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Introduction: Advanced Cutaneous Malignancies
ADVANCED CUTANEOUS MALIGNANCIES
Introduction: Advanced Cutaneous Malignancies
A
t first glance, it might appear that most oncologists would be indifferent to a publication about cutaneous malignancies. The focus of this issue of Seminars in Oncology is to demonstrate how broad and multifaceted the subspecialty of cutaneous oncology has become, and how important the contribution of oncologists is to the prevention, detection, and treatment of skin cancers. For most oncologists, the primary cutaneous malignancy that they are called upon to evaluate and treat is melanoma. Significant advances in the treatment of melanoma have derived from our understanding of oncogenic mutations, and their role in the development and progression of melanoma. There is now evidence that mutations in MAP kinase pathway genes, particularly BRAF, provide new targets for melanoma therapy. The BRAF inhibitor vemurafenib, which has selectivity for inhibiting the BRAFV600E mutant form of the protein compared to wild-type BRAF, showed remarkably high response rates in early phase clinical trials in patients with metastatic melanoma and proved far superior to standard single-agent chemotherapy with dacarbazine in a randomized phase III trial. Early phase trials with other selective BRAF inhibitors, such as dabrafenib, also are associated with very high response rates. Unfortunately, from these pioneering studies we have learned that melanomas ultimately develop resistance to these inhibitors, probably due to reactivation of common signaling pathways for melanoma growth, such as MEK/ERK and phosphatidylinositol-3-kinase (PI3K)/ AKT/mammalian target of rapamycin (mTOR). Indeed, there are already preclinical and clinical data with dual BRAF ⫹ MEK inhibitor combinations suggesting their ability to delay the onset of resistance and, as a fringe benefit, reduce some of the adverse effects of BRAF inhibition. One of the principal side effects of BRAF inhibitor therapy is the development of other skin cancers, in the form of keratoacanthomas and squamous cell carcinomas, likely due to paradoxical RAF-MEK-ERK signaling pathways in cells that do not harbor a BRAF mutation. It can be hypothesized that the development of these secondary skin cancers, and a host of inflammatory cutaneous reactions—such as follicular cystic 0270-9295/ - see front matter © 2012 Published by Elsevier Inc. doi:10.1053/j.seminoncol.2012.01.012
132
lesions, keratosis pilaris, and others—are due to an “anti-senescence effect” of BRAF protein inhibition. The observation from early phase trials of BRAF ⫹ MEK inhibitor therapy that patients seem to have fewer of these second-primary squamous cell carcinomas is a potentially highly significant observation, and certainly points to a future where combination inhibitor therapy plays a more prominent role than single-agent treatment. Another very promising approach to the treatment of metastatic melanoma is immunotherapy using antibodies to inhibit T-cell “checkpoint” proteins, such as CTLA-4. Ipilimumab, a recently approved anti–CTLA-4 antibody, has been shown in two randomized phase III trials to improve survival in patients with metastatic melanoma. The adverse events from anti-CTLA4, as would be expected, stem from immune-mediated inflammatory reactions, and while potentially serious are manageable by experienced multidisciplinary teams. Another approach to immunotherapy involves the ex vivo expansion of autologous tumor-specific T cells (tumor-infiltrating lymphocytes [TILs]), with adoptive transfer of the cells back to the patient in combination with lymphodepletion and high-dose bolus interleukin-2 (IL-2). This adoptive cellular therapy approach has been demonstrated to produce clinical response rates in about 50% of patients with metastatic melanoma who actually receive the cells, and many of these responses are durable ones. Because not every patient has tumor readily accessible to harvest for TILs, has their cells successfully grown and expanded in vivo, and is still in good enough physical shape at the end of the expansion period to receive the lymphodepletion/ IL-2 regimen, and because the TIL growth process is currently an arduous and labor-intensive process, this remains a treatment available only to a highly selected few patients. But efforts are underway to make this more accessible and increase the potential number of long-term responders. The role of systemic therapy in patients with other advanced cutaneous malignancies, like squamous, basal, and Merkel cell carcinomas, is less familiar to the average oncologist. It is apparent that advanced squamous cell carcinoma is responsive to standard chemotherapy with combinations of familiar drugs such as cisplatin, 5-fluorouracil, methotrexate, and so on, but admittedly the optimal regimens are not defined. Experience has been accumulating with targeted therapies Seminars in Oncology, Vol 39, No 2, April 2012, pp 132-133
Introduction
like the epidermal growth factor receptor (EGFR) inhibitor gefitinib for lesions expressing EGFR, but treatment approaches for this disease remain suboptimal. For basal cell carcinoma, targeted agents to the Hedgehog (HH) signaling pathway initiated by binding of the HH ligand to the transmembrane receptor Patched (PTCH1) are available for the small number of patients with advanced or metastatic tumors and those with basal cell nevus syndrome. Vismodegib was the first agent of this class to be approved by the US Food and Drug Administration. A multicenter, randomized, placebo-controlled trial with vismodegib is underway to assess the chemoprotective effects of this drug in patients with basal cell nevus syndrome, which would mark the first effort of its kind to use targeted therapy to protect patients with defined mutations from the oncogenic consequences of their genotype. Vismodegib and similar agents appear to be well tolerated, and many of the cutaneous side effects such as alopecia are the result of activated HH pathway in hair follicles. There is other progress being made in the prevention of cutaneous malignancies in high-risk individuals. Evidence is mounting that systemic retinoids, such as acitretin and bexarotene, may be effective in chemoprophylaxis of high-risk squamous cell carcinomas, especially in patients who are immunosuppressed after solid organ transplantation. Synthetic retinoids are usually prescribed for the treatment of psoriasis, and in some patients with cutaneous T-cell lymphoma (CTCL), but they also reduce the frequency of tumors in renal and cardiac transplant recipients, at oral doses well tolerated by the patient. CTCL is another area that should be of interest to the oncologist. Although early forms of the disease are treated by dermatologists with topical therapies and other interventions like retinoids or UV light therapy, multiple new systemic agents have been introduced to treat more advanced stages. Despite its rarity, the progress we have seen in CTCL is indeed dramatic. Also rare are the cutaneous sarcomas and Merkel cell carcinomas, but progress has been made in understanding and treating these disease as well, and prospects for further breakthroughs are great. Recently, platelet-derived growth factor receptor, insulin-like growth factor
133
receptor, and KIT have been recognized to affect the growth of certain cutaneous sarcomas. Dysregulated angiogenesis, through VEGF and other signaling pathways, is associated with the growth of cutaneous angiosarcomas, for example, and trials with anti-angiogenic agents are underway with the hope of finding targeted therapy to alter the mostly dismal outcome for patients with this aggressive malignancy. Another example of targeted therapy is for dermatofibrosarcoma protuberans (DFSP), where tumors frequently express the COL1A1-PDGF fusion gene, and imatinib has emerged as the primary systemic therapy for rare DFSP patients with inoperable or metastatic disease, and as a neoadjuvant in the setting when the surgical approach is initially difficult. Merkel cell carcinoma is very responsive to standard chemotherapy similar to that used for small cell lung carcinoma, but responses tend to be of relatively short duration. We currently lack a detailed understanding of the molecular pathobiology of Merkel cell carcinoma, but the recent breakthrough of identifying a polyomavirus as an etiologic agent in many cases of this disease (known for years to be much more common in immunosuppressed individuals), has clearly opened the door for new therapeutic strategies to be developed. In summary, in this issue, we discuss the current standard therapies for the broad spectrum of advanced cutaneous malignancies, including cutaneous lymphomas, and Merkel cell carcinoma. It is clear that recent advances and ongoing investigations have impacted the management of these malignancies and enhanced the role of the oncologist in the process. We believe the future is bright, and the time is now for oncologists to focus on cutaneous malignancies and become a full partner in the multidisciplinary management of advanced skin cancers of all types, and not just melanoma.
L. Frank Glass, MD Ronald C. DeConti, MD Vernon K. Sondak, MD Moffitt Cancer Center Tampa, FL Guest Editors
Introduction: Advanced Cutaneous Malignancies
A
t first glance, it might appear that most oncologists would be indifferent to a publication about cutaneous malignancies. The focus of this issue of Seminars in Oncology is to demonstrate how broad and multifaceted the subspecialty of cutaneous oncology has become, and how important the contribution of oncologists is to the prevention, detection, and treatment of skin cancers. For most oncologists, the primary cutaneous malignancy that they are called upon to evaluate and treat is melanoma. Significant advances in the treatment of melanoma have derived from our understanding of oncogenic mutations, and their role in the development and progression of melanoma. There is now evidence that mutations in MAP kinase pathway genes, particularly BRAF, provide new targets for melanoma therapy. The BRAF inhibitor vemurafenib, which has selectivity for inhibiting the BRAFV600E mutant form of the protein compared to wild-type BRAF, showed remarkably high response rates in early phase clinical trials in patients with metastatic melanoma and proved far superior to standard single-agent chemotherapy with dacarbazine in a randomized phase III trial. Early phase trials with other selective BRAF inhibitors, such as dabrafenib, also are associated with very high response rates. Unfortunately, from these pioneering studies we have learned that melanomas ultimately develop resistance to these inhibitors, probably due to reactivation of common signaling pathways for melanoma growth, such as MEK/ERK and phosphatidylinositol-3-kinase (PI3K)/ AKT/mammalian target of rapamycin (mTOR). Indeed, there are already preclinical and clinical data with dual BRAF ⫹ MEK inhibitor combinations suggesting their ability to delay the onset of resistance and, as a fringe benefit, reduce some of the adverse effects of BRAF inhibition. One of the principal side effects of BRAF inhibitor therapy is the development of other skin cancers, in the form of keratoacanthomas and squamous cell carcinomas, likely due to paradoxical RAF-MEK-ERK signaling pathways in cells that do not harbor a BRAF mutation. It can be hypothesized that the development of these secondary skin cancers, and a host of inflammatory cutaneous reactions—such as follicular cystic 0270-9295/ - see front matter © 2012 Published by Elsevier Inc. doi:10.1053/j.seminoncol.2012.01.012
132
lesions, keratosis pilaris, and others—are due to an “anti-senescence effect” of BRAF protein inhibition. The observation from early phase trials of BRAF ⫹ MEK inhibitor therapy that patients seem to have fewer of these second-primary squamous cell carcinomas is a potentially highly significant observation, and certainly points to a future where combination inhibitor therapy plays a more prominent role than single-agent treatment. Another very promising approach to the treatment of metastatic melanoma is immunotherapy using antibodies to inhibit T-cell “checkpoint” proteins, such as CTLA-4. Ipilimumab, a recently approved anti–CTLA-4 antibody, has been shown in two randomized phase III trials to improve survival in patients with metastatic melanoma. The adverse events from anti-CTLA4, as would be expected, stem from immune-mediated inflammatory reactions, and while potentially serious are manageable by experienced multidisciplinary teams. Another approach to immunotherapy involves the ex vivo expansion of autologous tumor-specific T cells (tumor-infiltrating lymphocytes [TILs]), with adoptive transfer of the cells back to the patient in combination with lymphodepletion and high-dose bolus interleukin-2 (IL-2). This adoptive cellular therapy approach has been demonstrated to produce clinical response rates in about 50% of patients with metastatic melanoma who actually receive the cells, and many of these responses are durable ones. Because not every patient has tumor readily accessible to harvest for TILs, has their cells successfully grown and expanded in vivo, and is still in good enough physical shape at the end of the expansion period to receive the lymphodepletion/ IL-2 regimen, and because the TIL growth process is currently an arduous and labor-intensive process, this remains a treatment available only to a highly selected few patients. But efforts are underway to make this more accessible and increase the potential number of long-term responders. The role of systemic therapy in patients with other advanced cutaneous malignancies, like squamous, basal, and Merkel cell carcinomas, is less familiar to the average oncologist. It is apparent that advanced squamous cell carcinoma is responsive to standard chemotherapy with combinations of familiar drugs such as cisplatin, 5-fluorouracil, methotrexate, and so on, but admittedly the optimal regimens are not defined. Experience has been accumulating with targeted therapies Seminars in Oncology, Vol 39, No 2, April 2012, pp 132-133
Introduction
like the epidermal growth factor receptor (EGFR) inhibitor gefitinib for lesions expressing EGFR, but treatment approaches for this disease remain suboptimal. For basal cell carcinoma, targeted agents to the Hedgehog (HH) signaling pathway initiated by binding of the HH ligand to the transmembrane receptor Patched (PTCH1) are available for the small number of patients with advanced or metastatic tumors and those with basal cell nevus syndrome. Vismodegib was the first agent of this class to be approved by the US Food and Drug Administration. A multicenter, randomized, placebo-controlled trial with vismodegib is underway to assess the chemoprotective effects of this drug in patients with basal cell nevus syndrome, which would mark the first effort of its kind to use targeted therapy to protect patients with defined mutations from the oncogenic consequences of their genotype. Vismodegib and similar agents appear to be well tolerated, and many of the cutaneous side effects such as alopecia are the result of activated HH pathway in hair follicles. There is other progress being made in the prevention of cutaneous malignancies in high-risk individuals. Evidence is mounting that systemic retinoids, such as acitretin and bexarotene, may be effective in chemoprophylaxis of high-risk squamous cell carcinomas, especially in patients who are immunosuppressed after solid organ transplantation. Synthetic retinoids are usually prescribed for the treatment of psoriasis, and in some patients with cutaneous T-cell lymphoma (CTCL), but they also reduce the frequency of tumors in renal and cardiac transplant recipients, at oral doses well tolerated by the patient. CTCL is another area that should be of interest to the oncologist. Although early forms of the disease are treated by dermatologists with topical therapies and other interventions like retinoids or UV light therapy, multiple new systemic agents have been introduced to treat more advanced stages. Despite its rarity, the progress we have seen in CTCL is indeed dramatic. Also rare are the cutaneous sarcomas and Merkel cell carcinomas, but progress has been made in understanding and treating these disease as well, and prospects for further breakthroughs are great. Recently, platelet-derived growth factor receptor, insulin-like growth factor
133
receptor, and KIT have been recognized to affect the growth of certain cutaneous sarcomas. Dysregulated angiogenesis, through VEGF and other signaling pathways, is associated with the growth of cutaneous angiosarcomas, for example, and trials with anti-angiogenic agents are underway with the hope of finding targeted therapy to alter the mostly dismal outcome for patients with this aggressive malignancy. Another example of targeted therapy is for dermatofibrosarcoma protuberans (DFSP), where tumors frequently express the COL1A1-PDGF fusion gene, and imatinib has emerged as the primary systemic therapy for rare DFSP patients with inoperable or metastatic disease, and as a neoadjuvant in the setting when the surgical approach is initially difficult. Merkel cell carcinoma is very responsive to standard chemotherapy similar to that used for small cell lung carcinoma, but responses tend to be of relatively short duration. We currently lack a detailed understanding of the molecular pathobiology of Merkel cell carcinoma, but the recent breakthrough of identifying a polyomavirus as an etiologic agent in many cases of this disease (known for years to be much more common in immunosuppressed individuals), has clearly opened the door for new therapeutic strategies to be developed. In summary, in this issue, we discuss the current standard therapies for the broad spectrum of advanced cutaneous malignancies, including cutaneous lymphomas, and Merkel cell carcinoma. It is clear that recent advances and ongoing investigations have impacted the management of these malignancies and enhanced the role of the oncologist in the process. We believe the future is bright, and the time is now for oncologists to focus on cutaneous malignancies and become a full partner in the multidisciplinary management of advanced skin cancers of all types, and not just melanoma.
L. Frank Glass, MD Ronald C. DeConti, MD Vernon K. Sondak, MD Moffitt Cancer Center Tampa, FL Guest Editors