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In recent years, cancer research has highlighted the role of disrupted microbiota in carcinogenesis and cancer recurrence. However, microbiota may also interfere with drug metabolism, influencing the efficacy of cancer drugs, especially immunotherapy, and modulating the onset of adverse events. Intestinal micro-organisms can be altered by external factors, such as use of antibiotics, proton pump inhibitors treatment, lifestyle and the use of prebiotics or probiotics. The aim of our review is to provide a picture of the current evidence about preclinical and clinical data of the role of gut and local microbiota in malignancies and its potential clinical role in cancer treatments. Standardization of microbiota sequencing approaches and its modulating strategies within prospective clinical trials could be intriguing for two aims: first, to provide novel potential biomarkers both for early cancer detection and for therapeutic effectiveness; second, to propose personalized and "microbiota-tailored" treatment strategies.
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Microbioma Gastrointestinal , Neoplasias , Humanos , Microbioma Gastrointestinal/efectos de los fármacos , Neoplasias/microbiología , Neoplasias/terapia , Probióticos/uso terapéutico , Prebióticos/administración & dosificación , Microbiota/efectos de los fármacosRESUMEN
Although adrenocortical carcinoma (ACC) during pregnancy is rare, a retrospective review of a case series at our hospital revealed that almost one third of our patients were women in childbearing age. Given that the age of maternity is increasing, dealing with a tumor diagnosis during pregnancy and the need for fertility planning in cancer survivors is likely to become more frequent.We thus carried out a case-based discussion regarding: i) diagnosing and treating an ACC during pregnancy; ii) patients conceiving while on mitotane; iii) ACC survivors with a maternal desire.In each of these cases, it is important to provide patients with sufficient information, to offer medical advice and psychological support, to personalize treatments in accordance with the wishes of the patient and her relatives, and to collaborate with other specialists since a multidisciplinary expert team is required to manage each case individually.
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Neoplasias de la Corteza Suprarrenal , Carcinoma Corticosuprarrenal , Humanos , Femenino , Embarazo , Masculino , Carcinoma Corticosuprarrenal/diagnóstico , Carcinoma Corticosuprarrenal/terapia , Carcinoma Corticosuprarrenal/patología , Neoplasias de la Corteza Suprarrenal/diagnóstico , Neoplasias de la Corteza Suprarrenal/terapia , Neoplasias de la Corteza Suprarrenal/patología , Mitotano , Estudios RetrospectivosRESUMEN
This study investigated the clinical management of non small cell lung cancer (NSCLC) patients during the first wave of coronavirus disease 2019 (COVID-19) outbreak in Italy. A 29-questions survey was sent to 95 Italian thoracic oncologists, with 77 % of them declaring significant changes in the outpatients management and treatment. The results of this survey pointed out a significant delay of lung cancer diagnosis along with a relevant reduction of patients' accrual within clinical trials. Telemedicine emerged as a valid support for patient-healthcare interactions. Therapeutic indications followed the guidelines for adjuvant chemotherapy and concurrent chemo-radiation. Clinical indications to first-line therapies were largely confirmed, while major changes regarded the selection of second line treatment options as well as the management of elderly population. This work may represent a valid source of information to improve the clinical management of NSCLC patients during second wave of COVID-19 pandemic.
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COVID-19 , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , COVID-19/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Quimioradioterapia , Humanos , Italia/epidemiología , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/terapia , Pandemias , SARS-CoV-2 , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Luteinized thecoma (thecomatosis) with sclerosing peritonitis (LTSP) is a very uncommon syndrome, characterized by the presence of single or bilateral ovarian thecomas and peritoneal fibrotic lesions. The disease occurs in young women and it can lead to peritoneal fibrosis and bowel obstruction. The pathogenesis of this syndrome remains still largely unknown. Surgery represents the cornerstone of treatment, but resection alone does not always allow a complete disease control. Attempts at medical treatments have been reported in recent years, but a real standard therapy has not yet been defined. AREAS COVERED: We performed a systematic review of literature, collecting all the papers that reported cases of LTSP, since its first description in 1994. We found that, in these 25 years, less than 50 cases have been described in literature. EXPERT OPINION: Along with the established role of surgery, adjuvant treatment with hormonal agents, in particular in estrogen receptor expression, seems to be a promising approach. However, more efforts must be carried out to describe treatment and outcome of new cases, improving knowledge about this rare condition.
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Neoplasias Ováricas/diagnóstico , Peritonitis/patología , Neoplasia Tecoma/diagnóstico , Femenino , Humanos , Obstrucción Intestinal/etiología , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Esclerosis/patología , Neoplasia Tecoma/patología , Neoplasia Tecoma/terapiaRESUMEN
BACKGROUND: Endometrial carcinoma is one of the most common female cancers in developed countries. Disease stage is associated with the risk of disease relapse after radical treatment. Typically, the risk of disease relapse peaks at 3 years from local radical treatment and then diminishes over time, so that late relapses (i.e., from year 5 afterward) are extremely infrequent. Here, we report two cases of women with endometrial cancer who developed a disease relapse more than 15 years after radical treatment. A review of the literature revealed other seven reports of women with relapse from endometrial cancer occurring more than 10 years after radical treatment. CASE PRESENTATION: Case report 1 is a 56-year-old woman with an endometrioid cancer who underwent a hysterectomy with bilateral salpingo-oophorectomy in 1998. She relapsed in the lung in 2014, 16 years from radical surgery. Case report 2, a 75-year-old woman, with an endometrioid cancer, was treated by hysterectomy with bilateral salpingo-oophorectomy and adjuvant radiotherapy. The disease relapse in the lung was detected in 2019, 22 years from radical treatment. CONCLUSION: Although guidelines do not support oncological follow-up beyond 5 years from surgery, oncologists should consider late recurrence of endometrial carcinoma in the differential diagnosis of women presenting with metastases of uncertain origin and prior history of this disease.
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Neoplasias Endometriales , Histerectomía , Recurrencia Local de Neoplasia , Anciano , Neoplasias Endometriales/patología , Neoplasias Endometriales/cirugía , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Radioterapia AdyuvanteRESUMEN
Background: The world, and Italy on the front lines, has experienced a major medical emergency due to the novel coronavirus outbreak. Cancer patients are one of the potentially most vulnerable cohorts of people, but data about their management are still few. Patients and Methods: In this monocentric retrospective study we included all SARS-CoV-2 oncological patients accepted, between March 27th and April 19th 2020, at the Onco-COVID Unit at San Luigi Gonzaga Hospital, one of the few Italian oncological-COVID wards. Data were obtained from medical records. Results: Eighteen cancer patients with COVID-19 were included. The mean (±SD) age of patients was 67 ± 14 years, 89% were men. Seven (39%) developed infection in communities and 11 (61%) during hospitalization. Lung cancer was the most frequent type of cancer (10, 56%). Seven patients (39%) were symptomatic for COVID-19 at the time of diagnosis and symptoms began 2 (±2) days before. The most common were shortness of breath and diarrhea. Fever was present in 5 patients (28%). Among the 11 asymptomatic patients, 8 (73%) became symptomatic during the hospitalization (mean time of symptoms onset 4 days ±4). Six patients (33%) were on active anti-tumor treatment: 2 (33%) received anti-tumor therapy within 2 weeks before the infection diagnosis and 2 (33%) continued oncological treatment after SARS-CoV-2 positivity. Eight (44%) patients died within a mean of 12 days (±8) from the infection diagnosis. Conclusions: Our series confirms the high mortality among cancer patients with COVID-19. The presence of asymptomatic cases evidences that typical symptoms and fever are not the only parameters to suspect the infection. The Onco-Covid unit suggests the importance of a tailored and holistic approach, even in this difficult situation.
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INTRODUCTION: Adrenocortical carcinoma (ACC) is a rare neoplasm characterized by a high risk of recurrence after radical resection. The role of adjuvant systemic therapy in radically resected patients is unclear. Mitotane, a steroidogenesis inhibitor, is the only drug approved for the systemic treatment of advanced ACC. In 2007, a retrospective case-control study provided the evidence that mitotane, administered for two years after successful surgery, could prolong recurrence-free survival. Adrenal insufficiency (AI), which occurs in almost all patients during the first 12 months of treatment, is an expected side effect of mitotane and requires steroid replacement therapy. Due to its long halflife, mitotane-induced AI persists several months after treatment discontinuation and is managed by cautious tapering of glucocorticoid replacement therapy. RESULTS: We report a case of symptomatic AI diagnosed after a severe allergic reaction occurring three years after the discontinuation of adjuvant mitotane therapy. CONCLUSION: The case suggests that mitotane-induced AI should be monitored for a long time to asses full recovery of adrenal function, in order to prevent adrenal crises.
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Insuficiencia Suprarrenal/sangre , Insuficiencia Suprarrenal/diagnóstico por imagen , Antineoplásicos Hormonales/administración & dosificación , Mitotano/administración & dosificación , Privación de Tratamiento/tendencias , Insuficiencia Suprarrenal/etiología , Adulto , Humanos , MasculinoRESUMEN
Pure red cell aplasia (PRCA) represents one of the most common paraneoplastic syndromes in patients with advanced thymoma. Ciclosporin is a very effective treatment in this condition, and it seems to have also a direct anti-cancer effect. We provide a case of radiological response of thymoma associated with the total absence of response of PRCA in a patient treated with ciclosporin. A 60-year-old man with advanced thymoma underwent first-line chemotherapy, achieving a partial disease response followed by 2 years of stable disease. After disease progression, the patient developed a PRCA, later expanded to platelets, and then he started therapy with ciclosporin, without any blood improvement. The CT revaluation after three months of ciclosporin therapy showed tumor shrinkage, although the inefficacy in the treatment of PRCA. The paper reports a case of dissociation between oncological and hematological response in a patient with thymoma-related PRCA, suggesting that the pathology of this condition deserves novel investigations. Further studies should be conducted to acquire more exhaustive knowledge and permit the integrated treatment of oncological and hematological conditions.
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Recurrent or metastatic disease occurs in two-thirds of head and neck squamous cell carcinomas and it is associated with poor prognosis. Systemic treatment with platinum-based chemotherapy in combination with the epidermal growth factor receptor-targeting monoclonal antibody cetuximab represents a preferred option for these patients. Upon the achievement of tumor response by combined treatment, maintenance with single-agent cetuximab is usually administered with the aim of prolonging disease control at the price of reasonable toxicity. Although rarely, however, cetuximab needs to be discontinued in the absence of disease progression because of intolerable side effects. Here we describe the case of a 66-year-old man with a metastatic cancer of oral cavity, who had to discontinue maintenance cetuximab and who achieved prolonged disease control with metronomic capecitabine. We suggest that capecitabine could be an effective and safe maintenance option in case of cetuximab intolerance.
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Capecitabina/uso terapéutico , Neoplasias de la Boca/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cetuximab/efectos adversos , Cetuximab/uso terapéutico , Humanos , Masculino , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patologíaRESUMEN
We report a case of a 37-year-old man with metastatic differentiated thyroid carcinoma, previously submitted to total thyroidectomy, radio-iodine therapy and lung metastasectomy, who underwent systemic treatment with lenvatinib for tumor recurrence in the lung, mediastinal lymph nodes, left gluteus and left orbit. Lenvatinib induced rapid and durable disease regression; the drug effect has continued after >1 year, as well as a very considerable clinical benefit. The results achieved by lenvatinib in treatment of metastatic differentiated thyroid carcinoma are clear and irrefutable. Real-life data, obtained by case reports and retrospective studies, are equally important to increase the knowledge about this drug and improve the clinical management.
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Neoplasias Pulmonares/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Quinolinas/administración & dosificación , Neoplasias de la Tiroides/tratamiento farmacológico , Adulto , Terapia Combinada , Humanos , Radioisótopos de Yodo/administración & dosificación , Radioisótopos de Yodo/efectos adversos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/secundario , Neoplasias Pulmonares/cirugía , Masculino , Metastasectomía , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/radioterapia , Recurrencia Local de Neoplasia/cirugía , Compuestos de Fenilurea/efectos adversos , Quinolinas/efectos adversos , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/radioterapia , Neoplasias de la Tiroides/cirugía , TiroidectomíaRESUMEN
Recurrent or metastatic head and neck squamous-cell carcinomas (R/M HNSCC) are a group of cancers with a very poor prognosis. Many clinical trials testing novel target therapies in this setting are currently ongoing. We performed a systematic review focusing our attention on all clinical trials, ongoing or already published, concerning the use of novel drugs for treatment of R/M HNSCC. We found that the research of novel molecules effective in treatment of R/M HNSCC has been intense during last decade, and nowadays it is still very active. Unfortunately, the results in this setting have been, overall, disappointing: until now, only cetuximab and, recently, nivolumab and pembrolizumab received authorization for treatment of R/M HNSCC. Nevertheless, the promising results showed by some novel drugs may lead to continue the research in this field, with the aim of producing more evidence and finding new therapeutic indication.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Terapia Molecular Dirigida , Proteínas de Neoplasias/antagonistas & inhibidores , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/secundario , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Proteínas de Neoplasias/metabolismo , Pronóstico , RecurrenciaRESUMEN
Topoisomerase II alpha (TOP2A) and thymidylate synthase (TS) are known prognostic parameters in several tumors and also predictors of efficacy of anthracyclines, topoisomerase inhibitors and fluoropirimidines, respectively. Expression of TOP2A and TS mRNA was assessed in 98 patients with adrenocortical carcinoma (ACC) and protein expression was assessed by immunohistochemistry in a subset of 39 tumors. Ninety-two patients were radically resected for stage II-III disease and 38 of them received adjuvant mitotane. Twenty-six patients with metastatic disease received the EDP-M (etoposide, doxorubicin, Adriamycin, cisplatin plus mitotane). TOP2A and TS expression in ACC tissue was directly correlated with the clinical data. Both markers were not associated with either disease free survival (DFS) or overall survival (OS) in multivariate analyses and failed to be associated to mitotane efficacy. Disease response or stabilization to EDP-M treatment was observed in 12/17 (71%) and 1/9 (11%) patients with high and low TOP2A expressing tumors (P = 0.0039) and 9/13 (69%) and 4/13 (31%) patients with high and low TS expressing ACC, respectively (P = 0.049). High TOP2A expression was significantly associated with longer time to progression (TTP) after EDP-M. TOP2A and TS proteins assessed by immunohistochemistry significantly correlated with mRNA expression. Immunohistochemical TOP2A expression was associated with a non-significant better response and longer TTP after EDP-M. TOP2A and TS were neither prognostic nor predictive of mitotane efficacy in ACC patients. The predictive role of TOP2A expression of EDP-M activity suggests a significant contribution of Adriamycin and etoposide for the efficacy of the EDP scheme.
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Neoplasias de la Corteza Suprarrenal/enzimología , ADN-Topoisomerasas de Tipo II/biosíntesis , Timidilato Sintasa/biosíntesis , Adolescente , Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/genética , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , ADN-Topoisomerasas de Tipo II/genética , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mitotano/administración & dosificación , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Timidilato Sintasa/genética , Adulto JovenRESUMEN
BACKGROUND: Although prognostic parameters are important to guide adjuvant treatment, very few have been identified in patients with completely resected adrenocortical carcinoma (ACC). OBJECTIVE: To assess the prognostic role of clinical symptoms of hypercortisolism in a large series of patients with completely resected ACC. DESIGN, SETTING, AND PARTICIPANTS: A total of 524 patients followed at referral centers for ACC in Europe and the United States entered the study. Inclusion criteria were ≥18 yr of age, a histologic diagnosis of ACC, and complete surgery (R0). Exclusion criteria were a history of other malignancies and adjuvant systemic therapies other than mitotane. INTERVENTION: All ACC patients were completely resected, and adjuvant mitotane therapy was prescribed at the discretion of the investigators. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was overall survival (OS). The secondary end points were recurrence-free survival (RFS) and the efficacy of adjuvant mitotane therapy according to cortisol secretion. RESULTS AND LIMITATIONS: Overt hypercortisolism was observed in 197 patients (37.6%). Patients with cortisol excess were younger (p=0.002); no difference according to sex and tumor stage was observed. The median follow-up of the series was 50 mo. After adjustment for sex, age, tumor stage, and mitotane treatment, the prognostic significance of cortisol excess was highly significant for both RFS (hazard ratio [HR]: 1.30; 95% confidence interval [CI], 1.04-2.62; p=0.02) and OS (HR: 1.55; 95% CI, 1.15-2.09; p=0.004). Mitotane administration was associated with a reduction of disease progression (adjusted HR: 0.65; 95% CI, 0.49-0.86; p=0.003) that did not differ according to the patient's secretory status. A major limitation is that only symptomatic patients were considered as having hypercortisolism, thus excluding information on the prognostic role of elevated cortisol levels in the absence of a clinical syndrome. CONCLUSIONS: Clinically relevant hypercortisolism is a new prognostic factor in patients with completely resected ACC. The efficacy of adjuvant mitotane does not seem to be influenced by overt hypercortisolism.
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Neoplasias de la Corteza Suprarrenal/cirugía , Carcinoma Corticosuprarrenal/cirugía , Antineoplásicos Hormonales/uso terapéutico , Síndrome de Cushing/prevención & control , Mitotano/uso terapéutico , Adolescente , Neoplasias de la Corteza Suprarrenal/complicaciones , Carcinoma Corticosuprarrenal/complicaciones , Adulto , Anciano , Síndrome de Cushing/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE: Mitotane is the most broadly used systemic therapy for adrenocortical carcinoma (ACC), but its mechanism of action and possible predictors of treatment response are currently poorly defined. Our aim was to evaluate the gene expression of ribonucleotide reductase large subunit 1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) in ACC as potential biomarkers for clinical outcome and response to mitotane. EXPERIMENTAL DESIGN: Forty-five and 47 tissue samples from two cohorts (Orbassano, Italy; Wuerzburg, Germany) of completely resected ACC were centrally analyzed using real-time PCR for RRM1 and ERCC1 expression. Fifty-four patients received surgery alone and 38 received adjuvant mitotane after surgery. Clinical and pathologic features were highly comparable in the two series. H295R and SW-13 ACC cell lines were also used for pharmacologic tests. RESULTS: ERCC1 gene expression was not associated to clinical outcome. In contrast, high RRM1 gene expression was associated to shorter disease-free survival (DFS) and overall survival at both univariate and multivariate analysis. In patients with low RRM1 gene expression, adjuvant mitotane was associated with improved DFS, whereas this effect was lost in cases with high RMM1 expression. In vitro mitotane induced strong up regulation of RRM1 transcription (up to 25-fold increase) in mitotane-insensitive SW-13 but not in mitotane-sensitive H295R cells. Furthermore, RRM1 silencing in SW-13 cells induced sensitivity to mitotane. CONCLUSION: Our in vitro and in vivo data indicate that RRM1 gene expression is functionally associated to mitotane sensitivity and support a possible role of RRM1 determination as a novel molecular biomarker predicting response to adjuvant mitotane in ACC.
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Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Neoplasias de la Corteza Suprarrenal/genética , Antineoplásicos/uso terapéutico , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Mitotano/uso terapéutico , Proteínas Supresoras de Tumor/genética , Adolescente , Neoplasias de la Corteza Suprarrenal/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Quimioterapia Adyuvante , Proteínas de Unión al ADN/biosíntesis , Supervivencia sin Enfermedad , Endonucleasas/biosíntesis , Femenino , Marcadores Genéticos , Humanos , Masculino , Persona de Mediana Edad , Interferencia de ARN , ARN Interferente Pequeño , Ribonucleósido Difosfato Reductasa , Resultado del Tratamiento , Proteínas Supresoras de Tumor/biosíntesis , Adulto JovenRESUMEN
BACKGROUND: Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. METHODS: We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. RESULTS: For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. CONCLUSIONS: Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).
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Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mitotano/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mitotano/efectos adversos , Calidad de Vida , Estreptozocina/administración & dosificación , Estreptozocina/efectos adversos , Adulto JovenRESUMEN
BACKGROUND: There is a strong rationale in the use of antiangiogenic therapy in the management of adrenocortical carcinoma (ACC). Metronomic administration of chemotherapy and antiangiogenic drugs can be synergistic in targeting endothelial cells. OBJECTIVE: We assessed the activity of sorafenib plus metronomic paclitaxel as second/third-line therapy in advanced ACC patients. We also tested the activity of sorafenib and paclitaxel against NCI-H295R in vitro. DESIGN: Multicenter, prospective phase II trial. Setting Referral centers for ACC. METHODS: Twenty-five consecutive metastatic ACC patients who progressed after mitotane plus one or two chemotherapy lines were planned to be enrolled. The patients received a combination of i.v. paclitaxel (60 mg/m(2) every week) and oral sorafenib (400 mg twice a day) till progression. The primary aim was to measure the progression-free survival rate after 4 months and the secondary aims were to assess the objective response rate and toxicity. RESULTS: Tumor progression was observed in nine evaluable patients at the first assessment. These results led to the premature interruption of the trial. The treatment was well tolerated. The most relevant toxicities were fatigue, being grade 2 or 3 in four patients, and hypophosphatemia, being grade 3 in three patients. In the in vitro study, sorafenib impaired the viability of H295R cells with dose-response and time-response relationships. The in vitro sorafenib activity was not increased in combination with paclitaxel. CONCLUSIONS: Despite the in vitro activity, sorafenib plus weekly paclitaxel is an inactive salvage treatment in patients with advanced ACC and should not be recommended.
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Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/patología , Adulto , Anciano , Bencenosulfonatos/administración & dosificación , Línea Celular Tumoral , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Niacinamida/análogos & derivados , Paclitaxel/administración & dosificación , Compuestos de Fenilurea , Estudios Prospectivos , Piridinas/administración & dosificación , SorafenibRESUMEN
Metronomic chemotherapy is the administration of cytotoxic drugs at low doses, on a frequent or continuous schedule, with no extended interruption. This treatment approach can target tumor cells indirectly since it can affect the endothelium of the growing tumor vasculature and stimulates the anticancer immune response. Both the antiangiogenetic and the immunomodulatory roles of metronomic chemotherapy favor a tumor dormancy, a condition that may improve the patient outcome. Prospective clinical trials conducted in several malignancies have shown that metronomic chemotherapy can obtain disease stabilization or responses in tumors that had been made resistant in vivo to conventional chemotherapeutic regimens. Three prospective phase II trials have been conducted in patients with adrenocortical carcinoma (ACC). In all of them, patients heavily pretreated with conventional chemotherapy and mitotane have been enrolled. One trial tested the activity of the association of gemcitabine and fluoropyrimidines administered on a metronomic schedule. In this trial, 40% of patients attained a disease stabilization or disease response that was long lasting in some of them. In the remaining two trials, metronomic chemotherapy was administered in association with antiangiogenetic drugs, and the results were disappointing since no response or stable disease was obtained. In conclusion, metronomic chemotherapy can delay tumor progression in advanced ACC and deserves to be further tested. The concomitant administration of antiangiogenetic drugs may be detrimental. Several important questions remain to be addressed such as the optimal dose and most effective dosing interval, when to use the metronomic approach in the natural history of the disease, the choice of cytotoxic drugs, and the most efficacious way to integrate metronomic chemotherapy with standard therapy protocols.
Asunto(s)
Administración Metronómica , Neoplasias de las Glándulas Suprarrenales/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de las Glándulas Suprarrenales/patología , Neoplasias de las Glándulas Suprarrenales/fisiopatología , Carcinoma Corticosuprarrenal/patología , Carcinoma Corticosuprarrenal/fisiopatología , Animales , Ensayos Clínicos Fase III como Asunto , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/patología , Humanos , Inmunidad/efectos de los fármacos , Mitotano/administración & dosificación , Mitotano/efectos adversos , Neovascularización Patológica , Resultado del TratamientoRESUMEN
Adrenocortical carcinoma (ACC) is a rare neoplasm characterized by poor prognosis. First-line systemic treatments in advanced disease include mitotane, either alone or in combination with chemotherapy. Studies evaluating second-line therapy options have obtained disappointing results. This trial assessed the activity and toxicity of gemcitabine plus metronomic fluoropyrimidines in heavily pretreated advanced ACC patients. From 1998 to 2008, 28 patients with advanced ACC progressing after mitotane plus one or two systemic chemotherapy lines were enrolled. They received a combination of i.v. gemcitabine (800 mg/m(2), on days 1 and 8, every 21 days) and i.v. 5-fluorouracil protracted infusion (200 mg/m(2)/daily without interruption until progression) in the first six patients, or oral capecitabine (1500 mg/daily) in the subsequent patients. Mitotane administration was maintained in all cases. The rate of non-progressing patients after 4 months of treatment was 46.3%. A complete response was observed in 1 patient (3.5%); 1 patient (3.5%) obtained a partial regression, 11 patients (39.3%) obtained a disease stabilization and 15 patients (53.7%) progressed. Treatment was well tolerated, with grade III and IV toxicities consisting of leukopenia in six patients (21.4%), thrombocytopenia in one patient (3.5%), and mucositis in one patient (3.5%). Median time to progression and overall survival in the patient population were 5.3 (range: 1-43) and 9.8 months (range: 3-73) respectively. Gemcitabine plus metronomic fluoropyrimidines is a well-tolerated and moderately active regimen in heavily pretreated ACC patients.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/tratamiento farmacológico , Carcinoma Corticosuprarrenal/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Fluorouracilo/administración & dosificación , Neoplasias de la Corteza Suprarrenal/mortalidad , Carcinoma Corticosuprarrenal/mortalidad , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Progresión de la Enfermedad , Esquema de Medicación , Femenino , Fluorouracilo/efectos adversos , Humanos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Mucositis/inducido químicamente , Trombocitopenia/inducido químicamente , Resultado del Tratamiento , GemcitabinaRESUMEN
AIMS: Pathological diagnosis of adrenocortical carcinoma relies on several microscopic features commonly used in combination in different scoring systems that are sometimes subjective and/or time consuming. The aim was to investigate the impact of individual pathological parameters in the diagnosis and prognosis of adrenocortical carcinoma. METHODS AND RESULTS: The series included 92 malignant cases and a control series of 47 adenomas, all classified according to Weiss score criteria. The presence of disruption of the reticular network, as highlighted by histochemical staining, was present in all adrenocortical carcinomas and the inclusion of at least one of the three following additional parameters - mitotic index >5/50 high-power fields (HPF), presence of necrosis and presence of vascular invasion - gave an algorithm with 100% sensitivity and specificity to recognize malignant tumours according to the Weiss system, with easier and more practical applicability. Moreover, on multivariate analysis, stage III/IV and mitotic count >9/50 HPF showed a strong adverse impact on disease-free and overall survival, leading to the identification of three risk groups affected by a significantly different prognosis. CONCLUSIONS: We have defined an easy-to-perform and highly specific and sensitive algorithm for the diagnosis and prognostic categorization of adrenocortical tumours.
Asunto(s)
Neoplasias de la Corteza Suprarrenal/patología , Carcinoma Corticosuprarrenal/patología , Algoritmos , Adenoma/patología , Neoplasias de la Corteza Suprarrenal/mortalidad , Carcinoma Corticosuprarrenal/mortalidad , Diagnóstico Diferencial , Supervivencia sin Enfermedad , Humanos , Pronóstico , Modelos de Riesgos Proporcionales , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Adrenocortical carcinoma (ACC) is an extremely rare aggressive disease. Few data are available on the efficacy of systemic antineoplastic treatments (mitotane and cytotoxic therapy) in the treatment of advanced disease. OBJECTIVE/METHODS: this paper will review the existing treatment strategies and new perspectives in the management of ACC patients. RESULTS/CONCLUSION: An ongoing randomized international trial aims to define the best combination chemotherapy plus mitotane regimen. Based on the results of a case control study, mitotane is being explored as adjuvant therapy. Genetic and biological studies have identified molecular targets for specific targeted drugs such as IGF receptor inhibitors and antiangiogenetic drugs. Phase II trials are exploring the activity of these drugs either alone or in combination with chemotherapy.