Melanoma

NEW ORLEANS – A higher baseline percentage of monocytes in patients with Sézary syndrome constitutes a previously unrecognized and potent predictor of clinical response to multimodality therapy incorporating extracorporeal photopheresis.

"Our theory as to why a higher number of monocytes is associated with better outcome is that it possibly leads to increased apoptosis of tumor cells and production of monocyte-derived cytokines, including interleukin-12 and interferon-alpha," Brian Raphael explained at the annual meeting of the American Academy of Dermatology.

Mr. Raphael, a fourth-year medical student at the University of Pennsylvania, Philadelphia, presented a retrospective cohort study analyzing response predictors in 97 patients with Sézary syndrome treated with multimodality therapy, defined as more than 2 months of extracorporeal photopheresis (ECP) plus at least one other systemic immunostimulatory therapy, such as interferon-alpha, interferon-gamma, sargramostim, or systemic retinoids.

This is believed to be the largest-ever such study looking at response markers, according to Mr. Raphael. Sézary syndrome is the leukemic form of cutaneous T-cell lymphoma. The prognosis is poor, with published average 5-year survival rates of only 30%.

ECP has long been considered first-line therapy for erythrodermic patients. At some centers it is employed as monotherapy, but at the University of Pennsylvania, it is typically utilized in a multimodal approach. The rationale is that combining ECP with various systemic immunostimulatory agents enhances antigen presentation, augments antitumor immunity, induces apoptosis through multiple mechanisms, and discourages tumor cell resistance, he said.

In this series, 49 of the 97 patients had stage IIIA or IIIB disease using the 1979 National Cancer Institute classification. The remainder had stage IVA or IVB Sézary syndrome.

One of the most impressive study findings, in the investigators' view, was the 30% complete response rate seen with multimodality therapy. Studies of ECP monotherapy typically cite complete response rates of about 20%, with a complete response being defined in the standard way as resolution of both skin and blood disease.

The partial response rate in the University of Pennsylvania series – defined as at least 50% improvement in both skin and blood disease – was 45%. This made for an overall 75% significant improvement rate with multimodality therapy, compared with a mean 63% significant improvement in previously reported studies of ECP monotherapy.

"These better outcomes suggest multimodality therapy is more effective than monotherapy," Mr. Raphael observed.

More than 50 patient and treatment variables were examined as potential predictors of outcome in the University of Pennsylvania series. The new one to emerge was monocyte percentage at initiation of therapy, which was a median of 9.5% in complete responders, significantly higher than the 7.8% in partial responders and 7.3% in nonresponders and those with progressive disease.

The other three significant predictors of a complete response had previously been identified in other studies. They included a lower ratio of CD4 to CD8 cells – 13.2 in complete responders, 48.7 in partial responders, and 44.2 in nonresponders – and fewer peripherally circulating abnormal T cells at baseline. The mean percentage of circulating CD26-negative lymphocytes was 27.4% in complete responders, 50.7% in partial responders, and 57.2% in nonresponders. Similarly, the mean percentage of circulating lymphocytes that were CD7 negative was 20.1% in complete responders, 36.4% in partial responders, and 41.3% in nonresponders.

Unlike in studies of ECP monotherapy for Sézary syndrome, age at diagnosis, white blood cell count, and disease stage were not significant predictors of a complete response to multimodality therapy in the new study.

Complete responders underwent a mean of 27 ECP sessions, compared with 35.5 in partial responders and 15 in nonresponders.

Mean baseline serum lactate dehydrogenase was 593 U/L in partial responders, compared with 707 U/L in nonresponders. This rather marked difference didn't achieve statistical significance, but that may change with greater patient numbers. In addition to expanding the study size, the investigators hope eventually to identify the most effective multimodality therapeutic combinations for particular patients.

Mr. Raphael said he had no relevant financial disclosures.

NEW ORLEANS – A higher baseline percentage of monocytes in patients with Sézary syndrome constitutes a previously unrecognized and potent predictor of clinical response to multimodality therapy incorporating extracorporeal photopheresis.

"Our theory as to why a higher number of monocytes is associated with better outcome is that it possibly leads to increased apoptosis of tumor cells and production of monocyte-derived cytokines, including interleukin-12 and interferon-alpha," Brian Raphael explained at the annual meeting of the American Academy of Dermatology.

Mr. Raphael, a fourth-year medical student at the University of Pennsylvania, Philadelphia, presented a retrospective cohort study analyzing response predictors in 97 patients with Sézary syndrome treated with multimodality therapy, defined as more than 2 months of extracorporeal photopheresis (ECP) plus at least one other systemic immunostimulatory therapy, such as interferon-alpha, interferon-gamma, sargramostim, or systemic retinoids.

This is believed to be the largest-ever such study looking at response markers, according to Mr. Raphael. Sézary syndrome is the leukemic form of cutaneous T-cell lymphoma. The prognosis is poor, with published average 5-year survival rates of only 30%.

ECP has long been considered first-line therapy for erythrodermic patients. At some centers it is employed as monotherapy, but at the University of Pennsylvania, it is typically utilized in a multimodal approach. The rationale is that combining ECP with various systemic immunostimulatory agents enhances antigen presentation, augments antitumor immunity, induces apoptosis through multiple mechanisms, and discourages tumor cell resistance, he said.

In this series, 49 of the 97 patients had stage IIIA or IIIB disease using the 1979 National Cancer Institute classification. The remainder had stage IVA or IVB Sézary syndrome.

One of the most impressive study findings, in the investigators' view, was the 30% complete response rate seen with multimodality therapy. Studies of ECP monotherapy typically cite complete response rates of about 20%, with a complete response being defined in the standard way as resolution of both skin and blood disease.

The partial response rate in the University of Pennsylvania series – defined as at least 50% improvement in both skin and blood disease – was 45%. This made for an overall 75% significant improvement rate with multimodality therapy, compared with a mean 63% significant improvement in previously reported studies of ECP monotherapy.

"These better outcomes suggest multimodality therapy is more effective than monotherapy," Mr. Raphael observed.

More than 50 patient and treatment variables were examined as potential predictors of outcome in the University of Pennsylvania series. The new one to emerge was monocyte percentage at initiation of therapy, which was a median of 9.5% in complete responders, significantly higher than the 7.8% in partial responders and 7.3% in nonresponders and those with progressive disease.

The other three significant predictors of a complete response had previously been identified in other studies. They included a lower ratio of CD4 to CD8 cells – 13.2 in complete responders, 48.7 in partial responders, and 44.2 in nonresponders – and fewer peripherally circulating abnormal T cells at baseline. The mean percentage of circulating CD26-negative lymphocytes was 27.4% in complete responders, 50.7% in partial responders, and 57.2% in nonresponders. Similarly, the mean percentage of circulating lymphocytes that were CD7 negative was 20.1% in complete responders, 36.4% in partial responders, and 41.3% in nonresponders.

Unlike in studies of ECP monotherapy for Sézary syndrome, age at diagnosis, white blood cell count, and disease stage were not significant predictors of a complete response to multimodality therapy in the new study.

Complete responders underwent a mean of 27 ECP sessions, compared with 35.5 in partial responders and 15 in nonresponders.

Mean baseline serum lactate dehydrogenase was 593 U/L in partial responders, compared with 707 U/L in nonresponders. This rather marked difference didn't achieve statistical significance, but that may change with greater patient numbers. In addition to expanding the study size, the investigators hope eventually to identify the most effective multimodality therapeutic combinations for particular patients.

Mr. Raphael said he had no relevant financial disclosures.

NEW ORLEANS – A higher baseline percentage of monocytes in patients with Sézary syndrome constitutes a previously unrecognized and potent predictor of clinical response to multimodality therapy incorporating extracorporeal photopheresis.

"Our theory as to why a higher number of monocytes is associated with better outcome is that it possibly leads to increased apoptosis of tumor cells and production of monocyte-derived cytokines, including interleukin-12 and interferon-alpha," Brian Raphael explained at the annual meeting of the American Academy of Dermatology.

Mr. Raphael, a fourth-year medical student at the University of Pennsylvania, Philadelphia, presented a retrospective cohort study analyzing response predictors in 97 patients with Sézary syndrome treated with multimodality therapy, defined as more than 2 months of extracorporeal photopheresis (ECP) plus at least one other systemic immunostimulatory therapy, such as interferon-alpha, interferon-gamma, sargramostim, or systemic retinoids.

This is believed to be the largest-ever such study looking at response markers, according to Mr. Raphael. Sézary syndrome is the leukemic form of cutaneous T-cell lymphoma. The prognosis is poor, with published average 5-year survival rates of only 30%.

ECP has long been considered first-line therapy for erythrodermic patients. At some centers it is employed as monotherapy, but at the University of Pennsylvania, it is typically utilized in a multimodal approach. The rationale is that combining ECP with various systemic immunostimulatory agents enhances antigen presentation, augments antitumor immunity, induces apoptosis through multiple mechanisms, and discourages tumor cell resistance, he said.

In this series, 49 of the 97 patients had stage IIIA or IIIB disease using the 1979 National Cancer Institute classification. The remainder had stage IVA or IVB Sézary syndrome.

One of the most impressive study findings, in the investigators' view, was the 30% complete response rate seen with multimodality therapy. Studies of ECP monotherapy typically cite complete response rates of about 20%, with a complete response being defined in the standard way as resolution of both skin and blood disease.

The partial response rate in the University of Pennsylvania series – defined as at least 50% improvement in both skin and blood disease – was 45%. This made for an overall 75% significant improvement rate with multimodality therapy, compared with a mean 63% significant improvement in previously reported studies of ECP monotherapy.

"These better outcomes suggest multimodality therapy is more effective than monotherapy," Mr. Raphael observed.

More than 50 patient and treatment variables were examined as potential predictors of outcome in the University of Pennsylvania series. The new one to emerge was monocyte percentage at initiation of therapy, which was a median of 9.5% in complete responders, significantly higher than the 7.8% in partial responders and 7.3% in nonresponders and those with progressive disease.

The other three significant predictors of a complete response had previously been identified in other studies. They included a lower ratio of CD4 to CD8 cells – 13.2 in complete responders, 48.7 in partial responders, and 44.2 in nonresponders – and fewer peripherally circulating abnormal T cells at baseline. The mean percentage of circulating CD26-negative lymphocytes was 27.4% in complete responders, 50.7% in partial responders, and 57.2% in nonresponders. Similarly, the mean percentage of circulating lymphocytes that were CD7 negative was 20.1% in complete responders, 36.4% in partial responders, and 41.3% in nonresponders.

Unlike in studies of ECP monotherapy for Sézary syndrome, age at diagnosis, white blood cell count, and disease stage were not significant predictors of a complete response to multimodality therapy in the new study.

Complete responders underwent a mean of 27 ECP sessions, compared with 35.5 in partial responders and 15 in nonresponders.

Mean baseline serum lactate dehydrogenase was 593 U/L in partial responders, compared with 707 U/L in nonresponders. This rather marked difference didn't achieve statistical significance, but that may change with greater patient numbers. In addition to expanding the study size, the investigators hope eventually to identify the most effective multimodality therapeutic combinations for particular patients.

Mr. Raphael said he had no relevant financial disclosures.

Matthew R. Donaldson, MD, and Brett M. Coldiron, MD

The incidence of nonmelanoma skin cancer (NMSC) continues to increase.  Multiple reports from the United States and Europe suggest we are in the midst of an epidemic. European studies show substantial NMSC incidence increases during the last 2 decades. In the United States, a recent analysis of Medicare Claims data showed that procedures performed for NMSC nearly doubled from 1994 to 2006. From these data, the total number of new NMSC in 2006 was estimated to be 3,507,693. Procedure data for 2006-2008 from the 5% Medicare Claims sample dataset corroborate the reported trajectory of incidence increase. Destructions, excisions, and Mohs procedures for NMSC have increased by 2.6% per year during the last 2 years. On the basis of this current rate of increase, the annual incidence of NMSC in the United States in 2008 would be nearly 3.69 million. Recognizing the NMSC epidemic is critical as the incidence—and cost—will continue to increase.

*For a PDF of the full article, click on the link to the left of this introduction.

Matthew R. Donaldson, MD, and Brett M. Coldiron, MD

The incidence of nonmelanoma skin cancer (NMSC) continues to increase.  Multiple reports from the United States and Europe suggest we are in the midst of an epidemic. European studies show substantial NMSC incidence increases during the last 2 decades. In the United States, a recent analysis of Medicare Claims data showed that procedures performed for NMSC nearly doubled from 1994 to 2006. From these data, the total number of new NMSC in 2006 was estimated to be 3,507,693. Procedure data for 2006-2008 from the 5% Medicare Claims sample dataset corroborate the reported trajectory of incidence increase. Destructions, excisions, and Mohs procedures for NMSC have increased by 2.6% per year during the last 2 years. On the basis of this current rate of increase, the annual incidence of NMSC in the United States in 2008 would be nearly 3.69 million. Recognizing the NMSC epidemic is critical as the incidence—and cost—will continue to increase.

*For a PDF of the full article, click on the link to the left of this introduction.

Matthew R. Donaldson, MD, and Brett M. Coldiron, MD

The incidence of nonmelanoma skin cancer (NMSC) continues to increase.  Multiple reports from the United States and Europe suggest we are in the midst of an epidemic. European studies show substantial NMSC incidence increases during the last 2 decades. In the United States, a recent analysis of Medicare Claims data showed that procedures performed for NMSC nearly doubled from 1994 to 2006. From these data, the total number of new NMSC in 2006 was estimated to be 3,507,693. Procedure data for 2006-2008 from the 5% Medicare Claims sample dataset corroborate the reported trajectory of incidence increase. Destructions, excisions, and Mohs procedures for NMSC have increased by 2.6% per year during the last 2 years. On the basis of this current rate of increase, the annual incidence of NMSC in the United States in 2008 would be nearly 3.69 million. Recognizing the NMSC epidemic is critical as the incidence—and cost—will continue to increase.

*For a PDF of the full article, click on the link to the left of this introduction.

William L. Camp, MD, MPH, Jennifer W. Turnham, BS, Mohammad Athar, PhD, and Craig A. Elmets, MD

With the incidence of nonmelanoma skin cancer on the rise, current prevention methods, such as the use of sunscreens, have yet to prove adequate to reverse this trend. There has been considerable interest in identifying compounds that will inhibit or reverse the biochemical changes required for skin cancers to develop, either by pharmacologic intervention or by dietary manipulation. By targeting different pathways identified as important in the pathogenesis of nonmelanoma skin cancers, a combination approach with multiple agents or the addition of chemopreventative agents to topical sunscreens may offer the potential for novel and synergistic therapies in treating nonmelanoma skin cancer.

*For a PDF of the full article, click on the link to the left of this introduction.

William L. Camp, MD, MPH, Jennifer W. Turnham, BS, Mohammad Athar, PhD, and Craig A. Elmets, MD

With the incidence of nonmelanoma skin cancer on the rise, current prevention methods, such as the use of sunscreens, have yet to prove adequate to reverse this trend. There has been considerable interest in identifying compounds that will inhibit or reverse the biochemical changes required for skin cancers to develop, either by pharmacologic intervention or by dietary manipulation. By targeting different pathways identified as important in the pathogenesis of nonmelanoma skin cancers, a combination approach with multiple agents or the addition of chemopreventative agents to topical sunscreens may offer the potential for novel and synergistic therapies in treating nonmelanoma skin cancer.

*For a PDF of the full article, click on the link to the left of this introduction.

William L. Camp, MD, MPH, Jennifer W. Turnham, BS, Mohammad Athar, PhD, and Craig A. Elmets, MD

With the incidence of nonmelanoma skin cancer on the rise, current prevention methods, such as the use of sunscreens, have yet to prove adequate to reverse this trend. There has been considerable interest in identifying compounds that will inhibit or reverse the biochemical changes required for skin cancers to develop, either by pharmacologic intervention or by dietary manipulation. By targeting different pathways identified as important in the pathogenesis of nonmelanoma skin cancers, a combination approach with multiple agents or the addition of chemopreventative agents to topical sunscreens may offer the potential for novel and synergistic therapies in treating nonmelanoma skin cancer.

*For a PDF of the full article, click on the link to the left of this introduction.

Lori Brightman, MD, Melanie Warycha, MD, Robert Anolik, MD, and Roy Geronemus, MD*

Novel strategies are urgently needed to address the millions of nonmelanoma skin cancers treated in the United States annually. The need is greatest for those patients who are poor surgical candidates or those prone to numerous nonmelanoma skin cancers and therefore at risk for marked disfigurement. Traditional treatment strategies include electrosurgery with curettage, radiation therapy, cryotherapy, excision, and Mohs micrographic surgery. Alternatives to traditional treatment, including topical medications and light or laser therapies, are becoming popular; however, there are various degrees of efficacy among these alternative tactics. These alternatives include topical retinoids, peels, 5-fluorouracil, imiquimod, photodynamic therapy, and lasers. The purpose of this paper is to review the available data regarding these alternative strategies and permit the reader to have a sense of which therapies are reasonable options for care.

*For a PDF of the full article, click on the link to the left of this introduction.

Lori Brightman, MD, Melanie Warycha, MD, Robert Anolik, MD, and Roy Geronemus, MD*

Novel strategies are urgently needed to address the millions of nonmelanoma skin cancers treated in the United States annually. The need is greatest for those patients who are poor surgical candidates or those prone to numerous nonmelanoma skin cancers and therefore at risk for marked disfigurement. Traditional treatment strategies include electrosurgery with curettage, radiation therapy, cryotherapy, excision, and Mohs micrographic surgery. Alternatives to traditional treatment, including topical medications and light or laser therapies, are becoming popular; however, there are various degrees of efficacy among these alternative tactics. These alternatives include topical retinoids, peels, 5-fluorouracil, imiquimod, photodynamic therapy, and lasers. The purpose of this paper is to review the available data regarding these alternative strategies and permit the reader to have a sense of which therapies are reasonable options for care.

*For a PDF of the full article, click on the link to the left of this introduction.

Lori Brightman, MD, Melanie Warycha, MD, Robert Anolik, MD, and Roy Geronemus, MD*

Novel strategies are urgently needed to address the millions of nonmelanoma skin cancers treated in the United States annually. The need is greatest for those patients who are poor surgical candidates or those prone to numerous nonmelanoma skin cancers and therefore at risk for marked disfigurement. Traditional treatment strategies include electrosurgery with curettage, radiation therapy, cryotherapy, excision, and Mohs micrographic surgery. Alternatives to traditional treatment, including topical medications and light or laser therapies, are becoming popular; however, there are various degrees of efficacy among these alternative tactics. These alternatives include topical retinoids, peels, 5-fluorouracil, imiquimod, photodynamic therapy, and lasers. The purpose of this paper is to review the available data regarding these alternative strategies and permit the reader to have a sense of which therapies are reasonable options for care.

*For a PDF of the full article, click on the link to the left of this introduction.

Nicole R. LeBoeuf, MD, and Chrysalyne D. Schmults, MD, MSCE

Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy occurring in white patients in the United States and incidence rates are increasing. While the majority of the 87,000-760,000 cases that occur yearly in the U.S. are curable, 4% develop lymph node metastases and 1.5% die from the disease. Given the frequency of occurrence of CSCC, it is estimated to cause as many deaths yearly as melanoma, with the majority occurring in patients with high risk tumors or in those at high risk for metastasis due to a variety of host factors, most commonly systemic immunosuppression. There are currently no standardized prognostic or treatment models to assist clinicians in most effectively identifying and managing these patients. Identification of patients at risk for poor outcomes as well as standardization regarding classification, staging, and treatment of high-risk tumors is critical for optimizing patient care. In this article, available literature on the classification and management of high risk CSCC is briefly summarized, emphasizing new information.

*For a PDF of the full article, click on the link to the left of this introduction.

Nicole R. LeBoeuf, MD, and Chrysalyne D. Schmults, MD, MSCE

Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy occurring in white patients in the United States and incidence rates are increasing. While the majority of the 87,000-760,000 cases that occur yearly in the U.S. are curable, 4% develop lymph node metastases and 1.5% die from the disease. Given the frequency of occurrence of CSCC, it is estimated to cause as many deaths yearly as melanoma, with the majority occurring in patients with high risk tumors or in those at high risk for metastasis due to a variety of host factors, most commonly systemic immunosuppression. There are currently no standardized prognostic or treatment models to assist clinicians in most effectively identifying and managing these patients. Identification of patients at risk for poor outcomes as well as standardization regarding classification, staging, and treatment of high-risk tumors is critical for optimizing patient care. In this article, available literature on the classification and management of high risk CSCC is briefly summarized, emphasizing new information.

*For a PDF of the full article, click on the link to the left of this introduction.

Nicole R. LeBoeuf, MD, and Chrysalyne D. Schmults, MD, MSCE

Cutaneous squamous cell carcinoma (CSCC) is the second most common malignancy occurring in white patients in the United States and incidence rates are increasing. While the majority of the 87,000-760,000 cases that occur yearly in the U.S. are curable, 4% develop lymph node metastases and 1.5% die from the disease. Given the frequency of occurrence of CSCC, it is estimated to cause as many deaths yearly as melanoma, with the majority occurring in patients with high risk tumors or in those at high risk for metastasis due to a variety of host factors, most commonly systemic immunosuppression. There are currently no standardized prognostic or treatment models to assist clinicians in most effectively identifying and managing these patients. Identification of patients at risk for poor outcomes as well as standardization regarding classification, staging, and treatment of high-risk tumors is critical for optimizing patient care. In this article, available literature on the classification and management of high risk CSCC is briefly summarized, emphasizing new information.

*For a PDF of the full article, click on the link to the left of this introduction.

Meena K. Singh, MD, and Jerry D. Brewer, MD

Approximately 225,000 people are living with organ transplants in the United States. Organ transplant recipients have a greater risk of developing skin cancer, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, with an approximately 250 times greater incidence of squamous cell carcinoma in certain transplant recipients, compared with the general population. Because skin cancers are the most common posttransplant malignancy, the resultant morbidity and mortality in these high-risk patients is quite significant.

*For a PDF of the full article, click on the link to the left of this introduction.

Meena K. Singh, MD, and Jerry D. Brewer, MD

Approximately 225,000 people are living with organ transplants in the United States. Organ transplant recipients have a greater risk of developing skin cancer, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, with an approximately 250 times greater incidence of squamous cell carcinoma in certain transplant recipients, compared with the general population. Because skin cancers are the most common posttransplant malignancy, the resultant morbidity and mortality in these high-risk patients is quite significant.

*For a PDF of the full article, click on the link to the left of this introduction.

Meena K. Singh, MD, and Jerry D. Brewer, MD

Approximately 225,000 people are living with organ transplants in the United States. Organ transplant recipients have a greater risk of developing skin cancer, including basal cell carcinoma, squamous cell carcinoma, and malignant melanoma, with an approximately 250 times greater incidence of squamous cell carcinoma in certain transplant recipients, compared with the general population. Because skin cancers are the most common posttransplant malignancy, the resultant morbidity and mortality in these high-risk patients is quite significant.

*For a PDF of the full article, click on the link to the left of this introduction.

Timothy S. Wang, MD, Patrick J. Byrne, MD, FACS, Lisa K. Jacobs, MD, and Janis M. Taube, MD

Merkel cell carcinoma (MCC) is a rare, aggressive, and often fatal cutaneous malignancy that is not usually suspected at the time of biopsy. Because of its increasing incidence and the discovery of a possible viral association, interest in MCC has escalated. Recent effort has broadened our breadth of knowledge regarding MCC and developed instruments to improve data collection and future study. This article provides an update on current thinking about the Merkel cell and MCC.

*For a PDF of the full article, click on the link to the left of this introduction.

Timothy S. Wang, MD, Patrick J. Byrne, MD, FACS, Lisa K. Jacobs, MD, and Janis M. Taube, MD

Merkel cell carcinoma (MCC) is a rare, aggressive, and often fatal cutaneous malignancy that is not usually suspected at the time of biopsy. Because of its increasing incidence and the discovery of a possible viral association, interest in MCC has escalated. Recent effort has broadened our breadth of knowledge regarding MCC and developed instruments to improve data collection and future study. This article provides an update on current thinking about the Merkel cell and MCC.

*For a PDF of the full article, click on the link to the left of this introduction.

Timothy S. Wang, MD, Patrick J. Byrne, MD, FACS, Lisa K. Jacobs, MD, and Janis M. Taube, MD

Merkel cell carcinoma (MCC) is a rare, aggressive, and often fatal cutaneous malignancy that is not usually suspected at the time of biopsy. Because of its increasing incidence and the discovery of a possible viral association, interest in MCC has escalated. Recent effort has broadened our breadth of knowledge regarding MCC and developed instruments to improve data collection and future study. This article provides an update on current thinking about the Merkel cell and MCC.

*For a PDF of the full article, click on the link to the left of this introduction.

Kevin W. O’Bryan, MD, and Desiree Ratner, MD

Surgical treatment remains the standard of care for nonmelanoma skin cancer and is successful for the vast majority of patients with these tumors. The treatment of patients with metastatic or unresectable nonmelanoma skin cancer, however, has until recently been based solely on traditional methods of chemotherapy and radiation. However, these methods have high rates of treatment failure, morbidity, and mortality, and alternative treatment modalities for patients with aggressive or advanced disease are needed. As in other areas of cancer therapeutics, recent research elucidating the molecular basis of cancer development, and the subsequent arrival of targeted molecular inhibitors for cancer therapy, have been met with much excitement. In this review, we seek to illuminate recent developments and future possibilities in the use of targeted molecular inhibitors for treatment of advanced squamous cell carcinoma, basal cell carcinoma, and dermatofibrosarcoma protuberans.

*For a PDF of the full article, click on the link to the left of this introduction.

Kevin W. O’Bryan, MD, and Desiree Ratner, MD

Surgical treatment remains the standard of care for nonmelanoma skin cancer and is successful for the vast majority of patients with these tumors. The treatment of patients with metastatic or unresectable nonmelanoma skin cancer, however, has until recently been based solely on traditional methods of chemotherapy and radiation. However, these methods have high rates of treatment failure, morbidity, and mortality, and alternative treatment modalities for patients with aggressive or advanced disease are needed. As in other areas of cancer therapeutics, recent research elucidating the molecular basis of cancer development, and the subsequent arrival of targeted molecular inhibitors for cancer therapy, have been met with much excitement. In this review, we seek to illuminate recent developments and future possibilities in the use of targeted molecular inhibitors for treatment of advanced squamous cell carcinoma, basal cell carcinoma, and dermatofibrosarcoma protuberans.

*For a PDF of the full article, click on the link to the left of this introduction.

Kevin W. O’Bryan, MD, and Desiree Ratner, MD

Surgical treatment remains the standard of care for nonmelanoma skin cancer and is successful for the vast majority of patients with these tumors. The treatment of patients with metastatic or unresectable nonmelanoma skin cancer, however, has until recently been based solely on traditional methods of chemotherapy and radiation. However, these methods have high rates of treatment failure, morbidity, and mortality, and alternative treatment modalities for patients with aggressive or advanced disease are needed. As in other areas of cancer therapeutics, recent research elucidating the molecular basis of cancer development, and the subsequent arrival of targeted molecular inhibitors for cancer therapy, have been met with much excitement. In this review, we seek to illuminate recent developments and future possibilities in the use of targeted molecular inhibitors for treatment of advanced squamous cell carcinoma, basal cell carcinoma, and dermatofibrosarcoma protuberans.

*For a PDF of the full article, click on the link to the left of this introduction.

NEW ORLEANS - There were approximately 3.7 million nonmelanoma skin cancers in the United States in 2009, up almost 2% from the previous year, said Dr. Brett Coldiron.

This number marks the continuation of an upwards trend in the incidence of skin cancer, noted Dr. Coldiron, a private practice dermatologic surgeon and member of the dermatology faculty at the University of Cincinnati. He presented his preliminary 2009 data at the meeting, and noted that the vast numbers of those affected seem to indicate an epidemic.

"At this rate of increase, the total number of nonmelanoma skin cancer [NMSC] will double every 15-20 years," said Dr. Coldiron.

The data update a study he and his colleagues published last year estimating that there were 3.5 million NMSCs, affecting 2.1 million people in the United States in 2006 (Arch. Dermatol. 2010;146:283-7) . He and his colleagues estimated that the number of skin cancer procedures increased by 77% from 1992 to 2006. During this time, there was a 16% increase in procedures for NMSCs in the Medicare population.

NMSC is not a reportable disease, so there have not been good estimates for how many Americans are affected. For his initial paper, said Dr. Coldiron, "It occurred to me one day that you can't treat NMSC without a positive pathologic diagnosis, or they'll send you off to jail."

So he sought procedure data from Medicare's Fee-for-Service Physicians Claims database and the National Ambulatory Medical Care Service database. Procedures are "a pretty good proxy for the actual number of NMSCs," said Dr. Coldiron.

To get a total number of NMSCs, he and his colleagues multiplied the estimated crude number of skin cancers by the proportion of skin cancer procedure code claims associated with the ICD-9-CM diagnoses for invasive nonmelanoma cutaneous malignancy (173.0-173.9) and in situ malignancy (232.0-232.9).

Looking at trends, it appears the number of procedures have been levelling off at about a 2% rate the last few years, said Dr. Coldiron. However, the continued increase should be of concern to physicians, patients, and policy makers, he said.

The cost of treating NMSCs is around $8 billion a year, "so it's serious money," he said.

In commenting on Dr. Coldiron's findings, Dr. Darrell S. Rigel, who is a professor of dermatology and dermatologic surgery at New York University Medical Center, said that the number of NMSCs is "a surprisingly high number." Overall, skin cancer is much more common than all other cancers combined, said Dr. Rigel, adding that he had conducted studies showing that the lifetime risk of developing melanoma--invasive and in situ--now stood at 1 in 35 in the U.S.

And, more than 10,000 Americans will die from skin cancer this year. "So it is a serious public health problem," said Dr. Rigel.

For his part, Dr. Coldiron said, "We have to convince people there is an epidemic out there." In addition to increasing Medicare funding to treat NMSCs, "it's prudent and cost effective to focus on prevention," he said.

Dr. Coldiron reported no conflicts related to his talk. His study was self funded.

NEW ORLEANS - There were approximately 3.7 million nonmelanoma skin cancers in the United States in 2009, up almost 2% from the previous year, said Dr. Brett Coldiron.

This number marks the continuation of an upwards trend in the incidence of skin cancer, noted Dr. Coldiron, a private practice dermatologic surgeon and member of the dermatology faculty at the University of Cincinnati. He presented his preliminary 2009 data at the meeting, and noted that the vast numbers of those affected seem to indicate an epidemic.

"At this rate of increase, the total number of nonmelanoma skin cancer [NMSC] will double every 15-20 years," said Dr. Coldiron.

The data update a study he and his colleagues published last year estimating that there were 3.5 million NMSCs, affecting 2.1 million people in the United States in 2006 (Arch. Dermatol. 2010;146:283-7) . He and his colleagues estimated that the number of skin cancer procedures increased by 77% from 1992 to 2006. During this time, there was a 16% increase in procedures for NMSCs in the Medicare population.

NMSC is not a reportable disease, so there have not been good estimates for how many Americans are affected. For his initial paper, said Dr. Coldiron, "It occurred to me one day that you can't treat NMSC without a positive pathologic diagnosis, or they'll send you off to jail."

So he sought procedure data from Medicare's Fee-for-Service Physicians Claims database and the National Ambulatory Medical Care Service database. Procedures are "a pretty good proxy for the actual number of NMSCs," said Dr. Coldiron.

To get a total number of NMSCs, he and his colleagues multiplied the estimated crude number of skin cancers by the proportion of skin cancer procedure code claims associated with the ICD-9-CM diagnoses for invasive nonmelanoma cutaneous malignancy (173.0-173.9) and in situ malignancy (232.0-232.9).

Looking at trends, it appears the number of procedures have been levelling off at about a 2% rate the last few years, said Dr. Coldiron. However, the continued increase should be of concern to physicians, patients, and policy makers, he said.

The cost of treating NMSCs is around $8 billion a year, "so it's serious money," he said.

In commenting on Dr. Coldiron's findings, Dr. Darrell S. Rigel, who is a professor of dermatology and dermatologic surgery at New York University Medical Center, said that the number of NMSCs is "a surprisingly high number." Overall, skin cancer is much more common than all other cancers combined, said Dr. Rigel, adding that he had conducted studies showing that the lifetime risk of developing melanoma--invasive and in situ--now stood at 1 in 35 in the U.S.

And, more than 10,000 Americans will die from skin cancer this year. "So it is a serious public health problem," said Dr. Rigel.

For his part, Dr. Coldiron said, "We have to convince people there is an epidemic out there." In addition to increasing Medicare funding to treat NMSCs, "it's prudent and cost effective to focus on prevention," he said.

Dr. Coldiron reported no conflicts related to his talk. His study was self funded.

NEW ORLEANS - There were approximately 3.7 million nonmelanoma skin cancers in the United States in 2009, up almost 2% from the previous year, said Dr. Brett Coldiron.

This number marks the continuation of an upwards trend in the incidence of skin cancer, noted Dr. Coldiron, a private practice dermatologic surgeon and member of the dermatology faculty at the University of Cincinnati. He presented his preliminary 2009 data at the meeting, and noted that the vast numbers of those affected seem to indicate an epidemic.

"At this rate of increase, the total number of nonmelanoma skin cancer [NMSC] will double every 15-20 years," said Dr. Coldiron.

The data update a study he and his colleagues published last year estimating that there were 3.5 million NMSCs, affecting 2.1 million people in the United States in 2006 (Arch. Dermatol. 2010;146:283-7) . He and his colleagues estimated that the number of skin cancer procedures increased by 77% from 1992 to 2006. During this time, there was a 16% increase in procedures for NMSCs in the Medicare population.

NMSC is not a reportable disease, so there have not been good estimates for how many Americans are affected. For his initial paper, said Dr. Coldiron, "It occurred to me one day that you can't treat NMSC without a positive pathologic diagnosis, or they'll send you off to jail."

So he sought procedure data from Medicare's Fee-for-Service Physicians Claims database and the National Ambulatory Medical Care Service database. Procedures are "a pretty good proxy for the actual number of NMSCs," said Dr. Coldiron.

To get a total number of NMSCs, he and his colleagues multiplied the estimated crude number of skin cancers by the proportion of skin cancer procedure code claims associated with the ICD-9-CM diagnoses for invasive nonmelanoma cutaneous malignancy (173.0-173.9) and in situ malignancy (232.0-232.9).

Looking at trends, it appears the number of procedures have been levelling off at about a 2% rate the last few years, said Dr. Coldiron. However, the continued increase should be of concern to physicians, patients, and policy makers, he said.

The cost of treating NMSCs is around $8 billion a year, "so it's serious money," he said.

In commenting on Dr. Coldiron's findings, Dr. Darrell S. Rigel, who is a professor of dermatology and dermatologic surgery at New York University Medical Center, said that the number of NMSCs is "a surprisingly high number." Overall, skin cancer is much more common than all other cancers combined, said Dr. Rigel, adding that he had conducted studies showing that the lifetime risk of developing melanoma--invasive and in situ--now stood at 1 in 35 in the U.S.

And, more than 10,000 Americans will die from skin cancer this year. "So it is a serious public health problem," said Dr. Rigel.

For his part, Dr. Coldiron said, "We have to convince people there is an epidemic out there." In addition to increasing Medicare funding to treat NMSCs, "it's prudent and cost effective to focus on prevention," he said.

Dr. Coldiron reported no conflicts related to his talk. His study was self funded.

MIAMI BEACH – A novel percutaneous system for isolating hepatic blood flow allowed clinicians to treat hepatic melanoma metastases with a high concentration of melphalan and then filter out the drug to minimize its entry into the systemic circulation in a study of 93 patients.

This method for percutaneous hepatic perfusion (PHP) produced a more than fourfold increase in the average duration of hepatic progression-free survival in PHP patients compared with control patients in the phase III, randomized controlled trial, Dr. Charles W. Nutting said at ISET 2011, an international symposium on endovascular therapy.

Based on these results, the company that developed the percutaneous catheter system, Delcath Systems, filed a new drug application with the Food and Drug Administration.

"High-dose melphalan, delivered via intra-arterial administration with subsequent hepatic hemofiltration, is effective against hepatic metastases from ocular and cutaneous melanoma and provides improved disease control when compared with standard treatment regimens," said Dr. Nutting, an interventional radiologist at Swedish Medical Center in Denver.

"The FDA told us what result they would want to see" to approve PHP – an average duration of hepatic progression-free survival of 7.7 months in PHP patients and an average 4.0-month survival in control patients, Dr. Nutting said in an interview.

"The results exceeded that," he noted, with an average hepatic progression-free survival of 245 days (8.2 months) in the patients randomized to initial PHP and an average of 49 days (1.6 months) in control patients who received best alternative care. The hazard ratio for the PHP patients compared with the controls for this primary end point was 0.301 (P =.0001.)

PHP is "now one of the primary treatments" for inoperable melanoma liver metastases in patients whose most significant disease is in the liver, he added.

The clear success of PHP also suggested that the method might also help patients with other types of liver tumors, including primary cancers and other malignancies that often metastasize to the liver, such as colon cancer, Dr. Nutting said.

The researchers who developed PHP envisioned it as a potentially easier-to-tolerate variation on isolated hepatic perfusion, a method first used more than a decade ago that involved an open surgical procedure to isolate the hepatic circulation (J. Am. Coll. Surg. 2000;191:519-30). It was so invasive, however, that each patient could tolerate only a single treatment, Dr. Nutting said.

The percutaneous approach, developed as a more tolerable alternative, was applied serially one to six times to each patient in the PHP arm of the current trial with a 4-week interval between treatments.

The procedure involves inserting a double-balloon catheter from the patient’s groin through the hepatic artery and into the inferior vena cava. The superior balloon is then inflated and brought down to occlude the upper hepatic veins, while the second balloon is inflated below the hepatic veins to isolate hepatic venous return. A continuous infusion of melphalan enters the patient via a second catheter into the hepatic artery. After the drug distributes through the liver, the first catheter sucks out the hepatic venous blood (which is blocked by the two balloons from entering the systemic venous flow) via a set of holes and shunts it to an externally placed filter at a rate of 500 mL/min. After the blood is cleansed of the drug, it is returned to the patient.

The total melphalan dose delivered is 3.0 mg/kg ideal body weight of the patient, with the total dose diluted in 500 mL of fluid. The system takes 30 minutes to pump the entire dose into the patient, after which the balloons isolating the hepatic venous system and the filtration mechanism remain in place for another 30 minutes to continue to cleanse the drug from the patient’s liver. The system cuts systemic exposure to the melphalan by 80% compared with the intrahepatic dose delivered, Dr. Nutting said.

The study enrolled 44 patients into the PHP arm and 49 into the control arm at 12 U.S. centers. All patients had metastatic melanoma that primarily affected the liver and was judged too extensive for surgical removal. Patients had a median of 20 hepatic metastases (range, 4-100). In 88% of patients the primary tumor was ocular melanoma, and 12% had cutaneous melanoma. Their average age was 55 years.

Despite the high melphalan dose used, the 40 PHP patients included in the safety analysis had "minimal toxicity that was well within acceptable limits for the doses of medication we gave," he said.

During the 116 total treatments these patients received, grade 3 or 4 neutropenia occurred after 61% of treatments, thrombocytopenia after 74%, and anemia after 47%. Grade 5 neutropenia occurred following two treatments, but these episodes were usually transient and manageable. A total of three patients in the PHP group died, two from neutropenia sepsis and one from hepatic failure.

In a secondary efficacy analysis, no patient in either treatment arm had a complete response. The incidence of patient responses was 34% in the PHP patients and 2% in the controls. The combined rate of partial response or stable disease reached 86% in the PHP-treated patients and 28% in the control patients.

The trial was sponsored in part by Delcath, the company developing the PHP system. Dr. Notting said that he has received research support from, and has spoken on behalf of, Delcath.

MIAMI BEACH – A novel percutaneous system for isolating hepatic blood flow allowed clinicians to treat hepatic melanoma metastases with a high concentration of melphalan and then filter out the drug to minimize its entry into the systemic circulation in a study of 93 patients.

This method for percutaneous hepatic perfusion (PHP) produced a more than fourfold increase in the average duration of hepatic progression-free survival in PHP patients compared with control patients in the phase III, randomized controlled trial, Dr. Charles W. Nutting said at ISET 2011, an international symposium on endovascular therapy.

Based on these results, the company that developed the percutaneous catheter system, Delcath Systems, filed a new drug application with the Food and Drug Administration.

"High-dose melphalan, delivered via intra-arterial administration with subsequent hepatic hemofiltration, is effective against hepatic metastases from ocular and cutaneous melanoma and provides improved disease control when compared with standard treatment regimens," said Dr. Nutting, an interventional radiologist at Swedish Medical Center in Denver.

"The FDA told us what result they would want to see" to approve PHP – an average duration of hepatic progression-free survival of 7.7 months in PHP patients and an average 4.0-month survival in control patients, Dr. Nutting said in an interview.

"The results exceeded that," he noted, with an average hepatic progression-free survival of 245 days (8.2 months) in the patients randomized to initial PHP and an average of 49 days (1.6 months) in control patients who received best alternative care. The hazard ratio for the PHP patients compared with the controls for this primary end point was 0.301 (P =.0001.)

PHP is "now one of the primary treatments" for inoperable melanoma liver metastases in patients whose most significant disease is in the liver, he added.

The clear success of PHP also suggested that the method might also help patients with other types of liver tumors, including primary cancers and other malignancies that often metastasize to the liver, such as colon cancer, Dr. Nutting said.

The researchers who developed PHP envisioned it as a potentially easier-to-tolerate variation on isolated hepatic perfusion, a method first used more than a decade ago that involved an open surgical procedure to isolate the hepatic circulation (J. Am. Coll. Surg. 2000;191:519-30). It was so invasive, however, that each patient could tolerate only a single treatment, Dr. Nutting said.

The percutaneous approach, developed as a more tolerable alternative, was applied serially one to six times to each patient in the PHP arm of the current trial with a 4-week interval between treatments.

The procedure involves inserting a double-balloon catheter from the patient’s groin through the hepatic artery and into the inferior vena cava. The superior balloon is then inflated and brought down to occlude the upper hepatic veins, while the second balloon is inflated below the hepatic veins to isolate hepatic venous return. A continuous infusion of melphalan enters the patient via a second catheter into the hepatic artery. After the drug distributes through the liver, the first catheter sucks out the hepatic venous blood (which is blocked by the two balloons from entering the systemic venous flow) via a set of holes and shunts it to an externally placed filter at a rate of 500 mL/min. After the blood is cleansed of the drug, it is returned to the patient.

The total melphalan dose delivered is 3.0 mg/kg ideal body weight of the patient, with the total dose diluted in 500 mL of fluid. The system takes 30 minutes to pump the entire dose into the patient, after which the balloons isolating the hepatic venous system and the filtration mechanism remain in place for another 30 minutes to continue to cleanse the drug from the patient’s liver. The system cuts systemic exposure to the melphalan by 80% compared with the intrahepatic dose delivered, Dr. Nutting said.

The study enrolled 44 patients into the PHP arm and 49 into the control arm at 12 U.S. centers. All patients had metastatic melanoma that primarily affected the liver and was judged too extensive for surgical removal. Patients had a median of 20 hepatic metastases (range, 4-100). In 88% of patients the primary tumor was ocular melanoma, and 12% had cutaneous melanoma. Their average age was 55 years.

Despite the high melphalan dose used, the 40 PHP patients included in the safety analysis had "minimal toxicity that was well within acceptable limits for the doses of medication we gave," he said.

During the 116 total treatments these patients received, grade 3 or 4 neutropenia occurred after 61% of treatments, thrombocytopenia after 74%, and anemia after 47%. Grade 5 neutropenia occurred following two treatments, but these episodes were usually transient and manageable. A total of three patients in the PHP group died, two from neutropenia sepsis and one from hepatic failure.

In a secondary efficacy analysis, no patient in either treatment arm had a complete response. The incidence of patient responses was 34% in the PHP patients and 2% in the controls. The combined rate of partial response or stable disease reached 86% in the PHP-treated patients and 28% in the control patients.

The trial was sponsored in part by Delcath, the company developing the PHP system. Dr. Notting said that he has received research support from, and has spoken on behalf of, Delcath.

MIAMI BEACH – A novel percutaneous system for isolating hepatic blood flow allowed clinicians to treat hepatic melanoma metastases with a high concentration of melphalan and then filter out the drug to minimize its entry into the systemic circulation in a study of 93 patients.

This method for percutaneous hepatic perfusion (PHP) produced a more than fourfold increase in the average duration of hepatic progression-free survival in PHP patients compared with control patients in the phase III, randomized controlled trial, Dr. Charles W. Nutting said at ISET 2011, an international symposium on endovascular therapy.

Based on these results, the company that developed the percutaneous catheter system, Delcath Systems, filed a new drug application with the Food and Drug Administration.

"High-dose melphalan, delivered via intra-arterial administration with subsequent hepatic hemofiltration, is effective against hepatic metastases from ocular and cutaneous melanoma and provides improved disease control when compared with standard treatment regimens," said Dr. Nutting, an interventional radiologist at Swedish Medical Center in Denver.

"The FDA told us what result they would want to see" to approve PHP – an average duration of hepatic progression-free survival of 7.7 months in PHP patients and an average 4.0-month survival in control patients, Dr. Nutting said in an interview.

"The results exceeded that," he noted, with an average hepatic progression-free survival of 245 days (8.2 months) in the patients randomized to initial PHP and an average of 49 days (1.6 months) in control patients who received best alternative care. The hazard ratio for the PHP patients compared with the controls for this primary end point was 0.301 (P =.0001.)

PHP is "now one of the primary treatments" for inoperable melanoma liver metastases in patients whose most significant disease is in the liver, he added.

The clear success of PHP also suggested that the method might also help patients with other types of liver tumors, including primary cancers and other malignancies that often metastasize to the liver, such as colon cancer, Dr. Nutting said.

The researchers who developed PHP envisioned it as a potentially easier-to-tolerate variation on isolated hepatic perfusion, a method first used more than a decade ago that involved an open surgical procedure to isolate the hepatic circulation (J. Am. Coll. Surg. 2000;191:519-30). It was so invasive, however, that each patient could tolerate only a single treatment, Dr. Nutting said.

The percutaneous approach, developed as a more tolerable alternative, was applied serially one to six times to each patient in the PHP arm of the current trial with a 4-week interval between treatments.

The procedure involves inserting a double-balloon catheter from the patient’s groin through the hepatic artery and into the inferior vena cava. The superior balloon is then inflated and brought down to occlude the upper hepatic veins, while the second balloon is inflated below the hepatic veins to isolate hepatic venous return. A continuous infusion of melphalan enters the patient via a second catheter into the hepatic artery. After the drug distributes through the liver, the first catheter sucks out the hepatic venous blood (which is blocked by the two balloons from entering the systemic venous flow) via a set of holes and shunts it to an externally placed filter at a rate of 500 mL/min. After the blood is cleansed of the drug, it is returned to the patient.

The total melphalan dose delivered is 3.0 mg/kg ideal body weight of the patient, with the total dose diluted in 500 mL of fluid. The system takes 30 minutes to pump the entire dose into the patient, after which the balloons isolating the hepatic venous system and the filtration mechanism remain in place for another 30 minutes to continue to cleanse the drug from the patient’s liver. The system cuts systemic exposure to the melphalan by 80% compared with the intrahepatic dose delivered, Dr. Nutting said.

The study enrolled 44 patients into the PHP arm and 49 into the control arm at 12 U.S. centers. All patients had metastatic melanoma that primarily affected the liver and was judged too extensive for surgical removal. Patients had a median of 20 hepatic metastases (range, 4-100). In 88% of patients the primary tumor was ocular melanoma, and 12% had cutaneous melanoma. Their average age was 55 years.

Despite the high melphalan dose used, the 40 PHP patients included in the safety analysis had "minimal toxicity that was well within acceptable limits for the doses of medication we gave," he said.

During the 116 total treatments these patients received, grade 3 or 4 neutropenia occurred after 61% of treatments, thrombocytopenia after 74%, and anemia after 47%. Grade 5 neutropenia occurred following two treatments, but these episodes were usually transient and manageable. A total of three patients in the PHP group died, two from neutropenia sepsis and one from hepatic failure.

In a secondary efficacy analysis, no patient in either treatment arm had a complete response. The incidence of patient responses was 34% in the PHP patients and 2% in the controls. The combined rate of partial response or stable disease reached 86% in the PHP-treated patients and 28% in the control patients.

The trial was sponsored in part by Delcath, the company developing the PHP system. Dr. Notting said that he has received research support from, and has spoken on behalf of, Delcath.