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1.
Oncologist ; 28(8): 714-721, 2023 08 03.
Artículo en Inglés | MEDLINE | ID: mdl-36952233

RESUMEN

BACKGROUND: Despite the clinical benefit of immune checkpoint inhibitors (ICIs), patients with a viral hepatitis have been excluded from clinical trials because of safety concerns. The purpose of this study was to determine the incidence rate of adverse events (AEs) in patients with viral hepatitis who received ICIs for cancer treatment. MATERIALS AND METHODS: We conducted a retrospective study in patients with cancer and concurrent hepatitis B or C, who had undergone treatment with ICI at MD Anderson Cancer Center from January 1, 2010 to December 31, 2019. RESULTS: Of the 1076 patients screened, we identified 33 with concurrent hepatitis. All 10 patients with HBV underwent concomitant antiviral therapy during ICI treatment. Sixteen of the 23 patients with HCV received it before the initiation of ICI. The median follow-up time was 33 months (95% CI, 23-45) and the median duration of ICI therapy was 3 months (IQR, 1.9-6.6). Of the 33 patients, 12 (39%) experienced irAEs (immune-related adverse events) of any grade, with 2 (6%) having grade 3 or higher. None of the patients developed hepatitis toxicities. CONCLUSION: ICIs may be a therapeutic option with an acceptable safety profile in patients with cancer and advanced liver disease.


Asunto(s)
Hepatitis Viral Humana , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Estudios Retrospectivos , Neoplasias/tratamiento farmacológico , Antivirales
2.
Int J Mol Sci ; 24(14)2023 Jul 14.
Artículo en Inglés | MEDLINE | ID: mdl-37511202

RESUMEN

Leptomeningeal disease (LMD) is a devastating complication of cancer with a particularly poor prognosis. Among solid tumours, malignant melanoma (MM) has one of the highest rates of metastasis to the leptomeninges, with approximately 10-15% of patients with advanced disease developing LMD. Tumour cells that metastasise to the brain have unique properties that allow them to cross the blood-brain barrier, evade the immune system, and survive in the brain microenvironment. Metastatic colonisation is achieved through dynamic communication between metastatic cells and the tumour microenvironment, resulting in a tumour-permissive milieu. Despite advances in treatment options, the incidence of LMD appears to be increasing and current treatment modalities have a limited impact on survival. This review provides an overview of the biology of LMD, diagnosis and current treatment approaches for MM patients with LMD, and an overview of ongoing clinical trials. Despite the still limited efficacy of current therapies, there is hope that emerging treatments will improve the outcomes for patients with LMD.


Asunto(s)
Melanoma , Carcinomatosis Meníngea , Neoplasias Meníngeas , Neoplasias Cutáneas , Humanos , Carcinomatosis Meníngea/diagnóstico , Carcinomatosis Meníngea/secundario , Carcinomatosis Meníngea/terapia , Melanoma/diagnóstico , Melanoma/terapia , Melanoma/secundario , Encéfalo , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/terapia , Microambiente Tumoral , Melanoma Cutáneo Maligno
3.
Cancer ; 128(5): 975-983, 2022 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-34724197

RESUMEN

BACKGROUND: In response to the increased use of combination checkpoint inhibitors (CPIs) and the resulting increased cutaneous adverse events (CAEs), this study reviewed patients with melanoma treated with combination CPIs to characterize CAE features and their clinical impact, correlation to adverse events in other organs, and correlation to tumor response. METHODS: Patients from the authors' institutional database who received at least 1 dose of ipilimumab in combination with either nivolumab or pembrolizumab between January 1, 2012, and December 31, 2017, for stage IV or unresectable stage III melanoma were identified. The time to next treatment (TTNT) was calculated from the start of CPI therapy to the start of the next treatment or death, and the development of CAEs was tested in a time-dependent Cox regression to identify associations with TTNT. RESULTS: Eighty-one patients (52.3%) experienced a total of 92 CAEs, including eczematous dermatitis (25.0%), morbilliform eruption (22.8%), vitiligo (12.0%), and pruritus without rash (8.7%). The median times to the onset and resolution of CAEs were 21 days (range, 0-341 days) and 50 days (range, 1-352 days), respectively. Most CAEs resolved after patients entered the CPI maintenance phase and treatment with oral antihistamines with or without topical steroids. CPI discontinuation occurred in 4 patients (2.6%) because of CAEs, in 49 (31.6%) because of other immune-related adverse events, and in 20 (12.9%) because of melanoma progression or death. For patients definitively treated with CPIs (n = 134; 86.5%), TTNT was significantly longer with CAEs than without CAEs (hazard ratio, 0.567; 95% CI, 0.331-0.972; P = .039). CONCLUSIONS: CAEs were mostly reversible and rarely required therapy discontinuation. The development of CAEs was associated with a longer TTNT, and this suggested a possible clinical benefit.


Asunto(s)
Inmunoterapia , Melanoma , Enfermedades de la Piel/inducido químicamente , Neoplasias Cutáneas , Anticuerpos Monoclonales Humanizados , Humanos , Inmunoterapia/efectos adversos , Incidencia , Ipilimumab , Melanoma/patología , Nivolumab , Neoplasias Cutáneas/patología
4.
Adv Exp Med Biol ; 1342: 81-111, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34972963

RESUMEN

Melanoma is the leading cause of death from skin cancer and is responsible for over 7000 deaths in the USA each year alone. For many decades, limited treatment options were available for patients with metastatic melanoma; however, over the last decade, a new era in treatment dawned for oncologists and their patients. Targeted therapy with BRAF and MEK inhibitors represents an important cornerstone in the treatment of metastatic melanoma; however, this chapter carefully reviews the past and current therapy options available, with a significant focus on immunotherapy-based approaches. In addition, we provide an overview of the results of recent advances in the adjuvant setting for patients with resected stage III and stage IV melanoma, as well as in patients with melanoma brain metastases. Finally, we provide a brief overview of the current research efforts in the field of immuno-oncology for melanoma.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Factores Inmunológicos , Inmunoterapia , Melanoma/terapia , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico
5.
J Natl Compr Canc Netw ; 19(6): 700-708, 2020 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-33316767

RESUMEN

BACKGROUND: Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes. METHODS: We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (≤3 months) and chronic (>3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis. RESULTS: In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use (odds ratio [OR], 3.96; P=.026), long duration of IMDC symptoms (OR, 1.05; P<.001) and hospitalization (OR, 1.07; P=.043), a histologic feature of chronic active colitis (OR, 4.8; P=.025) or microscopic colitis (OR, 5.0; P=.045), and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab; OR, 1.06; P=.047). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%; P=.002) and was accompanied by improved overall survival (P=.035). Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival (P=.018). CONCLUSIONS: Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.


Asunto(s)
Colitis , Neoplasias , Colitis/etiología , Diarrea/complicaciones , Diarrea/etiología , Humanos , Neoplasias/complicaciones , Neoplasias/epidemiología , Neoplasias/terapia , Pronóstico , Estudios Retrospectivos
6.
J Cutan Pathol ; 47(10): 954-959, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32394425

RESUMEN

Immune checkpoint inhibitors (ICIs) for cancer treatment have revolutionized the field of medicine. However, an unintended but frequent consequence of ICI therapy is the development of cutaneous immune-related adverse events (irAEs), such as lichenoid dermatitis irAEs (LD-irAEs). The hypertrophic variant of LD-irAE may be a diagnostic challenge since it can mimic superficially invasive squamous cell carcinoma (SCC). A 79-year-old woman with metastatic melanoma who began treatment with an ICI-pembrolizumab-plus exportin-1 (XPO1) inhibitor presented after 1 month of therapy with symmetrical violaceous papules coalescing into plaques and with two nodules of the bilateral dorsal hands. Biopsy of the nodules revealed an actinic keratosis and atypical epidermal proliferation concerning for SCC. However, in the ensuing 3 weeks, the patient developed multiple new erythematous, violaceous, and scaly macules and papules, some coalescing into plaques on the extremities. Biopsies of these lesions revealed exuberant irregular epidermal hyperplasia with hypermaturation and lichenoid infiltrate concentrated at the base of the elongated, broadened rete ridges, consistent with hypertrophic LD-irAE. Treatment included topical fluocinonide ointment, intralesional triamcinolone injections and oral acitretin. Distinguishing hypertrophic LD-irAE and SCC can be challenging since both entities share histopathologic features; thus, correlation with clinical presentation is essential for diagnosis and optimal patient management.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico/efectos adversos , Carioferinas/antagonistas & inhibidores , Erupciones Liquenoides/patología , Melanoma/secundario , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Acitretina/administración & dosificación , Acitretina/uso terapéutico , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas , Dermatitis/inmunología , Dermatitis/patología , Erupciones por Medicamentos/patología , Quimioterapia Combinada , Femenino , Fluocinonida/administración & dosificación , Fluocinonida/uso terapéutico , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Humanos , Hipertrofia/patología , Carioferinas/efectos adversos , Carioferinas/uso terapéutico , Queratolíticos/administración & dosificación , Queratolíticos/uso terapéutico , Erupciones Liquenoides/inducido químicamente , Erupciones Liquenoides/inmunología , Melanoma/tratamiento farmacológico , Resultado del Tratamiento , Triamcinolona/administración & dosificación , Triamcinolona/uso terapéutico , Proteína Exportina 1
7.
Adv Exp Med Biol ; 1244: 51-68, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32301010

RESUMEN

While melanoma is less common than some other skin cancers, it is responsible for nearly 10,000 deaths in the USA each year alone. For many decades, very limited treatment options were available for patients with metastatic melanoma. However, recent breakthroughs have brought new hopes for patients and providers. While targeted therapy with BRAF and MEK inhibitors represents an important cornerstone in the treatment of metastatic melanoma, this chapter carefully reviews the past and current therapy options available, with a significant focus on immunotherapy-based approaches. In addition, we provide an overview of the results of recent advances in the adjuvant setting for patients with resected stage III and stage IV melanoma, as well as in patients with melanoma brain metastases. Finally, we provide a quick overview over the current research efforts in the field of immuno-oncology and melanoma.


Asunto(s)
Inmunoterapia , Melanoma/inmunología , Melanoma/terapia , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/terapia , Humanos , Factores Inmunológicos
8.
Cancer ; 125(23): 4193-4202, 2019 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-31398264

RESUMEN

BACKGROUND: Melanoma brain metastases (MBM) occur in up to 50% of patients with metastatic melanoma (MM) and represent a frequent site of systemic treatment failure for targeted therapies. However, to the authors' knowledge, little is known regarding the incidence, patterns of disease progression, and outcomes of MBM in patients treated with anti-PD-1 immunotherapy. METHODS: A total of 320 patients with MM who were treated with anti-PD-1 at The University of Texas MD Anderson Cancer Center in Houston were reviewed. Analyses were performed to identify factors associated with brain metastasis-free survival and overall survival (OS) using Cox regression models. RESULTS: The median age of the patients was 63.3 years. OS from the initiation of anti-PD-1 therapy was not significantly different between patients without MBM prior to anti-PD-1 compared with patients with prior MBM (P = .359). Among patients without prior MBM, 21 patients (8.6%) developed MBM during anti-PD-1 therapy, 12 of whom (4.9%) presented with disease progression in the central nervous system (CNS) only. Developing MBM during or after therapy with anti-PD-1 (hazard ratio, 4.70; 95% CI, 3.18-6.93) was associated with shorter OS. Among patients with MBM prior to anti-PD-1 treatment, 15 (20.0%) progressed in the CNS only and 19 (25.3%) progressed both intracranially and extracranially; at the time of the last data cutoff, 27 patients (36.0%) had not developed disease progression. Radiation necrosis occurred in 11.3% of patients (7 of 62 patients) in the group with a prior MBM who received stereotactic radiosurgery. CONCLUSIONS: Anti-PD-1 therapy may change the natural history of patients with preexisting MBM. However, CNS failure during treatment with anti-PD-1 is predictive of a worse prognosis compared with extracranial progression. The results of the current study support the activity of anti-PD-1 in patients with MBM, although routine CNS imaging during therapy is warranted.


Asunto(s)
Neoplasias Encefálicas/secundario , Inmunoterapia/métodos , Melanoma/tratamiento farmacológico , Progresión de la Enfermedad , Femenino , Humanos , Incidencia , Masculino , Melanoma/complicaciones , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Resultado del Tratamiento
9.
Int J Mol Sci ; 20(8)2019 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-31003475

RESUMEN

Intratumoral infiltration of myeloid-derived suppressor cells (MDSCs) is known to promote neoplastic growth by inhibiting the tumoricidal activity of T cells. However, direct interactions between patient-derived MDSCs and circulating tumors cells (CTCs) within the microenvironment of blood remain unexplored. Dissecting interplays between CTCs and circulatory MDSCs by heterotypic CTC/MDSC clustering is critical as a key mechanism to promote CTC survival and sustain the metastatic process. We characterized CTCs and polymorphonuclear-MDSCs (PMN-MDSCs) isolated in parallel from peripheral blood of metastatic melanoma and breast cancer patients by multi-parametric flow cytometry. Transplantation of both cell populations in the systemic circulation of mice revealed significantly enhanced dissemination and metastasis in mice co-injected with CTCs and PMN-MDSCs compared to mice injected with CTCs or MDSCs alone. Notably, CTC/PMN-MDSC clusters were detected in vitro and in vivo either in patients' blood or by longitudinal monitoring of blood from animals. This was coupled with in vitro co-culturing of cell populations, demonstrating that CTCs formed physical clusters with PMN-MDSCs; and induced their pro-tumorigenic differentiation through paracrine Nodal signaling, augmenting the production of reactive oxygen species (ROS) by PMN-MDSCs. These findings were validated by detecting significantly higher Nodal and ROS levels in blood of cancer patients in the presence of naïve, heterotypic CTC/PMN-MDSC clusters. Augmented PMN-MDSC ROS upregulated Notch1 receptor expression in CTCs through the ROS-NRF2-ARE axis, thus priming CTCs to respond to ligand-mediated (Jagged1) Notch activation. Jagged1-expressing PMN-MDSCs contributed to enhanced Notch activation in CTCs by engagement of Notch1 receptor. The reciprocity of CTC/PMN-MDSC bi-directional paracrine interactions and signaling was functionally validated in inhibitor-based analyses, demonstrating that combined Nodal and ROS inhibition abrogated CTC/PMN-MDSC interactions and led to a reduction of CTC survival and proliferation. This study provides seminal evidence showing that PMN-MDSCs, additive to their immuno-suppressive roles, directly interact with CTCs and promote their dissemination and metastatic potency. Targeting CTC/PMN-MDSC heterotypic clusters and associated crosstalks can therefore represent a novel therapeutic avenue for limiting hematogenous spread of metastatic disease.


Asunto(s)
Neoplasias de la Mama/sangre , Carcinogénesis/genética , Melanoma/sangre , Células Supresoras de Origen Mieloide/metabolismo , Adulto , Anciano , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Trasplante de Células/métodos , Femenino , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Ratones , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/patología , Factor 2 Relacionado con NF-E2/genética , Metástasis de la Neoplasia , Células Neoplásicas Circulantes/metabolismo , Células Neoplásicas Circulantes/patología , Especies Reactivas de Oxígeno/metabolismo , Receptor Notch1/genética , Proteínas de Transporte Vesicular/genética
10.
J Cutan Pathol ; 45(7): 504-507, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29633300

RESUMEN

Immunotherapies targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) receptor and its ligand (PD-L1) have showed significant therapeutic benefit in patients with clinically advanced solid malignancies, including melanoma. However, immune-related adverse events (irAE) are common, and novel dermatologic toxicities continue to emerge as more patients are treated with immunotherapy. Here we describe a patient treated with combination immunotherapy of ipilimumab and pembrolizumab, who developed asymptomatic erythematous patches on both legs. Histopathologic examination revealed a cutaneous interstitial granulomatous dermatitis. Notably, our patient did not require cessation of immunotherapy for these lesions, which subsequently remained stable, while the patient's melanoma remained controlled. This case expands the dermatologic toxicity profile of immune checkpoint blockade, as recognition of such toxicities is critical to optimal patient management.


Asunto(s)
Erupciones por Medicamentos/patología , Inmunoterapia/efectos adversos , Ipilimumab , Neoplasias Cutáneas , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Humanos , Ipilimumab/administración & dosificación , Ipilimumab/efectos adversos , Masculino , Melanoma/tratamiento farmacológico , Melanoma/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología
11.
Adv Exp Med Biol ; 995: 43-63, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30539505

RESUMEN

While melanoma is less common than some other skin cancers, it is responsible for nearly 10,000 deaths in the USA each year alone. For many decades, very limited treatment options were available for patients with metastatic melanoma. However, recent breakthroughs have brought new hopes for patients and providers.While targeted therapy with BRAF and MEK inhibitors represents an important cornerstone in the treatment of metastatic melanoma, this chapter carefully reviews the past and current therapy options available, with a significant focus on immunotherapy-based approaches. In addition, we provide an overview of the results of recent advances in the adjuvant setting for patients with resected stage III and stage IV melanoma, as well as in patients with melanoma brain metastases. Finally, we provide a quick overview over the current research efforts in the field of immuno-oncology and melanoma.


Asunto(s)
Inmunoterapia , Melanoma/terapia , Neoplasias Cutáneas/terapia , Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores
12.
Cancer ; 123(S11): 2163-2175, 2017 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-28543697

RESUMEN

Substantial proportions of patients with metastatic melanoma develop brain metastases during the course of their disease, often resulting in significant morbidity and death. Despite recent advances with BRAF/MEK and immune-checkpoint inhibitors in the treatment of patients who have melanoma with extracerebral metastases, patients who have melanoma brain metastases still have poor overall survival, highlighting the need for further therapy options. A deeper understanding of the molecular pathways involved in the development of melanoma brain metastases is required to develop more brain-specific therapies. Here, the authors summarize the currently known preclinical data and describe steps involved in the development of melanoma brain metastases. Only by knowing the molecular background is it possible to design new therapeutic agents that can be used to improve the outcome of patients with melanoma brain metastases. Cancer 2017;123:2163-75. © 2017 American Cancer Society.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Melanoma/metabolismo , Neoplasias Cutáneas/metabolismo , Antineoplásicos/uso terapéutico , Antígeno B7-H1 , Barrera Hematoencefálica , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/terapia , Adhesión Celular , Irradiación Craneana , Citocinas/metabolismo , Matriz Extracelular/metabolismo , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Glucuronidasa/metabolismo , Humanos , Inmunoterapia , Integrinas/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Melanoma/secundario , Melanoma/terapia , Terapia Molecular Dirigida , Neovascularización Patológica/metabolismo , Radiocirugia , Receptores CCR4/metabolismo , Neoplasias Cutáneas/patología , Factor de Crecimiento Transformador beta2/metabolismo , Escape del Tumor , Factor A de Crecimiento Endotelial Vascular/metabolismo
14.
Neurooncol Pract ; 11(1): 56-63, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38222058

RESUMEN

Background: We report our experience with using a ventriculoperitoneal shunt (VPS) with an on-off valve and in-line Ommaya reservoir for the treatment of hydrocephalus or intracranial hypertension in patients with leptomeningeal disease (LMD). Our goal was to determine whether control of intracranial pressure elevation combined with intrathecal (IT) chemotherapy would extend patient survival. Methods: In this IRB-approved retrospective study, we reviewed 58 cases of adult patients with LMD from solid cancers who received a VPS with a reservoir and an on-off valve at M D Anderson Cancer Center from November 1996 through December 2021. Primary tumors were most often melanoma (n = 19) or breast carcinoma (n = 20). Hydrocephalus was diagnosed by clinical symptoms and findings on magnetic resonance imaging (MRI), and LMD by MRI or cerebrospinal fluid analysis. Differences in overall survival (OS) were assessed with standard statistical techniques. Results: Patients who received a VPS and more than 3 IT chemotherapy sessions survived longer (n = 26; OS time from implantation 11.7 ± 3.6 months) than those who received an occludable shunt but no IT chemotherapy (n = 24; OS time from implantation 2.8 ± 0.7 months, P < .018). Peritoneal seeding appeared after shunt insertion in only two patients (3%). Conclusions: This is the largest series reported to date of patients with LMD who had had shunts with on-off valves placed to relieve symptoms of intracranial hypertension. Use of IT chemotherapy and control of hydrocephalus via such shunts was associated with improved survival.

15.
Pigment Cell Melanoma Res ; 37(1): 51-67, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37622466

RESUMEN

Leptomeningeal disease (LMD) remains a major challenge in the clinical management of metastatic melanoma patients. Outcomes for patient remain poor, and patients with LMD continue to be excluded from almost all clinical trials. However, recent trials have demonstrated the feasibility of conducting prospective clinical trials in these patients. Further, new insights into the pathophysiology of LMD are identifying rational new therapeutic strategies. Here we present recent advances in the understanding of, and treatment options for, LMD from metastatic melanoma. We also annotate key areas of future focus to accelerate progress for this challenging but emerging field.


Asunto(s)
Melanoma , Radiocirugia , Humanos , Melanoma/secundario , Estudios Prospectivos , Radiocirugia/efectos adversos
16.
Neurooncol Pract ; 11(4): 452-463, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39006528

RESUMEN

Background: Melanoma leptomeningeal disease (LMD) has a poor prognosis. However, the management of patients with advanced melanoma has evolved with time, including those with LMD. We reviewed a large cohort of melanoma LMD patients to assess factors associated with survival. Methods: Retrospective clinical data was collected on patients diagnosed with LMD at MD Anderson Cancer Center from 2015 to 2020. Overall survival (OS) was determined from LMD diagnosis to date of death or last follow-up. The Kaplan-Meier method and log-rank test were used to estimate OS and to assess univariate group differences, respectively. Multivariable associations of survival with variables of interest were determined using Cox proportional hazards regression models. Results: A total of 172 patients were identified. The median age at LMD diagnosis was 53 (range 20-79) years, and all patients had radiographic evidence of LMD on magnetic resonance imaging of either brain or spine. In total 143 patients previously received systemic therapy (83%), with a median of 2 prior treatments (range 0-5). 81 patients (47%) had concurrent uncontrolled systemic disease and 80 patients (53%) had elevated serum LDH at the time of diagnosis. With a median follow-up of 4.0 months (range 0.1-65.3 months), median OS for all patients from LMD diagnosis was 4.9 months. Patients (n = 45) who received intrathecal therapy or systemic immunotherapy for LMD had a median OS of 8.0 months and 10.2 months, respectively. On multivariable analysis, decreased performance status, positive CSF cytology, elevated LDH, and whole brain radiation were associated with worse OS. Conclusions: Despite many advances in therapeutic options, the outcomes of melanoma patients with LMD remains poor. However, a subset of patients appears to derive benefit from LMD-directed treatment.

17.
Clin Transl Radiat Oncol ; 49: 100856, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39308633

RESUMEN

Background and purpose: As patients with advanced melanoma live longer in the context of systemic therapy advancements, better strategies for durable control of bulky tumors are needed. In this study, we evaluated if dose-escalated hypofractionated radiation therapy (HFRT) can provide durable local control and improve tumor-associated symptoms in patients with unresectable or bulky metastatic melanoma for whom stereotactic ablative radiotherapy (RT) approaches are not feasible due to tumor size or location. Materials and methods: We retrospectively reviewed 49 patients with unresectable or bulky metastatic melanoma who were treated to a total of 53 tumor targets with 12-17 fractions HFRT at our institution between 2015-2022. Clinical scenarios included: unresectable, locoregional only disease (26 %); oligometastatic disease (<3 total sites, 17 %); oligoprogressive disease (<3 sites progressing, 17 %); and aggressive palliation (>5 known sites of disease or with at least 3 sites progressing, 40 %). Results: Of the 53 HFRT targets, 91 % (n = 48) had radiographic evidence of response as defined by either stabilization (6 %, n = 3), decreased size (74 %, n = 39), or decreased FDG avidity (11 %, n = 6). Of the 43 symptomatic patients, 98 % (n = 42) had symptomatic improvement. One -year local control was 79 %, with 2-year progression-free and overall survival of 33 % and 39 % respectively. The most common acute toxicities were radiation dermatitis (16 %, n = 8) or a pain flare (14 %, n = 7). Late toxicities were uncommon and typically grade 1. Conclusion: HFRT provides favorable local control and symptomatic relief with limited toxicity in tumors not amenable to surgical resection or stereotactic ablative RT.

18.
Eur J Cancer ; 199: 113563, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38278007

RESUMEN

IMPORTANCE: Acral (AM) and mucosal melanomas (MM) are rare subtypes with a poor prognosis. In those with advanced disease, anti-PD-1 (PD1) therapy has reduced activity compared to that seen in non-acral cutaneous melanoma. OBJECTIVE: To determine the efficacy of adjuvant PD1 in resected AM or MM. DESIGN: An international, retrospective cohort study SETTING: Data up to November 2021 collected from 20 centres across 10 countries. PARTICIPANTS: One hundred and ninety four patients with resected stage III or IV1 AM or MM who received adjuvant PD1 were included and compared to matched patients from the Melanoma Institute Australia (MIA) database using a propensity score matching analysis. MAIN OUTCOMES AND MEASURES: Recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS) were investigated. RESULTS: Forty five of 139 (32%) AM and 9 of 55 (16%) MM patients completed adjuvant therapy. The main reason for early treatment cessation in both groups was disease recurrence: 51 (37%) and 30 (55%) in the AM and MM groups, respectively. In the AM group adjuvant PD1 was associated with a longer RFS [HR-0.69 (0.52-0.92, p = 0.0127)], DMFS [HR0.58 (0.38-0.89, p = 0.0134)] and OS [HR of 0.59 (0.38-0.92, p-value 0.0196)] when compared to the historical cohort. In the MM group there was no statistical difference in RFS [HR1.36 (0.69-2.68,p-value 0.3799], DMFS or OS. CONCLUSION AND RELEVANCE: After adjuvant PD1, both AM and MM have a high risk of recurrence. Our data suggests a benefit to using adjuvant PD1 therapy in resected AM but not in resected MM. Additional studies to investigate the efficacy of adjuvant PD1 for MM are needed.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/tratamiento farmacológico , Melanoma/cirugía , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/cirugía , Estudios Retrospectivos , Recurrencia Local de Neoplasia , Terapia Combinada
19.
J Cancer Res Clin Oncol ; 149(9): 5989-5998, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-36611109

RESUMEN

PURPOSE: Exposure to immune checkpoint inhibitors (ICIs) can predispose to immune-related adverse events (irAEs) involving the gastrointestinal tract. The association between ICIs and bowel perforation has not been well studied. We aimed to describe the clinical course, complications, treatment, and outcomes of patients experiencing bowel perforation during or after ICI treatment. METHODS: This retrospective, single-center study included adult cancer patients with bowel perforation that occurred between the first dose of ICI treatment and up to 1 year thereafter between 1/1/2010 and 4/30/2021. Patients' clinical course, imaging, treatment, and outcomes related to bowel perforation were collected and analyzed. RESULTS: Of the 13,991 patients who received ICIs during the study period, 90 (0.6%) met the inclusion criteria. A majority were male (54.4%), the most common cancer type was melanoma (23.3%), and most patients had received PD-1/L1 inhibitor treatment (58.8%). Onset of perforation occurred after a median of four ICI treatment cycles. The most common symptom was abdominal pain (95.5%). The colon was the most common location for the perforation (37.7%). Evidence of diverticulitis, enterocolitis, or appendicitis was seen in 32 (35.6%) patients, and 6 (6.6%) patients had luminal cancer involvement at the time of perforation. The overall hospitalization rate related to perforation was 95.5%, with mortality of 15.5% during the same admission. Antibiotics were given in 95% of our sample; 37.8% of patients also required surgical/interventional radiology intervention. Forty-six patients (51.1%) had perforation-related complications (e.g., sepsis, fistula, abscess), which were associated with a higher mortality rate (30%). CONCLUSION: Our findings suggest a low incidence of bowel perforation after ICI treatment (0.6%), with 40% of patients having coexisting bowel inflammation as a potential contributing factor. Patients with bowel perforation had an aggressive disease course and high rates of hospitalization, complications, and mortality. Early recognition and prompt intervention is critical to improve patient outcomes. Future studies are warranted to further investigate the cause, predictive markers, and optimal treatment for this patient population.


Asunto(s)
Antineoplásicos Inmunológicos , Perforación Intestinal , Neoplasias , Adulto , Humanos , Masculino , Femenino , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Estudios Retrospectivos , Perforación Intestinal/inducido químicamente , Perforación Intestinal/epidemiología , Perforación Intestinal/tratamiento farmacológico , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Progresión de la Enfermedad
20.
Am J Clin Oncol ; 46(8): 360-365, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-37219360

RESUMEN

OBJECTIVES: Immune checkpoint inhibitors (ICI) can cause immune-related adverse events (irAEs) such as colitis. irAEs can be managed by selective immunosuppressive therapy (SIT) agents such as infliximab and vedolizumab. We aimed to elucidate the incidence of subsequent new irAEs after exposure to SIT by describing patients' clinical course. METHODS: We conducted a retrospective chart review of adult patients at a tertiary cancer center diagnosed with ICI-mediated colitis (IMC) treated with SIT from February 2013 through October 2021. Patients' clinical courses, treatments, and outcomes of new irAEs after SIT were collected and analyzed. RESULTS: The study included 156 patients. Most were male (67.3%), 44.8% had melanoma, and 43.5% received anti-PD1/L1 ICIs. For IMC treatment, 51.9% received infliximab and 37.8% received vedolizumab. Twenty-six patients (16.6%) resumed ICI treatment after their colitis event. Twenty-five patients (16%) developed a new irAE after receiving SIT. The most common new irAE involved skin (44%), and most (60%) were treated with steroids. Higher diarrhea grade and ≥2 doses of SIT were associated with lower incidence of post-SIT irAEs ( P =0.038, P =0.050). However, the type of SIT or individual dosage of infliximab did not affect the occurrence of subsequent irAEs. CONCLUSIONS: New irAEs usually occur more than 6 months after SIT completion for initial colitis event. Severe diarrhea grade and higher number of SIT infusions appeared to have protective effect to lower the occurrence of new irAEs. Otherwise, the type of SIT or individual dosage of infliximab did not affect the occurrence of subsequent irAEs.


Asunto(s)
Antineoplásicos Inmunológicos , Colitis , Melanoma , Adulto , Humanos , Masculino , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Infliximab/efectos adversos , Estudios Retrospectivos , Antineoplásicos Inmunológicos/uso terapéutico , Melanoma/tratamiento farmacológico , Colitis/inducido químicamente , Terapia de Inmunosupresión/efectos adversos , Diarrea/inducido químicamente
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