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Melanoma has been the most important cancer to drive immunotherapy development in the field of solid tumors. Where immune-stimulating approaches with cytokines in the 1980s and 1990s lead to approvals of interferon-alpha and... more
Melanoma has been the most important cancer to drive immunotherapy development in the field of solid tumors. Where immune-stimulating approaches with cytokines in the 1980s and 1990s lead to approvals of interferon-alpha and interleukin-2, the clinical impact was rather small. Since 2010 immunotherapy has been revolutionized by the concept of breaking tolerance. It represents a major paradigm shift that marks the beginning of a new era. The impact of the first checkpoint inhibitors, i.e., anti-CTLA-4 (cytotoxic T lymphocyte antigen-4) and anti-PD1/anti-PDL1 (programmed death-1 receptor and its ligand PD-L1), is unprecedented. In only 5 years advanced melanoma has been transformed from an incurable disease into a curable disease in over 50% of metastatic patients. We are only at the beginning of discovering its transversal impact throughout oncology. FDA-approved treatments for melanoma are at present: interferon-alpha as adjuvant therapy (1996), interleukin-2 (1998) for advanced disease, and more recently pegylated interferon-alpha as adjuvant therapy (2011). For the treatment of advanced disease approvals were obtained for the immune checkpoint inhibitors ipilimumab (2011), nivolumab (2014), pembrolizumab (2014) and the combination ipilimumab + nivolumab (2015), and the oncolytic virus vaccine laherparepvec (T-VEC) in 2015. Ipilimumab is the first checkpoint inhibitor that has also been approved as adjuvant therapy for high-risk stage III melanoma (2015). Results regarding adjuvant therapy with either nivolumab or pembrolizumab are expected in 2018. Further developments in the field of melanoma are focused on combination therapies between various immunotherapeutic agents, such as vaccines and antibodies, and combination therapies between immunotherapeutic agents with chemotherapeutic or targeted agents or even radiation therapy. Thanks to in particular anti-PD1/anti-PDL1-based immunotherapies, the activity of the combination of anti-PD1/anti-CTLA4 immunotherapy is now developed in a transversal manner across multiple tumor types (a.o. lung, head and neck, esophageal/gastric, liver, MSI-colorectal, MSI-any tumor type, renal, bladder cancers, and Hodgkin lymphoma) with unprecedented success.
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For cancer therapies to succeed, induction of an anticancer immune response is required. Immuno-oncology approaches are shaping the treatment landscape for patients with advanced-stage melanoma and other solid tumours. These new... more
For cancer therapies to succeed, induction of an anticancer immune response is required. Immuno-oncology approaches are shaping the treatment landscape for patients with advanced-stage melanoma and other solid tumours. These new approaches may enhance immune system activity to improve outcomes, including the potential to achieve long-term survival benefits in many patients.
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Melanoma has emerged as the paradigm tumor for drug development through mutation-targeted therapies (inhibitors targeting BRAF, MEK, and c-KIT) and immunotherapy. Exploring the combinations of both approaches is a challenge that will... more
Melanoma has emerged as the paradigm tumor for drug development through mutation-targeted therapies (inhibitors targeting BRAF, MEK, and c-KIT) and immunotherapy. Exploring the combinations of both approaches is a challenge that will require scientific rationale and the cooperation of the pharmaceutical industry. But, with these challenges comes another opportunity to change the paradigms in drug development.
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Elective lymph node dissection is selectively performed in patients with clinically localised melanoma. Randomised studies suggest that survival is improved only in a few subgroups of patients, whereas all patients are exposed to the... more
Elective lymph node dissection is selectively performed in patients with clinically localised melanoma. Randomised studies suggest that survival is improved only in a few subgroups of patients, whereas all patients are exposed to the substantial risk of operative morbidity. Sentinel node biopsy enables the early detection of lymph node metastases from melanoma with less morbidity. The technique has been standardised. The sentinel node can be identified in almost 100% of the patients. The tumour status of the node is the most important prognostic factor in patients with clinically localised melanoma. This information is essential for studies of adjuvant systemic treatment. Regrettably, there is confusion about the definition of a sentinel node. In addition, the sensitivity of the sentinel node approach is unclear. Furthermore, it is uncertain whether early lymph node dissection improves regional control and survival. Sentinel node biopsy is not yet the standard of care.
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Purpose A pegylated interferon, peginterferon alfa-2a (PEG-IFNα-2a; 40 kd), has the potential for improved tumor response and survival with lower toxicity than IFNα. This open-label, randomized study evaluated the safety, tolerability,... more
Purpose A pegylated interferon, peginterferon alfa-2a (PEG-IFNα-2a; 40 kd), has the potential for improved tumor response and survival with lower toxicity than IFNα. This open-label, randomized study evaluated the safety, tolerability, and efficacy of subcutaneous PEG-IFNα-2a in patients with metastatic malignant melanoma (stage IV American Joint Committee on Cancer staging system). Patients and Methods PEG-IFNα-2a was administered subcutaneously at 180 (n = 48), 360 (n = 53), or 450 μg (n = 49) once weekly for 24 weeks, with maintenance therapy for responders. Efficacy was assessed by the proportion of patients with complete response (CR) or partial response (PR). Results The major response rate (CR or PR) was 6% in the 180-μg group (CR, 2%; PR, 4%), 8% in the 360-μg group (CR, 2%; PR, 6%), and 12% in the 450-μg group (CR, 6%; PR, 6%). The times to achieve a major response, duration of major response, rate of disease progression, and 12-month survival were similar between groups, a...
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Purpose Adjuvant pegylated interferon alfa-2b (PEG-IFN-α-2b) was approved for treatment of resected stage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial. Patients and Methods In all, 1,256... more
Purpose Adjuvant pegylated interferon alfa-2b (PEG-IFN-α-2b) was approved for treatment of resected stage III melanoma in 2011. Here, we present long-term follow-up results of this pivotal trial. Patients and Methods In all, 1,256 patients with resected stage III melanoma were randomly assigned to observation (n = 629) or PEG-IFN-α-2b (n = 627) for an intended duration of 5 years. Stratification factors were microscopic (N1) versus macroscopic (N2) nodal involvement, number of positive nodes, ulceration and tumor thickness, sex, and center. Recurrence-free survival (RFS; primary end point), distant metastasis-free survival (DMFS), and overall survival (OS) were analyzed for the intent-to-treat population. Results At 7.6 years median follow-up, 384 recurrences or deaths had occurred with PEG-IFN-α-2b versus 406 in the observation group (hazard ratio [HR], 0.87; 95% CI, 0.76 to 1.00; P = .055); 7-year RFS rate was 39.1% versus 34.6%. There was no difference in OS (P = .57). In stage I...
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Background The therapeutic value of immediate completion lymph node dissection (CLND) for sentinel node (SN)-positive melanoma is unknown. The aim of this study was to evaluate the impact of immediate CLND on the outcome of patients with... more
Background The therapeutic value of immediate completion lymph node dissection (CLND) for sentinel node (SN)-positive melanoma is unknown. The aim of this study was to evaluate the impact of immediate CLND on the outcome of patients with SN-positive melanoma. Methods Patients with SN metastases treated between 1993 and 2008 at ten cancer centres from the European Organization for Research and Treatment of Cancer Melanoma Group were included in this retrospective study. Maximum tumour size, intranodal location and penetrative depth of SN metastases were measured. Outcome in those who had CLND was compared with that in patients who did not undergo completion lymphadenectomy. Results Of 1174 patients with SN-positive melanoma, 1113 (94·8 per cent) underwent CLND and 61 (5·2 per cent) did not. Median follow-up for the two groups was 34 and 48 months respectively. In univariable survival analysis, CLND did not significantly influence disease-specific survival (hazard ratio (HR) 0·89, 95 ...
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The Italian Network for Tumor Biotherapy (Network Italiano per la Bioterapia dei Tumori [NIBIT]) Foundation hosted its annual 2020 Think Tank meeting virtually, at which representatives from academic, clinical, industry, philanthropic,... more
The Italian Network for Tumor Biotherapy (Network Italiano per la Bioterapia dei Tumori [NIBIT]) Foundation hosted its annual 2020 Think Tank meeting virtually, at which representatives from academic, clinical, industry, philanthropic, and regulatory organisations discussed the role of neoadjuvant immunotherapy for the treatment of cancer. Although the number of neoadjuvant immunotherapeutic trials is increasing across all malignancies, the Think Tank focused its discussion on the status of neoadjuvant trials in cutaneous melanoma (CM), muscle-invasive urothelial bladder cancer (MIBC), head and neck squamous cell carcinoma (HNSCC), and pancreatic adenocarcinoma (PDAC). Neoadjuvant developments in CM are nothing short of trailblazing. Pathologic Complete Response (pCR), pathologic near Complete Response, and partial Pathologic Responses reduce 90-100% of recurrences. This is in sharp contrast to targeted therapies in neoadjuvant CM trials, where only a pCR seems to reduce recurrence. The pCR rate after neoadjuvant immunotherapy varies among the different malignancies of CM, MIBC, HNSCC, and PDAC and may be associated with different reductions of recurrence rates. In CM, emerging evidence suggests that neoadjuvant immunotherapy with anti-CTLA-4 plus anti-PD1 is a game changer in patients with palpable nodal Stage III or resectable Stage IV disease by curing more patients, reducing recurrences and the need for surgical interventions, such as lymph node dissections and metastasectomies. The Think Tank panel discussed future approaches on how to optimise results across different tumour types. Future approaches should include reducing monocyte-mediated (tumour-associated macrophages) and fibroblast-mediated (cancer-associated fibroblasts) barriers in the tumour microenvironment to facilitate the recruitment of immune cells to the tumour site, to reduce immune-suppressive mediators, and to increase antigen presentation at the site of the tumour.
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Summary: Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions provide the basis of precision cancer medicine. In this issue of Cancer Discovery, continued progress in this field is demonstrated by two large... more
Summary: Comprehensive genomic and transcriptomic analysis for guiding therapeutic decisions provide the basis of precision cancer medicine. In this issue of Cancer Discovery, continued progress in this field is demonstrated by two large collaborative studies: Horak and colleagues in the MASTER trial for patients with rare cancers and Van Tilburg and colleagues in the INFORM registry in pediatric tumors. See related article by van Tilburg et al., p. 2764. See related article by Horak et al., p. 2780.
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Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-L1 inhibitor, has been shown to prolong survival... more
Bempegaldesleukin (BEMPEG: NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to deliver a controlled, sustained and preferential IL-2 pathway signal. Nivolumab (NIVO), a PD-L1 inhibitor, has been shown to prolong survival in patients with advanced melanoma and recurrence-free survival in the adjuvant setting. PIVOT-02 showed that BEMPEG plus NIVO was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. PIVOT-12 is a randomized, Phase III, global, multicenter, open-label study comparing adjuvant therapy with BEMPEG plus NIVO versus NIVO alone in adult and adolescent patients with completely resected cutaneous stage III/IV melanoma at high risk of recurrence. The primary objective is to compare the efficacy, as measured by recurrence-free survival, of BEMPEG plus NIVO versus NIVO.
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Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanoma. Most melanoma guidelines recommend re-excision plus SNB as soon as possible after primary excision. To date, there is no evidence to... more
Worldwide, sentinel node biopsy (SNB) is the recommended staging procedure for stage I/II melanoma. Most melanoma guidelines recommend re-excision plus SNB as soon as possible after primary excision. To date, there is no evidence to support this timeframe. To determine melanoma specific survival (MSS) for time intervals between excisional biopsy and SNB in SNB positive patients. Between 1993 and 2008, 1080 patients were diagnosed with a positive SNB in nine Melanoma Group centers. We selected 1015 patients (94%) with known excisional biopsy date. Time interval was calculated from primary excision until SNB. Kaplan-Meier estimated MSS was calculated for different cutoff values. Multivariable analysis was performed to correct for known prognostic factors. Median age was 51 years (Inter Quartile Range (IQR) 40-62 years), 535 (53%) were men, 603 (59%) primary tumors were located on extremities. Median Breslow thickness was 3.00 mm (IQR 1.90-4.80 mm), 442 (44%) were ulcerated. Median fol...
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Research Interests: Biology, Cancer Research, Medicine, Chemokines and chemokine receptors, Humans, and 15 moreFemale, Melanoma, Animals, Male, Monoclonal Antibodies, ROC Curve, Middle Aged, Adult, Clinical Investigation, Antineoplastic Agents, Proportional Hazards Models, Case Control Studies, Skin Neoplasms, Medical and Health Sciences, and lung neoplasms
BRAF inhibitors (BRAFi) elicit therapeutic responses in metastatic melanoma, but alarmingly, also induce the formation of secondary benign and malignant skin tumors. Here, we report the emergence and molecular characterization of 73 skin... more
BRAF inhibitors (BRAFi) elicit therapeutic responses in metastatic melanoma, but alarmingly, also induce the formation of secondary benign and malignant skin tumors. Here, we report the emergence and molecular characterization of 73 skin and extracutaneous tumors in 31 patients who underwent BRAFi therapy. The majority of patients presented with classic epidermal tumors such as verrucous papillomas, keratoacanthomas, and squamous cell carcinomas (SCC). However, 15 patients exhibited new or rapidly progressing tumors distinct from these classic subtypes, such as lymph node metastasis, new melanomas, and genital and oral mucosal SCCs. Genotyping of the tumors revealed that oncogenic RAS mutations were found in 58% of the evaluable tumor samples (38/66) and 49% of the control tumors from patients not treated with BRAFi (30/62). Notably, proximity ligation assays demonstrated that BRAF-CRAF heterodimerization was increased in fixed tumor samples from BRAFi-treated patients compared to u...
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To evaluate pharmacokinetic profile, biodistribution and therapeutic effect of cationic thermosensitive liposomes (CTSL) encapsulating doxorubicin (Dox) upon mild hyperthermia (HT). Non-targeted thermosensitive liposomes (TSL) and CTSL... more
To evaluate pharmacokinetic profile, biodistribution and therapeutic effect of cationic thermosensitive liposomes (CTSL) encapsulating doxorubicin (Dox) upon mild hyperthermia (HT). Non-targeted thermosensitive liposomes (TSL) and CTSL were developed, loaded with Dox and characterized. Blood kinetics and biodistribution of Dox-TSL and Dox-CTSL were followed in B16BL6 tumor bearing mice upon normothermia (NT) or initial hyperthermia conditions. Efficacy study in B16BL6 tumor bearing mice was followed with Dox-TSL or Dox-CTSL upon NT or HT. Efficacy study in LLC tumor bearing mice was performed upon two HT conditions. Intravital microscopy was performed on B16BL6 tumors implanted in dorsal-skin fold window-bearing mice. Targeting did not cause faster blood clearance of CTSL compared to TSL. Highest uptake of liposomes was observed in spleen, kidneys and liver. Applying HT prior to CTSL administration increased drug delivery to the tumor and CTSL delivered ~1.7 fold higher Dox concentr...
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During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European... more
During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into…
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Adjuvant therapies for patients with melanoma at high risk of relapse whether local, such as excision margins, elective regional lymph node dissection (ELND), and prophylactic isolated limb perfusion (ILP), or systemic, such as... more
Adjuvant therapies for patients with melanoma at high risk of relapse whether local, such as excision margins, elective regional lymph node dissection (ELND), and prophylactic isolated limb perfusion (ILP), or systemic, such as chemotherapy, immunotherapy, immunochemotherapy, or vaccination therapy, have little or no impact on survival when evaluated in randomized trials. The European approach to the treatment of each stage of malignant melanoma is characterized by thoughtful caution with particular attention being paid to the avoidance of unwarranted mutilation or toxicity because phase 3 studies have failed to demonstrate unequivocal benefits for a more aggressive approach. In Europe, there is no standard adjuvant systemic therapy; high-dose interferon (IFN) is used sporadically in individual patients by some physicians, but there is little enthusiasm for adopting this regimen as the standard of care because of its high toxicity profile and the lack of a clear beneficial impact on long-term survival. Less toxic lower-dose maintenance IFN regimens, antiangiogenic agents, and vaccine therapies are currently being explored.
Research Interests: Medicine, Cancer Vaccines, Humans, Europe, Melanoma, and 15 moreImmunotherapy, Risk factors, Randomized Trial, Malignant Melanoma, Survival Rate, Risk Factors, ADJUVANT THERAPY, Standard of Care, Antineoplastic Agents, Interferon Alpha, Skin Neoplasms, Randomized Controlled Trials as Topic, neoadjuvant therapy, Angiogenesis inhibitors, and High risk
The following meeting highlights are from the Perspectives in Melanoma XII conference, held in Scheveningen/The Hague, the Netherlands, on October 2-4, 2008. Selected reviews are included but further discussions of these and other... more
The following meeting highlights are from the Perspectives in Melanoma XII conference, held in Scheveningen/The Hague, the Netherlands, on October 2-4, 2008. Selected reviews are included but further discussions of these and other presentations are posted at http://www.MelanomaCare.org.
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Research Interests: Molecular Biology, Clinical Trial, Research, Medicine, Signal Transduction, and 15 moreItaly, Pharmaceutical industry, Clinical Practice, Humans, Medical Oncology, Clinical research, Mutation, Mice, Melanoma, Animals, Immunotherapy, Prognosis, Antineoplastic Agents, Clinical Trials as Topic, and Medical and Health Sciences
Purpose This phase III, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of sorafenib with carboplatin and paclitaxel (CP) in patients with advanced melanoma who had progressed on a... more
Purpose This phase III, randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of sorafenib with carboplatin and paclitaxel (CP) in patients with advanced melanoma who had progressed on a dacarbazine- or temozolomide-containing regimen. Patients and Methods A total of 270 patients were randomly assigned to receive intravenous paclitaxel 225 mg/m2 plus intravenous carboplatin at area under curve 6 (AUC 6) on day 1 of a 21-day cycle followed by either placebo (n = 135) or oral sorafenib 400 mg (n = 135) twice daily on days 2 to 19. The primary efficacy end point was progression-free survival (PFS); secondary and tertiary end points included overall survival and incidence of best response, respectively. Results The median PFS was 17.9 weeks for the placebo plus CP arm and 17.4 weeks for the sorafenib plus CP arm (hazard ratio, 0.91; 99% CI, 0.63 to 1.31; two-sided log-rank test P = .49). Response rate was 11% with placebo versus 12% with so...
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Purpose To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. Methods The melanoma staging recommendations were made on the basis of... more
Purpose To revise the staging system for cutaneous melanoma on the basis of data from an expanded American Joint Committee on Cancer (AJCC) Melanoma Staging Database. Methods The melanoma staging recommendations were made on the basis of a multivariate analysis of 30,946 patients with stages I, II, and III melanoma and 7,972 patients with stage IV melanoma to revise and clarify TNM classifications and stage grouping criteria. Results Findings and new definitions include the following: (1) in patients with localized melanoma, tumor thickness, mitotic rate (histologically defined as mitoses/mm2), and ulceration were the most dominant prognostic factors. (2) Mitotic rate replaces level of invasion as a primary criterion for defining T1b melanomas. (3) Among the 3,307 patients with regional metastases, components that defined the N category were the number of metastatic nodes, tumor burden, and ulceration of the primary melanoma. (4) For staging purposes, all patients with microscopic n...
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Research Interests: Medicine, Humans, Internal Medicine, Female, Male, and 15 moreTransferrin, Clinical Sciences, Aged, Middle Aged, Time Factors, Tumor necrosis factor-alpha, Acute Phase Proteins, Recombinant Proteins, Acute Phase Response, Alpha-1 Antitrypsin, Interleukin, Colorectal Neoplasms, liver metastases, Liver neoplasms, and Tumour Necrosis Factor-α\
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In this issue of Annals of Surgical Oncology, Starritt et al. present their experience with ultrasound (US) examination of sentinel nodes (SNs) in the initial assessment of patients with primary cutaneous melanoma. In 304 patients,... more
In this issue of Annals of Surgical Oncology, Starritt et al. present their experience with ultrasound (US) examination of sentinel nodes (SNs) in the initial assessment of patients with primary cutaneous melanoma. In 304 patients, histopathology of the SN revealed metastatic disease in 33 node fields in 31 patients. Only 7 of 33 node fields had been also identified by US. Metastatic deposits <4.5 mm had not been identified by US. The authors concluded that because most metastatic deposits in SNs are smaller, US is not cost-effective in this setting. The authors suggest, on the basis not of their own findings, but of the results of a study by Garbe et al. (which demonstrated that the ability of US to detect melanoma recurrence in lymph nodes during followup was greatest in stage IIb patients), that in this subset of patients with more aggressive melanomas, US of the SN in the primary assessment is likely to be positive more often and should therefore be considered. This is mixed message indicating that this chapter is not closed. In breast cancer, it has been clearly demonstrated that US of the axilla can reduce the number of SN procedures. A multicenter study in 116 patients in Rotterdam demonstrated in 1999 that US-guided fine-needle aspiration (US-FNA) identified positive lymph nodes in 17% of clinically node-negative cancer patients. For T1 tumors, the detection rate for US-FNA was only 6%, but for T2 tumors it was 25%, and for T3 tumors it was 50%. This was recently confirmed in a Japanese study in 262 women, in which US was positive in 6% of T1, 20% of T2, and 70% of T3 tumors. These findings indicate that USFNA can significantly reduce the number of SN procedures and that it is cost-effective in breast cancer for T2/3 tumors. Similar results were also reported by Deurloo et al. in 266 patients. These authors demonstrated a reduction of SN procedures of 14% in the overall clinically node-negative breast cancer population. In melanoma, one might expect a similar situation, and indeed there are reports pointing in that direction. Rossi et al. published a prospective study on the preoperative assessment of the regional lymph nodes by US in 125 patients with primary cutaneous melanoma. US correctly detected 12 of 31 histologically positive lymphatic basins in the total population of 125 patients and thus avoided an SN procedure in approximately 10% of patients. Whether this 10% reduction for the total population of melanoma patients considered for SN is cost-effective remains to be shown, because no formal calculations were presented. Of note, in this article, no metastasis <2 mm was picked up by US. Starritt et al. correctly note that there is no formal proof in the report by Rossi et al. that a different node with a different-sized micrometastasis from the histopathologically reported SN was not detected by US. Still, the 10% reduction of SN procedures, as the outcome of the Rossi study stands, is not that much different from the 14% to 17% reported in overall breast cancer populations, and that result is the most important outcome. Moreover, the conclusion that the yield will be higher if one implements US only in thicker melanomas, be Received September 13, 2004; accepted October 18, 2004. Address correspondence and reprint requests to: Alexander M. M. Eggermont, MD, PhD; E-mail: a.m.m.eggermont@ erasmusmc.nl.