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BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).
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OBJECTIVE: To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma. SUMMARY BACKGROUND DATA: Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear. METHODS: In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8âweeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection. RESULTS: Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50âmonths (interquartile range 37.7-57.1âmonths), median recurrence-free survival was 9.9âmonths (95% confidence interval 7.52-not reached) in patients undergoing surgery. CONCLUSIONS: This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Procedimientos Quirúrgicos de Citorreducción , Melanoma/tratamiento farmacológico , Melanoma/cirugía , Adulto , Anciano , Femenino , Humanos , Imidazoles/administración & dosificación , Imagen por Resonancia Magnética , Masculino , Melanoma/genética , Melanoma/patología , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Países Bajos , Oximas/administración & dosificación , Tomografía Computarizada por Tomografía de Emisión de Positrones , Estudios Prospectivos , Proteínas Proto-Oncogénicas B-raf , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificaciónRESUMEN
BACKGROUND: Talimogene laherparepvec (T-VEC) is a genetically modified herpes simplex type 1 virus and known as an effective oncolytic immunotherapy for injectable cutaneous, subcutaneous and nodal melanoma lesions in stage IIIB-IVM1a patients. This study set out to identify prognostic factors for achieving a complete response that can be used to optimize patient selection for T-VEC monotherapy. METHODS: Patients with stage IIIB-IVM1a melanoma, treated with T-VEC at the Netherlands Cancer Institute between 2016-12 and 2020-01 with a follow-up time > 6 months, were included. Data were collected on baseline characteristics, responses and adverse events (AEs). Uni- and multivariable analyses were conducted, and a prediction model was developed to identify prognostic factors associated with CR. RESULTS: A total of 93 patients were included with a median age of 69 years, median follow-up time was 16.6 months. As best response, 58 patients (62%) had a CR, and the overall response rate was 79%. The durable response rate (objective response lasting > 6 months) was 51%. Grade 1-2 AEs occurred in almost every patient. Tumor size, type of metastases, prior treatment with systemic therapy and stage (8Th AJCC) were independent prognostic factors for achieving CR. The prediction model includes the predictors tumor size, type of metastases and number of lesions. CONCLUSIONS: This study shows that intralesional T-VEC monotherapy is able to achieve high complete and durable responses. The prediction model shows that use of T-VEC in patients with less tumor burden is associated with better outcomes, suggesting use earlier in the course of the disease.
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Productos Biológicos/inmunología , Herpesvirus Humano 1/inmunología , Melanoma/inmunología , Melanoma/terapia , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Carga Tumoral/inmunología , Anciano , Femenino , Humanos , Inmunoterapia/métodos , Inyecciones Intralesiones/métodos , Masculino , Melanoma/patología , Viroterapia Oncolítica/métodos , Virus Oncolíticos/inmunología , Pronóstico , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: With the approval of adjuvant therapy for stage III melanoma, accurate staging is more important than ever. Sentinel node biopsy (SNB) is an accurate staging tool, yet the presence of capsular nevi (CN) can lead to a false-positive diagnosis. PATIENTS AND METHODS: Retrospective analysis of the American Joint Committee on Cancer 7th edition stage IIIA melanoma patients who were treated at our institute between 2000 and 2015. SNB slides were reviewed for this study by an expert melanoma pathologist. RESULTS: Of 159 eligible patients, 14 originally diagnosed with metastatic melanoma merely had CN (8.8%). Another two merely had melanophages (1.3%). Thus, 10.1% of SNs were considered false positive after revision. In 12 patients, the SN tumor burden was originally reported as larger than 1 mm but turned out to be less than 1 mm. Four patients originally reported as SN tumor burden less than 1 mm before revision turned out to have larger than 1 mm. These patients might have been over- or undertreated in the current era of adjuvant therapy for stage III melanoma. CONCLUSIONS: Distinguishing metastatic melanoma from benign CN and melanophages can be a diagnostic challenge. We plead for an expert pathologists' review, especially when using the SNB + results to determine treatment consequences.
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Melanoma/patología , Melanoma/terapia , Ganglio Linfático Centinela/patología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Adulto , Anciano , Estudios de Cohortes , Terapia Combinada , Reacciones Falso Positivas , Femenino , Humanos , Escisión del Ganglio Linfático , Masculino , Melanoma/cirugía , Persona de Mediana Edad , Estadificación de Neoplasias , Nevo Pigmentado/patología , Estudios Retrospectivos , Ganglio Linfático Centinela/cirugía , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/cirugía , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective. METHODS: OpACIN-neo is a multicentre, open-label, phase 2, randomised, controlled trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0-1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients were enrolled from three medical centres in Australia, Sweden, and the Netherlands, and were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously. The investigators, site staff, and patients were aware of the treatment assignment during the study participation. Pathologists were masked to treatment allocation and all other data. The primary endpoints were the proportion of patients with grade 3-4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks. Analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02977052, and is ongoing with an additional extension cohort and to complete survival analysis. FINDINGS: Between Nov 24, 2016 and June 28, 2018, 105 patients were screened for eligibility, of whom 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups. Three patients were excluded after randomisation because they were found to be ineligible, and 86 received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board on June 4, 2018 because of severe adverse events). Within the first 12 weeks, grade 3-4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. The difference in grade 3-4 toxicity between group B and A was -20% (95% CI -46 to 6; p=0·158) and between group C and group A was 10% (-20 to 40; p=0·591). The most common grade 3-4 adverse events were elevated liver enzymes in group A (six [20%)]) and colitis in group C (five [19%]); in group B, none of the grade 3-4 adverse events were seen in more than one patient. One patient (in group A) died 9·5 months after the start of treatment due to the consequences of late-onset immune-related encephalitis, which was possibly treatment-related. 19 (63% [95% CI 44-80]) of 30 patients in group A, 17 (57% [37-75]) of 30 in group B, and nine (35% [17-56]) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% [61-92]) patients in group A, 23 (77% [58-90]) in group B, and 17 (65% [44-83]) in group C. INTERPRETATION: OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomised phase 3 studies versus adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma. FUNDING: Bristol-Myers Squibb.
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Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ipilimumab/administración & dosificación , Melanoma/tratamiento farmacológico , Terapia Neoadyuvante , Nivolumab/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Esquema de Medicación , Femenino , Humanos , Masculino , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Cutáneas/patología , Adulto JovenRESUMEN
Advances in the treatment of metastatic melanoma have improved responses and survival. However, many patients continue to experience resistance or toxicity to treatment, highlighting a crucial need to identify biomarkers and understand mechanisms of response and toxicity. Neoadjuvant therapy for regional metastases might improve operability and clinical outcomes over upfront surgery and adjuvant therapy, and has become an established role for drug development and biomarker discovery in other cancers (including locally advanced breast cancer, head and neck squamous cell carcinomas, gastroesophageal cancer, and anal cancer). Patients with clinically detectable stage III melanoma are ideal candidates for neoadjuvant therapy, because they represent a high-risk patient population with poor outcomes when treated with upfront surgery alone. Neoadjuvant therapy is now an active area of research for melanoma with numerous completed and ongoing trials (since 2014) with disparate designs, endpoints, and analyses under investigation. We have, therefore, established the International Neoadjuvant Melanoma Consortium with experts in medical oncology, surgical oncology, pathology, radiation oncology, radiology, and translational research to develop recommendations for investigating neoadjuvant therapy in melanoma to align future trial designs and correlative analyses. Alignment and consistency of neoadjuvant trials will facilitate optimal data organisation for future regulatory review and strengthen translational research across the melanoma disease continuum.
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Melanoma/terapia , Terapia Neoadyuvante , Ensayos Clínicos como Asunto , Humanos , Melanoma/secundario , Selección de PacienteRESUMEN
Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1 (HSV-1), which can be administered intralesionally in patients with stage IIIB/C-IVM1a unresectable melanoma (EMA label). The phase 3 OPTiM registration study showed an overall response rate (ORR) of 26%. Since December 2016, 48 eligible patients started treatment at the Netherlands Cancer Institute. We included 26 patients in this study with a follow up time ≥6 months, reporting Overall Response Rate (ORR), Disease Control Rate (DCR), Adverse Events (AE), prior treatment for melanoma and baseline characteristics, documented in a prospectively maintained database. In house developed treatment protocol consists of clinical evaluation, periodic PET-CT and histological biopsies for response evaluation. Median follow-up was 12.5 months. Of 26 patients, 16 (61.5%) had a Complete Response (CR) as their best response. Seven (26.9%) patients had a Partial Response (PR) as their best response, 1 (3.8%) patient Stable Disease (SD) and 2 (7.7%) patients Progressive Disease (PD). Best ORR was 88.5%. DCR was 92.3%. Grade 1-2 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms and injection site erythema. All patients underwent prior treatment. Prior treatment did not influence response or toxicity of T-VEC. Best ORR for T-VEC monotherapy at our institute was 88.5% with 61.5% achieving a CR. This prospective study for T-VEC in early metastatic (stage IIIB/C-IVM1a) melanoma demonstrated superior results to the phase 3 OPTiM study and confirms the role of oncolytic immunotherapy for melanoma.
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Herpesvirus Humano 1/inmunología , Melanoma/inmunología , Melanoma/terapia , Melanoma/virología , Metástasis de la Neoplasia/inmunología , Metástasis de la Neoplasia/terapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunoterapia/métodos , Inyecciones Intralesiones , Masculino , Persona de Mediana Edad , Países Bajos , Viroterapia Oncolítica/métodos , Virus Oncolíticos/inmunología , Estudios Prospectivos , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Neoplasias Cutáneas/virologíaRESUMEN
BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with 18F-Fluorodeoxyglucose (18F-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of 18F-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. 18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than 18F-FDG. METHODS: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by 18F-FDG/18F-FLT PET can predict progression-free survival and whether early changes in 18F-FDG/18F-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo 18F-FDG PET/CT and in 25 patients additional 18F-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. DISCUSSION: The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both 18F-FDG and 18F-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02414750. Registered 10 April 2015, retrospectively registered.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Azetidinas/administración & dosificación , Ensayos Clínicos Fase II como Asunto , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Humanos , Indoles/administración & dosificación , Melanoma/diagnóstico por imagen , Melanoma/secundario , Estudios Multicéntricos como Asunto , Estadificación de Neoplasias , Piperidinas/administración & dosificación , Tomografía de Emisión de Positrones , Proyectos de Investigación , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/patología , Sulfonamidas/administración & dosificación , Resultado del Tratamiento , VemurafenibRESUMEN
BACKGROUND: Combined superficial (inguinal) and deep (iliac and obturator) groin dissection (CGD) is the standard treatment of patients with stage IIIB and IIIC melanoma groin metastases; however, the additional value of iliac lymphadenectomy is debated. In our institute, imaging with positron emission tomography/computed tomography (PET/CT) is part of the regular preoperative work-up. The aim of this study was to evaluate the diagnostic value of PET/CT in detecting iliac lymph node metastases. PATIENTS AND METHODS: This retrospective study included 70 melanoma patients with stage IIIB or IIIC melanoma and an indication for therapeutic CGD, who were treated at our institution between 2003 and 2013. Median disease-free survival (DFS) was 9 months and median follow-up time was 16 months. The results of PET/CT were compared with the results of pathological analysis after CGD. Additional quantitative analysis of PET/CT imaging was performed. RESULTS: For superficial melanoma groin metastases, sensitivity of PET/CT was 97 %, specificity was 50 %, positive predictive value (PPV) was 90 %, and negative predictive value (NPV) was 71 %. For iliac lymph node metastases, sensitivity of PET/CT was 67 %, specificity was 91 %, PPV was 73 %, NPV was 81 %, and false negative rate was 33 %. CONCLUSIONS: The results of this retrospective study indicate that PET/CT imaging could be a valuable method in preoperative work-up in this patient category; however, PET/CT alone should not be used as a tool to determine the extent of surgery, since one-third of patients with iliac lymph node involvement will be missed on PET/CT.
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Ingle/patología , Ganglios Linfáticos/patología , Melanoma/diagnóstico , Neoplasias Primarias Secundarias/diagnóstico , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias Cutáneas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Ingle/diagnóstico por imagen , Ingle/cirugía , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Escisión del Ganglio Linfático , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/cirugía , Metástasis Linfática , Masculino , Melanoma/diagnóstico por imagen , Melanoma/cirugía , Persona de Mediana Edad , Neoplasias Primarias Secundarias/diagnóstico por imagen , Neoplasias Primarias Secundarias/cirugía , Pronóstico , Estudios Retrospectivos , Neoplasias Cutáneas/diagnóstico por imagen , Neoplasias Cutáneas/cirugía , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Locoregional treatment is often insufficient to guarantee long-term disease-free survival (DFS) in American Joint Committee on Cancer stage IIIB melanoma, and, in order to improve survival, effective neoadjuvant and adjuvant strategies are needed . Selecting patients for these strategies requires risk stratification, for which clinical and molecular biomarkers can be used. We aimed to detect clinical biomarkers to identify high-risk stage IIIB melanoma patients. PATIENTS AND METHODS: We performed retrospective analysis of stage IIIB melanoma patients who underwent lymph node dissection (LND) in our institution between 2000 and 2015. Sentinel node-positive patients with ulcerated primary tumors, as well as patients with clinically detectable nodal metastasis with non-ulcerated tumors, were included. Baseline characteristics, melanoma-specific survival (MSS), and DFS were assessed, and prognostic factors for recurrence and survival were analyzed, using univariate and multivariate analysis. RESULTS: Overall, 250 patients were included. Median follow-up was 52 months (interquartile range 29-108 months), median MSS was 141 months, and median DFS was 36 months. Five- and 10-year MSS was 59 and 52 %, respectively, and 5- and 10-year DFS was 47 and 41 %, respectively. Age >50 years, Breslow thickness >2 versus ≤2 mm, and N2 versus N1 disease all carried an increased risk of death by melanoma. Age >50 years and extracapsular extension carried an increased risk of disease recurrence after LND. CONCLUSIONS: Age >50 years, Breslow thickness >2 mm and N2 versus N1 disease are prognostic factors for poor survival in stage IIIB melanoma. These characteristics can be used to further stratify risk of death by melanoma in this already high-risk patient population and to help select the appropriate population for adjuvant therapy (trials).
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Escisión del Ganglio Linfático , Melanoma/secundario , Ganglio Linfático Centinela/patología , Neoplasias Cutáneas/patología , Adulto , Factores de Edad , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Metástasis Linfática , Masculino , Melanoma/radioterapia , Melanoma/cirugía , Persona de Mediana Edad , Estadificación de Neoplasias , Radioterapia Adyuvante , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Ganglio Linfático Centinela/cirugía , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/radioterapia , Neoplasias Cutáneas/cirugía , Úlcera Cutánea/etiología , Tasa de Supervivencia , Carga TumoralRESUMEN
Here, we describe a fatal serious adverse event observed in a patient infused with autologous T-cell receptor (TCR) transduced T cells. This TCR, originally obtained from a melanoma patient, recognizes the well-described HLA-A*0201 restricted 26-35 epitope of MART-1, and was not affinity enhanced. Patient 1 with metastatic melanoma experienced a cerebral hemorrhage, epileptic seizures, and a witnessed cardiac arrest 6 days after cell infusion. Three days later, the patient died from multiple organ failure and irreversible neurologic damage. After T-cell infusion, levels of IL-6, IFN-γ, C-reactive protein (CRP), and procalcitonin increased to extreme levels, indicative of a cytokine release syndrome or T-cell-mediated inflammatory response. Infused T cells could be recovered from blood, broncho-alveolar lavage, ascites, and after autopsy from tumor sites and heart tissue. High levels of NT-proBNP indicate semi-acute heart failure. No cross reactivity of the modified T cells toward a beating cardiomyocyte culture was observed. Together, these observations suggest that high levels of inflammatory cytokines alone or in combination with semi-acute heart failure and epileptic seizure may have contributed substantially to the occurrence of the acute and lethal event. Protocol modifications to limit the risk of T-cell activation-induced toxicity are discussed.
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Tratamiento Basado en Trasplante de Células y Tejidos/efectos adversos , Inmunoterapia Adoptiva/efectos adversos , Antígeno MART-1/inmunología , Receptores de Antígenos de Linfocitos T/genética , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto , Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Resultado Fatal , Femenino , Humanos , Inmunoterapia Adoptiva/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Antígeno MART-1/metabolismo , Melanoma/diagnóstico , Melanoma/genética , Melanoma/inmunología , Melanoma/terapia , Estadificación de Neoplasias , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción GenéticaRESUMEN
The objective of this study is to give more insight in the diagnosis, clinical course and therapy of skin adnexal carcinoma of the head and neck. Forty cases of skin adnexal carcinoma of the head and neck treated from 1977 to 2011 were identified by searching the hospitals cancer registration database. After pathology review by a pathologist specialized in skin cancer, 17 cases were excluded. A retrospective chart review of the remaining 23 patients was performed. Clinical course was recorded by endpoints including survival, loco-regional control and recurrence free survival. Prognostic factors considered for analysis were differentiation of the tumor and location of the tumor. Five-year overall survival (OS) was 78 % (95 % CI 61-100 %). Five-year recurrence free survival (RFS) was 58 % (95 % CI 40-84 %). Poor differentiation of the tumor significantly reduced OS (p = 0.002) and RFS (p = 0.01). Tumor location 'face' demonstrated a significantly better survival than other tumor locations (p < 0.001). Local recurrence occurred in five cases, regional metastasis was seen in seven patients, distant metastasis in three patients. Three cases with distant metastases died of disease. Based on the findings of this small group of patients in a tertiary referral center, we conclude that skin adnexal carcinoma is a very rare skin carcinoma that can behave locally aggressive but also has the potential for regional and distant metastasis. The recognition of skin adnexal carcinoma and subsequent wide excision in an early stage of the disease is of major importance for loco-regional control and survival.
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Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Estadificación de Neoplasias/métodos , Neoplasias Cutáneas/patología , Centros de Atención Terciaria , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/terapia , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/terapia , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Países Bajos/epidemiología , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello , Tasa de Supervivencia/tendenciasRESUMEN
Identification of sentinel node (SN) metastases can set the adjuvant systemic therapy indication for stage III melanoma patients. For stage IIIA patients, a 1.0 mm threshold for the largest SN tumour diameter is used. Therefore, uniform reproducible measurement of its size is crucial. At present, the number of deposits or their microanatomical sites are not part of the inclusion criteria for adjuvant treatment. The goal of the current study was to show examples of the difficulty of measuring SN melanoma tumour diameter and teach how it should be measured. Histopathological slides of SN-positive melanoma patients were retrieved using the Dutch Pathology Registry (PALGA). Fourteen samples with the largest SN metastasis around 1.0 mm were uploaded via tele-pathology and digitally measured by 12 pathologists to reflect current practice of measurements in challenging cases. Recommendations as educational examples were provided. Microanatomical location of melanoma metastases was 1 subcapsular, 2 parenchymal and 11 combined. The smallest and largest difference in measurements were 0.24 mm and 4.81 mm, respectively. 11/14 cases (78.6%) showed no agreement regarding the 1.0 mm cut-off. The median discrepancy for cases ≤5 deposits was 0.5 mm (range 0.24-0.60, n=3) and 2.51 mm (range 0.71-4.81, n=11) for cases with ≥6 deposits. Disconcordance in measuring SN tumour burden is correlated with the number of deposits. Awareness of this discordance in challenging cases, for example, cases with multiple small deposits, is important for clinical management. Illustrating cases to reduce differences in size measurement are provided.
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Metástasis Linfática , Melanoma , Biopsia del Ganglio Linfático Centinela , Ganglio Linfático Centinela , Neoplasias Cutáneas , Humanos , Melanoma/patología , Melanoma/secundario , Ganglio Linfático Centinela/patología , Neoplasias Cutáneas/patología , Metástasis Linfática/patología , Estadificación de Neoplasias , Carga Tumoral , Reproducibilidad de los Resultados , Femenino , Países Bajos , MasculinoRESUMEN
BACKGROUND: Lentigo maligna melanoma (LMM) predominantly presents in the head and neck of the elderly. The value of sentinel lymph node biopsy (SLNB) for LMM patients remains to be determined, as the reported average yield of positive lymph nodes is less than 10%. In this nationwide cohort study, we wanted to identify LMM patients with an increased risk of SLNB-positivity. METHODS: LMM with an SLNB indication according to the 8th AJCC melanoma guidelines were retrospectively identified from the nationwide network and registry of histo- and cytopathology in the Netherlands (PALGA). A penalized (LASSO) logistic regression analysis was performed to determine the optimal combination of clinicopathological factors to predict a positive SLNB. RESULTS: Between 1991 and 2020, 1989 LMM patients met our inclusion criteria. SLNB was performed in 16.7% (n = 333) and was positive in 7.5% (25/333). The false-negative rate was 21.9%. Clinically detectable regional lymph node (LN) metastases were found in 1.3% (n = 25). Clinicopathological characteristics best predictive for SLNB-positivity (Odds ratio; 95% CI) were age (0.95; 0.91-0.99), ulceration 1.59 (0.44-4.83), T4-stage (1.81; 0.43-6.2), male sex (1.97; 0.79-5.27), (lymph)angioinvasion (5.07; 0.94-23.31), and microsatellites (7.23; 1.56-32.7) (C-statistic 0.75). During follow-up, regional LN recurrences were detected in 4.2% (83/1989) of patients, of which the majority (74/83) had no evidence of regional LN metastases at baseline. CONCLUSION: Our findings confirm the limited SLNB-positivity in LMM patients. Based on the identified high-risk clinicopathological features, a nomogram was developed to predict the risk of a positive SLNB.
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Peca Melanótica de Hutchinson , Melanoma , Neoplasias Cutáneas , Humanos , Masculino , Anciano , Biopsia del Ganglio Linfático Centinela , Peca Melanótica de Hutchinson/cirugía , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/patología , Estudios de Cohortes , Nomogramas , Estudios Retrospectivos , Melanoma/cirugía , Melanoma/patologíaRESUMEN
Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1, intralesionally administered in patients with stage IIIB/C-IVM1a unresectable melanoma. When surgery is not a treatment option in the head and neck region, T-VEC can be an elegant alternative to systemic immunotherapy. Ten patients with metastatic melanoma in the head and neck region started treatment with T-VEC monotherapy at the Netherlands Cancer Institute. We collected data on response, adverse events (AEs), and baseline characteristics. For response evaluation, we used clinical evaluation with photography, 3-monthly PET/computed tomography (PET/CT) using 18F-fluoro-2-D-deoxyglucose, and histological biopsies. Median age at baseline was 78.2 (35-97) years with a median follow-up of 11.6months. Of these 10 patients, 5 had a complete response (CR), 3 had a partial response, 1 had stable disease and 1 showed progressive disease (PD) as their best response. Best overall response rate (ORR) was 80%. Median progression-free survival was 10.8 months (95% confidence interval, 2.2-19.4). Grade 1 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms, and injection site pain. PET-CT and histological biopsies proved to be clinically useful tools to evaluate treatment response for T-VEC monotherapy, confirming pCR or PD to stage IV disease requiring systemic treatment. ORR for T-VEC monotherapy for melanoma in the head and neck region at our institute was 80% with 50% achieving a CR. This realworld data demonstrates promising results and suggests T-VEC can be an alternative to systemic therapy in this select, mostly elderly patient population.
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Melanoma , Viroterapia Oncolítica , Neoplasias Cutáneas , Humanos , Anciano , Anciano de 80 o más Años , Melanoma/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias Cutáneas/patología , Viroterapia Oncolítica/efectos adversos , Inmunoterapia/métodosRESUMEN
Neoadjuvant ipilimumab + nivolumab has demonstrated high pathologic response rates in stage III melanoma. Patients with low intra-tumoral interferon-γ (IFN-γ) signatures are less likely to benefit. We show that domatinostat (a class I histone deacetylase inhibitor) addition to anti-PD-1 + anti-CTLA-4 increased the IFN-γ response and reduced tumor growth in our murine melanoma model, rationalizing evaluation in patients. To stratify patients into IFN-γ high and low cohorts, we developed a baseline IFN-γ signature expression algorithm, which was prospectively tested in the DONIMI trial. Patients with stage III melanoma and high intra-tumoral IFN-γ scores were randomized to neoadjuvant nivolumab or nivolumab + domatinostat, while patients with low IFN-γ scores received nivolumab + domatinostat or ipilimumab + nivolumab + domatinostat. Domatinostat addition to neoadjuvant nivolumab ± ipilimumab did not delay surgery but induced unexpected severe skin toxicity, hampering domatinostat dose escalation. At studied dose levels, domatinostat addition did not increase treatment efficacy. The baseline IFN-γ score adequately differentiated patients who were likely to benefit from nivolumab alone versus patients who require other therapies.
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Melanoma , Neoplasias Cutáneas , Humanos , Animales , Ratones , Nivolumab/efectos adversos , Ipilimumab/uso terapéutico , Ipilimumab/efectos adversos , Terapia Neoadyuvante , Interferón gamma , Melanoma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAFV600-mutated melanoma. Short-term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD-1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab. METHODS: Patients with treatment-naïve BRAFV600E/K-mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS. RESULTS: Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4. CONCLUSIONS: The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER: NCT02625337.
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Melanoma , Proteínas Proto-Oncogénicas B-raf , Melanoma/tratamiento farmacológico , Melanoma/genética , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , AncianoRESUMEN
PURPOSE: The aim of this study was to investigate whether 18F-FDG PET/CT can predict histopathological response or recurrence in BRAF-mutated unresectable locally advanced stage III melanoma treated with neoadjuvant BRAF/MEK inhibition followed by resection and the value of PET in detecting early recurrence after resection. PATIENTS AND METHODS: Twenty BRAF-mutated, unresectable stage III melanoma patients received BRAF/MEK inhibitors before surgery. 18F-FDG PET/CT was performed at baseline and 2 and 8 weeks after initiation of therapy. After resection, PET/CT was performed at specific time points during 5 years of follow-up. Pathological response was assessed on the dissection specimen. Response monitoring was measured with SUVmax, SUVpeak, MATV, and TLG and according to EORTC and PERCIST criteria. RESULTS: Pathological response was assessed in 18 patients. Nine patients (50%) had a pathologic complete or near-complete response, and 9 (50%) had a pathologic partial or no response. EORTC or PERCIST response measurements did not correspond with pathologic outcome. SUVmax, SUVpeak, MATV, and TLG at all time points and absolute or percentage change among the 3 initial time points did not differ between the groups.During follow-up, 8 of 17 patients with R0 resection developed a recurrence, 6 recurrences were detected with imaging only, 4 of which with PET/CT in less than 6 months after surgery. PET parameters before surgery did not predict recurrence. CONCLUSIONS: Baseline 18F-FDG PET or PET response in previous unresectable stage III melanoma patients seems not useful to predict pathologic response after neoadjuvant BRAF/MEK inhibitors treatment. However, PET/CT seems valuable in detecting recurrence early after R0 resection.
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Fluorodesoxiglucosa F18 , Melanoma , Humanos , Melanoma/diagnóstico por imagen , Melanoma/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por Mitógenos , Terapia Neoadyuvante , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Radiofármacos , Neoplasias Cutáneas , Melanoma Cutáneo MalignoRESUMEN
Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus type 1, which can be administered intralesionally in patients with stage IIIB/C-IVM1a (American Joint Committee of Cancer; AJCC 7th edition) unresectable melanoma. In the case of disease recurrence, T-VEC can be re-introduced for the same category of patients. Five patients with recurrent disease after a prior achieved complete response (CR) recommenced treatment with T-VEC monotherapy at the Netherlands Cancer Institute. We collected data on response, adverse events and baseline characteristics. All 5 patients that were re-treated with T-VEC presented with in-transit metastases on the lower limb. Median age at baseline was 72.1 years with a median follow-up time of 30.4 months. Histologically proven CR was achieved after a median of 8 T-VEC courses on the initial exposure. Duration of response (time between first CR and recurrence) varied between 3.8 and 14.2 months. All 5 patients achieved a histologically and/or positron emission tomography/computed tomography proven CR again after re-introduction of T-VEC with a median of 5 courses. One patient (20%) developed a second recurrence and is currently still on treatment with T-VEC. No patients developed distant metastases. Grade 1 adverse events occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms and injection site pain. Response to re-introduction of T-VEC monotherapy in this select patient population is promising. This real world data on re-introduction of T-VEC monotherapy in stage IIIB/C-IVM1a melanoma suggests T-VEC could be a treatment option for chronic disease control.
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Herpesvirus Humano 1 , Melanoma , Viroterapia Oncolítica , Neoplasias Cutáneas , Productos Biológicos , Enfermedad Crónica , Humanos , Inmunoterapia/métodos , Melanoma/tratamiento farmacológico , Melanoma/patología , Viroterapia Oncolítica/efectos adversos , Viroterapia Oncolítica/métodos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
Single-agent Talimogene Laherparepvec (T-VEC) was developed for treatment of unresectable and injectable stage III-IV melanoma. Since its approval and reimbursement, studies have reported varying response rates. The purpose of this systematic review and meta-analysis was to investigate the efficacy and safety of T-VEC. Of 341 publications that were identified, eight studies with a total of 642 patients were included. In patients with stage IIIB-IVM1a, the pooled complete- and overall response rate (CRR and ORR) were 41% and 64%, respectively. In patients with stage IIIB-IVM1c, the pooled CRR and ORR were 30% and 44%, respectively. In patients with stage IVM1b and IVM1c, the pooled CRR and ORR were 4% and 9%, respectively. Adverse events (AEs) were seen in 41-100% of all patients and 0-11% of AEs were severe. In conclusion, single agent T-VEC achieves the highest response rates in patients with early metastatic melanoma and is well-tolerated with generally only mild toxicities.