Melanoma

Apigenin (5,7,4′-trihydroxyflavone) is a low-toxic, nonmutagenic plant flavonoid that is widely found in herbs (endive, clove, and German chamomile), fruit (apples, cherries, and grapes), beverages (tea and wine), vegetables (beans, broccoli, celery, leeks, onions, barley, parsley, and tomatoes), and propolis (Skin Pharmacol. Appl. Skin Physiol. 2002;15:297–306; Eur. J. Cancer 1996;32A:146–51; J. Cell Biochem. [Suppl.] 1997;28–9:39–48).

Apigenin shows promising chemopreventive activity against skin cancer (J. Pharm. Sci. 1997;86:721–5) and has demonstrated anti-inflammatory properties (Skin Pharmacol. Appl. Skin Physiol. 2001;14:373–85). It is also believed to be partly responsible for the soothing, antispasmodic, anxiolytic activity that has been attributed to chamomile (Planta Medica 1995;61:213–6).

 Antitumor Actions in Animals

In a series of studies conducted almost 2 decades ago, the topical application of apigenin to Sencar mice inhibited, in a dose-dependent manner, skin tumorigenesis initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). In the first study, 48% of DMBA/TPA-treated mice developed carcinomas by 33 weeks after DMBA initiation, but no carcinomas occurred in the DMBA/apigenin/TPA-treated groups. In the second study, apigenin prolonged the latency period of papilloma formation by 3 weeks and dose dependently reduced papilloma incidence. Apigenin also significantly inhibited carcinoma incidence and reduced the number of tumors. In addition, the researchers concluded that apigenin exhibited the tendency to reduce conversion of papillomas to carcinomas (Cancer Res. 1990;50:499–502).

Several studies conducted since then established that the topical application of apigenin inhibits UV-induced skin tumorigenesis in mouse skin (Mol. Carcinog. 2002;33:36–43; Carcinogenesis 1996;17:2367–75; Mol. Carcinog. 1997;19:74–82). Apigenin also has been shown to suppress TPA-mediated tumor promotion in mouse skin, partly because of its inhibitory effects on protein kinase C and expression of c-Jun and c-Fos (Eur. J. Cancer 1996;32A:146–51).

In addition to its ability to inhibit tumors, apigenin has been noted for its in vitro antioxidant properties against the superoxide anion and peroxyl radicals. In a study performed 15 years ago, the compound demonstrated anti-inflammatory activity in rats. Intradermal application of liposomal apigenin-7-glucoside dose-dependently inhibited skin inflammation previously induced by injection of xanthine oxidase and cumene hydroperoxide (Arzneimittelforschung 1993;43:370–2).

Researchers who studied the effects of apigenin using the mouse keratinocyte 308 cell line, which contains a wild-type p53 gene, determined that the compound may exert antitumorigenic activity by stimulating the p53-p21/waf1 response pathway (Carcinogenesis 2000;21:633–9).

In another study of apigenin's inhibitory influence on skin tumorigenesis, investigators found, using DNA flow cytometric analysis, interruptions in the cell cycle. Keratinocytes cultured for 24 hours in apigenin-containing medium induced a G2/M arrest in two mouse skin-derived cell lines, C50 and 308, and in human HL-60 cells. This effect was fully reversible after an additional 24 hours in apigenin-free medium (Carcinogenesis 1996;17:2367–75).

Subsequent research from the same laboratory provided evidence that apigenin can induce G1 arrest in human diploid fibroblasts by inhibiting cyclin-dependent kinase 2 (cdk2) activity and phosphorylation of retinoblastoma protein, and by inducing the cdk inhibitor p21/waf1.

These activities, the researchers wrote, may mediate the flavonoid's in vivo chemopreventive activities (Mol. Carcinog. 1997;19:74–82).

The preponderance of research on this botanical antioxidant points toward anticarcinogenic activity. In a study evaluating 15 flavonoids for their effects on morphologic changes in soft agar and cellular growth in v-H-ras-transformed NIH3T3 cells, only apigenin, kaempferol, and genistein had a reversing effect on the transformed morphology of these cells. The researchers concluded that the suppression of protein kinase C activity and nuclear oncogene expression might contribute to the molecular mechanism of action exhibited by apigenin (as well as curcumin) in its inhibition of TPA-induced tumor promotion (J. Cell Biochem. [Suppl.] 1997;28–9:39–48).

Other authors have expressed optimistism that apigenin will show a broad spectrum of chemopreventive effects by influencing various molecular targets that affect pathways in the cell (J. Nutr. 2003;133:3800S-4S).

Alternative Sunscreen?

In a study aimed at ascertaining the efficacy of apigenin as a chemopreventive agent against UV-induced skin cancer as well as DNA damage in a cell-free system, investigators found that apigenin treatment from 12 hours before and until 1 hour after UVA/B exposure inhibited 25%–45% of ornithine decarboxylase activity. Further, apigenin treatment of SKH-1 mouse skin before each UVB exposure lowered cancer incidence (52% inhibition) and increased tumor-free survival, compared with control mice (Anticancer Res. 1997;17:85–91).

Of particular interest related to several promising studies is the speculation among some authors that apigenin may represent an alternative sunscreen agent for humans (Mol. Carcinog. 1997;19:74–82; Carcinogenesis 1996;17:2367–75).

For an apigenin formulation to prevent skin cancer, though, it has been determined that the apigenin must be delivered into viable epidermis (Pharm. Res. 1996;13:1710–5). In vivo skin penetration studies of the flavonoids apigenin, luteolin, and apigenin 7-O-?-glucoside demonstrated several years ago that the compounds were adsorbed at the skin surface, but also penetrated into deeper layers (Pharmazie 1994;49:509–11).

Down the Road

The stage may be set for apigenin to be included in formulations, because, in addition to the expanding body of evidence indicating its anticarcinogenic properties, recent work has shown apigenin's potential as an antiphotoaging agent.

Researchers focusing on identifying antiphotoaging compounds assessed the antioxidative activity and inhibitory effects on matrix metalloproteinase-1 (MMP-1) of the extracts of a marine plant, Zostera marina L. These extracts contained apigenin-7-O-β-D-glucoside, chrysoeriol, and luteolin. All of the compounds were found to scavenge the 1,1-diphenyl-2-picrylhydrazyl radical and the superoxide radical. These botanical constituents are deemed to have antioxidative activity and inhibitory effects on MMP-1 expression, and are considered promising targets for inclusion in antiphotoaging formulations (Arch. Pharm. Res. 2004;27:177–83).

Conclusions

The great upsurge in research and interest in plant polyphenols in recent years has been characterized by greater understanding of these compounds' potential health benefits. The body of research on the phenolic flavonoid apigenin is relatively small, with the preponderance of data accumulating in the past 15 years.

Apigenin is found in German chamomile and is most likely to be included in dermatologic products featuring chamomile. It is also an active ingredient in propolis.

With its promising research profile indicating anticarcinogenic and antiphotoaging effects, in vitro and in vivo, much more research regarding this potent antioxidant is likely and warranted.

Apigenin (5,7,4′-trihydroxyflavone) is a low-toxic, nonmutagenic plant flavonoid that is widely found in herbs (endive, clove, and German chamomile), fruit (apples, cherries, and grapes), beverages (tea and wine), vegetables (beans, broccoli, celery, leeks, onions, barley, parsley, and tomatoes), and propolis (Skin Pharmacol. Appl. Skin Physiol. 2002;15:297–306; Eur. J. Cancer 1996;32A:146–51; J. Cell Biochem. [Suppl.] 1997;28–9:39–48).

Apigenin shows promising chemopreventive activity against skin cancer (J. Pharm. Sci. 1997;86:721–5) and has demonstrated anti-inflammatory properties (Skin Pharmacol. Appl. Skin Physiol. 2001;14:373–85). It is also believed to be partly responsible for the soothing, antispasmodic, anxiolytic activity that has been attributed to chamomile (Planta Medica 1995;61:213–6).

 Antitumor Actions in Animals

In a series of studies conducted almost 2 decades ago, the topical application of apigenin to Sencar mice inhibited, in a dose-dependent manner, skin tumorigenesis initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). In the first study, 48% of DMBA/TPA-treated mice developed carcinomas by 33 weeks after DMBA initiation, but no carcinomas occurred in the DMBA/apigenin/TPA-treated groups. In the second study, apigenin prolonged the latency period of papilloma formation by 3 weeks and dose dependently reduced papilloma incidence. Apigenin also significantly inhibited carcinoma incidence and reduced the number of tumors. In addition, the researchers concluded that apigenin exhibited the tendency to reduce conversion of papillomas to carcinomas (Cancer Res. 1990;50:499–502).

Several studies conducted since then established that the topical application of apigenin inhibits UV-induced skin tumorigenesis in mouse skin (Mol. Carcinog. 2002;33:36–43; Carcinogenesis 1996;17:2367–75; Mol. Carcinog. 1997;19:74–82). Apigenin also has been shown to suppress TPA-mediated tumor promotion in mouse skin, partly because of its inhibitory effects on protein kinase C and expression of c-Jun and c-Fos (Eur. J. Cancer 1996;32A:146–51).

In addition to its ability to inhibit tumors, apigenin has been noted for its in vitro antioxidant properties against the superoxide anion and peroxyl radicals. In a study performed 15 years ago, the compound demonstrated anti-inflammatory activity in rats. Intradermal application of liposomal apigenin-7-glucoside dose-dependently inhibited skin inflammation previously induced by injection of xanthine oxidase and cumene hydroperoxide (Arzneimittelforschung 1993;43:370–2).

Researchers who studied the effects of apigenin using the mouse keratinocyte 308 cell line, which contains a wild-type p53 gene, determined that the compound may exert antitumorigenic activity by stimulating the p53-p21/waf1 response pathway (Carcinogenesis 2000;21:633–9).

In another study of apigenin's inhibitory influence on skin tumorigenesis, investigators found, using DNA flow cytometric analysis, interruptions in the cell cycle. Keratinocytes cultured for 24 hours in apigenin-containing medium induced a G2/M arrest in two mouse skin-derived cell lines, C50 and 308, and in human HL-60 cells. This effect was fully reversible after an additional 24 hours in apigenin-free medium (Carcinogenesis 1996;17:2367–75).

Subsequent research from the same laboratory provided evidence that apigenin can induce G1 arrest in human diploid fibroblasts by inhibiting cyclin-dependent kinase 2 (cdk2) activity and phosphorylation of retinoblastoma protein, and by inducing the cdk inhibitor p21/waf1.

These activities, the researchers wrote, may mediate the flavonoid's in vivo chemopreventive activities (Mol. Carcinog. 1997;19:74–82).

The preponderance of research on this botanical antioxidant points toward anticarcinogenic activity. In a study evaluating 15 flavonoids for their effects on morphologic changes in soft agar and cellular growth in v-H-ras-transformed NIH3T3 cells, only apigenin, kaempferol, and genistein had a reversing effect on the transformed morphology of these cells. The researchers concluded that the suppression of protein kinase C activity and nuclear oncogene expression might contribute to the molecular mechanism of action exhibited by apigenin (as well as curcumin) in its inhibition of TPA-induced tumor promotion (J. Cell Biochem. [Suppl.] 1997;28–9:39–48).

Other authors have expressed optimistism that apigenin will show a broad spectrum of chemopreventive effects by influencing various molecular targets that affect pathways in the cell (J. Nutr. 2003;133:3800S-4S).

Alternative Sunscreen?

In a study aimed at ascertaining the efficacy of apigenin as a chemopreventive agent against UV-induced skin cancer as well as DNA damage in a cell-free system, investigators found that apigenin treatment from 12 hours before and until 1 hour after UVA/B exposure inhibited 25%–45% of ornithine decarboxylase activity. Further, apigenin treatment of SKH-1 mouse skin before each UVB exposure lowered cancer incidence (52% inhibition) and increased tumor-free survival, compared with control mice (Anticancer Res. 1997;17:85–91).

Of particular interest related to several promising studies is the speculation among some authors that apigenin may represent an alternative sunscreen agent for humans (Mol. Carcinog. 1997;19:74–82; Carcinogenesis 1996;17:2367–75).

For an apigenin formulation to prevent skin cancer, though, it has been determined that the apigenin must be delivered into viable epidermis (Pharm. Res. 1996;13:1710–5). In vivo skin penetration studies of the flavonoids apigenin, luteolin, and apigenin 7-O-?-glucoside demonstrated several years ago that the compounds were adsorbed at the skin surface, but also penetrated into deeper layers (Pharmazie 1994;49:509–11).

Down the Road

The stage may be set for apigenin to be included in formulations, because, in addition to the expanding body of evidence indicating its anticarcinogenic properties, recent work has shown apigenin's potential as an antiphotoaging agent.

Researchers focusing on identifying antiphotoaging compounds assessed the antioxidative activity and inhibitory effects on matrix metalloproteinase-1 (MMP-1) of the extracts of a marine plant, Zostera marina L. These extracts contained apigenin-7-O-β-D-glucoside, chrysoeriol, and luteolin. All of the compounds were found to scavenge the 1,1-diphenyl-2-picrylhydrazyl radical and the superoxide radical. These botanical constituents are deemed to have antioxidative activity and inhibitory effects on MMP-1 expression, and are considered promising targets for inclusion in antiphotoaging formulations (Arch. Pharm. Res. 2004;27:177–83).

Conclusions

The great upsurge in research and interest in plant polyphenols in recent years has been characterized by greater understanding of these compounds' potential health benefits. The body of research on the phenolic flavonoid apigenin is relatively small, with the preponderance of data accumulating in the past 15 years.

Apigenin is found in German chamomile and is most likely to be included in dermatologic products featuring chamomile. It is also an active ingredient in propolis.

With its promising research profile indicating anticarcinogenic and antiphotoaging effects, in vitro and in vivo, much more research regarding this potent antioxidant is likely and warranted.

Apigenin (5,7,4′-trihydroxyflavone) is a low-toxic, nonmutagenic plant flavonoid that is widely found in herbs (endive, clove, and German chamomile), fruit (apples, cherries, and grapes), beverages (tea and wine), vegetables (beans, broccoli, celery, leeks, onions, barley, parsley, and tomatoes), and propolis (Skin Pharmacol. Appl. Skin Physiol. 2002;15:297–306; Eur. J. Cancer 1996;32A:146–51; J. Cell Biochem. [Suppl.] 1997;28–9:39–48).

Apigenin shows promising chemopreventive activity against skin cancer (J. Pharm. Sci. 1997;86:721–5) and has demonstrated anti-inflammatory properties (Skin Pharmacol. Appl. Skin Physiol. 2001;14:373–85). It is also believed to be partly responsible for the soothing, antispasmodic, anxiolytic activity that has been attributed to chamomile (Planta Medica 1995;61:213–6).

 Antitumor Actions in Animals

In a series of studies conducted almost 2 decades ago, the topical application of apigenin to Sencar mice inhibited, in a dose-dependent manner, skin tumorigenesis initiated by 7,12-dimethylbenz[a]anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA). In the first study, 48% of DMBA/TPA-treated mice developed carcinomas by 33 weeks after DMBA initiation, but no carcinomas occurred in the DMBA/apigenin/TPA-treated groups. In the second study, apigenin prolonged the latency period of papilloma formation by 3 weeks and dose dependently reduced papilloma incidence. Apigenin also significantly inhibited carcinoma incidence and reduced the number of tumors. In addition, the researchers concluded that apigenin exhibited the tendency to reduce conversion of papillomas to carcinomas (Cancer Res. 1990;50:499–502).

Several studies conducted since then established that the topical application of apigenin inhibits UV-induced skin tumorigenesis in mouse skin (Mol. Carcinog. 2002;33:36–43; Carcinogenesis 1996;17:2367–75; Mol. Carcinog. 1997;19:74–82). Apigenin also has been shown to suppress TPA-mediated tumor promotion in mouse skin, partly because of its inhibitory effects on protein kinase C and expression of c-Jun and c-Fos (Eur. J. Cancer 1996;32A:146–51).

In addition to its ability to inhibit tumors, apigenin has been noted for its in vitro antioxidant properties against the superoxide anion and peroxyl radicals. In a study performed 15 years ago, the compound demonstrated anti-inflammatory activity in rats. Intradermal application of liposomal apigenin-7-glucoside dose-dependently inhibited skin inflammation previously induced by injection of xanthine oxidase and cumene hydroperoxide (Arzneimittelforschung 1993;43:370–2).

Researchers who studied the effects of apigenin using the mouse keratinocyte 308 cell line, which contains a wild-type p53 gene, determined that the compound may exert antitumorigenic activity by stimulating the p53-p21/waf1 response pathway (Carcinogenesis 2000;21:633–9).

In another study of apigenin's inhibitory influence on skin tumorigenesis, investigators found, using DNA flow cytometric analysis, interruptions in the cell cycle. Keratinocytes cultured for 24 hours in apigenin-containing medium induced a G2/M arrest in two mouse skin-derived cell lines, C50 and 308, and in human HL-60 cells. This effect was fully reversible after an additional 24 hours in apigenin-free medium (Carcinogenesis 1996;17:2367–75).

Subsequent research from the same laboratory provided evidence that apigenin can induce G1 arrest in human diploid fibroblasts by inhibiting cyclin-dependent kinase 2 (cdk2) activity and phosphorylation of retinoblastoma protein, and by inducing the cdk inhibitor p21/waf1.

These activities, the researchers wrote, may mediate the flavonoid's in vivo chemopreventive activities (Mol. Carcinog. 1997;19:74–82).

The preponderance of research on this botanical antioxidant points toward anticarcinogenic activity. In a study evaluating 15 flavonoids for their effects on morphologic changes in soft agar and cellular growth in v-H-ras-transformed NIH3T3 cells, only apigenin, kaempferol, and genistein had a reversing effect on the transformed morphology of these cells. The researchers concluded that the suppression of protein kinase C activity and nuclear oncogene expression might contribute to the molecular mechanism of action exhibited by apigenin (as well as curcumin) in its inhibition of TPA-induced tumor promotion (J. Cell Biochem. [Suppl.] 1997;28–9:39–48).

Other authors have expressed optimistism that apigenin will show a broad spectrum of chemopreventive effects by influencing various molecular targets that affect pathways in the cell (J. Nutr. 2003;133:3800S-4S).

Alternative Sunscreen?

In a study aimed at ascertaining the efficacy of apigenin as a chemopreventive agent against UV-induced skin cancer as well as DNA damage in a cell-free system, investigators found that apigenin treatment from 12 hours before and until 1 hour after UVA/B exposure inhibited 25%–45% of ornithine decarboxylase activity. Further, apigenin treatment of SKH-1 mouse skin before each UVB exposure lowered cancer incidence (52% inhibition) and increased tumor-free survival, compared with control mice (Anticancer Res. 1997;17:85–91).

Of particular interest related to several promising studies is the speculation among some authors that apigenin may represent an alternative sunscreen agent for humans (Mol. Carcinog. 1997;19:74–82; Carcinogenesis 1996;17:2367–75).

For an apigenin formulation to prevent skin cancer, though, it has been determined that the apigenin must be delivered into viable epidermis (Pharm. Res. 1996;13:1710–5). In vivo skin penetration studies of the flavonoids apigenin, luteolin, and apigenin 7-O-?-glucoside demonstrated several years ago that the compounds were adsorbed at the skin surface, but also penetrated into deeper layers (Pharmazie 1994;49:509–11).

Down the Road

The stage may be set for apigenin to be included in formulations, because, in addition to the expanding body of evidence indicating its anticarcinogenic properties, recent work has shown apigenin's potential as an antiphotoaging agent.

Researchers focusing on identifying antiphotoaging compounds assessed the antioxidative activity and inhibitory effects on matrix metalloproteinase-1 (MMP-1) of the extracts of a marine plant, Zostera marina L. These extracts contained apigenin-7-O-β-D-glucoside, chrysoeriol, and luteolin. All of the compounds were found to scavenge the 1,1-diphenyl-2-picrylhydrazyl radical and the superoxide radical. These botanical constituents are deemed to have antioxidative activity and inhibitory effects on MMP-1 expression, and are considered promising targets for inclusion in antiphotoaging formulations (Arch. Pharm. Res. 2004;27:177–83).

Conclusions

The great upsurge in research and interest in plant polyphenols in recent years has been characterized by greater understanding of these compounds' potential health benefits. The body of research on the phenolic flavonoid apigenin is relatively small, with the preponderance of data accumulating in the past 15 years.

Apigenin is found in German chamomile and is most likely to be included in dermatologic products featuring chamomile. It is also an active ingredient in propolis.

With its promising research profile indicating anticarcinogenic and antiphotoaging effects, in vitro and in vivo, much more research regarding this potent antioxidant is likely and warranted.

SAN DIEGO — When Dr. Michael Swann advises patients to apply sunscreen to protect against melanoma, the suggestion sometimes falls on deaf ears.

"Patients who don't want to wear sunscreen will say, 'I don't wear sunscreen because it's never been shown to protect against melanoma,'" he said in an update on melanoma sponsored by the Scripps Clinic. "There are a lot of arguments against using it. People will believe what they want to believe."

He acknowledges that retrospective studies have not shown a clear benefit or detriment to using sunscreen to reduce the risk of melanoma but points his patients to other evidence. In Hawaii, where residents apply more sunscreen regularly than in other states, melanoma rates are declining.

The same goes for Australia, where an estimated 74% of residents use sunscreen regularly.

He goes on to tell them that the sunscreens studied over the past 20 years lacked any appreciable UVA protection, which may be important in melanoma. In recent years, though, sunscreens have hit the market with effective protection against UVA. For everyday protection, Dr. Swann recommends Anthelios SX by L'Oréal La Roche-Possay, which contains the sun filter Mexoryl SX.

"At this point, it is only approved as an SPF 15, so it's not really a good one for being on the golf course all day," said Dr. Swann of the Scripps Clinic, La Jolla, Calif.

For periods of longer exposure, he recommends Neutrogena sunscreens with Helioplex, which contain stable avobenzone.

He said that he has no conflict of interest with either manufacturer.

SAN DIEGO — When Dr. Michael Swann advises patients to apply sunscreen to protect against melanoma, the suggestion sometimes falls on deaf ears.

"Patients who don't want to wear sunscreen will say, 'I don't wear sunscreen because it's never been shown to protect against melanoma,'" he said in an update on melanoma sponsored by the Scripps Clinic. "There are a lot of arguments against using it. People will believe what they want to believe."

He acknowledges that retrospective studies have not shown a clear benefit or detriment to using sunscreen to reduce the risk of melanoma but points his patients to other evidence. In Hawaii, where residents apply more sunscreen regularly than in other states, melanoma rates are declining.

The same goes for Australia, where an estimated 74% of residents use sunscreen regularly.

He goes on to tell them that the sunscreens studied over the past 20 years lacked any appreciable UVA protection, which may be important in melanoma. In recent years, though, sunscreens have hit the market with effective protection against UVA. For everyday protection, Dr. Swann recommends Anthelios SX by L'Oréal La Roche-Possay, which contains the sun filter Mexoryl SX.

"At this point, it is only approved as an SPF 15, so it's not really a good one for being on the golf course all day," said Dr. Swann of the Scripps Clinic, La Jolla, Calif.

For periods of longer exposure, he recommends Neutrogena sunscreens with Helioplex, which contain stable avobenzone.

He said that he has no conflict of interest with either manufacturer.

SAN DIEGO — When Dr. Michael Swann advises patients to apply sunscreen to protect against melanoma, the suggestion sometimes falls on deaf ears.

"Patients who don't want to wear sunscreen will say, 'I don't wear sunscreen because it's never been shown to protect against melanoma,'" he said in an update on melanoma sponsored by the Scripps Clinic. "There are a lot of arguments against using it. People will believe what they want to believe."

He acknowledges that retrospective studies have not shown a clear benefit or detriment to using sunscreen to reduce the risk of melanoma but points his patients to other evidence. In Hawaii, where residents apply more sunscreen regularly than in other states, melanoma rates are declining.

The same goes for Australia, where an estimated 74% of residents use sunscreen regularly.

He goes on to tell them that the sunscreens studied over the past 20 years lacked any appreciable UVA protection, which may be important in melanoma. In recent years, though, sunscreens have hit the market with effective protection against UVA. For everyday protection, Dr. Swann recommends Anthelios SX by L'Oréal La Roche-Possay, which contains the sun filter Mexoryl SX.

"At this point, it is only approved as an SPF 15, so it's not really a good one for being on the golf course all day," said Dr. Swann of the Scripps Clinic, La Jolla, Calif.

For periods of longer exposure, he recommends Neutrogena sunscreens with Helioplex, which contain stable avobenzone.

He said that he has no conflict of interest with either manufacturer.

SAN DIEGO — When it comes to follow-up surveillance of melanoma patients, history and physical examination remain the cornerstone of good care, with little solid evidence to support anything else.

"The literature on this aspect of melanoma management is incomplete, mainly because there are very few prospective studies," Dr. Peter R. Shumaker said at a melanoma update sponsored by the Scripps Clinic.

He discussed several goals for the postoperative follow-up of melanoma patients:

▸ Earliest possible detection of treatable recurrence. About one-quarter of patients with local disease and 60%–70% of patients with in-transit [and] nodal disease will develop recurrence, said Dr. Shumaker, clinical fellow in procedural dermatology at the Scripps Clinic in La Jolla, Calif.

One study that reviewed the rate of first recurrence after treatment for malignant melanoma among 250 Australian patients found that 52% of recurrences were in the regional lymph nodes, 17% were local, 8% were in-transit, and 23% were visceral (Plast. Reconstr. Surg. 1993;91:94–8).

"The majority of recurrences occur within the first couple of years," Dr. Shumaker said.

▸ Detection of other primary skin cancers. "These patients are at high risk for a second primary melanoma," he said.

▸ Patient education, emotional support, and reassurance. Most studies report that at least half of recurrences are found by the patients themselves, despite being in a structured follow-up program. "So these follow-ups, in addition to providing an opportunity to inspect and palpate lesions, also provide an opportunity to educate patients," Dr. Shumaker said.

▸ Quality assurance. By this Dr. Shumaker meant the collection of data to improve future treatment and surveillance, such as blood tests and imaging techniques.

Chest x-rays and blood tests are frequently used in the routine follow-up of melanoma patients, "but they offer little benefit in terms of cost effectiveness," Dr. Shumaker said. They generally provide low sensitivity and a high rate of false positives.

Dr. Shumaker considers

Ultrasound "appears to be more sensitive than physical exam in detecting tumor recurrence in in-transit routes and regional nodal basins," he said. "There is an increased likelihood of survival benefit from asymptomatic detection in these areas."

He noted that ultrasound can be combined with fine-needle aspiration to diagnose recurrent or metastatic disease, but there appears to be no role for abdominal ultrasound in routine follow-up.

At Scripps, Dr. Shumaker and his associates perform a comprehensive history and physical exam in melanoma patients every 3 months for 3 years, then every 6 months for life. "This includes baseline and an annual chest x-ray and lab tests," he said.

Most studies report that at least half of recurrences are found bythe patients themselves. DR. SHUMAKER

SAN DIEGO — When it comes to follow-up surveillance of melanoma patients, history and physical examination remain the cornerstone of good care, with little solid evidence to support anything else.

"The literature on this aspect of melanoma management is incomplete, mainly because there are very few prospective studies," Dr. Peter R. Shumaker said at a melanoma update sponsored by the Scripps Clinic.

He discussed several goals for the postoperative follow-up of melanoma patients:

▸ Earliest possible detection of treatable recurrence. About one-quarter of patients with local disease and 60%–70% of patients with in-transit [and] nodal disease will develop recurrence, said Dr. Shumaker, clinical fellow in procedural dermatology at the Scripps Clinic in La Jolla, Calif.

One study that reviewed the rate of first recurrence after treatment for malignant melanoma among 250 Australian patients found that 52% of recurrences were in the regional lymph nodes, 17% were local, 8% were in-transit, and 23% were visceral (Plast. Reconstr. Surg. 1993;91:94–8).

"The majority of recurrences occur within the first couple of years," Dr. Shumaker said.

▸ Detection of other primary skin cancers. "These patients are at high risk for a second primary melanoma," he said.

▸ Patient education, emotional support, and reassurance. Most studies report that at least half of recurrences are found by the patients themselves, despite being in a structured follow-up program. "So these follow-ups, in addition to providing an opportunity to inspect and palpate lesions, also provide an opportunity to educate patients," Dr. Shumaker said.

▸ Quality assurance. By this Dr. Shumaker meant the collection of data to improve future treatment and surveillance, such as blood tests and imaging techniques.

Chest x-rays and blood tests are frequently used in the routine follow-up of melanoma patients, "but they offer little benefit in terms of cost effectiveness," Dr. Shumaker said. They generally provide low sensitivity and a high rate of false positives.

Dr. Shumaker considers

Ultrasound "appears to be more sensitive than physical exam in detecting tumor recurrence in in-transit routes and regional nodal basins," he said. "There is an increased likelihood of survival benefit from asymptomatic detection in these areas."

He noted that ultrasound can be combined with fine-needle aspiration to diagnose recurrent or metastatic disease, but there appears to be no role for abdominal ultrasound in routine follow-up.

At Scripps, Dr. Shumaker and his associates perform a comprehensive history and physical exam in melanoma patients every 3 months for 3 years, then every 6 months for life. "This includes baseline and an annual chest x-ray and lab tests," he said.

Most studies report that at least half of recurrences are found bythe patients themselves. DR. SHUMAKER

SAN DIEGO — When it comes to follow-up surveillance of melanoma patients, history and physical examination remain the cornerstone of good care, with little solid evidence to support anything else.

"The literature on this aspect of melanoma management is incomplete, mainly because there are very few prospective studies," Dr. Peter R. Shumaker said at a melanoma update sponsored by the Scripps Clinic.

He discussed several goals for the postoperative follow-up of melanoma patients:

▸ Earliest possible detection of treatable recurrence. About one-quarter of patients with local disease and 60%–70% of patients with in-transit [and] nodal disease will develop recurrence, said Dr. Shumaker, clinical fellow in procedural dermatology at the Scripps Clinic in La Jolla, Calif.

One study that reviewed the rate of first recurrence after treatment for malignant melanoma among 250 Australian patients found that 52% of recurrences were in the regional lymph nodes, 17% were local, 8% were in-transit, and 23% were visceral (Plast. Reconstr. Surg. 1993;91:94–8).

"The majority of recurrences occur within the first couple of years," Dr. Shumaker said.

▸ Detection of other primary skin cancers. "These patients are at high risk for a second primary melanoma," he said.

▸ Patient education, emotional support, and reassurance. Most studies report that at least half of recurrences are found by the patients themselves, despite being in a structured follow-up program. "So these follow-ups, in addition to providing an opportunity to inspect and palpate lesions, also provide an opportunity to educate patients," Dr. Shumaker said.

▸ Quality assurance. By this Dr. Shumaker meant the collection of data to improve future treatment and surveillance, such as blood tests and imaging techniques.

Chest x-rays and blood tests are frequently used in the routine follow-up of melanoma patients, "but they offer little benefit in terms of cost effectiveness," Dr. Shumaker said. They generally provide low sensitivity and a high rate of false positives.

Dr. Shumaker considers

Ultrasound "appears to be more sensitive than physical exam in detecting tumor recurrence in in-transit routes and regional nodal basins," he said. "There is an increased likelihood of survival benefit from asymptomatic detection in these areas."

He noted that ultrasound can be combined with fine-needle aspiration to diagnose recurrent or metastatic disease, but there appears to be no role for abdominal ultrasound in routine follow-up.

At Scripps, Dr. Shumaker and his associates perform a comprehensive history and physical exam in melanoma patients every 3 months for 3 years, then every 6 months for life. "This includes baseline and an annual chest x-ray and lab tests," he said.

Most studies report that at least half of recurrences are found bythe patients themselves. DR. SHUMAKER

The brochure "Radiation Therapy for Skin Cancer" includes the up-to-date information for skin cancer patients who are deciding whether radiation therapy is the best option for them. It contains information about the different treatments available for these tumors. The brochure is available for download free at www.RTAnswers.org

The brochure "Radiation Therapy for Skin Cancer" includes the up-to-date information for skin cancer patients who are deciding whether radiation therapy is the best option for them. It contains information about the different treatments available for these tumors. The brochure is available for download free at www.RTAnswers.org

The brochure "Radiation Therapy for Skin Cancer" includes the up-to-date information for skin cancer patients who are deciding whether radiation therapy is the best option for them. It contains information about the different treatments available for these tumors. The brochure is available for download free at www.RTAnswers.org

SAN DIEGO — If you're confident that a primary lesion is melanoma, do an excisional biopsy and send the entire specimen to a pathologist.

If you're less certain about the diagnosis, you can do an incisional biopsy of the primary lesion and send the specimen for evaluation, Dr. Avis B. Yount said at an update on melanoma sponsored by the Scripps Clinic. "The goals of biopsy are to establish the diagnosis, determine the best treatment and prognosis for the patient, and determine the type of melanoma, accurate tumor thickness, and information on ulceration and regression," said Dr. Yount of the department of dermatology at the Medical College of Georgia, Augusta.

She defined excisional biopsy as a full thickness biopsy that conservatively excises the entire lesion; its margin is 2–3 mm around the lesion and includes subcutaneous fat. "I try to orient the excision to facilitate future wide excision while maintaining optimal cosmetic and functional results," she said.

Wide excision is not initially recommended because "the lesion may be benign, the excision may be insufficient because of the tumor thickness, and it may interfere with further treatment such as sentinel node biopsy," she said.

If the lesion is located where complete removal would cause substantial disfigurement or a skin graft or flap would be needed for repair, consider proceeding with incisional biopsy. "You can do an elliptical incision through part of the lesion, giving the pathologist the part that will give the best diagnosis, or you can do a punch biopsy or a saucerization-type biopsy," she said. Recent studies have suggested that saucerization might be the most effective approach (J. Am. Acad. Dermatol. 2005;52:798–802).

For incisional biopsy, "you want to biopsy the most nodular or deeply pigmented area into the subcutaneous fat," said Dr. Yount, who also practices in Augusta and Evans, Ga. "Biopsy by shaving, scissor excision, or curettage is not recommended."

She pointed out that there is no evidence that an incisional biopsy has a detrimental influence on the survival of the patient or on the rate of metastases.

When Dr. Yount detects a suspicious lesion on the nail, she removes the entire plate and submits it to the pathologist. "You want to do a transverse biopsy in the nail matrix and a longitudinal biopsy in the nail bed," she said. "Before I remove the nail plate I mark the area of pigment, so that I don't lose the lesion after the nail plate is removed."

Biopsies that are too small create certain challenges. "They may compromise histological assessment, including the accurate assessment of Breslow depth," she said. "You may see a dysplastic or congenital nevus but not the melanoma. I've had seborrheic keratoses abut against a melanoma."

Another problem of small biopsies is that in situ melanoma might coexist with an unidentified invasive component.

"After you've done the biopsy then you need to proceed with excision," Dr. Yount said. "The goals of excision are to cure the patient with low-risk disease, provide local control in patients with probably incurable disease, minimize functional impairment, and minimize cosmetic disfigurement."

Treatment is based primarily on the Breslow depth. "Use judgment in determining margins according to tumor thickness, anatomic location, and skin laxity," Dr. Yount said. She had no relevant conflicts of interest to disclose.

SAN DIEGO — If you're confident that a primary lesion is melanoma, do an excisional biopsy and send the entire specimen to a pathologist.

If you're less certain about the diagnosis, you can do an incisional biopsy of the primary lesion and send the specimen for evaluation, Dr. Avis B. Yount said at an update on melanoma sponsored by the Scripps Clinic. "The goals of biopsy are to establish the diagnosis, determine the best treatment and prognosis for the patient, and determine the type of melanoma, accurate tumor thickness, and information on ulceration and regression," said Dr. Yount of the department of dermatology at the Medical College of Georgia, Augusta.

She defined excisional biopsy as a full thickness biopsy that conservatively excises the entire lesion; its margin is 2–3 mm around the lesion and includes subcutaneous fat. "I try to orient the excision to facilitate future wide excision while maintaining optimal cosmetic and functional results," she said.

Wide excision is not initially recommended because "the lesion may be benign, the excision may be insufficient because of the tumor thickness, and it may interfere with further treatment such as sentinel node biopsy," she said.

If the lesion is located where complete removal would cause substantial disfigurement or a skin graft or flap would be needed for repair, consider proceeding with incisional biopsy. "You can do an elliptical incision through part of the lesion, giving the pathologist the part that will give the best diagnosis, or you can do a punch biopsy or a saucerization-type biopsy," she said. Recent studies have suggested that saucerization might be the most effective approach (J. Am. Acad. Dermatol. 2005;52:798–802).

For incisional biopsy, "you want to biopsy the most nodular or deeply pigmented area into the subcutaneous fat," said Dr. Yount, who also practices in Augusta and Evans, Ga. "Biopsy by shaving, scissor excision, or curettage is not recommended."

She pointed out that there is no evidence that an incisional biopsy has a detrimental influence on the survival of the patient or on the rate of metastases.

When Dr. Yount detects a suspicious lesion on the nail, she removes the entire plate and submits it to the pathologist. "You want to do a transverse biopsy in the nail matrix and a longitudinal biopsy in the nail bed," she said. "Before I remove the nail plate I mark the area of pigment, so that I don't lose the lesion after the nail plate is removed."

Biopsies that are too small create certain challenges. "They may compromise histological assessment, including the accurate assessment of Breslow depth," she said. "You may see a dysplastic or congenital nevus but not the melanoma. I've had seborrheic keratoses abut against a melanoma."

Another problem of small biopsies is that in situ melanoma might coexist with an unidentified invasive component.

"After you've done the biopsy then you need to proceed with excision," Dr. Yount said. "The goals of excision are to cure the patient with low-risk disease, provide local control in patients with probably incurable disease, minimize functional impairment, and minimize cosmetic disfigurement."

Treatment is based primarily on the Breslow depth. "Use judgment in determining margins according to tumor thickness, anatomic location, and skin laxity," Dr. Yount said. She had no relevant conflicts of interest to disclose.

SAN DIEGO — If you're confident that a primary lesion is melanoma, do an excisional biopsy and send the entire specimen to a pathologist.

If you're less certain about the diagnosis, you can do an incisional biopsy of the primary lesion and send the specimen for evaluation, Dr. Avis B. Yount said at an update on melanoma sponsored by the Scripps Clinic. "The goals of biopsy are to establish the diagnosis, determine the best treatment and prognosis for the patient, and determine the type of melanoma, accurate tumor thickness, and information on ulceration and regression," said Dr. Yount of the department of dermatology at the Medical College of Georgia, Augusta.

She defined excisional biopsy as a full thickness biopsy that conservatively excises the entire lesion; its margin is 2–3 mm around the lesion and includes subcutaneous fat. "I try to orient the excision to facilitate future wide excision while maintaining optimal cosmetic and functional results," she said.

Wide excision is not initially recommended because "the lesion may be benign, the excision may be insufficient because of the tumor thickness, and it may interfere with further treatment such as sentinel node biopsy," she said.

If the lesion is located where complete removal would cause substantial disfigurement or a skin graft or flap would be needed for repair, consider proceeding with incisional biopsy. "You can do an elliptical incision through part of the lesion, giving the pathologist the part that will give the best diagnosis, or you can do a punch biopsy or a saucerization-type biopsy," she said. Recent studies have suggested that saucerization might be the most effective approach (J. Am. Acad. Dermatol. 2005;52:798–802).

For incisional biopsy, "you want to biopsy the most nodular or deeply pigmented area into the subcutaneous fat," said Dr. Yount, who also practices in Augusta and Evans, Ga. "Biopsy by shaving, scissor excision, or curettage is not recommended."

She pointed out that there is no evidence that an incisional biopsy has a detrimental influence on the survival of the patient or on the rate of metastases.

When Dr. Yount detects a suspicious lesion on the nail, she removes the entire plate and submits it to the pathologist. "You want to do a transverse biopsy in the nail matrix and a longitudinal biopsy in the nail bed," she said. "Before I remove the nail plate I mark the area of pigment, so that I don't lose the lesion after the nail plate is removed."

Biopsies that are too small create certain challenges. "They may compromise histological assessment, including the accurate assessment of Breslow depth," she said. "You may see a dysplastic or congenital nevus but not the melanoma. I've had seborrheic keratoses abut against a melanoma."

Another problem of small biopsies is that in situ melanoma might coexist with an unidentified invasive component.

"After you've done the biopsy then you need to proceed with excision," Dr. Yount said. "The goals of excision are to cure the patient with low-risk disease, provide local control in patients with probably incurable disease, minimize functional impairment, and minimize cosmetic disfigurement."

Treatment is based primarily on the Breslow depth. "Use judgment in determining margins according to tumor thickness, anatomic location, and skin laxity," Dr. Yount said. She had no relevant conflicts of interest to disclose.

SAN DIEGO — What is an adequate margin for surgical excision of melanoma?

Beyond a clear margin, "we really don't know," Dr. Duane C. Whitaker said at a melanoma update sponsored by the Scripps Clinic.

That's why there's a place for Mohs surgery in the treatment of melanoma.

"Mohs for melanoma has not caught on terribly widely, but on the other hand I don't believe it will ever disappear because there are times when you simply need Mohs surgery to be able to treat the primary melanoma in a reasonable way," said Dr. Whitaker, a dermatologist and Mohs surgeon who practices in Tucson, Ariz.

He described Mohs surgery as "the best method we have to establish tumor-free margins when we remove any type of visible tumor. Any time that we don't truly know what margin beyond clear should be achieved to help the patient, then probably there is some role for Mohs surgery."

The best studies to date have demonstrated that the cure rate with Mohs surgery in stage I and stage II melanomas is at least equivalent to local excision with a predetermined margin, he said.

Mohs surgery has several traditional advantages. It spares tissue in the ear, nose, and other critical anatomic sites; determines margins precisely; allows for immediate reconstruction; allows minimum wound and repair; and allows physicians to start additional and adjunctive therapies right away.

The technique is especially useful for neurotrophic and desmoplastic melanomas since "they're often deeper and wider than you would anticipate," he said.

A key factor when deciding whether to perform Mohs or not "is your comfort with following [the patients], talking about the issues involved, and being ready for that patient who may come back with a lump that you didn't expect," continued Dr. Whitaker, who is the current vice president of the American College of Mohs Surgery.

Beyond the realm of melanoma, Mohs surgery seems to have applications as the method to establish free margins of a primary tumor when evidence does not support a survival benefit achieved by more radical surgery. "If all melanomas occurred in the trunk or proximal extremities where we can do a wider local excision with 3-cm margins, they wouldn't be so difficult to treat," he said, "but when they occur on the digits, the nose, or the periocular areas," that adds complexity.

Mohs surgery seems to be the most reliable method to obtain local free margins at the time of surgery. "It is considered one component of treatment for those tumors which have substantial metastatic risk," Dr. Whitaker said. "Assessment of the host and tumor characteristics will help you determine the full therapeutic plan."

Mohs is 'the best method we have to establish tumor-free margins when we remove any type of visible tumor.' DR. WHITAKER

A melanoma lesion on a patient's nose is shown before Mohs surgery.

The same patient is shown after Mohs was performed to remove the lesion. Photos courtesy Dr. Duane C. Whitaker

SAN DIEGO — What is an adequate margin for surgical excision of melanoma?

Beyond a clear margin, "we really don't know," Dr. Duane C. Whitaker said at a melanoma update sponsored by the Scripps Clinic.

That's why there's a place for Mohs surgery in the treatment of melanoma.

"Mohs for melanoma has not caught on terribly widely, but on the other hand I don't believe it will ever disappear because there are times when you simply need Mohs surgery to be able to treat the primary melanoma in a reasonable way," said Dr. Whitaker, a dermatologist and Mohs surgeon who practices in Tucson, Ariz.

He described Mohs surgery as "the best method we have to establish tumor-free margins when we remove any type of visible tumor. Any time that we don't truly know what margin beyond clear should be achieved to help the patient, then probably there is some role for Mohs surgery."

The best studies to date have demonstrated that the cure rate with Mohs surgery in stage I and stage II melanomas is at least equivalent to local excision with a predetermined margin, he said.

Mohs surgery has several traditional advantages. It spares tissue in the ear, nose, and other critical anatomic sites; determines margins precisely; allows for immediate reconstruction; allows minimum wound and repair; and allows physicians to start additional and adjunctive therapies right away.

The technique is especially useful for neurotrophic and desmoplastic melanomas since "they're often deeper and wider than you would anticipate," he said.

A key factor when deciding whether to perform Mohs or not "is your comfort with following [the patients], talking about the issues involved, and being ready for that patient who may come back with a lump that you didn't expect," continued Dr. Whitaker, who is the current vice president of the American College of Mohs Surgery.

Beyond the realm of melanoma, Mohs surgery seems to have applications as the method to establish free margins of a primary tumor when evidence does not support a survival benefit achieved by more radical surgery. "If all melanomas occurred in the trunk or proximal extremities where we can do a wider local excision with 3-cm margins, they wouldn't be so difficult to treat," he said, "but when they occur on the digits, the nose, or the periocular areas," that adds complexity.

Mohs surgery seems to be the most reliable method to obtain local free margins at the time of surgery. "It is considered one component of treatment for those tumors which have substantial metastatic risk," Dr. Whitaker said. "Assessment of the host and tumor characteristics will help you determine the full therapeutic plan."

Mohs is 'the best method we have to establish tumor-free margins when we remove any type of visible tumor.' DR. WHITAKER

A melanoma lesion on a patient's nose is shown before Mohs surgery.

The same patient is shown after Mohs was performed to remove the lesion. Photos courtesy Dr. Duane C. Whitaker

SAN DIEGO — What is an adequate margin for surgical excision of melanoma?

Beyond a clear margin, "we really don't know," Dr. Duane C. Whitaker said at a melanoma update sponsored by the Scripps Clinic.

That's why there's a place for Mohs surgery in the treatment of melanoma.

"Mohs for melanoma has not caught on terribly widely, but on the other hand I don't believe it will ever disappear because there are times when you simply need Mohs surgery to be able to treat the primary melanoma in a reasonable way," said Dr. Whitaker, a dermatologist and Mohs surgeon who practices in Tucson, Ariz.

He described Mohs surgery as "the best method we have to establish tumor-free margins when we remove any type of visible tumor. Any time that we don't truly know what margin beyond clear should be achieved to help the patient, then probably there is some role for Mohs surgery."

The best studies to date have demonstrated that the cure rate with Mohs surgery in stage I and stage II melanomas is at least equivalent to local excision with a predetermined margin, he said.

Mohs surgery has several traditional advantages. It spares tissue in the ear, nose, and other critical anatomic sites; determines margins precisely; allows for immediate reconstruction; allows minimum wound and repair; and allows physicians to start additional and adjunctive therapies right away.

The technique is especially useful for neurotrophic and desmoplastic melanomas since "they're often deeper and wider than you would anticipate," he said.

A key factor when deciding whether to perform Mohs or not "is your comfort with following [the patients], talking about the issues involved, and being ready for that patient who may come back with a lump that you didn't expect," continued Dr. Whitaker, who is the current vice president of the American College of Mohs Surgery.

Beyond the realm of melanoma, Mohs surgery seems to have applications as the method to establish free margins of a primary tumor when evidence does not support a survival benefit achieved by more radical surgery. "If all melanomas occurred in the trunk or proximal extremities where we can do a wider local excision with 3-cm margins, they wouldn't be so difficult to treat," he said, "but when they occur on the digits, the nose, or the periocular areas," that adds complexity.

Mohs surgery seems to be the most reliable method to obtain local free margins at the time of surgery. "It is considered one component of treatment for those tumors which have substantial metastatic risk," Dr. Whitaker said. "Assessment of the host and tumor characteristics will help you determine the full therapeutic plan."

Mohs is 'the best method we have to establish tumor-free margins when we remove any type of visible tumor.' DR. WHITAKER

A melanoma lesion on a patient's nose is shown before Mohs surgery.

The same patient is shown after Mohs was performed to remove the lesion. Photos courtesy Dr. Duane C. Whitaker

ORLANDO — Topical 5% imiquimod is an effective treatment for squamous cell carcinoma in situ and should be considered as an option for this disease, Dr. Theodore Rosen reported at the annual meeting of the Florida Society of Dermatologic Surgeons.

Imiquimod (Aldara) is approved for the treatment of superficial basal cell carcinomas, and although it has been used for Bowen's disease, data are lacking on its efficacy for this use, said Dr. Rosen, who is professor of dermatology at Baylor College of Medicine in Houston.

A review of 49 of his patients with Bowen's disease who were compliant with their treatment showed that nearly 90% had a complete response at an average follow-up of 2 years. About one-third of the cleared cases were verified on biopsy.

Importantly, five patients who were believed to be compliant had no response whatsoever. This supports the premise that about 1% of the population will fail to respond to imiquimod, Dr. Rosen noted.

An alternative approach to treatment should be used in such patients, he said.

In general, though, the response rate with imiquimod is reasonable. Findings from the three best studies of this treatment suggest that the overall response rate is about 85%, which is enough to warrant its consideration by physicians, Dr. Rosen said.

In his study, patients ranged in age from 48 to 85 years, and 96% were male.

The lesion was located on the extremities in 30% of patients, on the face in 25%, on the trunk or neck in 18%, on the genitalia in 11%, on the scalp in 9%, on the ears in 5%, and on the lips in 2%, he reported.

Lesions on the genitalia had a significantly greater risk of progressing to invasive disease (10% vs. 3% for other areas), yet all of the genital lesions in this study cleared with imiquimod treatment, he noted (Dermatol. Surg. 2007;33:427–31).

Patients were treated daily for 6–16 weeks (every other day for patients with genital lesions) until the target area was heavily crusted and eroded.

"I tend to push it a little bit," Dr. Rosen said of the therapy, adding that it is important to monitor patients.

There have been a few case reports of Bowen's disease ostensibly being cleared with imiquimod, only to have a subsequent invasive lesion develop, he noted.

Patients who undergo treatment with imiquimod for Bowen's disease are at high risk and "shouldn't be out of your grasp," Dr. Rosen said.

Although some cases of invasive squamous cell carcinoma have been treated with imiquimod and the overall treatment success rate appears to be about 70%, it is not his treatment of choice for invasive disease, as it is for Bowen's disease, he said.

Dr. Rosen disclosed that he has served on the speakers bureau for Graceway Pharmaceuticals, the maker of Aldara, and has received honoraria from the company.

ORLANDO — Topical 5% imiquimod is an effective treatment for squamous cell carcinoma in situ and should be considered as an option for this disease, Dr. Theodore Rosen reported at the annual meeting of the Florida Society of Dermatologic Surgeons.

Imiquimod (Aldara) is approved for the treatment of superficial basal cell carcinomas, and although it has been used for Bowen's disease, data are lacking on its efficacy for this use, said Dr. Rosen, who is professor of dermatology at Baylor College of Medicine in Houston.

A review of 49 of his patients with Bowen's disease who were compliant with their treatment showed that nearly 90% had a complete response at an average follow-up of 2 years. About one-third of the cleared cases were verified on biopsy.

Importantly, five patients who were believed to be compliant had no response whatsoever. This supports the premise that about 1% of the population will fail to respond to imiquimod, Dr. Rosen noted.

An alternative approach to treatment should be used in such patients, he said.

In general, though, the response rate with imiquimod is reasonable. Findings from the three best studies of this treatment suggest that the overall response rate is about 85%, which is enough to warrant its consideration by physicians, Dr. Rosen said.

In his study, patients ranged in age from 48 to 85 years, and 96% were male.

The lesion was located on the extremities in 30% of patients, on the face in 25%, on the trunk or neck in 18%, on the genitalia in 11%, on the scalp in 9%, on the ears in 5%, and on the lips in 2%, he reported.

Lesions on the genitalia had a significantly greater risk of progressing to invasive disease (10% vs. 3% for other areas), yet all of the genital lesions in this study cleared with imiquimod treatment, he noted (Dermatol. Surg. 2007;33:427–31).

Patients were treated daily for 6–16 weeks (every other day for patients with genital lesions) until the target area was heavily crusted and eroded.

"I tend to push it a little bit," Dr. Rosen said of the therapy, adding that it is important to monitor patients.

There have been a few case reports of Bowen's disease ostensibly being cleared with imiquimod, only to have a subsequent invasive lesion develop, he noted.

Patients who undergo treatment with imiquimod for Bowen's disease are at high risk and "shouldn't be out of your grasp," Dr. Rosen said.

Although some cases of invasive squamous cell carcinoma have been treated with imiquimod and the overall treatment success rate appears to be about 70%, it is not his treatment of choice for invasive disease, as it is for Bowen's disease, he said.

Dr. Rosen disclosed that he has served on the speakers bureau for Graceway Pharmaceuticals, the maker of Aldara, and has received honoraria from the company.

ORLANDO — Topical 5% imiquimod is an effective treatment for squamous cell carcinoma in situ and should be considered as an option for this disease, Dr. Theodore Rosen reported at the annual meeting of the Florida Society of Dermatologic Surgeons.

Imiquimod (Aldara) is approved for the treatment of superficial basal cell carcinomas, and although it has been used for Bowen's disease, data are lacking on its efficacy for this use, said Dr. Rosen, who is professor of dermatology at Baylor College of Medicine in Houston.

A review of 49 of his patients with Bowen's disease who were compliant with their treatment showed that nearly 90% had a complete response at an average follow-up of 2 years. About one-third of the cleared cases were verified on biopsy.

Importantly, five patients who were believed to be compliant had no response whatsoever. This supports the premise that about 1% of the population will fail to respond to imiquimod, Dr. Rosen noted.

An alternative approach to treatment should be used in such patients, he said.

In general, though, the response rate with imiquimod is reasonable. Findings from the three best studies of this treatment suggest that the overall response rate is about 85%, which is enough to warrant its consideration by physicians, Dr. Rosen said.

In his study, patients ranged in age from 48 to 85 years, and 96% were male.

The lesion was located on the extremities in 30% of patients, on the face in 25%, on the trunk or neck in 18%, on the genitalia in 11%, on the scalp in 9%, on the ears in 5%, and on the lips in 2%, he reported.

Lesions on the genitalia had a significantly greater risk of progressing to invasive disease (10% vs. 3% for other areas), yet all of the genital lesions in this study cleared with imiquimod treatment, he noted (Dermatol. Surg. 2007;33:427–31).

Patients were treated daily for 6–16 weeks (every other day for patients with genital lesions) until the target area was heavily crusted and eroded.

"I tend to push it a little bit," Dr. Rosen said of the therapy, adding that it is important to monitor patients.

There have been a few case reports of Bowen's disease ostensibly being cleared with imiquimod, only to have a subsequent invasive lesion develop, he noted.

Patients who undergo treatment with imiquimod for Bowen's disease are at high risk and "shouldn't be out of your grasp," Dr. Rosen said.

Although some cases of invasive squamous cell carcinoma have been treated with imiquimod and the overall treatment success rate appears to be about 70%, it is not his treatment of choice for invasive disease, as it is for Bowen's disease, he said.

Dr. Rosen disclosed that he has served on the speakers bureau for Graceway Pharmaceuticals, the maker of Aldara, and has received honoraria from the company.

SAN DIEGO — There's no need to grade the level of architectural disorder when assessing dysplastic nevi. Just acknowledge if it's present or not.

"It doesn't matter how much architectural disorder is there; it only matters that it's present or absent," Dr. Terry L. Barrett said at an update on melanoma sponsored by the Scripps Clinic. "It's like being pregnant. Every single person in the world can be divided into one of two categories: You're either pregnant or you're not."

His minimal criterion for defining the presence of architectural disorder in a lesion is a well-defined junctional nevus with nests at the base of the rete and lentiginous proliferation. Concentric eosinophilic fibroplasia and lamellar fibroplasia are commonly seen.

In addition to architectural disorder, dysplastic nevi may or may not have cytologic atypia, which may include large nuclei with variation of nuclear size; irregular nuclear membrane; variably staining chromatin; large eosinophilic nucleoli; and fine dusty melanin pigment in cytoplasm.

Some experts recommend that cytologic atypia be graded as mild, moderate, or severe, but Dr. Barrett does not use the term moderate. "If there's none there's none, but if there's some cytologic atypia it's either mild or severe," said Dr. Barrett of the departments of pathology and dermatology at the University of Texas, Dallas.

He favors a modified version of Dr. Arthur R. Rhodes' atypia grading system (Mod. Pathol. 1989;2:306–19). Cytologic atypia is considered mild if the size of the nucleus of the melanocyte is 1.5–2 times the size of the nucleus of the keratinocyte and if nucleoli are not present; if they are present, there should be no more than one per cell, he explained.

"I can tell that in 2 microseconds," Dr. Barrett said. "It's very easy."

Cytologic atypia is severe if there are multiple nucleoli per cell, or if the nucleus is more than two times the size of the basal keratinocyte nucleus, or if there is chromatin clumping or nuclear membrane notching.

"I can tell that very quickly," said Dr. Barrett, who also directs an outpatient pathology group in Dallas.

"More importantly, it's reproducible. I'll grant you that it's arbitrary. But the important thing is, no matter which one of the dermatopathologists who works with me signs this case out, it's going to be the same. For the dermatologist who gets the report, it's always going to be the same. If they ask me to review the case later because they want to know what I think, it's going to be the same because it's easy to do and it's reproducible."

Common acquired nevi begin to appear in childhood and increase in number from approximately 6 months of age until the third decade. At that point, they begin to decline in number. "They usually stabilize at 3–5 mm and rarely develop in patients over age 40," said Dr. Barrett, who had no relevant conflicts of interest to disclose.

In contrast, dysplastic nevi begin to appear near puberty and continue to develop throughout adulthood. "If you do serial photography of these lesions, they will increase and decrease in atypicality," he said. "They are usually greater than 5 mm."

Dysplastic nevi were originally classified as familial dysplastic nevi syndrome and sporadic nevus syndrome. Current concepts include the familial atypical mole/melanoma syndrome, which came out of the 1992 National Institutes of Health consensus statement on the diagnosis and treatment of early melanoma, and the abnormal mole phenotype. The latter definition was developed by researchers who proposed a spectrum approach that considers both the number and atypicality of nevi (West. J. Med. 1994;160:343–50). Melanoma risk increases along this continuum.

Initially, that theory "went nowhere because people didn't believe that you could have large numbers of common acquired nevi and no dysplastic nevi, and you [would nevertheless be] at increased risk for melanoma. But we now know that is absolutely true, and a number of studies have shown that patients who have large numbers of common acquired nevi have an increased risk of developing melanoma," Dr. Barrett said.

Melanoma risk also appears to increase in the presence of dysplastic nevi. A significant factor is the presence or absence of family history of either condition.

Intermittent sun exposure correlates with the risk of developing malignant melanoma and with the risk of developing multiple nevi. "Whether melanoma arises from nevi or not is unclear, but it appears that the stimulus for formation of both is the same," he said.

The risk of melanoma in a patient who has "one dysplastic nevus and nothing else" is the about the same as someone who has red or blond hair. "Not everybody with red or blond hair is going to get melanoma, but they are at an increased risk," he said.

Dr. Barrett likened dysplastic lesions to amoebae. These lesions "go through quiescent phases and they go through active phases," he said. "If we do serial photographs, we can document this change. If the lesion is quiescent and you biopsy it, you see no atypia because there is minimal cellular activity. If you biopsy it in an active phase, it's going to have some degree of atypia. That doesn't mean that atypia equates with dysplasia or premalignancy. That's what I think is happening."

No cytologic atypia can be seen in this slide from a patient with dysplastic nevi, per Dr. Terry L. Barrett.

The atypia seen above is considered mild according to Dr. Barrett's modified dysplastic nevi grading system.

This patient has severe cytologic atypia. Dr. Barrett avoids the term moderate when assessing atypia. Photos courtesy Dr. Terry L. Barrett

SAN DIEGO — There's no need to grade the level of architectural disorder when assessing dysplastic nevi. Just acknowledge if it's present or not.

"It doesn't matter how much architectural disorder is there; it only matters that it's present or absent," Dr. Terry L. Barrett said at an update on melanoma sponsored by the Scripps Clinic. "It's like being pregnant. Every single person in the world can be divided into one of two categories: You're either pregnant or you're not."

His minimal criterion for defining the presence of architectural disorder in a lesion is a well-defined junctional nevus with nests at the base of the rete and lentiginous proliferation. Concentric eosinophilic fibroplasia and lamellar fibroplasia are commonly seen.

In addition to architectural disorder, dysplastic nevi may or may not have cytologic atypia, which may include large nuclei with variation of nuclear size; irregular nuclear membrane; variably staining chromatin; large eosinophilic nucleoli; and fine dusty melanin pigment in cytoplasm.

Some experts recommend that cytologic atypia be graded as mild, moderate, or severe, but Dr. Barrett does not use the term moderate. "If there's none there's none, but if there's some cytologic atypia it's either mild or severe," said Dr. Barrett of the departments of pathology and dermatology at the University of Texas, Dallas.

He favors a modified version of Dr. Arthur R. Rhodes' atypia grading system (Mod. Pathol. 1989;2:306–19). Cytologic atypia is considered mild if the size of the nucleus of the melanocyte is 1.5–2 times the size of the nucleus of the keratinocyte and if nucleoli are not present; if they are present, there should be no more than one per cell, he explained.

"I can tell that in 2 microseconds," Dr. Barrett said. "It's very easy."

Cytologic atypia is severe if there are multiple nucleoli per cell, or if the nucleus is more than two times the size of the basal keratinocyte nucleus, or if there is chromatin clumping or nuclear membrane notching.

"I can tell that very quickly," said Dr. Barrett, who also directs an outpatient pathology group in Dallas.

"More importantly, it's reproducible. I'll grant you that it's arbitrary. But the important thing is, no matter which one of the dermatopathologists who works with me signs this case out, it's going to be the same. For the dermatologist who gets the report, it's always going to be the same. If they ask me to review the case later because they want to know what I think, it's going to be the same because it's easy to do and it's reproducible."

Common acquired nevi begin to appear in childhood and increase in number from approximately 6 months of age until the third decade. At that point, they begin to decline in number. "They usually stabilize at 3–5 mm and rarely develop in patients over age 40," said Dr. Barrett, who had no relevant conflicts of interest to disclose.

In contrast, dysplastic nevi begin to appear near puberty and continue to develop throughout adulthood. "If you do serial photography of these lesions, they will increase and decrease in atypicality," he said. "They are usually greater than 5 mm."

Dysplastic nevi were originally classified as familial dysplastic nevi syndrome and sporadic nevus syndrome. Current concepts include the familial atypical mole/melanoma syndrome, which came out of the 1992 National Institutes of Health consensus statement on the diagnosis and treatment of early melanoma, and the abnormal mole phenotype. The latter definition was developed by researchers who proposed a spectrum approach that considers both the number and atypicality of nevi (West. J. Med. 1994;160:343–50). Melanoma risk increases along this continuum.

Initially, that theory "went nowhere because people didn't believe that you could have large numbers of common acquired nevi and no dysplastic nevi, and you [would nevertheless be] at increased risk for melanoma. But we now know that is absolutely true, and a number of studies have shown that patients who have large numbers of common acquired nevi have an increased risk of developing melanoma," Dr. Barrett said.

Melanoma risk also appears to increase in the presence of dysplastic nevi. A significant factor is the presence or absence of family history of either condition.

Intermittent sun exposure correlates with the risk of developing malignant melanoma and with the risk of developing multiple nevi. "Whether melanoma arises from nevi or not is unclear, but it appears that the stimulus for formation of both is the same," he said.

The risk of melanoma in a patient who has "one dysplastic nevus and nothing else" is the about the same as someone who has red or blond hair. "Not everybody with red or blond hair is going to get melanoma, but they are at an increased risk," he said.

Dr. Barrett likened dysplastic lesions to amoebae. These lesions "go through quiescent phases and they go through active phases," he said. "If we do serial photographs, we can document this change. If the lesion is quiescent and you biopsy it, you see no atypia because there is minimal cellular activity. If you biopsy it in an active phase, it's going to have some degree of atypia. That doesn't mean that atypia equates with dysplasia or premalignancy. That's what I think is happening."

No cytologic atypia can be seen in this slide from a patient with dysplastic nevi, per Dr. Terry L. Barrett.

The atypia seen above is considered mild according to Dr. Barrett's modified dysplastic nevi grading system.

This patient has severe cytologic atypia. Dr. Barrett avoids the term moderate when assessing atypia. Photos courtesy Dr. Terry L. Barrett

SAN DIEGO — There's no need to grade the level of architectural disorder when assessing dysplastic nevi. Just acknowledge if it's present or not.

"It doesn't matter how much architectural disorder is there; it only matters that it's present or absent," Dr. Terry L. Barrett said at an update on melanoma sponsored by the Scripps Clinic. "It's like being pregnant. Every single person in the world can be divided into one of two categories: You're either pregnant or you're not."

His minimal criterion for defining the presence of architectural disorder in a lesion is a well-defined junctional nevus with nests at the base of the rete and lentiginous proliferation. Concentric eosinophilic fibroplasia and lamellar fibroplasia are commonly seen.

In addition to architectural disorder, dysplastic nevi may or may not have cytologic atypia, which may include large nuclei with variation of nuclear size; irregular nuclear membrane; variably staining chromatin; large eosinophilic nucleoli; and fine dusty melanin pigment in cytoplasm.

Some experts recommend that cytologic atypia be graded as mild, moderate, or severe, but Dr. Barrett does not use the term moderate. "If there's none there's none, but if there's some cytologic atypia it's either mild or severe," said Dr. Barrett of the departments of pathology and dermatology at the University of Texas, Dallas.

He favors a modified version of Dr. Arthur R. Rhodes' atypia grading system (Mod. Pathol. 1989;2:306–19). Cytologic atypia is considered mild if the size of the nucleus of the melanocyte is 1.5–2 times the size of the nucleus of the keratinocyte and if nucleoli are not present; if they are present, there should be no more than one per cell, he explained.

"I can tell that in 2 microseconds," Dr. Barrett said. "It's very easy."

Cytologic atypia is severe if there are multiple nucleoli per cell, or if the nucleus is more than two times the size of the basal keratinocyte nucleus, or if there is chromatin clumping or nuclear membrane notching.

"I can tell that very quickly," said Dr. Barrett, who also directs an outpatient pathology group in Dallas.

"More importantly, it's reproducible. I'll grant you that it's arbitrary. But the important thing is, no matter which one of the dermatopathologists who works with me signs this case out, it's going to be the same. For the dermatologist who gets the report, it's always going to be the same. If they ask me to review the case later because they want to know what I think, it's going to be the same because it's easy to do and it's reproducible."

Common acquired nevi begin to appear in childhood and increase in number from approximately 6 months of age until the third decade. At that point, they begin to decline in number. "They usually stabilize at 3–5 mm and rarely develop in patients over age 40," said Dr. Barrett, who had no relevant conflicts of interest to disclose.

In contrast, dysplastic nevi begin to appear near puberty and continue to develop throughout adulthood. "If you do serial photography of these lesions, they will increase and decrease in atypicality," he said. "They are usually greater than 5 mm."

Dysplastic nevi were originally classified as familial dysplastic nevi syndrome and sporadic nevus syndrome. Current concepts include the familial atypical mole/melanoma syndrome, which came out of the 1992 National Institutes of Health consensus statement on the diagnosis and treatment of early melanoma, and the abnormal mole phenotype. The latter definition was developed by researchers who proposed a spectrum approach that considers both the number and atypicality of nevi (West. J. Med. 1994;160:343–50). Melanoma risk increases along this continuum.

Initially, that theory "went nowhere because people didn't believe that you could have large numbers of common acquired nevi and no dysplastic nevi, and you [would nevertheless be] at increased risk for melanoma. But we now know that is absolutely true, and a number of studies have shown that patients who have large numbers of common acquired nevi have an increased risk of developing melanoma," Dr. Barrett said.

Melanoma risk also appears to increase in the presence of dysplastic nevi. A significant factor is the presence or absence of family history of either condition.

Intermittent sun exposure correlates with the risk of developing malignant melanoma and with the risk of developing multiple nevi. "Whether melanoma arises from nevi or not is unclear, but it appears that the stimulus for formation of both is the same," he said.

The risk of melanoma in a patient who has "one dysplastic nevus and nothing else" is the about the same as someone who has red or blond hair. "Not everybody with red or blond hair is going to get melanoma, but they are at an increased risk," he said.

Dr. Barrett likened dysplastic lesions to amoebae. These lesions "go through quiescent phases and they go through active phases," he said. "If we do serial photographs, we can document this change. If the lesion is quiescent and you biopsy it, you see no atypia because there is minimal cellular activity. If you biopsy it in an active phase, it's going to have some degree of atypia. That doesn't mean that atypia equates with dysplasia or premalignancy. That's what I think is happening."

No cytologic atypia can be seen in this slide from a patient with dysplastic nevi, per Dr. Terry L. Barrett.

The atypia seen above is considered mild according to Dr. Barrett's modified dysplastic nevi grading system.

This patient has severe cytologic atypia. Dr. Barrett avoids the term moderate when assessing atypia. Photos courtesy Dr. Terry L. Barrett

SAN DIEGO — For patients with regionally advanced melanoma, the current standard of care is high-dose interferon.

"It's an imperfect standard, but nonetheless it is the standard," Dr. Michael P. Kosty said at a melanoma update sponsored by the Scripps Clinic.

To date, five randomized trials of high-dose interferon have shown a recurrence-free survival advantage, but an overall survival advantage "has been harder to demonstrate," said Dr. Kosty, program director of the hematology/oncology fellowship training program at the Scripps Clinic.

"One of the things about survival as an end point is that if you have a patient population and you treat them with your experimental therapy and they progress or recur, a lot of patients will go on standard therapy, which will impact your ability to assess their survival," he said.

Two studies have shown a survival advantage for high-dose interferon. In one study, patients were randomized to either 52 weeks of observation or to an induction phase of 20 megaunits/m

A more recent study assessed the impact of low-dose and high-dose interferon on overall survival compared with no treatment. It found that only high-dose interferon conferred a survival advantage: a median of 20 months, compared with a median of 9.6 months among those who did not receive treatment (J. Clin. Oncol. 2000; 18: 2444–58). A similar association was seen in the rates of recurrence-free survival.

"There is a dose-response relationship between the higher doses of interferon and the higher likelihood of recurrence-free benefit," said Dr. Kosty, who had no relevant conflicts of interest to disclose.

At this time, patients with stage III or stage IV disease are ideal candidates for systemic therapy. "If you look at the current data, there is no evidence in stage II disease of efficacy of adjuvant therapy, either in terms of progression free or overall survival," he noted.

The most common adverse events from high-dose interferon treatment include fatigue and depressive symptoms. Despite aggressive antidepressive therapy, "this impacts the function of many patients. Some are unable to work, particularly if they have physically demanding jobs or mentally challenging jobs," said Dr. Kosty.

In an effort to find a better alternative, a trial of 400 patients to compare standard high-dose interferon treatment to a chemoimmunotherapy combination has completed accrual. Results are expected in the coming year.

So far, no vaccine trial has shown improvement in overall survival, although some trials have shown an improvement in relapse-free survival. "There is about a 20% reduction in relapse rate and perhaps as high as a 10% reduction in death rate, although that 10% is probably the most optimistic number," he said. "Vaccines will probably have their ultimate utility in patients who have a very high risk of either developing melanoma or developing recurrence from their surgically treated melanoma, as opposed to patients with more advanced disease."

Effective treatment options for metastatic melanoma remain a challenge for researchers. Current therapies have little impact on median survival, although the combination of chemotherapy, interleukin-2, and interferon has "a fairly high response rate," Dr. Kosty said.

"That therapy might be useful if you have somebody with metastatic disease that is significantly symptomatic from the disease, such as somebody with bony metastasis and pain or somebody with liver metastasis and diminished appetite. They may benefit symptomatically but will not benefit from that therapy in terms of survival," he noted.

Recurrence-free survival has been shown, but overall survival 'has been harder to demonstrate.' DR. KOSTY

SAN DIEGO — For patients with regionally advanced melanoma, the current standard of care is high-dose interferon.

"It's an imperfect standard, but nonetheless it is the standard," Dr. Michael P. Kosty said at a melanoma update sponsored by the Scripps Clinic.

To date, five randomized trials of high-dose interferon have shown a recurrence-free survival advantage, but an overall survival advantage "has been harder to demonstrate," said Dr. Kosty, program director of the hematology/oncology fellowship training program at the Scripps Clinic.

"One of the things about survival as an end point is that if you have a patient population and you treat them with your experimental therapy and they progress or recur, a lot of patients will go on standard therapy, which will impact your ability to assess their survival," he said.

Two studies have shown a survival advantage for high-dose interferon. In one study, patients were randomized to either 52 weeks of observation or to an induction phase of 20 megaunits/m

A more recent study assessed the impact of low-dose and high-dose interferon on overall survival compared with no treatment. It found that only high-dose interferon conferred a survival advantage: a median of 20 months, compared with a median of 9.6 months among those who did not receive treatment (J. Clin. Oncol. 2000; 18: 2444–58). A similar association was seen in the rates of recurrence-free survival.

"There is a dose-response relationship between the higher doses of interferon and the higher likelihood of recurrence-free benefit," said Dr. Kosty, who had no relevant conflicts of interest to disclose.

At this time, patients with stage III or stage IV disease are ideal candidates for systemic therapy. "If you look at the current data, there is no evidence in stage II disease of efficacy of adjuvant therapy, either in terms of progression free or overall survival," he noted.

The most common adverse events from high-dose interferon treatment include fatigue and depressive symptoms. Despite aggressive antidepressive therapy, "this impacts the function of many patients. Some are unable to work, particularly if they have physically demanding jobs or mentally challenging jobs," said Dr. Kosty.

In an effort to find a better alternative, a trial of 400 patients to compare standard high-dose interferon treatment to a chemoimmunotherapy combination has completed accrual. Results are expected in the coming year.

So far, no vaccine trial has shown improvement in overall survival, although some trials have shown an improvement in relapse-free survival. "There is about a 20% reduction in relapse rate and perhaps as high as a 10% reduction in death rate, although that 10% is probably the most optimistic number," he said. "Vaccines will probably have their ultimate utility in patients who have a very high risk of either developing melanoma or developing recurrence from their surgically treated melanoma, as opposed to patients with more advanced disease."

Effective treatment options for metastatic melanoma remain a challenge for researchers. Current therapies have little impact on median survival, although the combination of chemotherapy, interleukin-2, and interferon has "a fairly high response rate," Dr. Kosty said.

"That therapy might be useful if you have somebody with metastatic disease that is significantly symptomatic from the disease, such as somebody with bony metastasis and pain or somebody with liver metastasis and diminished appetite. They may benefit symptomatically but will not benefit from that therapy in terms of survival," he noted.

Recurrence-free survival has been shown, but overall survival 'has been harder to demonstrate.' DR. KOSTY

SAN DIEGO — For patients with regionally advanced melanoma, the current standard of care is high-dose interferon.

"It's an imperfect standard, but nonetheless it is the standard," Dr. Michael P. Kosty said at a melanoma update sponsored by the Scripps Clinic.

To date, five randomized trials of high-dose interferon have shown a recurrence-free survival advantage, but an overall survival advantage "has been harder to demonstrate," said Dr. Kosty, program director of the hematology/oncology fellowship training program at the Scripps Clinic.

"One of the things about survival as an end point is that if you have a patient population and you treat them with your experimental therapy and they progress or recur, a lot of patients will go on standard therapy, which will impact your ability to assess their survival," he said.

Two studies have shown a survival advantage for high-dose interferon. In one study, patients were randomized to either 52 weeks of observation or to an induction phase of 20 megaunits/m

A more recent study assessed the impact of low-dose and high-dose interferon on overall survival compared with no treatment. It found that only high-dose interferon conferred a survival advantage: a median of 20 months, compared with a median of 9.6 months among those who did not receive treatment (J. Clin. Oncol. 2000; 18: 2444–58). A similar association was seen in the rates of recurrence-free survival.

"There is a dose-response relationship between the higher doses of interferon and the higher likelihood of recurrence-free benefit," said Dr. Kosty, who had no relevant conflicts of interest to disclose.

At this time, patients with stage III or stage IV disease are ideal candidates for systemic therapy. "If you look at the current data, there is no evidence in stage II disease of efficacy of adjuvant therapy, either in terms of progression free or overall survival," he noted.

The most common adverse events from high-dose interferon treatment include fatigue and depressive symptoms. Despite aggressive antidepressive therapy, "this impacts the function of many patients. Some are unable to work, particularly if they have physically demanding jobs or mentally challenging jobs," said Dr. Kosty.

In an effort to find a better alternative, a trial of 400 patients to compare standard high-dose interferon treatment to a chemoimmunotherapy combination has completed accrual. Results are expected in the coming year.

So far, no vaccine trial has shown improvement in overall survival, although some trials have shown an improvement in relapse-free survival. "There is about a 20% reduction in relapse rate and perhaps as high as a 10% reduction in death rate, although that 10% is probably the most optimistic number," he said. "Vaccines will probably have their ultimate utility in patients who have a very high risk of either developing melanoma or developing recurrence from their surgically treated melanoma, as opposed to patients with more advanced disease."

Effective treatment options for metastatic melanoma remain a challenge for researchers. Current therapies have little impact on median survival, although the combination of chemotherapy, interleukin-2, and interferon has "a fairly high response rate," Dr. Kosty said.

"That therapy might be useful if you have somebody with metastatic disease that is significantly symptomatic from the disease, such as somebody with bony metastasis and pain or somebody with liver metastasis and diminished appetite. They may benefit symptomatically but will not benefit from that therapy in terms of survival," he noted.

Recurrence-free survival has been shown, but overall survival 'has been harder to demonstrate.' DR. KOSTY