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Current efforts combining immunotherapy and radiation have focused on high-dose radiation delivered to few tumor lesions, aiming to generate diffuse abscopal effects; however, these effects are uncommon in patients. Three recent studies in mouse tumor models and human cancer patients show that low-dose radiation (LDRT) delivered to all tumor lesions effectively mobilizes innate and adaptive immunity and synergizes with immunotherapy. These new findings suggest LDRT's potential as an immune amplifier capable of reprogramming the tumor microenvironment, instigating inflammation, and sensitizing 'cold' tumors to immune checkpoint blockade responsiveness.
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Neoplasias , Inmunidad Adaptativa , Animales , Modelos Animales de Enfermedad , Humanos , Inmunoterapia , Ratones , Neoplasias/radioterapia , Microambiente TumoralRESUMEN
Approximately one-half of patients with newly diagnosed cancer and many patients with persistent or recurrent tumors receive radiotherapy (RT), with the explicit goal of eliminating tumors through direct killing. The current RT dose and schedule regimens have been empirically developed. Although early clinical studies revealed that RT could provoke important responses not only at the site of treatment but also on remote, nonirradiated tumor deposits-the so-called "abscopal effect"- the underlying mechanisms were poorly understood and were not therapeutically exploited. Recent work has elucidated the immune mechanisms underlying these effects and has paved the way for developing combinations of RT with immune therapy. In the wake of recent therapeutic breakthroughs in the field of immunotherapy, rational combinations of immunotherapy with RT could profoundly change the standard of care for many tumor types in the next decade. Thus, a deep understanding of the immunologic effects of RT is urgently needed to design the next generation of therapeutic combinations. Here, the authors review the immune mechanisms of tumor radiation and summarize the preclinical and clinical evidence on immunotherapy-RT combinations. Furthermore, a framework is provided for the practicing clinician and the clinician investigator to guide the development of novel combinations to more rapidly advance this important field. CA Cancer J Clin 2017;67:65-85. © 2016 American Cancer Society.
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Inmunoterapia/métodos , Neoplasias/inmunología , Neoplasias/radioterapia , Animales , Antígenos de Neoplasias/inmunología , Terapia Combinada , Humanos , Metástasis de la Neoplasia/inmunología , Metástasis de la Neoplasia/radioterapia , Dosificación RadioterapéuticaRESUMEN
Drug development is paramount to improve outcomes in patients with gynecologic cancers. A randomized clinical trial should measure whether a clinically relevant improvement is detected with the new intervention compared with the standard of care, using reproductible and appropriate endpoints. Clinically meaningful improvements in overall survival and/or quality of life (QoL) are the gold standards to measure benefit of new therapeutic strategies. Alternative endpoints, such as progression-free survival, provide an earlier measure of the effect of the new therapeutic drug, and are not confounded by the effect of subsequent lines of therapy. Yet, its surrogacy with improved overall survival or QoL is unclear in gynecologic malignancies. Of relevance to studies assessing maintenance strategies are other time-to-event endpoints, such as progression-free survival two and time to second subsequent treatment, which provide valuable information on the disease control in the longer term. Translational and biomarker studies are increasingly being incorporated into gynecologic oncology clinical trials, as they may allow understanding of the biology of the disease, resistance mechanisms, and enable a better selection of patients who might benefit from the new therapeutic strategy. Globally, the endpoint selection of a clinical trial will differ according to the type of study, population, disease setting, and type of therapeutic strategy. This review provides an overview of primary and secondary endpoint selection of relevance for gynecologic oncology clinical trials.
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Neoplasias de los Genitales Femeninos , Humanos , Femenino , Neoplasias de los Genitales Femeninos/terapia , Calidad de Vida , Desarrollo de Medicamentos , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Except for its use in palliative care, radiotherapy has been largely abandoned in the management of ovarian cancer because of the recognised efficacy and lower toxicity of systemic chemotherapy compared with radiotherapy. New data have emerged that show synergy of radiotherapy with immunotherapy to control or eradicate cancer. Different doses of hypofractionated radiotherapy have been shown to induce immunogenic cell death and in-situ vaccination in several tumour models. However, doses less than 2 Gy can also reprogramme the tumour microenvironment. This Series paper discusses the past and present use of radiotherapy for ovarian cancer, and the mechanisms by which radiotherapy can mobilise anticancer immunity. We provide emerging preclinical and clinical data for combining immunotherapy with radiotherapy for ovarian cancer treatment and offer a clinical development roadmap to guide the next generation of clinical trials for this combination strategy for this disease.
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Inmunoterapia/métodos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/radioterapia , Radioterapia/métodos , Animales , Terapia Combinada/métodos , Femenino , HumanosAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Oncología por Radiación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Humanos , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapiaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Adenoescamoso/terapia , Cesárea , Quimioradioterapia , Terapia Neoadyuvante , Complicaciones Neoplásicas del Embarazo/terapia , Neoplasias del Cuello Uterino/terapia , Anciano , Antineoplásicos/uso terapéutico , Braquiterapia/métodos , Carboplatino/administración & dosificación , Carcinoma Adenoescamoso/diagnóstico por imagen , Cisplatino/uso terapéutico , Femenino , Humanos , Recién Nacido , Imagen por Resonancia Magnética , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Tomografía Computarizada por Tomografía de Emisión de Positrones , Periodo Posparto , Embarazo , Complicaciones Neoplásicas del Embarazo/diagnóstico por imagen , Resultado del Embarazo , Segundo Trimestre del Embarazo , Radioterapia de Intensidad Modulada/métodos , Ultrasonografía , Neoplasias del Cuello Uterino/diagnóstico por imagenRESUMEN
INTRODUCTION: External beam radiotherapy (EBRT), with or without androgen deprivation therapy (ADT), is an established treatment option for nonmetastatic prostate cancer. Despite high-level evidence from several randomized trials, risk group stratification and treatment recommendations vary due to contradictory or inconclusive data, particularly with regard to EBRT dose prescription and ADT duration. Our aim was to investigate current patterns of practice in primary EBRT for prostate cancer in Switzerland. MATERIALS AND METHODS: Treatment recommendations on EBRT and ADT for localized and locally advanced prostate cancer were collected from 23 Swiss radiation oncology centers. Written recommendations were converted into center-specific decision trees, and analyzed for consensus and differences using a dedicated software tool. Additionally, specific radiotherapy planning and delivery techniques from the participating centers were assessed. RESULTS: The most commonly prescribed radiation dose was 78 Gy (range 70-80 Gy) across all risk groups. ADT was recommended for intermediate-risk patients for 6 months in over 80 % of the centers, and for high-risk patients for 2 or 3 years in over 90 % of centers. For recommendations on combined EBRT and ADT treatment, consensus levels did not exceed 39 % in any clinical scenario. Arc-based intensity-modulated radiotherapy (IMRT) is implemented for routine prostate cancer radiotherapy by 96 % of the centers. CONCLUSION: Among Swiss radiation oncology centers, considerable ranges of radiotherapy dose and ADT duration are routinely offered for localized and locally advanced prostate cancer. In the vast majority of cases, doses and durations are within the range of those described in current evidence-based guidelines.
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Consenso , Pautas de la Práctica en Medicina , Neoplasias de la Próstata/radioterapia , Antagonistas de Andrógenos/uso terapéutico , Terapia Combinada , Árboles de Decisión , Medicina Basada en la Evidencia , Adhesión a Directriz , Humanos , Masculino , Clasificación del Tumor , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias de la Próstata/patología , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador/métodos , SuizaRESUMEN
BACKGROUND: We retrospectively reviewed the long-term outcome and late side effects of endometrial cancer (EC) patients treated with different techniques of postoperative radiotherapy (PORT). METHODS: Between 1999 and 2012, 237 patients with EC were treated with PORT. Two-dimensional external beam radiotherapy (2D-EBRT) was used in 69 patients (30 %), three-dimensional EBRT (3D-EBRT) in 51 (21 %), and intensity-modulated RT (IMRT) with helical Tomotherapy in 47 (20 %). All patients received a vaginal brachytherapy (VB) boost. Seventy patients (29 %) received VB alone. RESULTS: After a median of 68 months (range, 6-154) of follow-up, overall survival was 75 % [95 % confidence interval (CI), 69-81], disease-free survival was 72 % (95% CI, 66-78), cancer-specific survival was 85 % (95 % CI, 80-89), and locoregional control was 86 % (95 % CI, 81-91). The 5-year estimates of grade 3 or more toxicity and second cancer rates were 0 and 7 % (95 % CI, 1-13) for VB alone, 6 % (95 % CI, 1-11) and 0 % for IMRT + VB, 9 % (95 % CI, 1-17) and 5 % (95 % CI, 1-9) for 3D-EBRT + VB, and 22 % (95 % CI, 12-32) and 12 % (95 % CI, 4-20) for 2D-EBRT + VB (P = 0.002 and P = 0.01), respectively. CONCLUSIONS: Pelvic EBRT should be tailored to patients with high-risk EC because the severe late toxicity observed might outweigh the benefits. When EBRT is prescribed for EC, IMRT should be considered, because it was associated with a significant reduction of severe late side effects.
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Adenocarcinoma de Células Claras/radioterapia , Braquiterapia , Carcinoma Papilar/radioterapia , Cistadenocarcinoma Seroso/radioterapia , Neoplasias Endometriales/radioterapia , Neoplasias Primarias Secundarias/epidemiología , Complicaciones Posoperatorias/epidemiología , Adenocarcinoma de Células Claras/mortalidad , Adenocarcinoma de Células Claras/patología , Adenocarcinoma de Células Claras/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Papilar/mortalidad , Carcinoma Papilar/patología , Carcinoma Papilar/cirugía , Terapia Combinada , Cistadenocarcinoma Seroso/mortalidad , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/cirugía , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Cuidados Posoperatorios , Pronóstico , Radioterapia Adyuvante , Estudios Retrospectivos , Tasa de Supervivencia , Suiza/epidemiologíaRESUMEN
Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment; yet their efficacy remains variable across patients. This review delves into the intricate interplay of tumour characteristics contributing to resistance against ICI therapy and suggests that combining with radiotherapy holds promise. Radiation, known for its ability to trigger immunogenic cell death and foster an in situ vaccination effect, may counteract these resistance mechanisms, enhancing ICI response and patient outcomes. However, particularly when delivered at high-dose, it may trigger immunosuppressive mechanism and consequent side-effects. Notably, low-dose radiotherapy (LDRT), with its capacity for tumour reprogramming and reduced side effects, offers the potential for widespread application. Preclinical and clinical studies have shown encouraging results in this regard.
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Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias , Humanos , Neoplasias/radioterapia , Neoplasias/inmunología , Neoplasias/terapia , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Resistencia a Antineoplásicos , Dosificación RadioterapéuticaRESUMEN
PURPOSE: Clinical translation of FLASH-radiotherapy (RT) to deep-seated tumours is still a technological challenge. One proposed solution consists of using ultra-high dose rate transmission proton (TP) beams of about 200-250 MeV to irradiate the tumour with the flat entrance of the proton depth-dose profile. This work evaluates the dosimetric performance of very high-energy electron (VHEE)-based RT (50-250 MeV) as a potential alternative to TP-based RT for the clinical transfer of the FLASH effect. METHODS: Basic physics characteristics of VHEE and TP beams were compared utilizing Monte Carlo simulations in water. A VHEE-enabled research treatment planning system was used to evaluate the plan quality achievable with VHEE beams of different energies, compared to 250 MeV TP beams for a glioblastoma, an oesophagus, and a prostate cancer case. RESULTS: Like TP, VHEE above 100 MeV can treat targets with roughly flat (within ± 20 %) depth-dose distributions. The achievable dosimetric target conformity and adjacent organs-at-risk (OAR) sparing is consequently driven for both modalities by their lateral beam penumbrae. Electron beams of 400[500] MeV match the penumbra of 200[250] MeV TP beams and penumbra is increased for lower electron energies. For the investigated patient cases, VHEE plans with energies of 150 MeV and above achieved a dosimetric plan quality comparable to that of 250 MeV TP plans. For the glioblastoma and the oesophagus case, although having a decreased conformity, even 100 MeV VHEE plans provided a similar target coverage and OAR sparing compared to TP. CONCLUSIONS: VHEE-based FLASH-RT using sufficiently high beam energies may provide a lighter-particle alternative to TP-based FLASH-RT with comparable dosimetric plan quality.
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Electrones , Método de Montecarlo , Neoplasias de la Próstata , Terapia de Protones , Dosificación Radioterapéutica , Planificación de la Radioterapia Asistida por Computador , Humanos , Electrones/uso terapéutico , Terapia de Protones/métodos , Planificación de la Radioterapia Asistida por Computador/métodos , Neoplasias de la Próstata/radioterapia , Masculino , Neoplasias Esofágicas/radioterapia , Glioblastoma/radioterapia , Radioterapia de Alta Energía/métodos , Órganos en Riesgo/efectos de la radiación , Radiometría/métodosRESUMEN
Therapeutic monoclonal antibodies blocking different immune checkpoints, have demonstrated efficacy against a wide variety of solid tumors. The exclusion or absence of lymphocytes within the tumor microenvironment (TME) is one of the main resistance mechanisms to immune checkpoint inhibitor (ICI)-based therapies. Therefore, there is a growing interest in identifying novel approaches to promote T cell infiltration on immune-deserted (cold) and immune-excluded tumors to turn them into inflamed (hot) tumors. Here, we provide a comprehensive overview of the recently published studies showing the potential of low-dose radiation (LDRT) to reprogram the TME to allow and promote T-cell infiltration and thus, improve currently approved ICI-based therapies.
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Anticuerpos Monoclonales , Inmunoterapia , Microambiente TumoralRESUMEN
PURPOSE: Compared with conventional dose rate irradiation (CONV), ultrahigh dose rate irradiation (UHDR) has shown superior normal tissue sparing. However, a clinically relevant widening of the therapeutic window by UHDR, termed "FLASH effect," also depends on the tumor toxicity obtained by UHDR. Based on a combined analysis of published literature, the current study examined the hypothesis of tumor isoefficacy for UHDR versus CONV and aimed to identify potential knowledge gaps to inspire future in vivo studies. METHODS AND MATERIALS: A systematic literature search identified publications assessing in vivo tumor responses comparing UHDR and CONV. Qualitative and quantitative analyses were performed, including combined analyses of tumor growth and survival data. RESULTS: We identified 66 data sets from 15 publications that compared UHDR and CONV for tumor efficacy. The median number of animals per group was 9 (range 3-15) and the median follow-up period was 30.5 days (range 11-230) after the first irradiation. Tumor growth assays were the predominant model used. Combined statistical analyses of tumor growth and survival data are consistent with UHDR isoefficacy compared with CONV. Only 1 study determined tumor-controlling dose (TCD50) and reported statistically nonsignificant differences. CONCLUSIONS: The combined quantitative analyses of tumor responses support the assumption of UHDR isoefficacy compared with CONV. However, the comparisons are primarily based on heterogeneous tumor growth assays with limited numbers of animals and short follow-up, and most studies do not assess long-term tumor control probability. Therefore, the assays may be insensitive in resolving smaller response differences, such as responses of radioresistant tumor subclones. Hence, tumor cure experiments, including additional TCD50 experiments, are needed to confirm the assumption of isoeffectiveness in curative settings.
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Neoplasias , Animales , Neoplasias/radioterapia , Conocimiento , Probabilidad , Proyectos de Investigación , Dosificación RadioterapéuticaRESUMEN
OBJECTIVES: We conducted a phase I/II prospective trial to determine whether stereotactic dose escalation to the dominant intra-prostatic nodule (DIN) up to 50 Gy incorporating a rectal balloon spacer is safe, does not affect patient quality of life, and preserves local control in patients with intermediate-high risk PCa. METHODS: Eligible patients included males with stage ≤T3b localized disease, a prostate-specific antigen (PSA) level ≤50 , International Prostate Symptom Score (IPSS) ≤14, and a gland volume ≤70 cm3. Patients underwent perirectal spacer placement, followed by a planning MRI and were subsequently treated with SBRT doses of 36.25 Gy in five fractions to the whole prostate while simultaneously escalating doses to the magnetic resonance image visible DIN up to 50 Gy. Primary endpoint: safety. Secondary endpoints: biochemical control, quality of life (QofL), and dosimetry outcome. RESULTS: Nine patients were treated in the Phase I part of the study. Dose limiting toxicities (DLTs) were not observed. Further characterization of tolerability and efficacy was conducted in the subsequent 24 patients irradiated at the recommended Phase II dose (50 Gy, RP2D). At a median follow-up of 61 months, biochemical control is 69%. Grade 1 and 2 acute GU and GI toxicity was 57.5 and 15%, and 24.2 and 6.1%, respectively. Grade 1 and 2 late GU and GI toxicity was 66.6 and 12.1%, and 15.1 and 3%, respectively. No Grade 3 or higher toxicity was reported. QofL data confirmed physician's reported side effects. Dosimetry analysis showed adherence to the doses prescribed in the protocol. CONCLUSIONS: SBRT of the whole prostate with 36.25 Gy in 5 fractions and dose escalation to 50 Gy to the DIN, when combined with a peri-rectal balloon spacer, was tolerable and established the RP2D. QofL analysis showed minimal negative impact in GU, GI, and sexual domains. ADVANCES IN KNOWLEDGE: Extreme hypofractionated prostate radiation therapy with focal dose escalation to the DIN is well tolerated with efficacy comparable to normal fractionated radiation therapy.
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Neoplasias de la Próstata , Radiocirugia , Masculino , Humanos , Antígeno Prostático Específico , Neoplasias de la Próstata/patología , Radiocirugia/efectos adversos , Radiocirugia/métodos , Estudios Prospectivos , Calidad de VidaRESUMEN
FLASH radiation therapy (RT) is a promising new paradigm in radiation oncology. However, a major question that remains is the robustness and reproducibility of the FLASH effect when different irradiators are used on animals or patients with different genetic backgrounds, diets, and microbiomes, all of which can influence the effects of radiation on normal tissues. To address questions of rigor and reproducibility across different centers, we analyzed independent data sets from The University of Texas MD Anderson Cancer Center and from Lausanne University (CHUV). Both centers investigated acute effects after total abdominal irradiation to C57BL/6 animals delivered by the FLASH Mobetron system. The two centers used similar beam parameters but otherwise conducted the studies independently. The FLASH-enabled animal survival and intestinal crypt regeneration after irradiation were comparable between the two centers. These findings, together with previously published data using a converted linear accelerator, show that a robust and reproducible FLASH effect can be induced as long as the same set of irradiation parameters are used.
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Focal radiation therapy (RT) has attracted considerable attention as a combinatorial partner for immunotherapy (IT), largely reflecting a well-defined, predictable safety profile and at least some potential for immunostimulation. However, only a few RT-IT combinations have been tested successfully in patients with cancer, highlighting the urgent need for an improved understanding of the interaction between RT and IT in both preclinical and clinical scenarios. Every year since 2016, ImmunoRad gathers experts working at the interface between RT and IT to provide a forum for education and discussion, with the ultimate goal of fostering progress in the field at both preclinical and clinical levels. Here, we summarize the key concepts and findings presented at the Sixth Annual ImmunoRad conference.
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Neoplasias , Humanos , Terapia Combinada , Neoplasias/radioterapia , Neoplasias/tratamiento farmacológico , InmunoterapiaRESUMEN
Prostate cancer is the second most common cancer in men and represents a significant healthcare burden worldwide. Therapeutic options in the metastatic castration-resistant setting remain limited, despite advances in androgen deprivation therapy, precision medicine and targeted therapies. In this review, we summarize the role of immunotherapy in prostate cancer and offer perspectives on opportunities for future development, based on current knowledge of the immunosuppressive tumor microenvironment. Furthermore, we discuss the potential for synergistic therapeutic strategies with modern radiotherapy, through modulation of the tumor microenvironment. Emerging clinical and pre-clinical data suggest that radiation can convert immune desert tumors into an inflamed immunological hub, potentially sensitive to immunotherapy.
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Neoplasias de la Próstata , Antagonistas de Andrógenos/uso terapéutico , Humanos , Inmunoterapia , Masculino , Medicina de Precisión , Neoplasias de la Próstata/patología , Microambiente TumoralRESUMEN
The use of low-dose irradiation (LDI) for mobilizing innate and adaptive immunity is gaining interest among the scientific community. Recent evidence suggests that LDI can reprogramme the tumor microenvironment, induce inflammation and turn cold tumors susceptible to immunecheckpoint blockade therapy. Translating immuno-radiation preclinical findings in the clinic is more challenging than expected. We propose therapeutic strategies for combining LDI with immunotherapy, and emphasize the importance of pursuing clinical research to determine optimal radiation dosage, fractionation, volumes, and sequencing to stimulate immune-mediated tumor responses.
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Inmunoterapia , Neoplasias , Inmunidad Adaptativa , Humanos , Factores Inmunológicos , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Microambiente TumoralRESUMEN
Stereotactic body radiation therapy (SBRT) is a form of radiation therapy (RT) in which a small number of high doses of radiation are delivered to a target volume using highly sophisticated equipment. Stereotactic body radiation therapy is crucial in two cancer stages: early primary cancer and oligometastatic disease, with the goal of inducing complete cancer remission in both. This treatment method is commonly used to treat a variety of disease types. Over the years, a growing body of clinical evidence on the use of SBRT for the treatment of primary and metastatic tumors has accumulated, with efficacy and safety demonstrated in randomized clinical trials. This article will review the technical and clinical aspects of SBRT according to disease type and clinical indication.
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Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell-infiltrated tumors. SIGNIFICANCE: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4+ effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors.This article is highlighted in the In This Issue feature, p. 1.
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Adenocarcinoma Papilar/radioterapia , Neoplasias Ováricas/radioterapia , Inmunidad Adaptativa , Adenocarcinoma Papilar/inmunología , Animales , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Modelos Animales de Enfermedad , Femenino , Humanos , Linfocitos Infiltrantes de Tumor , Ratones , Ratones Endogámicos C57BL , Neoplasias Ováricas/inmunología , Dosificación Radioterapéutica , Microambiente TumoralRESUMEN
Uterine perivascular epithelioid cell tumors (PEComas) are rare neoplasms. PI3K/AKT/mTOR pathway upregulation is critical for their pathogenesis and is often associated with TSC1/TSC2 inactivation. Although first line mTOR inhibitors are an effective treatment, metastatic PEComas eventually progress. A 53-year-old woman presented a 4-month history of post-menopausal vaginal bleeding. Clinical and radiological examination detected a uterine mass and a single S1 bone lesion. The patient underwent a radical hysterectomy and bone biopsy. The anatomopathological evaluation concluded to an oligo-metastatic uterine PEComa. The tumor harbored a heterozygous deletion of 9q34 that contains the TSC1 gene. Concerning the primary lesion, the resection was complete and the single bone metastasis was treated with radiotherapy. Three months later, the patient presented bone, lung and subcutaneous metastatic progression. An everolimus and denosumab treatment was initiated. After 2 years of treatment, a clinically significant bone, lung and subcutaneous progression was detected. Following a literature review of the possible therapeutic options, we initiated a second line treatment by pazopanib. This treatment resulted in regression of the subcutaneous lesions and stability of lung and bone metastases. In this challenging, rare setting, our report suggests single agent, anti-angiogenic, tyrosine kinase inhibitor to be effective as second line treatment of metastatic uterine PEComa progressing on mTOR inhibitors.