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Melanoma: HELP
Articles by Ahmad A. Tarhini
Based on 64 articles published since 2008

Between 2008 and 2019, A. A. Tarhini wrote the following 64 articles about Melanoma.
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Guideline The Society for Immunotherapy of Cancer consensus statement on tumour immunotherapy for the treatment of cutaneous melanoma. 2013

Kaufman, Howard L / Kirkwood, John M / Hodi, F Stephen / Agarwala, Sanjiv / Amatruda, Thomas / Bines, Steven D / Clark, Joseph I / Curti, Brendan / Ernstoff, Marc S / Gajewski, Thomas / Gonzalez, Rene / Hyde, Laura Jane / Lawson, David / Lotze, Michael / Lutzky, Jose / Margolin, Kim / McDermott, David F / Morton, Donald / Pavlick, Anna / Richards, Jon M / Sharfman, William / Sondak, Vernon K / Sosman, Jeffrey / Steel, Susan / Tarhini, Ahmad / Thompson, John A / Titze, Jill / Urba, Walter / White, Richard / Atkins, Michael B. ·Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA. ·Nat Rev Clin Oncol · Pubmed #23982524.

ABSTRACT: Immunotherapy is associated with durable clinical benefit in patients with melanoma. The goal of this article is to provide evidence-based consensus recommendations for the use of immunotherapy in the clinical management of patients with high-risk and advanced-stage melanoma in the USA. To achieve this goal, the Society for Immunotherapy of Cancer sponsored a panel of melanoma experts--including physicians, nurses, and patient advocates--to develop a consensus for the clinical application of tumour immunotherapy for patients with melanoma. The Institute of Medicine clinical practice guidelines were used as a basis for this consensus development. A systematic literature search was performed for high-impact studies in English between 1992 and 2012 and was supplemented as appropriate by the panel. This consensus report focuses on issues related to patient selection, toxicity management, clinical end points and sequencing or combination of therapy. The literature review and consensus panel voting and discussion were used to generate recommendations for the use of immunotherapy in patients with melanoma, and to assess and rate the strength of the supporting evidence. From the peer-reviewed literature the consensus panel identified a role for interferon-α2b, pegylated-interferon-α2b, interleukin-2 (IL-2) and ipilimumab in the clinical management of melanoma. Expert recommendations for how to incorporate these agents into the therapeutic approach to melanoma are provided in this consensus statement. Tumour immunotherapy is a useful therapeutic strategy in the management of patients with melanoma and evidence-based consensus recommendations for clinical integration are provided and will be updated as warranted.

2 Editorial The future of systemic therapy of melanoma: combinations, predictive biomarkers. 2015

Tarhini, Ahmad A. · ·Oncology (Williston Park) · Pubmed #25683827.

ABSTRACT: -- No abstract --

3 Editorial How much of a good thing? What duration for interferon alfa-2b adjuvant therapy? 2012

Tarhini, Ahmad A / Kirkwood, John M. · ·J Clin Oncol · Pubmed #23008298.

ABSTRACT: -- No abstract --

4 Editorial Biomarkers of therapeutic response in melanoma and renal cell carcinoma: potential inroads to improved immunotherapy. 2009

Kirkwood, John M / Tarhini, Ahmad A. · ·J Clin Oncol · Pubmed #19364958.

ABSTRACT: -- No abstract --

5 Review Predictive and on-treatment monitoring biomarkers in advanced melanoma: Moving toward personalized medicine. 2018

Tarhini, Ahmad / Kudchadkar, Ragini R. ·Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, United States. Electronic address: tarhina1@ccf.org. · Winship Cancer Institute of Emory University, 1365 Clifton Rd NE, Bldg C, Atlanta, GA 30322, United States. ·Cancer Treat Rev · Pubmed #30273812.

ABSTRACT: The treatment armamentarium for patients with metastatic melanoma has increased substantially over the past decade with the regulatory approval of targeted BRAF + MEK inhibitors and immune checkpoint inhibitors, which have vastly improved long-term outcomes. Recently, these advances have been rapidly translated to the high-risk adjuvant setting. Primary and acquired resistance to both immune and molecularly targeted agents, however, remains a challenge. Therefore, biomarkers predictive of response to therapy that can be assessed prior to initiation of treatment and early during the course of therapy are critical. Equally important is on-treatment biomarker monitoring that may predict the likelihood of treatment failure and disease relapse. This review will summarize recent advances in the understanding of biomarkers for patients with advanced melanoma, emphasizing emerging baseline predictive factors and on-treatment monitoring of biomarkers that aim to establish truly personalized treatment.

6 Review Operable Melanoma: Screening, Prognostication, and Adjuvant and Neoadjuvant Therapy. 2017

Tarhini, Ahmad A / Lorigan, Paul / Leachman, Sancy. ·From the University of Pittsburgh, Pittsburgh, PA; University of Manchester, Manchester, United Kingdom; Oregon Health & Science University, Portland, OR. ·Am Soc Clin Oncol Educ Book · Pubmed #28561661.

ABSTRACT: The importance of reducing the numbers of patients with late-stage melanoma, identifying which patients are most likely to progress, and treating these patients at the earliest possible stage cannot be overemphasized. Improved screening of patients prior to diagnosis has the advantage of identifying early-stage disease that is for the most part treatable by surgical methods. The process of melanoma screening is rapidly evolving through population-based programs, mobile health technologies, and advanced imaging tools. For patients with newly diagnosed melanoma, accurately estimating disease prognosis has important implications for management and follow-up. Prognostic factors are individual host- or tumor-related factors or molecules that correlate with genetic predisposition and clinical course. These include clinical covariates and host and tumor proteomic/genomic markers that allow the prognostic subclassification of patients. Adjuvant therapy for high-risk surgically resected melanoma targets residual micrometastatic disease with the goal of reducing the risk of relapse and mortality. In the United States, three regimens have achieved regulatory approval for adjuvant therapy, including high-dose interferon alpha, pegylated interferon alpha, and ipilimumab at 10 mg/kg. Phase III trials have reported benefits in relapse-free survival (all regimens) and overall survival (high-dose interferon alpha and ipilimumab). The management of locally/regionally advanced melanoma may benefit from neoadjuvant therapy, which is the subject of several ongoing studies. Recent studies have shown promising clinical activity and yielded important biomarker findings and mechanistic insights.

7 Review The use of immunotherapy in the treatment of melanoma. 2017

Achkar, Tala / Tarhini, Ahmad A. ·University of Pittsburgh, Pittsburgh, PA, USA. · University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Room 555, Pittsburgh, PA, 15232, USA. · University of Pittsburgh, Pittsburgh, PA, USA. tarhiniaa@upmc.edu. · University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Room 555, Pittsburgh, PA, 15232, USA. tarhiniaa@upmc.edu. ·J Hematol Oncol · Pubmed #28434398.

ABSTRACT: Patients with advanced melanoma have a compromised anti-tumor immune response leading to tumor immune tolerance and a tumor microenvironment conducive to disease progression. Immunotherapy that successfully overcomes this tumor-mediated immune suppression has made the greatest impact in the management of this disease over the past few years. This progress through immunotherapy builds upon earlier successes that interferon-α had in the treatment of melanoma in the adjuvant setting, as well as that of high-dose interleukin-2 in advanced melanoma. The development of immune checkpoint inhibitors has led to dramatic clinical activity in advanced melanoma. In particular, anti-CTLA4 and anti-PD1 monoclonal antibodies have taken us forward into the realm of longer survival and durable responses with the possibility of cure in a continuously increasing proportion of patients. Combination immunotherapeutic strategies and novel immunotherapeutic agents are being tested at an accelerated pace where the outlook for long-term survival benefits for the majority of patients appears brighter than ever.

8 Review Adjuvant Therapy for Melanoma. 2017

Agha, Aya / Tarhini, Ahmad A. ·University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. · University of Pittsburgh, 5117 Centre Avenue, Pittsburgh, PA, 15213, USA. tarhiniaa@upmc.edu. · University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Room 555, Pittsburgh, PA, 15232, USA. tarhiniaa@upmc.edu. ·Curr Oncol Rep · Pubmed #28417343.

ABSTRACT: Systemic adjuvant therapy for surgically resected cutaneous melanoma that is at high risk for disease recurrence and death targets residual micrometastatic disease which is the source of future local or distant relapse. Interferon-alfa (IFNα) has been the most extensively studied in regimens that varied by dosage, route of administration, formulation, and duration of therapy. Most regimens have demonstrated improvements in relapse-free survival (RFS), while the regimen administered at high dosage (HDI) showed improvements in overall survival (OS) in two out of three RCTs. HDI benefits as measured by the hazard ratios (HR) in E1684 (vs. observation), E1690 (vs. observation), and E1694 (vs. vaccine) trials were estimated at 0.61, 0.78, and 0.67 (RFS) and 0.67, 1.0, and 0.72 (OS) when first reported with lesser estimates on later updates. Pegylated IFNα (peg-IFN) as studied in the European Organisation for Research and Treatment of Cancer (EORTC) 18991 trial in patients with stage III melanoma significantly reduced the risk of relapse (HR 0.87) with no impact on OS. More recently (EORTC 18071), ipilimumab at the high dose of 10 mg/kg was shown to significantly improve RFS (HR 0.76) and OS (HR 0.72) of stage III melanoma patients but at a significant cost in terms of immune-related toxicities. Ongoing adjuvant studies are testing ipilimumab at 3 or 10 mg/kg versus HDI (E1609) and the anti-PD-1 antibodies nivolumab (CheckMate 238) and pembrolizumab (KEYNOTE-054 and S1404).

9 Review Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. 2016

Boutros, Celine / Tarhini, Ahmad / Routier, Emilie / Lambotte, Olivier / Ladurie, Francois Leroy / Carbonnel, Franck / Izzeddine, Hassane / Marabelle, Aurelien / Champiat, Stephane / Berdelou, Armandine / Lanoy, Emilie / Texier, Matthieu / Libenciuc, Cristina / Eggermont, Alexander M M / Soria, Jean-Charles / Mateus, Christine / Robert, Caroline. ·Dermatology Service, Department of Medicine, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · University of Pittsburgh, 4200 Fifth Avenue, Pittsburgh, Pennsylvania 15260, USA. · AP-HP, Internal Medicine Department, University Hospital of Bicêtre, 78 Rue du General Leclerc, 94270 Le Kremlin-Bicetre, France. · Paris Sud University, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicêtre, France. · INSERM Unit U1184, 63 Rue Gabriel Peri, 94270 Le Kremlin Bicêtre, France. · Thoracic and Vascular Surgery Service, Centre Chirurgical Marie Lannelongue, 133 Avenue de la Resistance, 92350 Le Plessis-Robinson, France. · AP-HP, Department of Gastroenterology, University Hospital of Bicêtre, Paris Sud University, 78 Rue du General Leclerc, 94270 Le Kremlin-Bicetre, France. · Department of Nephrology, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l'hopital, 75013 Paris, France. · Drug Development Department (DITEP), Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · INSERM Unit U981, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. · Biostatistic and Epidemiology Unit, Gustave Roussy, 114 Rue Edouard Vaillant, 94805 Villejuif, France. ·Nat Rev Clin Oncol · Pubmed #27141885.

ABSTRACT: Inhibition of immune checkpoints using anti-programmed cell death-1 (PD-1) or anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) monoclonal antibodies has revolutionized the management of patients with advanced-stage melanoma and is among the most promising treatment approaches for many other cancers. Use of CTLA-4 and PD-1 inhibitors, either as single agents, or in combination, has been approved by the US FDA for the treatment of metastatic melanoma. Treatment with these novel immunotherapies results in a unique and distinct spectrum of adverse events, which are mostly related to activation of the immune system and are, therefore, an unwanted consequence of their mechanisms of action. Adverse effects of CTLA-4 and/or PD-1 inhibition are most commonly observed in the skin, gastrointestinal tract, liver and endocrine systems and include pruritus, rash, nausea, diarrhoea and thyroid disorders. In this Review, the authors describe the adverse event profile of checkpoint inhibitors targeting CTLA-4 and PD-1, used both as monotherapies and in combination and aim to provide some general guidelines, based upon the mechanisms of action of these therapies and on the management of these immune-related adverse events.

10 Review Immunotherapy of Melanoma. 2016

Tarhini, Ahmad A. ·University of Pittsburgh Cancer Institute, 5150 Centre Avenue (555), Pittsburgh, PA 15232, USA. tarhiniaa@upmc.edu. ·Curr Mol Pharmacol · Pubmed #26177647.

ABSTRACT: The host antitumor immune response in patients with advanced melanoma is compromised with a bias towards tumor immune tolerance and a tumor microenvironment that facilitates disease survival and progression. Overcoming tumor-induced immune suppression has been one of the most significant advances in cancer therapy, making a cure an ever closer and achievable goal. Immunotherapeutic strategies in melanoma have been built upon the immunomodulatory qualities and the early successes of interferon-α in the melanoma adjuvant setting and interleukin-2 in the treatment of inoperable advanced melanoma. The recent advances in the field of immune checkpoint modulation and the unprecedented clinical activity in advanced melanoma opened the doors for novel agents and combinations that may potently overcome tumor tolerogenic mechanisms. Recent data with immune anti-CTLA4 and anti-PD1 monoclonal antibodies have moved the clinical management of advanced melanoma into a new era, an era of long-term survival and potential cures.

11 Review Neoadjuvant therapy for melanoma: a promising therapeutic approach and an ideal platform in drug development. 2015

Tarhini, Ahmad A. ·From the University of Pittsburgh School of Medicine and Cancer Institute, Pittsburgh, PA. ·Am Soc Clin Oncol Educ Book · Pubmed #25993220.

ABSTRACT: Patients with locoregionally advanced but surgically operable melanoma continue to carry a high risk of relapse and death despite the best available standard management approaches. Neoadjuvant studies targeting this patient population tested chemotherapy with temozolomide and biochemotherapy (BCT), in which BCT demonstrated high tumor response rates but was eventually abandoned with the failure of BCT to deliver survival benefits in randomized trials of metastatic disease. Smaller neoadjuvant immunotherapy studies with interferon (IFN) alfa and ipilimumab have yielded promising clinical activity and important mechanistic insights and biomarker findings. Newer targeted and immunotherapeutic agents and combinations currently are being translated into the neoadjuvant setting at an accelerated pace and carry significant clinical promise. In drug development, the neoadjuvant approach allows access to blood and tumor tissue before and after initiation of systemic therapy, which allows for the conduct of novel mechanistic and biomarker studies in the circulation and the tumor microenvironment. Such studies may guide drug development and allow for the discovery of predictive biomarkers selected on the basis of their capacity to classify patients according to the degree of benefit from treatment or the risk for significant toxicity.

12 Review Immune checkpoint blockade and interferon-α in melanoma. 2015

Rafique, Imran / Kirkwood, John M / Tarhini, Ahmad A. ·University of Pittsburgh Medical Center, Pittsburgh, PA. · University of Pittsburgh Medical Center, Pittsburgh, PA; University of Pittsburgh Cancer Institute, Pittsburgh, PA. · University of Pittsburgh Medical Center, Pittsburgh, PA; University of Pittsburgh Cancer Institute, Pittsburgh, PA. Electronic address: tarhiniaa@upmc.edu. ·Semin Oncol · Pubmed #25965362.

ABSTRACT: The quality of the host immune response in patients with advanced melanoma is compromised with a bias towards Th2-type polarization and a tumor microenvironment that facilitates disease progression. Overcoming tumor-induced immune suppression through strategies that build upon the immunomodulatory qualities and clinical activity of interferon-α as demonstrated in the melanoma adjuvant setting is a major clinical need. The recent advances in the field of immune checkpoint modulation and the unprecedented clinical activity in advanced melanoma opens the door on novel combinations that may overcome tumor tolerogenic mechanisms that are known to suppress the potent anti-tumor impact of interferon (IFN)-α. Promising preliminary data suggest that such combinations may move the clinical management of advanced melanoma into the next level, beyond what is currently seen with immune checkpoint blockers alone.

13 Review Intermediate-grade meningeal melanocytoma associated with nevus of Ota: a case report and review of the literature. 2015

Shin, Donghoon / Sinha, Milind / Kondziolka, Douglas S / Kirkwood, John M / Rao, Uma N M / Tarhini, Ahmad A. ·University of Pittsburgh, Pittsburgh, Pennsylvania, USA. ·Melanoma Res · Pubmed #25933209.

ABSTRACT: Meningeal melanocytomas are rare melanin-producing tumors that are often found to be benign. However, a small subset of these tumors can present as intermediate-grade melanocytomas (IGMs) that have histopathological features that are between those of benign melanocytomas and malignant melanomas. IGMs have the potential to recur and metastasize or progress to a more histologically high grade melanoma. Melanocytomas appear to differ from primary and metastatic melanoma by their prolonged clinical course and they appear to have different driver mutations (i.e. mutation of GNAQ gene). The association of a meningeal melanocytoma with nevus of Ota is extremely rare. To our knowledge, there have been only 10 reported cases of synchronous occurrence and only one of the cases involved an IGM. We report the second case of intermediate-grade meningeal melanocytoma that is associated with congenital nevus of Ota. Histopathological work-up confirmed the intermediate grade of the lesion and a driver GNAQ mutation was identified consistent with previous reports.

14 Review Melanoma adjuvant therapy. 2014

Tarhini, Ahmad A / Thalanayar, Prashanth M. ·Department of Medicine, Division of Hematology-Oncology, University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232, USA. Electronic address: tarhiniaa@upmc.edu. · Department of Internal Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA. ·Hematol Oncol Clin North Am · Pubmed #24880942.

ABSTRACT: Adjuvant therapy targets melanoma micrometastases in patients with surgically resected disease that carry a high risk of death from melanoma recurrence. In this setting, adjuvant therapy provides the greatest opportunity for cure before progression into advanced inoperable stages. In randomized clinical trials, interferon-alfa has been shown to have a significant impact on relapse-free survival and, at high dosage, on overall survival compared with observation (E1684) and the GMK vaccine (E1694). This article reviews melanoma adjuvant therapy along with the ongoing and planned clinical trials.

15 Review Advances in adjuvant therapy: potential for prognostic and predictive biomarkers. 2014

Davar, Diwakar / Tarhini, Ahmad A / Gogas, Helen / Kirkwood, John M. ·Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. ·Methods Mol Biol · Pubmed #24258973.

ABSTRACT: Melanoma is the third most common skin cancer but accounts for the majority of skin cancer-related mortality. The rapidly rising incidence and younger age at diagnosis has made melanoma a leading cause of lost productive years of life and has increased the urgency of finding improved adjuvant therapy for melanoma. Interferon-α was approved for the adjuvant treatment of resected high-risk melanoma following studies that demonstrated improvements in relapse-free survival and overall survival that were commenced nearly 30 years ago. The clinical benefits associated with this agent have been consistently observed across multiple studies and meta-analyses in terms of relapse rate, and to a smaller and less-consistent degree, mortality. However, significant toxicity and lack of prognostic and/or predictive biomarkers that would allow greater risk-benefit ratio have limited the more widespread adoption of this modality.Recent success with targeted agents directed against components of the MAP-kinase pathway and checkpoint inhibitors have transformed the treatment landscape in metastatic disease. Current research efforts are centered around discovering predictive/prognostic biomarkers and exploring the options for more effective regimens, either singly or in combination.

16 Review Adjuvant immunotherapy of melanoma and development of new approaches using the neoadjuvant approach. 2013

Davar, Diwakar / Tarhini, Ahmad A / Kirkwood, John M. ·Division of General Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. ·Clin Dermatol · Pubmed #23608443.

ABSTRACT: Melanoma is the third most common skin cancer but the leading cause of death from cutaneous malignancies. Although early-stage disease is frequently cured by surgical resection with excellent long-term survival, patients with deeper primary lesions (AJCC stage IIB-C) and those with microscopic (IIIA) or clinically evident regional lymph node or in-transit metastases (IIIB-C) have an increased risk of relapse and death, the latter approaching 70% or more at 5 years. In patients at high risk of recurrence/metastases, adjuvant therapy with high-dose interferon alpha-2b (HDI) following definitive surgical resection has been shown to improve relapse-free and overall survival. Neoadjuvant chemotherapy and/or radiotherapy have offered the prospect to improve regional recurrence risk and overall survival in several solid tumors. The advent of effective new molecularly targeted therapies for metastatic disease and new immunotherapies that overcome checkpoints of immune response have augmented the range of new options that are in current trial evaluation to determine their role as potential adjuvant therapies, alone and in combination with one another, and the established modality of IFN-α. The differential characteristics of the host immune response between early and advanced melanoma provide a strong mechanistic rationale for the use of neoadjuvant immunotherapeutic approaches in melanoma, and the opportunity to evaluate the mechanism of action suggest neoadjuvant trial evaluation for each of the new candidate agents and combinations of interest. Several neoadjuvant trials have been conducted in the phase II setting, which have illuminated the mechanism of IFN-α, as well as providing insight to the effects of anti-CTLA4 blocking antibodies. These agents (anti-CTLA4 blocking antibody ipilimumab, and BRAF inhibitor vemurafenib) are likely to be followed by other immunotherapies that may overcome the PD-1 checkpoint (anti-PD1 and anti-PDL-1) as well as other molecularly targeted agents such as the BRAF inhibitor dabrafenib and the MEK inhibitors trametinib, selumetinib, and MEK162 in the near future. Evaluation of the clinical role of these agents as adjuvant therapy will take years to accomplish to ascertain the relapse-free survival benefits and overall survival benefits of these agents, but neoadjuvant exploration may provide early critical evidence of the therapeutic benefits, as well as clarifying the mechanisms of these agents alone and in combination.

17 Review Tremelimumab: a review of development to date in solid tumors. 2013

Tarhini, Ahmad A. ·University of Pittsburgh Cancer Institute, University of Pittsburgh Medical Center Cancer Pavilion, 5150 Centre Avenue, Fifth Floor, Pittsburgh, PA 15232, USA. tarhiniaa@upmc.edu ·Immunotherapy · Pubmed #23444951.

ABSTRACT: Tremelimumab is an investigational, fully human IgG monoclonal antibody directed against CTLA-4, a coinhibitory receptor that represses effector T-cell activity in cancer. Tremelimumab has produced promising anticancer responses in early clinical trials. However, a phase III trial of tremelimumab monotherapy versus chemotherapy in advanced melanoma was stopped early when no statistically significant difference in overall survival was observed between the two interventions. This article describes tremelimumab's putative mechanism of action, its preclinical pharmacology and clinical results to date across a range of cancer settings as monotherapy, as well as in combination with other therapies. The failure of the Phase III trial in melanoma is examined and factors affecting the possible future clinical development of tremelimumab are also explored.

18 Review IFN-α in the treatment of melanoma. 2012

Tarhini, Ahmad A / Gogas, Helen / Kirkwood, John M. ·Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA. tarhiniaa@upmc.edu ·J Immunol · Pubmed #23042723.

ABSTRACT: Among the IFNs, IFN-α2 has been the most broadly evaluated clinically. At the molecular level, IFN-α has multiple effects in a variety of malignancies that range from antiangiogenic to potent immunoregulatory, differentiation-inducing, antiproliferative, and proapoptotic effects. A multitude of IFN-α2 regimens that may be classified as low dose, intermediate dose, and high dose have been evaluated as adjuvant therapy in melanoma. A durable impact on both relapse-free and overall survival was seen only with the regimen utilizing high-dose IFN-α2b tested in the Eastern Cooperative Oncology Group and intergroup trials E1684, E1690, and E1694 as adjuvant therapy for high-risk surgically resected melanoma (stage IIB or III). Adjuvant pegylated IFN-α2b has also been evaluated at maximally tolerable doses compared with the observation group in the European Organization for Research and Treatment of Cancer trial 18991 and has shown relapse-free survival benefits in patients with microscopic nodal disease.

19 Review Adjuvant therapy for melanoma. 2012

Davar, Diwakar / Tarhini, Ahmad A / Kirkwood, John M. ·Division of General Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA. ·Cancer J · Pubmed #22453021.

ABSTRACT: Estimates from the U.S. Surveillance, Epidemiology, and End Results registry suggest that melanoma incidence will reach 70,230 cases in 2011, of whom 8790 will die. The rising incidence and predilection for young individuals makes this tumor a leading source of lost productive years in the society.High-dose interferon-α-2b is the only agent approved for adjuvant therapy for melanoma; the improvement in relapse-free survival has been observed across nearly all published studies and meta-analyses. However, toxicity affects compliance, and current research is focusing on biomarkers that may allow selection of patients with greater likelihood of response and exploring new agents either singly or in combination that may improve on the benefit of interferon.In this article, we review the data for the adjuvant therapy for malignant melanoma--focusing on the results obtained with various regimens testing the several formulations of interferon-α2 and the adjuvant studies of vaccines and radiotherapy. Recent advances in the treatment of metastatic disease have established a role for CTLA-4 blockade and BRAF-inhibition, raising hopes that these agents may have a role in the adjuvant setting. At present, several trials investigating combinations of novel agents with existing immunomodulators are underway.

20 Review Neoadjuvant therapy for high-risk bulky regional melanoma. 2011

Tarhini, Ahmad A / Pahuja, Shalu / Kirkwood, John M. ·Department of Medicine and Division of Hematology-Oncology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. tarhiniaa@upmc.edu ·J Surg Oncol · Pubmed #21858833.

ABSTRACT: Clinically detectable regional lymph node melanoma metastasis (AJCC stage IIIB-C) carries a risk of relapse and death that approaches 70% at 5 years. Surgical management is the cornerstone of therapy, with postoperative adjuvant therapy utilizing high-dose interferon alfa-2b (HDI). Neoadjuvant chemotherapy or immunotherapy in addition to surgery has been demonstrated to improve outcome in the management of patients with a variety of solid tumors. In patients with melanoma, the characteristics of the host immune response differ between patients with earlier stage and those with more advanced stages of disease (and particularly between those with measurable active disease and those without measurable gross disease) providing rationale for neoadjuvant approaches with immunotherapy. Host immune tolerance is now understood to impede the results of therapy for advanced disease, but appears to be less an issue for patients with microscopic high-risk operable disease, where the host may be more susceptible to immunologic interventions. Phase II studies have shown that neoadjuvant biochemotherapy has limited activity in melanoma patients with local-regional metastases, where chemotherapy may potentially alter the effects of immunotherapeutic agents. Studies of neoadjuvant HDI therapy for high-risk melanoma patients with bulky regional stage IIIB-C lymphadenopathy have shown unexpectedly high clinical and pathologic response rates, without increased morbidity. Through the design of neoadjuvant trials utilizing promising emerging melanoma therapeutics in which it is possible to obtain biopsy samples before and after therapy, a greater understanding of the dynamic interaction between tumors and the immune system is possible. This should lead to the identification of new targets for the treatment of melanoma and aid the development of new immunotherapy that may have greater specificity and less toxicity. This will simplify the evaluation of promising new combinations of agents with HDI to build on the clinical, immunologic, and molecular effect of this therapy for patients with melanoma.

21 Review Cutaneous melanoma: a model to study cancer metastasis. 2011

Leong, Stanley P L / Gershenwald, Jeffrey E / Soong, Seng-Jaw / Schadendorf, Dirk / Tarhini, Ahmad A / Agarwala, Sanjiv / Hauschild, Axel / Soon, Christopher W M / Daud, Adil / Kashani-Sabet, Mohammed. ·Center for Melanoma Research and Treatment and Department of Surgery, California Pacific Medical Center and Research Institute, San Francisco, California 94115, USA. leongsx@cpmcri.org ·J Surg Oncol · Pubmed #21480247.

ABSTRACT: Nodal status in melanoma is a critically important prognostic factor for patient outcome. The survival rate drops to <10% when melanoma has spread beyond the regional lymph nodes and includes visceral involvement. In general, the process of melanoma metastasis is progressive in that dissemination of melanoma from the primary site to the regional lymph nodes occurs prior to systemic disease. The goal of this review article is to describe melanoma as a clinical model to study cancer metastasis. A future challenge is to develop a molecular taxonomy to subgroup melanoma patients at various stages of tumor progression for more accurate targeted treatment.

22 Review Prognostic significance of autoimmunity during treatment of melanoma with interferon. 2011

Krauze, Michal T / Tarhini, Ahmad / Gogas, Helen / Kirkwood, John M. ·University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA. ·Semin Immunopathol · Pubmed #21279809.

ABSTRACT: Since the pivotal cooperative group trials in the 1980's-90's,, high-dose interferon (HDI) has been the standard of adjuvant therapy. Despite multiple other trials evaluating potential new therapies in melanoma, HDI remains the only FDA-approved therapy for stage IIB and III melanoma. Initial reports from the more recent phase III international trials of modifications of the original HDI regimen linked the appearance of autoimmunity with improved outcomes of disease. Trials of high-dose interleukin-2, many years earlier, reported anecdotal observations that were consistent with the hypothesis that autoimmunity and clinical benefit of immunotherapies of melanoma are linked with one another. The only prospectively conducted study examining the appearance of clinical and laboratory evidence of autoimmunity during HDI therapy was published by Gogas and colleagues, demonstrating statistically significant impact on relapse-free survival and overall survival. Retrospectively conducted studies of different intermediate dosage regimens of interferon (IFN) have not fully confirmed the linkage of serological evidence of autoimmunity and improved survival outcomes. With the emergence of new immunotherapies in treatment of melanoma, this review highlights the importance of autoimmunity for future applications in melanoma and reviews significant differences of past studies evaluating the appearance of autoimmunity during IFN therapy in high-risk melanoma.

23 Review Releasing the brake on the immune system: ipilimumab in melanoma and other tumors. 2010

Tarhini, Ahmad / Lo, Ernest / Minor, David R. ·University of Pittsburgh Cancer Institute, Pennsylvania 15232, USA. tarhiniaa@upmc.edu ·Cancer Biother Radiopharm · Pubmed #21204754.

ABSTRACT: Advanced melanoma has proven difficult to treat for many years, and no previous agent has shown improved survival in a phase 3 trial. The deepening understanding of tumor immunobiology and the complexity of the interactions between host T cells and cancer have led to novel treatment approaches. Among these, ipilimumab is a first-in-class T-cell potentiator that works by blocking cytotoxic T-lymphocyte antigen-4, a critical negative regulator of the antitumor T-cell response. From phase 1 studies, ipilimumab has shown encouraging activity in melanoma and other cancers, with unusual response patterns and mechanism-related, predictable toxicities that are medically manageable and mostly reversible but can sometimes be life threatening unless recognized and treated early. Early indications of a survival benefit in phase 2 studies have been confirmed recently in the first randomized phase 3 trial; the primary endpoint of the trial, overall survival (OS), was met with ipilimumab significantly prolonging median OS both as a single agent (10.1 months; p = 0.003) and combined with gp100 vaccine (10.0 months; p < 0.001) compared with vaccine control (6.4 months). Even more noteworthy was the improvement in long-term survival at 24 months from 13.7% (gp100 alone) to 21.6% and 23.5% for the combination and single ipilimumab, respectively. The addition of gp100 vaccine did not appear to impact OS since data for ipilimumab alone were similar to those for the combination with vaccine. Re-induction with ipilimumab in selected patients who progressed gave further clinical benefits. Ipilimumab has also shown promising activity in melanoma patients with brain metastases, and patients with non-small cell lung cancer, renal cell cancer, and castrate-resistant prostate cancer. Ipilimumab not only has a novel mechanism of action but demonstrates unique immune-related toxicities that require particular care in their recognition and treatment.

24 Review Next generation of immunotherapy for melanoma. 2008

Kirkwood, John M / Tarhini, Ahmad A / Panelli, Monica C / Moschos, Stergios J / Zarour, Hassane M / Butterfield, Lisa H / Gogas, Helen J. ·Hillman Cancer Center, Research Pavilion, Suite 1.32, 5117 Centre Ave, Pittsburgh, PA 15213-2584, USA. kirkwoodjm@upmc.edu ·J Clin Oncol · Pubmed #18612161.

ABSTRACT: PURPOSE: Immunotherapy has a long history with striking but limited success in patients with melanoma. To date, interleukin-2 and interferon-alfa2b are the only approved immunotherapeutic agents for melanoma in the United States. DESIGN: Tumor evasion of host immune responses, and strategies for overcoming tumor-induced immunosuppression are reviewed. Several novel immunotherapies currently in worldwide phase III clinical testing for melanoma are discussed. RESULTS: The limitations of immunotherapy for melanoma stem from tumor-induced mechanisms of immune evasion that render the host tolerant of tumor antigens. For example, melanoma inhibits the maturation of antigen-presenting cells, preventing full T-cell activation and downregulating the effector antitumor immune response. New immunotherapies targeting critical regulatory elements of the immune system may overcome tolerance and promote a more effective antitumor immune response. These include monoclonal antibodies that block the cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and toll-like receptor 9 (TLR9) agonists. Blockade of CTLA4 prevents inhibitory signals that downregulate T-cell activation. TLR9 agonists stimulate dendritic cell maturation and ultimately induce a more effective immune response. These approaches have been shown to stimulate acute immune activation with concomitant appearance of transient adverse events mediated by the immune system. The pattern and duration of immune responses associated with these new modalities differ from those associated with cytokines and cytotoxic agents. In addition, vaccines are being developed that may ultimately target melanoma either alone or in combination with these immunomodulatory therapies. CONCLUSION: The successes of cytokine and interferon therapy of melanoma, coupled with an array of new approaches, are generating new enthusiasm for the immunotherapy of melanoma.

25 Review Practical guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant treatment for melanoma: expert opinion. 2008

Hauschild, Axel / Gogas, Helen / Tarhini, Ahmad / Middleton, Mark R / Testori, Alessandro / Dréno, Brigitte / Kirkwood, John M. ·Department of Dermatology, University of Kiel, Kiel, Germany. ·Cancer · Pubmed #18236459.

ABSTRACT: Interferon-alpha-2b (IFNalpha2b) is the only effective adjuvant therapy for melanoma patients at high risk of recurrence that has been approved by regulatory authorities worldwide. However, IFN toxicities increase the risk of poor treatment compliance and impair the potential for benefit from this agent. A review of the literature demonstrated little recent attention to supportive care in the management of IFN toxicities. An international group of experts with extensive personal experience in the use of IFNs worked together to develop practical guidelines for the use of IFNs. Practical recommendations were developed for patient education on the use of IFN; initial patient assessment and monitoring, including contraindications to the use of IFN, monitoring and managing adverse events, and IFN dose modification and discontinuation; IFN injection procedures; treatment of elderly patients; and use during pregnancy and nursing. Successful adjuvant therapy of melanoma with high-dose IFN requires close compliance with the treatment regimen. Recommendations for the recognition and management of adverse events are designed to enable more patients to complete the full planned course of treatment.