RESUMEN
Reducing the number of patients required for a clinical trial is important for shortening development time. Phase II cancer trials assess the tumour-shrinking effect of a novel compound through a binary end-point formed from the percentage change in total lesion diameter. We compare single-arm two-stage designs which use the binary end-point to those which directly use the continuous end-point. Using the continuous end-point results in lower expected and maximum sample sizes. For larger trials the reduction is around 37%. This assumes that the dichotomisation point of the continuous end-point is chosen to give the best sample size, with the trial design using the binary end-point performing even worse otherwise. We consider a previous trial designed using a Simon two-stage design and show that if the continuous end-point had been used, the expected and maximum sample sizes of the trial would be reduced by around 50%. Using the continuous end-point in a two-stage cancer trial results in large sample size reductions. The methods discussed in this paper work best when the number of complete responses is low, as is true in several types of cancer. We discuss what could be done if this is not the case.
Asunto(s)
Neoplasias/tratamiento farmacológico , Tamaño de la Muestra , Ensayos Clínicos Fase II como Asunto/métodos , Reacciones Falso Positivas , Humanos , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Proyectos de Investigación , Estadística como AsuntoRESUMEN
Mutations in the VHL gene lead to von Hippel-Lindau (VHL) disease, a clinically heterogeneous cancer syndrome. Here, we use software and database tools to understand and predict the phenotypes associated with missense mutations in the VHL gene product, pVHL. The protein product pVHL is known to interact with elongin B, elongin C, and the HIF substrate. By analyzing known and predicted interaction sites and predictions of thermodynamic stability change upon mutation, we generate new hypotheses regarding the molecular etiology of renal cell carcinoma (RCC) and pheochromocytoma (PCC) in VHL disease. We find that the molecular causes of RCC and PCC appear to be decoupled. RCC may arise through two distinct mechanisms: disruption of HIF interactions or binding at the elongin B interface. PCC is triggered by mutations which disrupt interactions at the elongin C binding site. These findings have important implications for VHL disease and for nonfamilial RCC, because most cases of clear cell RCC are linked with VHL inactivation. Additionally, predicting effects of genetic variation will be critical as genetic sequencing accelerates; the analytical strategy presented here may elucidate other systems as further data on genetic variation become available.
Asunto(s)
Biología Computacional/métodos , Fenotipo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/metabolismo , Enfermedad de von Hippel-Lindau/metabolismo , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Elonguina , Genotipo , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Mutación Missense , Feocromocitoma/genética , Feocromocitoma/metabolismo , Unión Proteica/genética , Unión Proteica/fisiología , Estructura Secundaria de Proteína , Factores de Transcripción/metabolismo , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Enfermedad de von Hippel-Lindau/genéticaRESUMEN
Metastatic renal cell carcinoma (RCC) has a highly variable natural history and carries a dismal prognosis. Unlike many other tumors, RCC is generally unresponsive to cytotoxic, hormonal, and radiation adjuvant therapies after cytoreductive surgery. Different modalities of treatment have been tried and tested with modest success. Until recently, only immunotherapies such as interleukin-2 and interferon-alpha have been shown to provide a response, albeit in a minority of patients and often with severe treatment-associated toxicities. Other adjuvant therapies, such as active specific immunotherapy with Bacillus Calmette-Guerin and autologous renal tumor cell vaccines, have not provided alternative solutions. Recent approaches include heat-shock protein peptide complex 96 vaccine and cG250 monoclonal antibody therapy. Novel targeted therapies have been developed using our knowledge of the molecular genetics that belie RCC. This culminated in sorafenib and sunitinib, the first Food and Drug Administration-approved drugs for RCC in more than a decade in the United States. The future will see further trials being carried out in the development of targeted therapies with emphasis placed on patient selection. Staging systems will need to be updated to integrate molecular biomarkers, which could potentially act not just as diagnostic and prognostic predictors, but also as tools for appropriate patient selection for treatment. In the future, this could potentially lead us to our ultimate goal of personalized medicine.
Asunto(s)
Carcinoma de Células Renales/terapia , Neoplasias Renales/terapia , Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante , Terapia Combinada , Humanos , Inmunoterapia , Radioterapia AdyuvanteAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Animales , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Ensayos Clínicos como Asunto , Receptores ErbB/química , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Modelos Moleculares , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
Antibodies to the cell surface disaccharide galactose(alpha1,3)galactose (alphaGal) are the most prevalent natural antibodies in human serum. The anti-alphaGal immunoglobulin M-dependent activation of complement causes hyperacute rejection of organ transplants from discordant species by human recipients. It has been shown in vitro that human tumour cells transduced with the gene that synthesizes alphaGal become sensitive to human serum. A prerequisite for anti-alphaGal antibody-based therapeutic strategies is that patients with cancer have adequate serum levels of anti-alphaGal immunoglobulins and complement. The objective of this work was to measure the levels and function of anti-alphaGal immunoglobulins and complement in the serum of patients with metastatic melanoma and healthy volunteers. Serum complement levels were assayed by radial immunodiffusion. Anti-alphaGal immunoglobulin G and immunoglobulin M titres were measured by enzyme-linked immunosorbent assay. Disaccharide sugar blocking was used to investigate antibody specificity. The functional integrity of anti-alphaGal antibodies and complement was investigated in cell lysis assays. It was found that the levels of the complement components C1q, C3 and C4 and the function of the classical complement pathway were normal in metastatic melanoma patients. Anti-alphaGal antibody titres were as variable in metastatic melanoma patients as in healthy controls, and the lysis of alphaGal-expressing cells correlated with anti-alphaGal immunoglobulin M titre (P < 0.0001). Anti-alphaGal antibody titres, complement levels and overall cytolytic function in the serum of patients with metastatic melanoma were indistinguishable from those of healthy controls. There is thus nothing intrinsic to the disease that will limit anti-alphaGal-based therapeutic strategies for enhanced antigen presentation or induced cell lysis, including the mimicry of hyperacute rejection.
Asunto(s)
Anticuerpos/sangre , Proteínas del Sistema Complemento/análisis , Citotoxicidad Inmunológica , Disacáridos/inmunología , Melanoma/sangre , Adulto , Especificidad de Anticuerpos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunodifusión , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Masculino , Melanoma/inmunología , Melanoma/secundario , Persona de Mediana EdadRESUMEN
The management of recurrent renal cell carcinoma is challenging as it requires close collaboration between surgeons, radiation oncologists and medical oncologists. To date, treatment options for metastatic disease have been of modest benefit. The disease has therefore been a good model for novel drug development programs. These endeavors are now bearing fruit with exciting preliminary data now emerging in relation to a number of novel agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/radioterapia , Terapia Combinada , Humanos , Neoplasias Renales/patología , Neoplasias Renales/radioterapia , Metástasis de la NeoplasiaRESUMEN
Different postsurgical therapies are used for the treatment of metastatic melanoma. This article reviews the use of chemotherapeutic agents in the treatment of patients with metastatic malignant melanoma. A variety of single chemotherapy agents have been evaluated, although the most widely used chemotherapeutic in the treatment of metastatic melanoma is dacarbazine. In order to improve the rate and duration of responses, combination chemotherapy was developed. The most common combined chemotherapy regimens used as standard for the treatment of metastatic melanoma are Dartmouth regimen, CVD (cisplatin + vinblastine + dacarbazine) and BOLD (bleomycin + vincristine + lomustine + dacarbazine). However, Phase III trials have failed to demonstrate a significant benefit in survival in patients treated with polychemotherapy compared to those treated with dacarbazine alone. The use of classical systemic chemotherapy still has a role in the treatment of patients with metastatic melanoma. Immunotherapy and biochemotherapy have no additional advantage over chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/uso terapéutico , Carmustina/uso terapéutico , Cisplatino/uso terapéutico , Ensayos Clínicos como Asunto , Ciclofosfamida/uso terapéutico , Dacarbazina/uso terapéutico , Humanos , Lomustina/uso terapéutico , Melanoma/mortalidad , Melanoma/secundario , Metástasis de la Neoplasia , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/secundario , Tamoxifeno/uso terapéutico , Resultado del Tratamiento , Vincristina/uso terapéuticoRESUMEN
The constitutive activity of a number of growth and cell survival pathways are thought to contribute to the inherent resistance of melanoma to chemotherapy and radiotherapy. Many of these pathways are driven through the small GTPase Ras. Novel drugs such as the farnesyl transferase inhibitors (FTIs) and farnesyl thiosalicylic acid (FTS) interfere with the signaling of oncogenic Ras. The aim of our study was to assess the anti-tumour activity of the FTI SCH66336 in melanoma and to assess whether SCH66336 and FTS could modulate chemoresistance in melanoma cells. SCH66336 had marked anti-proliferative activity in both human and mouse melanoma cell lines, but not in non-transformed NIH 3T3 cells. The anti-proliferative activity of SCH66336 was due to G1-phase cell cycle arrest and retinoblastoma protein inactivation, followed by apoptosis. Cisplatin, when administered alone, induced little apoptosis. In combination with cisplatin, both FTS and SCH66336 markedly enhanced the level of cisplatin-induced apoptosis, an effect that was associated with enhanced G2/M cell cycle arrest. Pharmacological inhibitors of either ERK or PI-3 kinase/Akt did not mimic the chemosensitising activity of either SCH66336 or FTS. In summary, our study demonstrates that SCH66336 has good in vitro anti-tumour activity in both human and mouse melanoma cell lines, and suggests that Ras antagonists could be useful in overcoming chemoresistance to cisplatin in melanoma.
Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Cisplatino/farmacología , Inhibidores Enzimáticos/farmacología , Farnesol/análogos & derivados , Melanoma/patología , Piperidinas/farmacología , Proteínas Serina-Treonina Quinasas , Piridinas/farmacología , Neoplasias Cutáneas/patología , Células 3T3 , Actinas/metabolismo , Animales , Western Blotting , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Ensayo de Unidades Formadoras de Colonias , Sinergismo Farmacológico , Farnesol/farmacología , Farnesiltransferasa , Humanos , Etiquetado Corte-Fin in Situ , Técnicas In Vitro , Melanoma/metabolismo , Ratones , Microscopía Confocal , Proteínas Quinasas Activadas por Mitógenos/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-akt , Proteína de Retinoblastoma/metabolismo , Salicilatos/farmacología , Neoplasias Cutáneas/metabolismo , Células Tumorales CultivadasRESUMEN
Biological therapies are claiming a place in the routine management of some solid tumours. In this review we focus on the biological treatment of melanoma and renal-cell carcinoma, identifying the background to current practice and areas of promise that may be in routine clinical use in the near future. Melanomas and renal-cell carcinomas are particularly resistant to chemotherapy and radiotherapy and are characterised by the host immune response to the tumours. For this reason there has been particular interest in the biological therapy of these diseases. Biological therapies differ from chemotherapeutic approaches in their mechanism of action, time to response, and side-effect profiles. Although biological treatment has a long history, it is only with recent advances in immunology and molecular biology that progress has been made. In the next few years investigators expect to build on their research experience with biotherapeutic agents to provide tangible benefits for patients.
Asunto(s)
Carcinoma de Células Renales/terapia , Inmunoterapia/métodos , Neoplasias Renales/terapia , Melanoma/terapia , Neoplasias Cutáneas/terapia , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Ensayos Clínicos como Asunto , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Interferón-alfa/administración & dosificación , Interleucina-2/administración & dosificación , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Melanoma/mortalidad , Melanoma/patología , Selección de Paciente , Pronóstico , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Tasa de Supervivencia , Talidomida/administración & dosificación , Vacunas/administración & dosificaciónRESUMEN
Novel classes of drug that interfere with the signalling of the small G-protein Ras, the so-called Ras antagonists, are showing much promise as novel anti-cancer agents. In this study, we demonstrate that the novel Ras antagonist farnesylthiosalicylic acid (FTS) inhibits the growth of Colo 853 melanoma cells through a combination of cytostatic and pro-apoptotic effects. Furthermore, these phenomena are seen under conditions of cell attachment and in the presence of serum. Treatment of Colo 853 cells with FTS led to time-dependent inhibition of constitutive Akt, retinoblastoma protein (pRB) and ERK activity, with a concurrent loss of Akt expression. Inhibition of Akt and ERK activity induces apoptosis in other human cancer cell lines. Here it is demonstrated that inhibition of Akt, or ERK and Akt in combination, leads to cell cycle arrest but not apoptosis in melanoma cells. FTS treatment was also found to upregulate activity of the stress-activated p38 MAP kinase. Inhibition of p38 MAP kinase, using the selective inhibitor SB 203580, followed by FTS treatment, significantly increased the proportion of apoptotic cells after 72 hr, possibly suggesting a modulatory role for p38 MAP kinase in FTS-induced melanoma cell apoptosis.