RESUMEN
The combination of Interferon-α-2b (IFN-α-2b) and phototherapy is highly effective in treating mycosis fungoides (MF) but side effects often lead to discontinuation of therapy.1.
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Interferón alfa-2/administración & dosificación , Interferón-alfa/administración & dosificación , Micosis Fungoide/tratamiento farmacológico , Terapia PUVA/métodos , Polietilenglicoles/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Relación Dosis-Respuesta a Droga , Estudios de Factibilidad , Femenino , Humanos , Interferón alfa-2/efectos adversos , Interferón-alfa/efectos adversos , Masculino , Persona de Mediana Edad , Micosis Fungoide/diagnóstico , Estadificación de Neoplasias , Terapia PUVA/efectos adversos , Proyectos Piloto , Polietilenglicoles/efectos adversos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Neoplasias Cutáneas/diagnóstico , Resultado del TratamientoRESUMEN
BACKGROUND: Renal-cell carcinoma is highly vascular, and proliferates primarily through dysregulation of the vascular endothelial growth factor (VEGF) pathway. We tested sunitinib and sorafenib, two oral anti-angiogenic agents that are effective in advanced renal-cell carcinoma, in patients with resected local disease at high risk for recurrence. METHODS: In this double-blind, placebo-controlled, randomised, phase 3 trial, we enrolled patients at 226 study centres in the USA and Canada. Eligible patients had pathological stage high-grade T1b or greater with completely resected non-metastatic renal-cell carcinoma and adequate cardiac, renal, and hepatic function. Patients were stratified by recurrence risk, histology, Eastern Cooperative Oncology Group (ECOG) performance status, and surgical approach, and computerised double-blind randomisation was done centrally with permuted blocks. Patients were randomly assigned (1:1:1) to receive 54 weeks of sunitinib 50 mg per day orally throughout the first 4 weeks of each 6 week cycle, sorafenib 400 mg twice per day orally throughout each cycle, or placebo. Placebo could be sunitinib placebo given continuously for 4 weeks of every 6 week cycle or sorafenib placebo given twice per day throughout the study. The primary objective was to compare disease-free survival between each experimental group and placebo in the intention-to-treat population. All treated patients with at least one follow-up assessment were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00326898. FINDINGS: Between April 24, 2006, and Sept 1, 2010, 1943 patients from the National Clinical Trials Network were randomly assigned to sunitinib (n=647), sorafenib (n=649), or placebo (n=647). Following high rates of toxicity-related discontinuation after 1323 patients had enrolled (treatment discontinued by 193 [44%] of 438 patients on sunitinib, 199 [45%] of 441 patients on sorafenib), the starting dose of each drug was reduced and then individually titrated up to the original full doses. On Oct 16, 2014, because of low conditional power for the primary endpoint, the ECOG-ACRIN Data Safety Monitoring Committee recommended that blinded follow-up cease and the results be released. The primary analysis showed no significant differences in disease-free survival. Median disease-free survival was 5·8 years (IQR 1·6-8·2) for sunitinib (hazard ratio [HR] 1·02, 97·5% CI 0·85-1·23, p=0·8038), 6·1 years (IQR 1·7-not estimable [NE]) for sorafenib (HR 0·97, 97·5% CI 0·80-1·17, p=0·7184), and 6·6 years (IQR 1·5-NE) for placebo. The most common grade 3 or worse adverse events were hypertension (105 [17%] patients on sunitinib and 102 [16%] patients on sorafenib), hand-foot syndrome (94 [15%] patients on sunitinib and 208 [33%] patients on sorafenib), rash (15 [2%] patients on sunitinib and 95 [15%] patients on sorafenib), and fatigue 110 [18%] patients on sunitinib [corrected]. There were five deaths related to treatment or occurring within 30 days of the end of treatment; one patient receiving sorafenib died from infectious colitis while on treatment and four patients receiving sunitinib died, with one death due to each of neurological sequelae, sequelae of gastric perforation, pulmonary embolus, and disease progression. Revised dosing still resulted in high toxicity. INTERPRETATION: Adjuvant treatment with the VEGF receptor tyrosine kinase inhibitors sorafenib or sunitinib showed no survival benefit relative to placebo in a definitive phase 3 study. Furthermore, substantial treatment discontinuation occurred because of excessive toxicity, despite dose reductions. These results provide a strong rationale against the use of these drugs for high-risk kidney cancer in the adjuvant setting and suggest that the biology of cancer recurrence might be independent of angiogenesis. FUNDING: US National Cancer Institute and ECOG-ACRIN Cancer Research Group, Pfizer, and Bayer.
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Antineoplásicos/administración & dosificación , Carcinoma de Células Renales/tratamiento farmacológico , Indoles/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Pirroles/administración & dosificación , Administración Oral , Antineoplásicos/efectos adversos , Carcinoma de Células Renales/mortalidad , Quimioterapia Adyuvante/mortalidad , Supervivencia sin Enfermedad , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Indoles/efectos adversos , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Compuestos de Fenilurea/efectos adversos , Pirroles/efectos adversos , Sorafenib , Sunitinib , Resultado del TratamientoRESUMEN
Although tyrosine kinase inhibitors (TKI) are the most common first-line therapy for metastatic renal cell carcinoma, high-dose interleukin-2 (HD-IL2) remains the only agent that provides durable complete responses. The optimal sequence of these agents remains uncertain. This retrospective multi-institutional study examined the safety and efficacy of HD-IL2 following TKI therapy. After IRB approval at 7 HD-IL2 centers, data relating to patient, disease, and treatment characteristics among 40 consecutive patients with metastatic renal cell carcinoma who were treated with HD-IL2 after at least 1 prior TKI therapy were retrospectively collected. The most common cardiac adverse events were grade 3 hypotension and vascular leak syndrome. Six patients (15%) experienced other grade ≥3 cardiac adverse events. There were 2 treatment-related deaths due to congestive heart failure, occurring in 1 patient with short TKI to HD-IL2 interval and another patient with an abnormal baseline cardiac stress test. Best responses included 2 CRs (5%, duration 40+ and 62+ mo), 3 PRs (8%, duration 6, 11, and 24 mo), 13 SD (32%, median duration 12 mo), 20 PD (50%), and 2 not evaluable patients. Median overall survival was 22 months. Administration of HD-IL2 could be safe and effective after TKI therapy; however, careful selection of patients is critical. We recommend baseline cardiac risk factor assessment, screening with both cardiac stress test and echocardiogram, and allowing a TKI to HD-IL2 interval of at least 2 months.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Interleucina-2/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Carcinoma de Células Renales/mortalidad , Enfermedades Cardiovasculares/etiología , Femenino , Humanos , Interleucina-2/efectos adversos , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios Retrospectivos , Factores de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: Temozolomide is efficacious as an oral alternative for patients with metastatic melanoma (MM). Calcitriol has anti-proliferative properties and vitamin D receptor (VDR) polymorphisms are associated with alterations in melanoma susceptibility and progression. METHODS: Tem 150 mg/m2 was administered on days 2-8 and 16-22 every 28 days. Calcitriol was given on days 1 and 15 every 28 days. VDR gene analysis was completed using PCR-RFLP based assays. Tolerability was the primary objective with secondary objectives of time to progression (TTP) and overall survival (OS). RESULTS: Twenty pts with MM were registered. Cytopenias and thrombosis were the most common grade 3 or 4 toxicities. Median TTP was 1.8 mo. Pts with high-risk VDR genotype tt+/-ff (n = 6) had an OS of 3.8 mo from time of enrollment, compared to 7.4 mo for those with non-tt/ff genotypes (n = 11), although not statistically significant (HR = 1.20, 95% CI 0.41-3.53, p = 0.74). CONCLUSIONS: The extended dosing of Tem with calcitriol is a well-tolerated regimen. The trend toward improved OS in non-tt/ff VDR genotypes is consistent with prior studies associating the tt/ff genotype with biologic aggressiveness.
RESUMEN
Treatment regimens of patients with CTCL vary widely based on clinician preference and patient tolerance. Skin directed therapies are recommended for patients with early stage IA and IB MF, with combinations used in refractory cases. While no regimen has been proven to prolong survival in advanced stages, immunomodulatory regimens should be used initially to reduce the need for cytotoxic therapies. In more advanced stages of disease, treatment efforts should strive for palliation and improvement of quality of life. With many new therapies and strategies on the horizon, the future looks promising for CTCL patients. Unfortunately, other than allogeneic HCT, there are no potential curative therapies for CTCL. Clinical trials are currently underway to identify new therapies to improve quality of life for patients, and researchers are hard at work to identify novel pathways and genes for prognostication and as targets for therapies. Importantly, collaborative clinical trials to enhance rates of accrual need to be conducted, and improved interpretation of data via standardizing end points and response criteria should be an emphasis. Recently, the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer (EORTC) met to develop consensus guidelines to facilitate collaboration on clinical trials. These proposed guidelines consist of: recommendations for standardizing general protocol design; a scoring system for assessing tumor burden in skin, lymph nodes, blood, and viscera; definition of response in skin, nodes, blood, and viscera; a composite global response score; and a definition of end points. Although these guidelines were generated by consensus panels, they have not been prospectively or retrospectively validated through analysis of large patient cohorts.
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Antineoplásicos/administración & dosificación , Trasplante de Médula Ósea/métodos , Linfoma Cutáneo de Células T/terapia , Terapia PUVA/métodos , Neoplasias Cutáneas/terapia , Piel/patología , Algoritmos , Femenino , Humanos , Ganglios Linfáticos/patología , Linfoma Cutáneo de Células T/epidemiología , Linfoma Cutáneo de Células T/patología , Masculino , Cuidados Paliativos/métodos , Guías de Práctica Clínica como Asunto , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/patología , Carga Tumoral , Estados Unidos/epidemiologíaRESUMEN
We present the results of an open-label clinical trial and the clinical use of alemtuzumab in 19 heavily pretreated patients with advanced erythrodermic cutaneous T-cell lymphomas (CTCL) (erythrodermic mycosis fungoides and Sézary syndrome). Ten patients received alemtuzumab intravenously using an escalating dose regimen with a final dose of 30 mg three times weekly for 4 weeks followed by subcutaneous administration for 8 weeks. Nine patients were treated with only the SQ or IV dosing. The overall response rate was 84%, with 9 (47%) complete and 7 (37%) partial remissions. The median follow-up was 24 months (range, 6 to 62+ months). Median overall survival was 41 months whereas median progression free survival was 6 months. Minimal residual disease by T-cell gene rearrangement studies was detected in 11 patients who achieved complete response and partial response. Toxicities included myelosuppression and infections; however, the majority of side effects were of Grade 2 in severity and transient. One patient was diagnosed with a concurrent lymphoma (mantle cell lymphoma) 6 months after completing alemtuzumab therapy. Alemtuzumab is particularly effective in patients with erythrodermic CTCL with acceptable toxicities. Combined strategies with alemtuzumab may achieve molecular remissions with longer response durations.
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Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Micosis Fungoide/tratamiento farmacológico , Síndrome de Sézary/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Alemtuzumab , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/efectos adversos , Antígenos CD/análisis , Antígenos de Neoplasias/análisis , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Antígeno CD52 , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Resistencia a Antineoplásicos , Fatiga/inducido químicamente , Femenino , Citometría de Flujo , Glicoproteínas/análisis , Humanos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Micosis Fungoide/patología , Neoplasia Residual/diagnóstico , Neoplasia Residual/tratamiento farmacológico , Prurito/inducido químicamente , Inducción de Remisión , Síndrome de Sézary/patología , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Linfocitos T/metabolismo , Linfocitos T/patología , Resultado del TratamientoRESUMEN
Primary cutaneous T-cell lymphomas encompass a spectrum of non-Hodgkin's lymphomas that are characterised by clonal proliferation of skin-homing malignant T lymphocytes. Mycosis fungoides and the leukaemic variant Sézary syndrome, collectively referred to as cutaneous T-cell lymphomas, are the most common entities. No curative therapy exists and patients ultimately develop advanced or relapsed disease that is refractory to standard treatment options. Therefore, there is a great need for the development of novel emerging therapies. Bexarotene is the first synthetic nuclear retinoid X receptor-selective retinoid approved by the FDA for the treatment of refractory cutaneous T-cell lymphoma in all stages, as both an oral capsule and a topical gel formulation. Bexarotene was found to induce apoptosis in a variety of preclinical in vitro and in vivo models including cutaneous T-cell lymphoma cells, and has shown efficacy in two multi-centre, open-label Phase II - III clinical trials for early and advanced stages of cutaneous T-cell lymphoma in patients who have failed or were refractory to standard therapies. New insights into the immunomodulatory function of bexarotene have indicated opportunities for combined treatment with IFN-alpha, denileukin diftitox or phototherapy. This article reviews the biological properties, pharmacokinetics, clinical efficacy, safety and role of bexarotene in the treatment of cutaneous T-cell lymphoma.
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Antineoplásicos/uso terapéutico , Linfoma Cutáneo de Células T/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Antineoplásicos/química , Humanos , Linfoma Cutáneo de Células T/clasificación , Neoplasias Cutáneas/clasificaciónRESUMEN
OBJECTIVES: To evaluate long-term outcomes, impact of maintenance therapy and potential curability of patients with mycosis fungoides (MF) treated with psoralen plus UV-A (PUVA) monotherapy. DESIGN: Single-center retrospective cohort analysis. SETTING: Academic referral center for cutaneous lymphoma. PATIENTS: A total of 66 of 104 patients with clinical stages IA to IIA MF who achieved complete remission (CR) after PUVA monotherapy between 1979 and 1995. MAIN OUTCOME MEASURES: Kaplan-Meier actuarial survival and disease-free survival curves were compared between stage IA and IB/IIA cases. Patients were stratified into relapse and nonrelapse groups based on whether their MF relapsed during study follow-up. Baseline characteristics and treatment were compared between these groups. RESULTS: Median follow-up time was 94 months (range, 5-242 months). Thirty-three patients maintained CR for 84 months (range, 5-238 months), and 33 patients experienced relapse with a median disease-free interval of 39 months (range, 2-127 months). There was no significant difference in baseline characteristics between patients in the nonrelapse and relapse groups. Those in the nonrelapse group received a higher cumulative dosage to CR (P = .03) and required longer treatment periods to achieve CR (P = .03). Disease-free survival rates at 5 and 10 years for all patients with stage IA were 56% and 30%, respectively, and for stage IB/IIA, 74% and 50%. Actuarial survival rates at 5, 10, and 15 years were 94%, 82%, and 82%, respectively, in patients with stage IA, and 80%, 69%, and 58% in patients with stage IB/IIA. The overall survival rate for the nonrelapse and relapse groups did not show any statistical difference. One third of the patients developed signs of chronic photodamage and secondary cutaneous malignancies. CONCLUSIONS: Psoralen UV-A is an effective treatment for MF, inducing long-term remissions and perhaps in some cases disease "cure." Thirty percent to 50% of patients remain disease free for 10 years, but late relapses occur. Long-term survival is not affected by relapse status, and the risk of photodamage needs to be measured against the possible benefit of greater disease elimination.
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Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Terapia PUVA/métodos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Linfoma Cutáneo de Células T/mortalidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Medición de Riesgo , Neoplasias Cutáneas/mortalidad , Análisis de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Primary cutaneous T-cell lymphomas are non-Hodgkin's lymphomas with varied clinical presentation and prognosis. The most common subtypes of cutaneous T-cell lymphomas are the epidermotropic variants mycosis fungoides and Sézary syndrome. Treatment of mycosis fungoides has encompassed a variety of modalities including the use of retinoids with several studies evaluating their efficacy. The reported benefits and duration of response have varied in published data. The biological effect of retinoids is mediated by specific receptor families, retinoic acid receptor (RAR) and retinoic X receptor (RXR), with subsequently altered gene expression. There are no data available on cutaneous T-cell lymphomas that compare RAR and RXR retinoids. The objective of our retrospective, nonrandomized, single-center study was to compare the response, survival outcomes, and toxic effects in our phase II trial of the RAR-specific retinoid, all-trans retinoic acid, with clinical use of the RXR-specific retinoid, bexarotene, in patients with mycosis fungoides/Sézary syndrome who have relapsed. There was no statistical difference in response rates (12% vs 21%), response duration (20.5 vs 7.3 months), event-free survival time (4 vs 5 months), or median survival when corrected for length of follow-up. Both have favorable toxicity profiles that can be managed with medications. The toxicity profile caused by bexarotene seems to be more limited to laboratory values and better tolerated, although generally associated with more severe grades of toxicity. In conclusion, both retinoids have modest objective response rates and, therefore, most likely will have limited impact as monotherapeutic agents. However, the immunomodulatory effects of RAR and RXR retinoids provide a rational basis for using retinoids in combination with other biologic immune response modifiers, phototherapy, or cytotoxic chemotherapy.
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Anticarcinógenos/uso terapéutico , Antineoplásicos/uso terapéutico , Linfoma Cutáneo de Células T/tratamiento farmacológico , Tetrahidronaftalenos/uso terapéutico , Tretinoina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticarcinógenos/efectos adversos , Antineoplásicos/efectos adversos , Bexaroteno , Femenino , Estudios de Seguimiento , Humanos , Linfoma Cutáneo de Células T/mortalidad , Masculino , Persona de Mediana Edad , Receptores de Ácido Retinoico , Receptores X Retinoide , Estudios Retrospectivos , Análisis de Supervivencia , Tetrahidronaftalenos/efectos adversos , Resultado del Tratamiento , Tretinoina/efectos adversosRESUMEN
Primary cutaneous T-cell lymphomas represent a wide variety of non-Hodgkin lymphomas that are characterized by a distinct clinical presentation. Advanced molecular and biological techniques have enhanced the recognition of cutaneous T-cell lymphomas. The most common subtypes of cutaneous T-cell lymphomas are the epidermotropic variants mycosis fungoides and Sézary syndrome. At present, a stage-adjusted therapy is the best concept available, since early aggressive treatment options did not improve the prognosis of patients with cutaneous T-cell lymphomas. Accurate diagnostic and clinical assessment as well as identification of prognostic factors provides a helpful basis for treatment strategies. Current medical literature on diagnosis, prognosis, and treatment is reviewed with emphasis on new biologic response-modifying treatment options.