RESUMEN
BACKGROUND: Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers. METHODS: In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib. RESULTS: A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias. CONCLUSIONS: These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.
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Síndrome de Jervell-Lange Nielsen/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Anciano , Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/epidemiología , Electrocardiografía/métodos , Femenino , Humanos , Incidencia , Italia/epidemiología , Síndrome de Jervell-Lange Nielsen/enzimología , Síndrome de Jervell-Lange Nielsen/epidemiología , Masculino , Persona de Mediana Edad , Países Bajos/epidemiología , Estudios Retrospectivos , RiesgoRESUMEN
Abnormal activity in peripheral blood of the cytosolic enzyme prolyl endopeptidase (PEP, EC 3.4.21.26, post prolyl cleaving enzyme, prolyl oligopeptidase) has been found in patients with a variety of psychiatric disorders, most consistently in mood disorders. Mood disturbance is a well-known side effect of immunotherapy with interferon-alpha (IFN-alpha). Earlier, we documented a decrease in serum PEP activity in the first 4 weeks of treatment with IFN-alpha. In 24 patients (16 men, 8 women, median age 60.5 years, range 47-72 years) with metastatic renal cell carcinoma (RCC), psychiatric assessment and blood sampling were performed before and at 4 and 8 weeks and at 6 months after initiation of treatment with IFN-alpha. No episodes of depression were observed, and the sum score and the scores on the subscales for depression and hostility of the Symptom Check List-90 (SCL-90) did not change during follow-up, whereas the anxiety scores were somewhat lower at 4 and 8 weeks compared with baseline. No change in plasma PEP activity and no relationships between change in psychiatric parameters and change in plasma PEP activity were found. As more subtle relationships between PEP activity and psychiatric status could have easily been obscured, a role for PEP in the pathophysiology of IFN-alpha-induced mood disturbance can neither be confirmed nor excluded.
Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/psicología , Inmunoterapia , Interferón-alfa/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/psicología , Serina Endopeptidasas/sangre , Anciano , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/enzimología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/sangre , Neoplasias Renales/enzimología , Masculino , Persona de Mediana Edad , Prolil Oligopeptidasas , PsicopatologíaRESUMEN
Treatment of patients with metastatic renal cell carcinoma is evolving rapidly due to the advent of novel targeted therapies. Improved knowledge of the underlying pathogenesis has led to the development of drugs that modulate the dominant signal transduction pathways for this disease, which results in inhibition of angiogenesis. Recent evidence indicates that the receptor tyrosine kinase inhibitor sunitinib prolongs progression-free survival compared with interferon-alpha, especially in patients with intermediate risk. Immunotherapy with interferon-alpha or high-dose interleukin-2 should still be considered for low-risk patients, particularly those with clear-cell tumours and metastases of the lung only. In patients who fail treatment with interferon-alpha, sorafenib has been shown to improve progression-free survival. High-risk patients may benefit from treatment with temsirolimus, which inhibits mammalian target of rapamycin (mTOR) kinase activity and has shown to improve overall survival. These angiogenesis inhibitors did not receive mention in the recently published guideline 'Renal cell carcinoma'.
Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Bencenosulfonatos/uso terapéutico , Bevacizumab , Supervivencia sin Enfermedad , Humanos , Inmunoterapia , Indoles/uso terapéutico , Metástasis de la Neoplasia , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/uso terapéutico , Pirroles/uso terapéutico , Transducción de Señal , Sirolimus/análogos & derivados , Sirolimus/uso terapéutico , Sorafenib , Sunitinib , Resultado del TratamientoRESUMEN
The sentinel lymph node procedure provides prognostic information for patients with cutaneous melanoma, but its therapeutic implications were unclear until now. The international multicentre selective lymphadenectomy trial has shown that sentinel lymph node biopsy confers no survival benefit for patients with cutaneous melanoma. The presence of melanoma cells in a sentinel lymph node, however, has prognostic value. Therefore, the Dutch Melanoma Working Group recommends discussing this procedure with all patients with melanoma of Breslow thickness 1.2-3.5 mm. There is no evidence to suggest that the sentinel lymph node procedure is beneficial when the Breslow thickness is less than 1.2 mm or greater than 3.5 mm.
Asunto(s)
Metástasis Linfática/diagnóstico , Melanoma/patología , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/patología , Melanoma/mortalidad , Recurrencia Local de Neoplasia/diagnóstico , Países Bajos , Pronóstico , Neoplasias Cutáneas/mortalidad , Tasa de SupervivenciaRESUMEN
The aim of this study was to evaluate the effect of pegylated interferon-alpha (PEG-IFN-alpha) on the plasma citrulline/arginine ratio, regarded as an index of nitric oxide (NO) synthesis, in patients with high-risk melanoma. Forty patients were randomly assigned to either PEG-IFN-alpha treatment (n = 22) or to observation only (control group, n = 18). The treatment group received 6 microg PEG-IFN-alpha/kg once a week during 8 weeks, followed by a maintenance dose of 3 microg/kg/wk. Blood was collected at different time points, plasma concentrations of citrulline and arginine were measured and the ratio of citrulline/arginine was calculated. Patients treated with PEG-IFN-alpha showed a significant decrease in the concentrations of citrulline and in the citrulline/arginine ratio during the whole study period, both compared to baseline values and to the control group. The data suggest that therapy with PEG-IFN-alpha results in a marked decrease in the synthesis of NO in melanoma patients.
Asunto(s)
Antivirales/administración & dosificación , Arginina/sangre , Citrulina/sangre , Interferón-alfa/administración & dosificación , Melanoma/sangre , Melanoma/terapia , Antivirales/efectos adversos , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/efectos adversos , Masculino , Óxido Nítrico/biosíntesis , Polietilenglicoles , Proteínas Recombinantes , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: Chemoimmunotherapy for patients with metastatic melanoma is associated with high toxicity, and only a subset of patients will benefit. This randomised phase II study was performed with the primary objective of exploring whether two cycles of dacarbazine monotherapy could select the subset of patients that would benefit most from more intensive chemoimmunotherapy. PATIENTS AND METHODS: Patients with metastatic melanoma were randomised to either receive chemoimmunotherapy with dacarbazine, cisplatin, interferon-alpha and interleukin-2 (arm A) or initial treatment with two cycles of dacarbazine monotherapy followed irrespective of response by the same 4-drug regimen of chemoimmunotherapy (arm B). Chemoimmunotherapy was continued in the absence of disease progression for a maximum of four cycles. Primary end-point was the disease stabilisation rate. RESULTS: A total of 93 patients were randomised, and 89 patients were eligible. Disease stabilisation (complete/partial response or stable disease) was achieved in 19 patients (42.2%) in arm A and 9 patients (20.5%) in arm B. In arm B 32 of the 44 patients continued chemoimmunotherapy after two cycles of dacarbazine. Of 20 patients with progressive disease (PD) after two cycles of dacarbazine in arm B, only 2 patients achieved an objective response. Median overall survival (OS) in arms A and B was 10.5 months and 9.5 months, respectively. CONCLUSIONS: Despite a lower initial stabilisation rate, the strategy of starting with 2 courses of DTIC prior to a 4-drug regimen led to comparable median overall survival. Only few transient responses were achieved with the 4-drug regimen in patients with disease progression on DTIC, suggesting frequent cross resistance. Two cycles of dacarbazine monotherapy cannot be recommended to select patients for more intensive chemoimmunotherapy.
Asunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Dacarbazina/uso terapéutico , Inmunoterapia/métodos , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Cisplatino/administración & dosificación , Terapia Combinada , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interleucina-2/administración & dosificación , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Proteínas RecombinantesRESUMEN
The guidelines 'Melanoma' (3rd revision) are evidence-based in nature. A number of outcomes are summarised in this article. Dermatoscopy deserves a standard role in the clinical diagnosis of pigmented skin abnormalities. Pathological findings from a diagnostic excision should be recorded meticulously to include anatomical localisation, type of intervention used, excision margin, diagnosis, Breslow thickness, and the completeness of the removal. The sentinel node procedure should be reserved for patients who want to be as informed as possible about their prognosis. The procedure is not considered a part of standard diagnosis. Sentinel node assessment should include stains for specific markers and should be conducted in multiple sections. The following margins of non-affected skin are recommended for therapeutic re-excision of melanoma: in situ melanoma, 0.5 cm; Breslow thickness < or = 2 mm, 1 cm; Breslow thickness > 2 mm, 2 cm. Pathological assessment of a re-excised specimen depends on the completeness of the first excision. Systematic adjuvant treatment of patients with melanoma is not recommended outside the context of a clinical study. Patients with metastatic melanoma are preferably treated within a clinical study. Outside of a clinical study, these patients should be treated with dacarbazine. There is no evidence to suggest that survival is improved by frequent follow-up. However, follow-up can be a useful way to meet the information needs of patients and care requirements for physicians.
Asunto(s)
Dermatología/normas , Melanoma/diagnóstico , Neoplasias Cutáneas/diagnóstico , Dermoscopía , Diagnóstico Diferencial , Medicina Basada en la Evidencia , Humanos , Melanoma/patología , Melanoma/terapia , Países Bajos , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Tasa de SupervivenciaRESUMEN
Adoptive transfer of antigen-specific T cells has recently shown therapeutic successes in the treatment of viral infections and tumors. T cells specific for the antigen of interest can be generated in vitro, and adoptively transferred back to provide patients with large numbers of immune-competent T cells. Adoptive T cell therapy, however, is a patient-tailored treatment that unfortunately is not universally applicable to treat viral infections and tumors. We and others have demonstrated that the transfer of genes encoding antigen-specific receptors into T cells (i.e., genetic retargeting) represents an attractive alternative to induce antigen-specific immunity. Currently, we evaluate this concept in a clinical protocol to treat patients with metastatic renal cell cancer (RCC) using autologous RCC-specific gene-modified T lymphocytes.
Asunto(s)
Carcinoma de Células Renales/terapia , Fragmentos de Inmunoglobulinas/genética , Inmunoterapia Adoptiva/métodos , Linfocitos T Citotóxicos/trasplante , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/inmunología , Ensayos Clínicos como Asunto , Pruebas Inmunológicas de Citotoxicidad , Citometría de Flujo , Humanos , Fragmentos de Inmunoglobulinas/inmunología , Inmunoterapia Adoptiva/efectos adversos , Interferón gamma/metabolismo , Hígado/fisiopatología , Recuento de Linfocitos , Ratones , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/inmunología , Transducción Genética , Trasplante Autólogo/inmunología , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A prospective study was performed to investigate the combination of the aromatase inhibitor aminoglutethimide and hydrocortisone in androgen-independent prostate cancer with changes in prostate-specific antigen (PSA) level as main determinant for response. Thirty-five patients were treated with aminoglutethimide 1000 mg daily and hydrocortisone acetate 40 mg daily. PSA measurements were performed every month. If evaluable lesions were present, objective tumor assessment was done by computed tomography scan and X-ray investigations. In 12 patients (37%) the PSA value showed a confirmed response with a decline in serum level of at least 50%. Median time to progression in responding and all patients was 10.5 and 4.5 months, respectively. Median duration of response in responding patients was 9 months. Median survival for these two groups was 23 and 14.5 months, respectively. Of seven patients with measurable disease, two showed a partial response and five a stable disease. Improvement in general condition, pain and feeling of well-being was noted in two-thirds of patients. Therapy was well tolerated with mainly grade I and II adverse events in 20% of patients. We conclude that aminoglutethimide is a valuable second-line therapy for patients with androgen-independent prostate cancer.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Aminoglutetimida/administración & dosificación , Intervalos de Confianza , Humanos , Hidrocortisona/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estudios Prospectivos , Neoplasias de la Próstata/patologíaRESUMEN
Immunotherapy with interferon-alpha (IFN-alpha) induces neuropsychiatric side effects, most notably depression. In hepatitis patients treated with IFN-alpha, severity of depression correlates with a decrease in serum activity of dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5), a membrane-bound protease involved in the cleavage of cytokines and neuroactive peptides. Abnormal serum activity of the cytosolic peptidase prolyl endopeptidase (PEP, EC 3.4.21.26, postprolyl cleaving enzyme, prolyl oligopeptidase) has been documented in patients with a variety of psychiatric disorders, most consistently in mood disorders. The serum activity of PEP and DPP-IV was measured before and after 4 weeks of high-dose induction treatment with IFN-alpha in 18 patients with high-risk melanoma. In this exploratory study, we show a clear decrease in the serum activity of PEP after 4 weeks of treatment with IFN-alpha. This decrease was not related to changes in hematologic parameters. In contrast, serum activity of DPP-IV did not change. Further studies focusing on a possible role of PEP in the pathophysiology of IFN-alpha-induced depression are warranted.
Asunto(s)
Depresión/sangre , Dipeptidil Peptidasa 4/sangre , Interferón-alfa/administración & dosificación , Melanoma/sangre , Serina Endopeptidasas/sangre , Depresión/etiología , Depresión/fisiopatología , Relación Dosis-Respuesta a Droga , Femenino , Hepatitis/psicología , Hepatitis/terapia , Humanos , Inmunoterapia/efectos adversos , Interferón-alfa/efectos adversos , Masculino , Melanoma/tratamiento farmacológico , Melanoma/patología , Melanoma/psicología , Trastornos del Humor/sangre , Prolil OligopeptidasasRESUMEN
This EORTC multicentre study analysed the efficacy and tolerability in patients with metastatic uveal melanoma of BOLD chemotherapy in combination with recombinant interferon alpha-2b. The dose of bleomycin was 15 mg on days 2 and 5, of vincristine 1 mg/m(2) on days 1 and 4, of lomustine 80 mg on day 1, and of dacarbazine (DTIC) 200 mg/m(2) on days 1-5, given every 4 weeks for a minimum of two cycles. Subcutaneous (s.c.) interferon alpha-2b at a dose of 3 x 10(6) IU was initiated on day 8 of the first cycle, and continued at a dose of 6 x 10(6) IU three times per week after 6 weeks. A median of two cycles were administered to 24 patients (median age 60.5 years). None achieved an objective response (0%; 95% Confidence Interval (CI): 0-14), 2 (8.3%) remained stable, 20 showed progression, and 2 (8.3%) were invaluable. The median progression-free survival was 1.9 months (95% CI: 1.8-3.4) and overall survival 10.6 months (95% CI: 6.9-16.4). Overall survival improved with increasingly favourable pretreatment characteristics (median, 14.7 versus 6.9 versus 6.0 months for Helsinki University Central Hospital (HUCH) Working Formulation stages IVBa, IVBb and IVBc, respectively; P=0.018). Grade 3 alopecia and neurotoxicity occurred in 13% of the patients. This multicentre study did not confirm earlier reports that BOLD with human leucocyte or recombinant interferon would induce at least 15% objective responses in metastatic uveal melanoma.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias de la Úvea/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Supervivencia sin Enfermedad , Estudios de Factibilidad , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Lomustina/administración & dosificación , Lomustina/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
Fifty-seven patients with MAGE-3-positive measurable metastatic cancer, most of them with melanoma, were vaccinated with escalating doses of a recombinant MAGE-3 protein combined with a fixed dose of the immunological adjuvant SBAS-2, which contained MPL and QS21. The immunisation schedule included 4 intramuscular (i.m.) injections at 3-week intervals. Patients whose tumour stabilised or regressed after 4 vaccinations received 2 additional vaccinations at 6-week intervals. The vaccine was generally well tolerated. Among the 33 melanoma patients who were evaluable for tumour response, we observed 2 partial responses, 2 mixed responses and 1 stabilisation. Time to progression in these 5 patients varied from 4 to 29 months. In addition, a partial response lasting 10 months was observed in 1 of the 3 metastatic bladder cancer patients included. None of the tumour responses described above involved visceral metastases. Immunological responses to the vaccine will be reported separately.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Antígenos de Neoplasias/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteínas de Neoplasias/administración & dosificación , Neoplasias/terapia , Adulto , Anciano , Vacunas contra el Cáncer/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Células Transicionales/terapia , Femenino , Humanos , Inmunización , Lípido A/administración & dosificación , Lípido A/análogos & derivados , Neoplasias Pulmonares/terapia , Masculino , Melanoma/terapia , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias/patología , Proteínas Recombinantes/administración & dosificación , Saponinas/administración & dosificación , Neoplasias Cutáneas/terapia , Análisis de Supervivencia , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/terapiaRESUMEN
BACKGROUND: Adult onset of Still's disease is characterized by very high serum ferritin levels, in disproportion with other acute phase proteins (APPs). Because interferon-alpha (IFN-alpha) was observed to cause hyperferritinaemia in three healthy people without increase of other APPs, we hypothesized that IFN-alpha stimulates specifically the synthesis of ferritin. To test this hypothesis, we studied ferritin and other APP levels in patients treated with IFN-alpha. PATIENTS AND METHODS: Fifteen patients treated with IFN-alpha-2b 3-5 times a week, as adjuvant treatment after excision of a high-risk melanoma, were compared with six patients without adjuvant treatment (controls). Serum levels of C-reactive protein (CRP) and secretory phospholipase A2 (sPLA2) were measured using ELISA. Levels of ferritin, alpha1-acid glycoprotein (AAG) and albumin were determined by nephelometry. RESULTS: CRP was decreased significantly after 4 weeks (P < 0.01) in the patients treated with IFN-alpha compared with the nontreated patients, after 6 months of treatment it was still decreased although not significantly. Ferritin increased significantly in the IFN-alpha-treated patients: 187% of pretreatment value after 4 weeks and 217% after 6 months (P < 0.01), while ferritin levels decreased in the nontreated patients. AAG increased significantly in IFN-alpha-treated patients (107, 114%) compared with the control-patients (91, 76%) but differences were less compared with CRP and ferritin. sPLA2 had a variable course, while albumin remained constant within the normal range in both patient groups. CONCLUSIONS: IFN-alpha induced a significant increase in ferritin, with a significant decrease in CRP, little increase in AAG, varying response of sPLA2 and no change in albumin. This finding suggests a specific role for IFN-alpha in the synthesis or secretion of ferritin. This mechanism may also be involved in the marked hyperferritinaemia in adult onset of Still's disease.
Asunto(s)
Antineoplásicos/administración & dosificación , Ferritinas/inmunología , Interferón-alfa/administración & dosificación , Interferón-alfa/inmunología , Enfermedad de Still del Adulto/tratamiento farmacológico , Enfermedad de Still del Adulto/inmunología , Reacción de Fase Aguda/inmunología , Reacción de Fase Aguda/metabolismo , Adulto , Anciano , Proteína C-Reactiva/metabolismo , Femenino , Ferritinas/sangre , Humanos , Interferón alfa-2 , Interferón-alfa/metabolismo , Masculino , Melanoma/tratamiento farmacológico , Persona de Mediana Edad , Fosfolipasas A/sangre , Fosfolipasas A2 , Proteínas Recombinantes , Neoplasias Cutáneas/tratamiento farmacológico , Enfermedad de Still del Adulto/sangreRESUMEN
We investigated the potential of weekly cisplatin and daily oral etoposide followed by oral etoposide maintenance therapy in patients with platinum-refractory ovarium cancer. One hundred and seven patients were entered on the study, 98 patients completed the induction therapy consisting of cisplatin at either 50 or 70 mg m(-2) weekly for six administrations plus oral etoposide at a dose of 50 mg daily. Of these 98 patients, 38 had a platinum treatment-free interval of more than 12 months, 32 had an interval between 4 and 12 months, and 28 had progressed during or within 4 months after last platinum therapy. We assessed response rates and time to progression, and also response duration and survival. Analyses were done on the 98 evaluable patients. All 107 patients were considered evaluable for toxicity. Of the 38 patients with a treatment-free interval of more than 12 months, 92% responded, with 63% complete responses. The median progression-free survival in these patients was 14 months, and the median survival was 26 months. Of the 32 patients with an interval of 4-12 months, 91% responded, with 31% complete responses, a median progression-free interval of 8 and a median overall survival of 16 months. Of the 28 patients with platinum-refractory disease, 46% as yet responded, with 29% complete responses, median progression-free interval of 5 and an overall survival of 13 months. Haematologic and non-haematologic, particularly renal toxicity and neurotoxicity, were notably mild. We conclude that this intensive regimen of weekly cisplatin plus daily etoposide is highly effective and well tolerated in patients with ovarian cancer relapsing after conventional platinum-based combination chemotherapy, including patients who have progressed during or within 4 months after platinum treatment.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Etopósido/administración & dosificación , Neoplasias Ováricas/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Cisplatino/efectos adversos , Esquema de Medicación , Etopósido/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/mortalidad , PronósticoRESUMEN
Interleukin 12 (IL-12) has potential efficacy in malignant, infectious and allergic diseases. Its side-effects include activation of coagulation and fibrinolysis, as documented in chimpanzees. We assessed the coagulative and fibrinolytic response in 18 patients with renal cell carcinoma after subcutaneous injection of 0.5 microg/kg recombinant human IL-12. IL-12 induced a fibrinolytic response in 17 patients (94%): plasmin-alpha2-anti-plasmin complexes (PAPc) increased from 11.8 +/- 6.6 nmol/l (mean +/- SD) to a maximum of 18.8 +/- 7.4 nmol/l at 72 h. Baseline levels of tissue plasminogen activator (tPA) and plasminogen-activator inhibitor-I (PAI) were elevated in eight and 14 patients respectively. tPA increased from 12.6 +/- 5.2 ng/ml to a maximum of 19.0 +/- 6.7 ng/ml at 72 h. PAI decreased from 111 +/- 69 ng/ml to a minimum of 65 +/- 53 ng/ml at 8 h, thereafter remaining below baseline. Elevation of PAPc correlated with elevation of tPA and reduction of PAI. A coagulative response occurred in nine patients (50%): thrombin-anti-thrombin III complexes increased from 29 +/- 53 ng/ml to a maximum of 460 +/- 322 ng/ml at 12 h. Patients with and without a coagulative response had similar levels of recombinant human IL-12, interferon-gamma or tumour necrosis factor-alpha. We conclude that IL-12 can activate both fibrinolysis and coagulation in a significant proportion of patients with cancer. The time-frame and sequence of these activation processes differ from those known for other cytokines.
Asunto(s)
Coagulación Sanguínea/efectos de los fármacos , Carcinoma de Células Renales/tratamiento farmacológico , Fibrinólisis/efectos de los fármacos , Interleucina-12/uso terapéutico , Adulto , Anciano , Antitrombina III/análisis , Biomarcadores/sangre , Carcinoma de Células Renales/sangre , Femenino , Fibrinolisina/análisis , Humanos , Interferón gamma/sangre , Interleucina-12/sangre , Neoplasias Renales/sangre , Neoplasias Renales/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/análisis , Proteínas Recombinantes/sangre , Proteínas Recombinantes/farmacología , Trombina/análisis , Trombina/metabolismo , Activador de Tejido Plasminógeno/análisis , Factor de Necrosis Tumoral alfa/análisis , alfa 2-Antiplasmina/análisisRESUMEN
BACKGROUND: Tumour necrosis factor-alpha (TNFalpha) has been found to be very effective in the isolated limb perfusion setting for advanced extremity tumours. In a phase I study of intrapleural administration of TNFalpha 5 patients were followed for inflammatory response patterns. PATIENTS AND METHODS: Malignant mesothelioma patients were treated with repeated intrapleural administration of 0. 1-0.2 mg recombinant TNFalpha. Samples of serum and pleural fluid were taken at different time-points before and after TNFalpha-administration. Levels of TNFalpha, interleukin-6 (IL-6), interleukin-8 (IL-8), C-reactive protein (CRP) and secretory phospholipase A2 (sPLA2) were measured using enzyme-linked immunosorbent assays (ELISAs). Alpha 1-acid glycoprotein (alpha1-AG) was measured by nephelometry. RESULTS: In pleural fluid TNFalpha and IL-8 reached peak levels, up to 50-700 ng mL-1 and 6-60 ng mL-1, respectively, 24 h after administration of TNFalpha. IL-6 (peak levels up to 250 ng mL-1) and sPLA2 peaked after 48 h. A slower and less dramatic pattern was observed for the levels of CRP and alpha1-AG. In serum no detectable levels of TNFalpha and no IL-8 were observed, whereas serum levels of IL-6, sPLA2 and CRP showed a clear increase after intrapleural administration of TNFalpha. Cytokines and acute-phase proteins showed the same pattern during subsequent cycles even up to 12 cycles. Tumour regression was not observed. CONCLUSIONS: In the setting of a phase I study of repetitive intrapleural administration of TNFalpha in mesothelioma patients, we studied the characteristics of the inflammatory response. Intrapleural administration was followed by a clear inflammatory response locoregionally. In spite of TNFalpha peak levels as high as 700 ng mL-1 systemic levels were never detectable. The secondary cytokine response led to very high intrapleural IL-6 and IL-8 levels. Systemically IL-8 levels were never detectable whereas high IL-6 levels were induced systemically initially, with a decreased response to each intrapleural TNFalpha administration over time. The acute-phase response in contrast remained remarkably constant throughout the course of repeated intrapleural administrations of TNFalpha. Intrapleural administration of TNFalpha is well tolerated but associated with inconsistent and rather moderate impact on production of pleural fluid. This can be achieved by other simpler and cheaper treatment, thus we see no justification for further studies.
Asunto(s)
Proteínas de Fase Aguda/metabolismo , Citocinas/sangre , Mesotelioma/tratamiento farmacológico , Mesotelioma/inmunología , Neoplasias Pleurales/tratamiento farmacológico , Neoplasias Pleurales/inmunología , Factor de Necrosis Tumoral alfa/administración & dosificación , Anciano , Proteína C-Reactiva/metabolismo , Ensayo de Inmunoadsorción Enzimática , Humanos , Inyecciones Intralesiones , Interleucina-6/sangre , Interleucina-8/sangre , Masculino , Mesotelioma/sangre , Persona de Mediana Edad , Estadificación de Neoplasias , Orosomucoide/metabolismo , Fosfolipasas A/sangre , Fosfolipasas A2 , Neoplasias Pleurales/sangre , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Factor de Necrosis Tumoral alfa/efectos adversos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
In patients with metastatic renal cell carcinoma response rates of 7-26% have been achieved with immunotherapy. A high response rate of 48% in 35 patients has been reported for treatment with the combination of interferon-alpha (IFN-alpha), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) (Atzpodien et al (1993a) Eur J Cancer29A: S6-8). We conducted a multicentre phase II study to confirm these results. Metastatic renal cell carcinoma patients were treated as outpatients with an 8-week treatment cycle. Recombinant human IL-2 20 MU m(-2) was administered subcutaneously (s.c.) three times a week (t.i.w) in weeks 1 and 4 and 5 MU m(-2) t.i.w. in weeks 2 and 3. Recombinant human IFN-alpha 2a 6 MU m(-2) was administered s.c. once in weeks 1 and 4 and t.i.w. in weeks 2 and 3, and 9 MU m(-2) t.i.w. in weeks 5-8. 5-FU (750 mg m(-2)) was given as a bolus injection intravenous once a week in weeks 5-8. The treatment cycle was repeated once in case of response or minor response. Fifty-two patients entered the study. All had undergone a nephrectomy and had progressive metastatic disease. The median WHO-performance status was 1, the median number of metastatic sites was 2 (range 1-5) and the median time between the diagnosis of the primary tumour and the start of treatment was 12.9 months (range 1-153). Among the 51 patients, including four patients with early progressive disease, who were evaluable for response, the response rate was 11.8% (95% confidence interval (CI) 2.9-20.7%), with no complete responses. Median duration of response was 8.3 (range 3.8-22.4+) months. Median survival was 16.5 (range 1.8-30.5+) months. Grade 3/4 toxicity (WHO) occurred in 29/52 (55.8%) of the patients in cycle 1 and in 6/16 (37.5%) of the patients in cycle 2. It consisted mainly of anorexia, fatigue, nausea, fever and leucocytopenia. We cannot confirm the high response rate in patients with metastatic renal cell carcinoma treated with the combination of IFN-alpha, IL-2 and 5-FU, as described by Atzpodien et al.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Interferón-alfa/uso terapéutico , Interleucina-2/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/uso terapéuticoRESUMEN
The cytokine interferon-alpha (IFN-alpha) is increasingly prescribed for a number of indications, especially viral hepatitis and several malignancies. Two patients are described who developed Raynaud's syndrome during treatment with IFN-alpha as adjuvant therapy for high-risk melanoma. With a review of the available literature the symptomatology, possible pathophysiologic mechanisms and treatment options are discussed.
Asunto(s)
Factores Inmunológicos/efectos adversos , Interferón-alfa/efectos adversos , Melanoma/tratamiento farmacológico , Enfermedad de Raynaud/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Quimioterapia Adyuvante , Terapia Combinada , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Interferón alfa-2 , Interferón-alfa/uso terapéutico , Metástasis Linfática , Melanoma/patología , Melanoma/cirugía , Proteínas Recombinantes , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/cirugíaRESUMEN
Renal dysfunction is a frequently encountered adverse event following treatment with high-dose interleukin-2 (IL-2). Information about parameters predicting the severity of IL-2-associated renal function abnormalities is limited. In this study the role of possible risk factors in the development of high-dose IL-2-associated acute and long-term renal dysfunction was investigated. A total of 72 patients, who were treated with a regimen consisting of IL-2 (18 MIU m(-2) day(-1) by continuous infusion), interferon alpha (IFNalpha; 5 MIU m(-2) day(-1), intramuscularly) and lymphokine-activated killer (LAK) lymphocytes, were analysed. Serum creatinine measurements were performed daily during treatment, weekly between courses and monthly during follow-up. Pre-and posttreatment 24-h urine samples were collected for calculation of creatinine clearances. Renal dysfunction was observed in 97% of patients. Grade 1 dysfunction (according to WHO criteria) was observed in 20 patients (28%), grade 2 in 37 (51%), grade 3 in 13 (14%) and grade 4 in 0 (0%). Renal dysfunction was reversible in more than 90% of patients. Only 6 patients (8%) suffered a certain amount of permanent function loss. More severe acute renal dysfunction occurred in patients who were experiencing hypertension prior to treatment, those who suffered sepsis during treatment and in men than in women. Sepsis was also associated with irreversible function loss. Other variables such as age, performance status, diabetes mellitus, interval between nephrectomy and start of IL-2 therapy and hypotension during treatment were not important. In conclusion, with high-dose IL-2, renal dysfunction develops in almost every patient and such abnormalities are mostly reversible. Predictors for severe acute renal dysfunction are pre-existing hypertension, sepsis and sex. A septic episode also carries a risk of permanent damage.