non-surgical approach to treatment is therefore of considerable potential value. Interferons are a range of glycoproteins first discovered by Isaacs and Lindenmann in 19571 and named after their ability to interfere with viral proliferation. Although this property has found few clinical applications, they have subsequently been shown to possess useful antineoplastic activity. Interferons have an antiproliferative action and promote cell differentiation2, they can suppress oncogene expression3, induce cell surface antigens such as HLA-DR and ICAM-1 on keratinocytes4 and tumour cells5'6 augment activity of cytotoxic T-cells and natural killer cells, and stimulate phago-
cytosis7'8. Initial studies9-"1 have suggested that intralesional injections of small doses of interferon alpha-2 are very effective in treating basal cell carcinoma. Greenway et al.9 and Grob et al.'0 reported complete clearance of eight and seven tumours respectively. Interferon gamma appears to have similar activity though the cure rate was only 50% in an initial study using nine intralesional injections of 100 000 units'2. Reported follow-up has so far been very limited, but if such results as those outlined above are sustained, and tumours do not recur more often than with other treatments, interferon alpha would seem likely to play a useful role in the management of basal
cell carcinoma. We describe here a series of 11 cases of randomly selected types of basal cell carcinoma treated with interferon alpha-2b and followed-up for over 12 months. Method Eleven patients were recruited at random from among patients attending our clinic for treatment of basal cell carcinoma. All gave signed informed consent to participation. The site, type and maximum diameter of each tumour were recorded. The diagnosis was confirmed histologically prior to treatment in each case, by 4 mm punch biopsy. Treatment consisted of a course of nine intralesional injections of interferon alpha-2b, on Monday, Wednesday and Friday each week for 3 weeks. Each injection contained 1.5 million units dissolved in 0.2-0.5 ml water. Side effects were recorded. Full blood counts were performed on each subject before and immediately after completion of treatment. After treatment subjects were reviewed monthly for a period of 3 months, after which time a 4 mm punch biopsy was performed. These were examined at several levels. In cases where residual tumour was present excision was undertaken. All subjects currently remain under review. In those where any clinical features compatible with basal cell carcinoma have persisted additional punch biopsies have been performed. Results Data on the subjects, tumours, response to treatment and length of follow-up are summarized in Table 1. Complete clinical and histological resolution was achieved at 3 months in six of 10 patients who completed the treatment. The cosmetic result was considered excellent by both patient and doctor in all these cases (Figure 1). In three other patients tumour bulk was reduced but without producing complete histological cure. Subsequent surgical removal was, however, much easier than would otherwise have been the case. One tumour grew larger during the 3 month period of observation. One patient found that flu-like symptoms resulting from treatment were intolerable. She was withdrawn from the study after a single injection, and the tumour was excised. In all other cases side effects were mild and well tolerated, and consisted only of myalgia and malaise. There were no significant haematological
0141-0768/91/
090524-03/$02.00/0 © 1991
changes. The Royal The subjects who were cured have now been Society of followed-up for between 12 and 26 months with Medicine
Journal of th6 Royal Society of Medicine Volume 84 September 1991
Si
Figure 1. Left, case 4: a solid basal cell carcinoma on the dorsum of the hand; right, the same hand three months after treatment Table 1. Patient data and results
Case No. Age/sex 1 2 3 4 5 6 7 8 9 10 11
69/M 46/F 51/M 641M 691M 81/M 51/F 70/M 681M 76/F 65/F
Tumour site
Tumour type
Size (mm)
Response,
Inner canthus Tip of nose Side of nose Dorsum of hand Cheek Inner canthus Ala nasi Cheek Abdomen Side of nose Ala nasi
Cystic Solid Solid Solid Solid Cystic Solid Cystic Superficial Solid Morphoeic
12 5 6 20 12 10 12 13 15 6 8
Tumour size reduced Cured Tumour size reduced Cured Cured Tumour size reduced Cured Tumour enlarged Cured Withdrawn Cured
no clinical or histological evidence of recurrence of the tumours.
Discussion Interferon alpha-2b seems to offer an alternative, non-surgical approach to the treatment of basal cell carcinoma. The most important advantage is the absence of scarring produced by the treatment. If the tumour has not caused too much tissue destruction the cosmetic result may be excellent. A further advantage is that, should this treatment fail, all other therapeutic options remain open. This is in contrast to radiotherapy or surgery after which treatment of future recurrence may be more difficult. The cure rate is probably not going to reach 100% as suggested in Greenway's initial series. In some cases, particularly those with soft fleshy cystic tumours, (eg case 6) it was difficult to ensure that the injection was retained within the tumour. Such lesions may be unsuitable for this treatment, and careful patient selection may therefore improve response rates. It is not yet known whether those tumours in which the injection is not retained might respond to perilesional injection. Nor is it clear whether apparently resistant tumours would regress further if observed for a longer period, or whether these would respond to a higher dose or longer or repeated courses of injections. With the exception of the soft cystic tumours discussed above, all of the clinical types of basal cell carcinoma appeared to respond equally well. There was no evidence from our series that response was related to tumour size. Before this treatinent can be recommended it is essential to quantify the risk of tumour recurrence. a
Follow-up (months)
15 21 16
26 13
12
In vitro, the antiproliferative effects of interferon appear to persist only for the duration of treatment'3. Little clinical evidence is so far available. In the series reported by Greenway et al.9 and by Edwards et al.1112 all the sites of the tumours were excised after treatment so that no follow-up to assess this risk was possible. Grob et al. reported follow-up of three tumours to 8 months with no evidence of recurrence'0. Those of our patients who responded completely have now been followed for between 12 and 26 months and it is very encouraging that none ofthe tumours which responded has recurred. The current cost ofthe interferon alpha-2b used for this treatment is approximately £150. In addition, nine clinic visits are required, and, at least for the present, prolonged follow-up will be necessary. These are the principal disadvantages of this regimen. At present, therefore, interferon could be recommended only for cases in which the cosmetic result is of paramount importance. However, the use of a sustained release preparation of interferon alpha-2b seems to be a potentially useful means of reducing the number of visits required for injections". If the recurrence rate remains as low as in this series, prolonged follow-up will not be necessary in future. Acknowledgment: The interferon alpha-2b used in this study was kindly provided by Schering-Plough. References 1 Isaacs A, Lindenmann J. Virus interference. Proc R Soc Lond [Biol] 1957;147:258-67 2 Sreevalsan T, Rozengurt E, Papadimitriou JT, Burchell J. Differential effect of interferon on DNA synthesis, 2-deoxyglucose uptake and ornithine decarboxylase
525
526
3 4
5
6
7 8
Journal of the Royal Society of Medicine Volume 84 September 1991
activity in 3T3 cells stimulated by polypeptide growth factors and tumourproducts. JCellPhysiol 1980;104:1-9 Einat M, Resnitzky D, Kimchi A. Close link between reduction of c-myc expression by interon and GO/Gl arrest. Nature 1985;313:597-600 Griffiths CEM, Voorhees JJ, Nickoloff BJ. Characterisation of intercellular adesion molecle-i and HLA-DR expression in normal and inflamed slkn: modulation by recombinant gamma ntrn and tumour necrosis factor. J Am Acad Dermatol 1989%29:617-29 Kameyama K, Tone T, Eto H, Takezaki S, Kanzaki T, Nishiyama S. Recombinant gamma interferon induces HLA-DR expression on squamous cell carcinoma, trichilemmoma, adenocarcinoma cell lines, and cultured human keratinocytes. Arch Dermatol Res 1987,2790.161-6 Taylor RS, Griffiths CEM, Brown MD, Swanson NA, NickoloffBJ. Constitutive absence and cytokine induced expression of adhesion molecules in basal cell carcinoma (Abstract). J Invest Dermatol 1989;92:530A Vilcek J, Gresser I, Merigan TC. Regulatory functions of interferons. Ann NY Acad Sci 1980;350:1-129 Schultz RM, Papamatheakis JD, Chirigos MA. Interferon: An inducer of macrophage activation by polyanions. Science 1977;197:674-6
9 Greenway HT, Cornell RC, Tanner DJ, Peets E, BordinWGM, Nagi C. Treatment ofbasal cell carcinoma with intralesional interferon. J Am Acad Dermatol 1986;15:437-43 10 Grob JJ, Collet AM, Munoz MH, Bonerandi JJ. Treatment of large basal-cell carcinomas with intralesional interferon-alpha-2a. Lancet 1988;i:878-9 11 Edwards L, Tucker SB, Perednia D, et al The effect of an intralesional sustained-release formulation of interferon alpha-2b on basal cell carcinomas. Arch Dermatol 1990;126:1029-32 12 Edwards L, Whiting D, Rogers D, Luck K, Smiles KA. The effect of intralesional gamma interferon on basal cell carcinomas. J Am Acad DLrmatol 1990;22: 496-500 13 Borden EC. Progress toward therapeutic application of interferons, 1979-1983. Cancer 1984;54(Suppl):2770-6
(Accepted 12 February 1991)
Journal of the Royal Society of Medicine Volume 84 September 1991
Treatment of basal cell carcinoma with intralesional interferon alpha-2b
M F Healsmith MB BS' J Berth-Jones mRCP' A Fletcher FRCPath2 R A C Graham-Brown FRCP1 Departments of 'Dermatology and 2Histopathology, Leicester Royal Infirmary, Leicester LE1 5WW Keywords: basal cell carcinoma, interferon
Summary We report a series of 11 basal cell carcinomas of various types treated with nine intra-lesional injections of 1.5 million units of interferon alpha-2b. The diagnosis was confirmed histologically in each case. After 3 months' follow-up six tumours had resolved both clinically and histologically. In three cases the tumour size was reduced. One tumour grew larger. Side effects were well tolerated except by one subject who was withdrawn. Those cases which responded have now been followed-up for between 12 and 26 months with no clinical or histological evidence of tumour recurrence. This is the longest period of follow-up so far reported for this novel treatment. The results are encouraging and, if maintained in future series, may indicate a useful role for interferon alpha in the management of this common cutaneous malignancy. Introduction Basal cell carcinoma is usually treated by radiotherapy or surgical techniques which carry a risk of scarring. These tumours may occur at sites on the face where excision is technically difficult and the cosmetic result is often important. A non-surgical approach to treatment is therefore of considerable potential value. Interferons are a range of glycoproteins first discovered by Isaacs and Lindenmann in 19571 and named after their ability to interfere with viral proliferation. Although this property has found few clinical applications, they have subsequently been shown to possess useful antineoplastic activity. Interferons have an antiproliferative action and promote cell differentiation2, they can suppress oncogene expression3, induce cell surface antigens such as HLA-DR and ICAM-1 on keratinocytes4 and tumour cells5'6 augment activity of cytotoxic T-cells and natural killer cells, and stimulate phago-
cytosis7'8. Initial studies9-"1 have suggested that intralesional injections of small doses of interferon alpha-2 are very effective in treating basal cell carcinoma. Greenway et al.9 and Grob et al.'0 reported complete clearance of eight and seven tumours respectively. Interferon gamma appears to have similar activity though the cure rate was only 50% in an initial study using nine intralesional injections of 100 000 units'2. Reported follow-up has so far been very limited, but if such results as those outlined above are sustained, and tumours do not recur more often than with other treatments, interferon alpha would seem likely to play a useful role in the management of basal
cell carcinoma. We describe here a series of 11 cases of randomly selected types of basal cell carcinoma treated with interferon alpha-2b and followed-up for over 12 months. Method Eleven patients were recruited at random from among patients attending our clinic for treatment of basal cell carcinoma. All gave signed informed consent to participation. The site, type and maximum diameter of each tumour were recorded. The diagnosis was confirmed histologically prior to treatment in each case, by 4 mm punch biopsy. Treatment consisted of a course of nine intralesional injections of interferon alpha-2b, on Monday, Wednesday and Friday each week for 3 weeks. Each injection contained 1.5 million units dissolved in 0.2-0.5 ml water. Side effects were recorded. Full blood counts were performed on each subject before and immediately after completion of treatment. After treatment subjects were reviewed monthly for a period of 3 months, after which time a 4 mm punch biopsy was performed. These were examined at several levels. In cases where residual tumour was present excision was undertaken. All subjects currently remain under review. In those where any clinical features compatible with basal cell carcinoma have persisted additional punch biopsies have been performed. Results Data on the subjects, tumours, response to treatment and length of follow-up are summarized in Table 1. Complete clinical and histological resolution was achieved at 3 months in six of 10 patients who completed the treatment. The cosmetic result was considered excellent by both patient and doctor in all these cases (Figure 1). In three other patients tumour bulk was reduced but without producing complete histological cure. Subsequent surgical removal was, however, much easier than would otherwise have been the case. One tumour grew larger during the 3 month period of observation. One patient found that flu-like symptoms resulting from treatment were intolerable. She was withdrawn from the study after a single injection, and the tumour was excised. In all other cases side effects were mild and well tolerated, and consisted only of myalgia and malaise. There were no significant haematological
0141-0768/91/
090524-03/$02.00/0 © 1991
changes. The Royal The subjects who were cured have now been Society of followed-up for between 12 and 26 months with Medicine
Journal of th6 Royal Society of Medicine Volume 84 September 1991
Si
Figure 1. Left, case 4: a solid basal cell carcinoma on the dorsum of the hand; right, the same hand three months after treatment Table 1. Patient data and results
Case No. Age/sex 1 2 3 4 5 6 7 8 9 10 11
69/M 46/F 51/M 641M 691M 81/M 51/F 70/M 681M 76/F 65/F
Tumour site
Tumour type
Size (mm)
Response,
Inner canthus Tip of nose Side of nose Dorsum of hand Cheek Inner canthus Ala nasi Cheek Abdomen Side of nose Ala nasi
Cystic Solid Solid Solid Solid Cystic Solid Cystic Superficial Solid Morphoeic
12 5 6 20 12 10 12 13 15 6 8
Tumour size reduced Cured Tumour size reduced Cured Cured Tumour size reduced Cured Tumour enlarged Cured Withdrawn Cured
no clinical or histological evidence of recurrence of the tumours.
Discussion Interferon alpha-2b seems to offer an alternative, non-surgical approach to the treatment of basal cell carcinoma. The most important advantage is the absence of scarring produced by the treatment. If the tumour has not caused too much tissue destruction the cosmetic result may be excellent. A further advantage is that, should this treatment fail, all other therapeutic options remain open. This is in contrast to radiotherapy or surgery after which treatment of future recurrence may be more difficult. The cure rate is probably not going to reach 100% as suggested in Greenway's initial series. In some cases, particularly those with soft fleshy cystic tumours, (eg case 6) it was difficult to ensure that the injection was retained within the tumour. Such lesions may be unsuitable for this treatment, and careful patient selection may therefore improve response rates. It is not yet known whether those tumours in which the injection is not retained might respond to perilesional injection. Nor is it clear whether apparently resistant tumours would regress further if observed for a longer period, or whether these would respond to a higher dose or longer or repeated courses of injections. With the exception of the soft cystic tumours discussed above, all of the clinical types of basal cell carcinoma appeared to respond equally well. There was no evidence from our series that response was related to tumour size. Before this treatinent can be recommended it is essential to quantify the risk of tumour recurrence. a
Follow-up (months)
15 21 16
26 13
12
In vitro, the antiproliferative effects of interferon appear to persist only for the duration of treatment'3. Little clinical evidence is so far available. In the series reported by Greenway et al.9 and by Edwards et al.1112 all the sites of the tumours were excised after treatment so that no follow-up to assess this risk was possible. Grob et al. reported follow-up of three tumours to 8 months with no evidence of recurrence'0. Those of our patients who responded completely have now been followed for between 12 and 26 months and it is very encouraging that none ofthe tumours which responded has recurred. The current cost ofthe interferon alpha-2b used for this treatment is approximately £150. In addition, nine clinic visits are required, and, at least for the present, prolonged follow-up will be necessary. These are the principal disadvantages of this regimen. At present, therefore, interferon could be recommended only for cases in which the cosmetic result is of paramount importance. However, the use of a sustained release preparation of interferon alpha-2b seems to be a potentially useful means of reducing the number of visits required for injections". If the recurrence rate remains as low as in this series, prolonged follow-up will not be necessary in future. Acknowledgment: The interferon alpha-2b used in this study was kindly provided by Schering-Plough. References 1 Isaacs A, Lindenmann J. Virus interference. Proc R Soc Lond [Biol] 1957;147:258-67 2 Sreevalsan T, Rozengurt E, Papadimitriou JT, Burchell J. Differential effect of interferon on DNA synthesis, 2-deoxyglucose uptake and ornithine decarboxylase
525
526
3 4
5
6
7 8
Journal of the Royal Society of Medicine Volume 84 September 1991
activity in 3T3 cells stimulated by polypeptide growth factors and tumourproducts. JCellPhysiol 1980;104:1-9 Einat M, Resnitzky D, Kimchi A. Close link between reduction of c-myc expression by interon and GO/Gl arrest. Nature 1985;313:597-600 Griffiths CEM, Voorhees JJ, Nickoloff BJ. Characterisation of intercellular adesion molecle-i and HLA-DR expression in normal and inflamed slkn: modulation by recombinant gamma ntrn and tumour necrosis factor. J Am Acad Dermatol 1989%29:617-29 Kameyama K, Tone T, Eto H, Takezaki S, Kanzaki T, Nishiyama S. Recombinant gamma interferon induces HLA-DR expression on squamous cell carcinoma, trichilemmoma, adenocarcinoma cell lines, and cultured human keratinocytes. Arch Dermatol Res 1987,2790.161-6 Taylor RS, Griffiths CEM, Brown MD, Swanson NA, NickoloffBJ. Constitutive absence and cytokine induced expression of adhesion molecules in basal cell carcinoma (Abstract). J Invest Dermatol 1989;92:530A Vilcek J, Gresser I, Merigan TC. Regulatory functions of interferons. Ann NY Acad Sci 1980;350:1-129 Schultz RM, Papamatheakis JD, Chirigos MA. Interferon: An inducer of macrophage activation by polyanions. Science 1977;197:674-6
9 Greenway HT, Cornell RC, Tanner DJ, Peets E, BordinWGM, Nagi C. Treatment ofbasal cell carcinoma with intralesional interferon. J Am Acad Dermatol 1986;15:437-43 10 Grob JJ, Collet AM, Munoz MH, Bonerandi JJ. Treatment of large basal-cell carcinomas with intralesional interferon-alpha-2a. Lancet 1988;i:878-9 11 Edwards L, Tucker SB, Perednia D, et al The effect of an intralesional sustained-release formulation of interferon alpha-2b on basal cell carcinomas. Arch Dermatol 1990;126:1029-32 12 Edwards L, Whiting D, Rogers D, Luck K, Smiles KA. The effect of intralesional gamma interferon on basal cell carcinomas. J Am Acad DLrmatol 1990;22: 496-500 13 Borden EC. Progress toward therapeutic application of interferons, 1979-1983. Cancer 1984;54(Suppl):2770-6
(Accepted 12 February 1991)
