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BACKGROUND: The INMUNOSUN trial had the objective of prospectively evaluating the efficacy and safety of sunitinib as a pure second-line treatment in patients with metastatic renal cell carcinoma (mRCC) who have progressed to first-line immune checkpoint inhibitor (ICI)-based therapies. PATIENTS AND METHODS: A multicenter, phase II, single-arm, open-label study was carried out in patients with a histologically confirmed diagnosis of mRCC with a clear-cell component who had progressed to a first-line regimen of ICI-based therapies. All patients received sunitinib 50 mg once daily orally for 4 weeks, followed by a 2-week rest period following package insert instructions. The primary outcome was the objective response rate. RESULTS: Twenty-one assessable patients were included in the efficacy and safety analyses. Four patients [19.0%, 95% confidence interval (CI) 2.3% to 35.8%] showed an objective response (OR), and all of them had partial responses. Additionally, 14 (67%) patients showed a stable response, leading to clinical benefit in 18 patients (85.7%, 95% CI 70.7% to 100%). Among the four assessable patients who showed an OR, the median duration of the response was 7.1 months (interquartile range 4.2-12.0 months). The median progression-free survival (PFS) was 5.6 months (95% CI 3.1-8.0 months). The median overall survival (OS) was 23.5 months (95% CI 6.3-40.7 months). Patients who had better antitumor response to first-line ICI-based treatment showed a longer PFS and OS with sunitinib. The most frequent treatment-emergent adverse events were diarrhea (n = 11, 52%), dysgeusia (n = 8, 38%), palmar-plantar erythrodysesthesia (n = 8, 38%), and hypertension (n = 8, 38%). There was 1 patient who exhibited grade 5 pancytopenia, and 11 patients experienced grade 3 adverse events. Eight (38%) patients had serious adverse events, four of which were considered to be related to sunitinib. CONCLUSION: Although the INMUNOSUN trial did not reach the pre-specified endpoint, it demonstrated that sunitinib is active and can be safely used as a second-line option in patients with mRCC who progress to new standard ICI-based regimens.
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Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Femenino , Humanos , Indoles/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Estudios Prospectivos , Sunitinib/efectos adversosAsunto(s)
Neoplasias Óseas , Osteosarcoma , Sarcoma , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/epidemiología , Neoplasias Óseas/terapia , Estudios de Seguimiento , Humanos , Osteosarcoma/diagnóstico , Osteosarcoma/epidemiología , Osteosarcoma/terapia , Sarcoma/diagnóstico , Sarcoma/epidemiología , Sarcoma/terapiaRESUMEN
Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.
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Hemangioendotelioma Epitelioide , Sarcoma , Adulto , Niño , Consenso , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/tratamiento farmacológico , Humanos , Oncología Médica , Defensa del Paciente , Sarcoma/diagnóstico , Sarcoma/tratamiento farmacológicoRESUMEN
PURPOSE: Active surveillance (AS) and adjuvant chemotherapy (AC) with carboplatin are valid alternatives for managing stage I seminoma, and most relapses can be cured with cisplatin-based chemotherapy. However, some reports suggest that AC may modify the classical pattern of recurrences. METHODS: We analyzed all relapses observed in a series of 879 patients with stage I seminoma included in 4 consecutive studies of the Spanish Germ Cell Cancer Group. After a median follow-up of 67 months, recurrences were detected in 56/467 (12%) low-risk cases on AS and 13/412 (3%) high-risk cases after AC (p < 0.001). The objective was to describe clinical features, treatment and outcome. Univariate comparisons were performed between both groups. RESULTS: No significant differences were found between relapses on AS and those after AC in terms of time to relapse (13 vs 17 months), size (26 vs 27 mm), location (retroperitoneum in 88% vs 85%), and method of detection (computed tomography in 77% vs 69%). Treatment consisted of chemotherapy (etoposide + cisplatin ± bleomycin) in 89% and 92%, respectively. Late relapses (after > 3 years) were seen in 11% vs 7.7% (p = NS) and second or successive recurrences in 1.8 vs 23% (p < 0.05). With a median follow-up of 130 moths, two patients died of seminoma-unrelated causes (AS group) and the rest are alive and disease-free. CONCLUSION: In the setting of a risk-adapted treatment of stage I seminoma, the administration of two courses of AC in patients with tumor size > 4 cm and/or rete testis invasion is associated with a higher incidence of second recurrences but does not significantly modify the pattern of relapses or their outcome.
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Antineoplásicos/uso terapéutico , Carboplatino/uso terapéutico , Recurrencia Local de Neoplasia , Neoplasias Testiculares , Espera Vigilante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/uso terapéutico , Quimioterapia Adyuvante , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Cisplatino/uso terapéutico , Supervivencia sin Enfermedad , Etopósido/uso terapéutico , Estudios de Seguimiento , Humanos , Masculino , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Orquiectomía , Red Testicular/patología , Neoplasias Retroperitoneales/patología , Estudios Retrospectivos , Seminoma/tratamiento farmacológico , Seminoma/patología , Seminoma/cirugía , España , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/patología , Neoplasias Testiculares/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: Incidence of a second testicular tumor is higher in patients diagnosed with testicular cancer than in the general population. As incidence of unilateral germ cell cancer is increasing worldwide and most of these patients are cured, a growing number of patients at risk of developing a contralateral testis cancer is expected. OBJECTIVE: To analyze clinical and histological characteristics, as well as the absolute and cumulative incidence of a second testicular cancer in a cohort of 3,834 patients diagnosed with germ cell testicular cancer between I/1994 and I/2018 in 18 referral hospitals of the Spanish Germ Cell Cancer Group. METHODS: Patients were treated according to stage and year of diagnoses. Contralateral testis biopsy was not routinely performed, according to European Association of Urology rules. Follow-up of the contra lateral testis consists of a physical exam only and an annual optional testicular ultrasound for 10 years. RESULTS: Median age of the patients included was 32 years (18-82). With a median follow-up of 61 months (0-240), 67/3,834 patients (1.74%) were diagnosed with a second testicular tumor. The second testicular tumor was synchronic (diagnosed within 6 months of the first orchiectomy) in 19 patients, and metachronous in 48. Pathology of the second tumor was reported as a seminomatous testis tumor in 47 patients and a nonseminomatous cancer in 20. Cumulative incidence of contralateral testicular cancer was 2% at 5 years, and 4% (IC 95% 3%-5%) at 14 years. Younger age was a risk factor for developing a second testicular tumor (P = 0.006), whereas chemotherapy reduced the risk for a metachronous testicular cancer (Pâ¯=â¯0.046). Within our cohort, 6 families with testicular cancer aggregation (more than 2 tumors in the same family) were identified. CONCLUSIONS: Incidence of second testicular neoplasm in this cohort of 3,834 patients was similar to that which has been reported in other countries. Metachronous tumors and seminomas are more common. Follow-up of the contralateral testis is mandatory, as well as adequate information for patients to prevent a second neoplasm if feasible, and to detect and treat it as soon as possible.
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Neoplasias de Células Germinales y Embrionarias/epidemiología , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias Primarias Múltiples/epidemiología , Neoplasias Primarias Múltiples/patología , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/patología , Neoplasias Testiculares/epidemiología , Neoplasias Testiculares/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
PURPOSE: Stage IS testicular cancer is defined by the persistence of elevated serum tumor markers, including α-fetoprotein and/or ß-human chorionic gonadotropin, after orchiectomy without radiological evidence of metastatic disease. Current treatment recommendations include cisplatin based chemotherapy up front but the recommendations are based on limited single center series. MATERIALS AND METHODS: We retrospectively analyzed clinical and pathological characteristics, and long-term outcomes in 110 patients uniformly treated with primary chemotherapy between 1994 and 2016. The primary objective was to evaluate long-term disease-free survival. We also explored factors associated with the need for additional treatment. RESULTS: The elevated prechemotherapy tumor markers were α-fetoprotein in 48% of cases, ß-human chorionic gonadotropin in 14%, and α-fetoprotein and ß-human chorionic gonadotropin in 38%. Median α-fetoprotein and ß-human chorionic gonadotropin values were 71 ng/ml and 80 mIU/ml, respectively. The IGCCCG (International Germ Cell Cancer Collaborative Group) prognostic classification was good in 94% of cases. Mixed nonseminomatous germ cell tumor was found in 78% of cases. Of the patients 103 achieved a complete response to chemotherapy. In 6 patients radiological signs of progressive disease developed during chemotherapy, while 8 experienced relapse after an initial complete response. At a median followup of 108 months 108 patients were alive and disease-free. Five and 10-year disease-free survival rates were 87% and 85%, respectively. The predominance of embryonal carcinoma in the primary tumor was the only factor associated with the probability of needing additional therapy. CONCLUSIONS: Stage IS testicular cancer is more commonly associated with elevated α-fetoprotein, an IGCCCG good prognosis and mixed nonseminomatous germ cell tumor. Treatment with cisplatin based chemotherapy leads to cure in most cases. However, a proportion of patients require the integration of additional therapies, including more frequently when embryonal carcinoma is not predominant.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Embrionario/tratamiento farmacológico , Recurrencia Local de Neoplasia/epidemiología , Neoplasias de Células Germinales y Embrionarias/terapia , Orquiectomía , Neoplasias Testiculares/terapia , Adulto , Carcinoma Embrionario/sangre , Carcinoma Embrionario/mortalidad , Quimioterapia Adyuvante/métodos , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Supervivencia sin Enfermedad , Estudios de Seguimiento , Humanos , Masculino , Recurrencia Local de Neoplasia/prevención & control , Neoplasias de Células Germinales y Embrionarias/sangre , Neoplasias de Células Germinales y Embrionarias/mortalidad , Neoplasias Testiculares/sangre , Neoplasias Testiculares/mortalidad , Testículo/diagnóstico por imagen , Testículo/patología , Adulto Joven , alfa-Fetoproteínas/análisisRESUMEN
The conflict of interest declaration was published incorrectly in the original version.
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OBJECTIVE: To evaluate the prevalence and type of rheumatic immune-related adverse events (IRAEs) in patients receiving programmed cell death protein-1 (PD-1) inhibitors. METHODS: This is a single-center prospective observational study, including all cancer patients receiving PD-1 inhibitors between January 2016 and January 2018. RESULTS: During the period analyzed, we evaluated a total of 11 patients. No patient had pre-existing rheumatic or autoimmune disease. In this period, a total of 220 patients were treated with PD1 inhibitors in our center; therefore, the estimated minimum prevalence of rheumatic IRAEs related to these therapies in our population was 5%. The rheumatic IRAEs evaluated included 5 cases of oligo- or polyarthritis, 1 with a polymialgia rheumatica-type syndrome, 2 cases of immunotherapy-induced sicca syndrome, 2 patients who presented symptomatic inflammatory myositis with fasciitis in lower extremities, and 1 patient with a paraneoplastic acral vascular syndrome. The median time to IRAE after anti-PD1 exposure was 8â¯weeks (range: 2-24). In 5 patients, immunotherapy was discontinued (due to the adverse effect in three and cancer progression in two). In general terms the symptoms resolved completely with symptomatic treatment. Disease-modifying antirheumatic drugs were needed for 2 patients. CONCLUSION: Rheumatic IRAEs should be kept in mind during the follow-up and evaluation of patients treated with PD-1 inhibitors. The concomitant development of symptomatic inflammatory myositis with fasciitis in lower extremities appears to be a new adverse effect of anti-PD-1 immunotherapy. Additional studies are needed to determine how to adequately control and manage these complications.
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Antineoplásicos Inmunológicos/efectos adversos , Inmunoterapia/efectos adversos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Enfermedades Reumáticas/inducido químicamente , Humanos , Inflamación/inducido químicamente , Neoplasias/tratamiento farmacológico , Estudios Prospectivos , Enfermedades Reumáticas/inmunologíaRESUMEN
The goal of this article is to provide recommendations about the management of kidney cancer. Based on pathologic and molecular features, several kidney cancer variants were described. Nephron-sparing techniques are the gold standard of localized disease. After a randomized trial, sunitinib could be considered in adjuvant treatment in high-risk patients. Patients with advanced disease constitute a heterogeneous population. Prognostic classification should be considered. Both sunitinib and pazopanib are the standard options for first-line systemic therapy in advanced renal cell carcinoma. Based on the results of two randomized trials, both nivolumab and cabozantinib should be considered the standard for second and further lines of therapy. Response evaluation for present therapies is a challenge.
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Carcinoma de Células Renales/terapia , Neoplasias Renales/terapia , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/patología , Humanos , Neoplasias Renales/diagnóstico , Neoplasias Renales/patologíaRESUMEN
BACKGROUND: Patients with relapsed unresectable osteosarcoma represents an unmet need, so active and safe systemic treatments are required. Fas cell surface death receptor and mammalian target of rapamycin pathways are implicated in progressing osteosarcoma, and we had preclinical and clinical experience with a scheme that targets both pathways. Therefore, we designed a phase II trial with gemcitabine plus rapamycin, to determine the efficacy and safety, in this subset of patients. PATIENTS AND METHODS: A multicenter, single-arm phase II trial was sponsored by the Spanish Group for Research on Sarcoma. Osteosarcoma patients, relapsed or progressing after standard chemotherapy and unsuitable for metastasectomy received gemcitabine and rapamycin p.o. 5 mg/day except for the same day of gemcitabine administration, and the day before. The main end point was 4-month progression-free survival rate (PFSR), with the assumption that rates higher than 40% would be considered as an active regimen. Translational research aimed to correlate biomarkers with the clinical outcome. RESULTS: Thirty-five patients were enrolled and received at least one cycle. PFSR at 4 months was 44%, and after central radiologic assessment, 2 partial responses and 14 stabilizations (48.5%) were reported from 33 assessable patients. The most frequent grade 3-4 adverse events were: neutropenia (37%), thrombocytopenia (20%), anemia (23%), and fatigue (15%); however, only three patients had febrile neutropenia. Positive protein expression of RRM1 significantly correlated with worse PFS and overall survival, while positivity of P-ERK1/2 was correlated with significant better overall survival. CONCLUSION: Gemcitabine plus sirolimus exhibits satisfactory antitumor activity and safety in this osteosarcoma population, exceeding the prespecified 40% of 4-month PFSR. The significant correlation of biomarkers with clinical outcome encourages further prospective investigation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Óseas/patología , Niño , Preescolar , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Osteosarcoma/patología , Recurrencia , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Adulto Joven , GemcitabinaRESUMEN
BACKGROUND: First Spanish trial of Ewing sarcoma (ES) including adults and children with the aim to test the efficacy of Gemcitabine and Docetaxel (G/D) in newly diagnosed high-risk (HR) patients. METHODS: This was a prospective, multicentric, non-randomised, open study for patients ⩽40 years with newly diagnosed ES. HR patients (metastatic, axial-pelvic primaries or bone marrow micrometastasis) received 2 window cycles of G/D. Patients with an objective response (OR) to G/D received 12 monthly cycles of G/D after completion of mP6. The primary end point was the OR rate to the G/D window phase and the event-free survival (EFS) and overall survival (OS) for all patients. The study is registered at ClinicalTrials.gov (identifier: NCT00006734). RESULTS: Forty-three patients were enroled, median age 17 years (range, 3-40). After a median follow-up of 43.4 months, the 5-year OS rate is 55.0% (95% CI, 41-74%) with an EFS of 50.0% (95% CI, 36-68%). The 5-year OS and EFS rates for standard risk (SR) patients was 76.0% (95% CI, 57-100%) and 71.0% (CI, 54-94%); for HR 36.0% (CI, 20-65%) and 29.0% (CI, 15-56%). Twelve of 17 (70.6%) high-risk (HR) patients showed an OR (7 PR and 5 SD) to G/D window therapy. The 5-year OS rate for patients ⩽18 years of age was 74.0% (CI, 56-97%) and 31.0% for >18 years (95% CI, 15-66%), P<0.001. Grade 4 adverse events during mP6 occurred in 28/39 of patients (72%) and did not correlate with age. Multivariate survival analyses with <18 vs ⩾18 and risk groups significant differences, P<0.00001. Using a Cox model for OS, both age and risk group were statistically significant (P=0.0011 and P=0.0065, respectively). CONCLUSIONS: Age at diagnosis is an independent prognostic factor superior to the presence of metastases with 18 years as the strongest cut-off. The mP6 regimen provided survival curves that plateau at 3 years and G/D produced significant responses in HR-ES that is worth further exploring.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Supervivencia sin Enfermedad , Docetaxel , Humanos , Estimación de Kaplan-Meier , Oportunidad Relativa , Pronóstico , Estudios Prospectivos , Sarcoma de Ewing/mortalidad , España , Tasa de Supervivencia , Taxoides/administración & dosificación , GemcitabinaRESUMEN
Soft-tissue sarcomas are uncommon and heterogeneous tumors of mesenchymal origin. A soft-tissue mass that is increasing in size, greater than 5 cm, or located under deep fascia are criteria for suspicion of sarcoma. Diagnosis, treatment, and management should preferably be performed by a multidisciplinary team in reference centers. MRI and lung CT scan are mandatory for local and distant assessment. A biopsy indicating histological type and grade is needed previous to the treatment. Wide surgical resection with tumor-free tissue margin is the primary treatment for localized disease. Radiotherapy is indicated in large, deep, high-grade tumors, or after marginal resection not likely of being improved with reexcision. Neoadjuvant and adjuvant chemotherapy improve survival in selected cases, usually in high-grade sarcomas of the extremities. In the case of metastatic disease, patients with exclusive lung metastasis could be considered for surgery. First-line treatment with anthracyclines (or in combination with ifosfamide) is the treatment of choice. New drugs have shown activity in second-line therapy and in specific histological subtypes.
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Guías de Práctica Clínica como Asunto , Sarcoma/diagnóstico , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/terapia , Humanos , Clasificación del Tumor , Metástasis de la Neoplasia , EspañaRESUMEN
Testicular cancer represents the most common malignancy in males aged 15-34 years and is considered a model of curable neoplasm. Maintaining success, reducing treatment burden, and focusing on survivorship are then key objectives. Inguinal orchiectomy is the first recommended maneuver that has both diagnostic and therapeutic aims. Most patients are diagnosed with stage I disease (confined to the testicle). Close surveillance and selective, short-course adjuvant chemotherapy are accepted alternatives for these cases. In patients with more advanced disease (stages II and III), 3-4 courses of cisplatin-based chemotherapy (according to IGCCCG risk classification) followed by the judicious surgical removal of residual masses represent the cornerstone of therapy. Poor-risk patients and those failing a first-line therapy should be referred to specialized tertiary centers. Paclitaxel-based conventional chemotherapy and high-dose chemotherapy plus autologous hematopoietic support can cure a proportion of patients with relapsing or refractory disease.
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Neoplasias de Células Germinales y Embrionarias/diagnóstico , Neoplasias de Células Germinales y Embrionarias/terapia , Guías de Práctica Clínica como Asunto , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/terapia , Adolescente , Adulto , Humanos , Masculino , Estadificación de Neoplasias , Factores de Riesgo , España , Adulto JovenRESUMEN
This review provides updated information published in 2014 regarding advances and major achievements in genitourinary cancer. Sections include the best in prostate cancer, renal cancer, bladder cancer, and germ cell tumors. In the field of prostate cancer, data related to treatment approach of hormone-sensitive disease, castrate-resistant prostate cancer, mechanisms of resistance, new drugs, and molecular research are presented. In relation to renal cancer, relevant aspects in the treatment of advanced renal cell carcinoma, immunotherapy, and molecular research, including angiogenesis and von Hippel-Lindau gene, molecular biology of non-clear cell histologies, and epigenetics of clear renal cell cancer are described. New strategies in the management of muscle-invasive localized bladder cancer and metastatic disease are reported as well as salient findings of biomolecular research in urothelial cancer. Some approaches intended to improve outcomes in poor prognosis patients with metastatic germ cell cancer are also reported. Results of clinical trials in these areas are discussed.
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Neoplasias Urogenitales/terapia , HumanosRESUMEN
BACKGROUND: We aimed to analyze prognostic factors for relapse in stage I seminoma managed by either active surveillance or adjuvant chemotherapy, and to describe the long-term patterns of recurrence in both groups. PATIENTS AND METHODS: From 1994 to 2008, 744 patients were included in three consecutive, prospective risk-adapted studies by the Spanish Germ Cell Cancer Group. Low-risk patients were managed by surveillance and high-risk patients were given two courses of adjuvant carboplatin. Relapses were treated mainly with chemotherapy. Patient age, tumor size, histological variant, pT staging, rete testis invasion, and preoperative serum BHCG levels were assessed for prediction of disease-free survival (DFS). RESULTS: After a median follow-up of 80 months, 63 patients (11.1%) have relapsed: 51/396 (14.8%) on surveillance and 12/348 (3.2%) following adjuvant carboplatin. Actuarial overall 5-year DFS was 92.3% (88.3% for surveillance versus 96.8% for chemotherapy, P = 0.0001). Median time to relapse was 14 months. Most recurrences were located at retroperitoneum (86%), with a median tumor size of 26 mm. All patients were rendered disease-free with chemotherapy (92%), radiotherapy (5%), or surgery followed by chemotherapy (3%). A nomogram was developed from surveillance patients that includes two independent, predictive factors for relapse: rete testis invasion and tumor size (as a continuous variable). CONCLUSION: Long-term follow-up confirms the risk-adapted approach as an effective option for patients with stage I seminoma. The pattern of relapses after adjuvant chemotherapy is similar to that observed following surveillance. A new nomogram for prediction of DFS among patients on surveillance is proposed. Rete testis invasion and tumor size should be taken into account when considering the administration of adjuvant carboplatin. Prospective validation is warranted.
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Quimioterapia Adyuvante , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pronóstico , Seminoma/tratamiento farmacológico , Seminoma/radioterapia , Adolescente , Adulto , Terapia Combinada , Supervivencia sin Enfermedad , Humanos , Masculino , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias , Nomogramas , Orquiectomía , Factores de Riesgo , Seminoma/patología , Seminoma/cirugíaRESUMEN
BACKGROUND: We conducted a phase I study in patients with advanced solid tumours to identify the recommended dose, assess pharmacokinetics (PK), pharmacodynamic activity and preclinical antitumour efficacy of the combination of sirolimus and gemcitabine. METHODS: Nineteen patients were treated with sirolimus 2 or 5 mg daily and gemcitabine 800 or 1000 mg m(-2) on days 1 and 8. Dose escalation depended on dose-limiting toxicity (DLT) rate during the first 3-week period. Paired skin biopsies were evaluated for phosphorylated S6 (pS6) as marker of mTOR (mammalian target of rapamycin) inhibition. Pharmacokinetics and preclinical evaluation of efficacy using two different sarcoma cell lines and leiomyosarcoma xenografts were also conducted. RESULTS: Three DLTs were observed: grade 3 transaminitis, grade 3 thrombocytopenia and grade 4 thrombocytopenia. Common treatment-related adverse events included anaemia, neutropenia, thrombocytopenia and transaminitis. Pharmacodynamic analyses demonstrated mTOR inhibition with sirolimus 5 mg and PK showed no influence of sirolimus concentrations on gemcitabine clearance. In vitro and in vivo studies suggested mTOR pathway hyperactivation by gemcitabine that was reversed by sirolimus. Tumour growth in leiomyosarcoma xenografts was dramatically inhibited by the treatment. CONCLUSIONS: Recommended dose was sirolimus 5 mg per 24 h plus gemcitabine 800 mg m(-2). Antitumour activity in preclinical sarcoma models and mTOR signalling inhibition were observed. A phase II study is currently ongoing.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias/tratamiento farmacológico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adulto , Anciano , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Línea Celular Tumoral , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Neoplasias/metabolismo , Sirolimus/administración & dosificación , GemcitabinaRESUMEN
BACKGROUND: Brain metastases of testicular germ cell tumor (TGCT) are a rare event. Prognostic is poor and there is not much evidence on optimal management of these patients. PATIENTS AND METHODS: A review of case records of germ cell tumor patients within the Spanish Germ Cell Cancer Group data base from 1994 to 2012 was conducted. RESULTS: Thirty-three out of 6,200 cases (0.5 %). Nineteen patients (57 %) group 1: synchronous, 13 (40 %) group 2: metachronous and only one developed brain metastasis during cisplatin-based chemotherapy (excluded from the analysis). Median serum BHCG levels at initial diagnosis was higher in group 1, whereas elevated AFP serum levels were more common in group 2. Histology in the primary tumor: chorionic carcinoma for group 1 versus embryonal carcinoma for group 2. Mainly solitary brain metastasis in group 2 (54 versus 21 %, respectively). The median overall survival from the diagnosis of central nervous system involvement was 16 months for group 1 (CI 95 % 13.9-18) and 23 months (95 % CI 0-165) for group 2 (log rank p = 0.84). Long-term survivors were practically identical in the two groups (38.9 % group 1 versus 38.5 % group 2). Regardless of the timing of brain metastasis, those patients that achieved complete response to the treatment had better survival (log rank p 0.003). CONCLUSION: Although some distinctive clinical characteristics have been found between patients with synchronous versus metachronous brain metastasis from TGCT, the timing of brain metastasis did not seem to have prognostic influence, but due to the retrospective nature of the analysis and the results should be interpreted with caution.
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Neoplasias Encefálicas/secundario , Neoplasias de Células Germinales y Embrionarias/secundario , Neoplasias Testiculares/patología , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/mortalidad , Análisis de Supervivencia , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/mortalidad , Adulto JovenRESUMEN
In this work, we have analyzed the expression of different members of the ErbB family in human samples of testicular germ cell tumors (GCTs). We observed expression of ErbB1 or ErbB2 in different tumor subtypes, but we also found high expression of ErbB3 in all GCTs tested. This pattern of expression was maintained when primary tumors were orthotopically implanted in nude mice. We have chosen a choriocarcinoma model characterized by high levels of ErbB1, but also of ErbB2 and ErbB3, to assay the in vivo effect of ErbB inhibitors on tumoral growth. Our results showed a complete lack of effect (refractoriness) to the pure ErbB1 receptor inhibitors cetuximab and gefitinib. While these inhibitors blocked ErbB1 phosphorylation, ErbB2 phosphorylation was not affected, suggesting an ErbB1-independent activation of this receptor. To confirm the importance of ErbB2 activation, animals were treated with lapatinib, a dual ErbB1 and ErbB2 inhibitor. Lapatinib treatment caused a 50% inhibition in tumor growth, an effect correlated with a blockade of both ErbB1 and ErbB2 phosphorylation levels, and of downstream signaling pathways (Akt, ERKs and Stat3). ErbB2 activation could still occur due to the formation of ErbB2/ErbB3 heterodimers, and ErbB3 activation was completely inhibited by lapatinib. Finally, combined inhibition of ErbB1 (gefitinib) and ErbB3 activities (knockdown expression by shRNA) inhibited tumoral testicular cells proliferation in a similar way to lapatinib. Our results explain why lapatinib but not anti-ErbB1 agents might be effective for treatment of testicular GCT patients.
Asunto(s)
Antineoplásicos/farmacología , Receptores ErbB/antagonistas & inhibidores , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias de Células Germinales y Embrionarias/metabolismo , Quinazolinas/farmacología , Neoplasias Testiculares/tratamiento farmacológico , Neoplasias Testiculares/metabolismo , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Western Blotting , Carcinoma Embrionario/tratamiento farmacológico , Carcinoma Embrionario/metabolismo , Supervivencia Celular/efectos de los fármacos , Cetuximab , Coriocarcinoma/tratamiento farmacológico , Coriocarcinoma/metabolismo , Tumor del Seno Endodérmico/tratamiento farmacológico , Tumor del Seno Endodérmico/metabolismo , Receptores ErbB/metabolismo , Gefitinib , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoprecipitación , Lapatinib , Masculino , Ratones , Ratones Desnudos , Neoplasias Experimentales , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-3/antagonistas & inhibidores , Teratocarcinoma/tratamiento farmacológico , Teratocarcinoma/metabolismo , Trasplante HeterólogoRESUMEN
BACKGROUND: To describe chemotherapy treatment patterns and clinical outcomes in metastatic soft tissue sarcoma (mSTS) patients with favorable response to chemotherapy. PATIENTS AND METHODS: Multicenter (25) multi-country (9) retrospective chart review of mSTS patients with favorable response to chemotherapy, defined as stable disease or better following four cycles. RESULTS: Two hundred and thirteen patients (58% female; mean age 54.7 years) received a mean of 2.7 lines of chemotherapy and 5.2 cycles per line. The most common first-line regimens were doxorubicin (34%) and anthracycline plus ifosfamide (30%). Favorable response was achieved by 83% to first-line and 42% and 38% in second- and third-line chemotherapy. The most common reason for chemotherapy discontinuation in lines with a favorable response was reaching a predefined number of cycles in first line (64% of 213) and disease progression in second or later lines (41% of 138). The mean time off chemotherapy was 38.0 weeks after first line, falling to 2.7-6.4 weeks in second or later lines. Median overall and progression-free survival were 23.5 (95% confidence interval 20.5-28.1) and 8.3 (7.4-9.9) months from first favorable response to chemotherapy. CONCLUSIONS: mSTS patients achieving favorable response to chemotherapy have poor outcomes. Additional treatment options are needed.