RESUMEN
PURPOSE: Previously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit. METHODS AND MATERIALS: Clinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed. RESULTS: Rectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (<40 mL) and 12% and 2% for the largest (>80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had >0.5 (7.6; P < .01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines. CONCLUSIONS: There was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the >95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits.
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Próstata/cirugía , Neoplasias de la Próstata/cirugía , Recto/cirugía , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Próstata/efectos de la radiación , Neoplasias de la Próstata/radioterapia , Recto/efectos de la radiaciónRESUMEN
Selective targeting of up-regulated integrins on tumor cells is a novel antiangiogenesis strategy for treating solid tumors. CNTO 95 is a fully human anti-alpha(v) integrin monoclonal antibody and has shown antitumor activity when used as a single agent in preclinical studies. We previously showed that radiation combined with an integrin alpha(v)beta(3) antagonist cRGD peptide increased the therapeutic efficacy of radiation in preclinical tumor models. We hypothesized that the combination of radiation and CNTO 95 would synergistically enhance the efficacy of radiation therapy. The in vitro studies showed that CNTO 95 radiosensitized and induced apoptosis in M21 cells in vitronectin-coated dishes. In mice bearing established human cancer xenograft tumors, CNTO 95 alone had only a moderate effect on tumor growth. The combined therapy of CNTO 95 and fractionated radiation significantly inhibited tumor growth and produced the longer tumor growth delay time in multiple tumor models. Maintenance dosing of CNTO 95 following irradiation contributed to efficacy and was important for continued inhibition of tumor regrowth. Immunohistochemistry studies showed that the combined use of CNTO 95 and radiation reduced the alpha(v) integrin and vascular endothelial growth factor receptor expression and the microvessel density and increased apoptosis in tumor cells and the tumor microenvironment. CNTO 95 alone and in combination with radiation did not produce any obvious signs of systemic toxicity. These results show that CNTO 95 can potentiate the efficacy of fractionated radiation therapy in a variety of human cancer xenograft tumor types in nude mice. These findings are very promising and may have high translational relevance for the treatment of patients with solid tumors.
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Anticuerpos Monoclonales/farmacología , Fraccionamiento de la Dosis de Radiación , Integrinas/inmunología , Radioinmunoterapia , Animales , Anticuerpos Monoclonales Humanizados , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular , Terapia Combinada , Citometría de Flujo , Humanos , Inmunohistoquímica , Masculino , Ratones , Ratones Desnudos , Neovascularización Patológica , Factores de TiempoRESUMEN
BACKGROUND: There is minimal experience with less rigid syndesmotic fixation devices which may approximate the normal distal tibio-fibular mechanics during healing. This study evaluates the ability of a FiberWire-button implant (Arthrex, Naples, FL) to maintain syndesmotic reduction as compared with a metallic screw. METHODS: Ten matched fresh-frozen cadaveric ankle pairs with intact ligaments were tested (12.5 Nm external rotation force) to establish physiologic syndesmotic diastasis. The same force was applied to the ankles after sectioning of the syndesmotic and deltoid ligaments. Within the pairs, each limb was randomized to receive a FiberWire-button implant or a metallic screw (Synthes, Paoli, PA); the ankles were tested for syndesmotic diastasis with progressive external rotation force, from 2.5 Nm to 25 Nm (or failure). RESULTS: There was no significant difference in diastasis amongst pairs with intact or sectioned syndesmosis (p=0.64 and p=0.80, respectively). There was a significantly greater diastasis in the FiberWire-button group at all external rotation loads (p<0.0001). Nine of the ten pairs failed (all through fracture of the distal fibula). There were no hardware failures. The metallic screw group failed at a lower load (mean 15 Nm) compared to the FiberWire-button group (mean 18 Nm, p=0.0004). The metallic screw group maintained syndesmotic reduction up to 5 Nm of force. CONCLUSIONS: The FiberWire-button was unable to maintain syndesmotic reduction of the ankles at any of the forces applied. The ankles fixed with the FiberWire-button demonstrated significantly greater widening of the syndesmosis compared to the screw, at all loads. CLINICAL RELEVANCE: The FiberWire-button implant may not maintain adequate ankle syndesmotic reduction in the immediate post-operative period relative to a metallic screw.
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Traumatismos del Tobillo/cirugía , Tornillos Óseos , Ligamentos Articulares/cirugía , Ensayo de Materiales , Prótesis e Implantes , Anciano , Cadáver , Análisis de Falla de Equipo , Femenino , Peroné/lesiones , Fracturas Óseas/etiología , Humanos , Ligamentos Articulares/lesiones , Masculino , Persona de Mediana Edad , Distribución Aleatoria , Rotación , Soporte de PesoRESUMEN
BACKGROUND: We previously reported the results of a phase 3 trial evaluating a prostate/rectal hydrogel spacer during prostate intensity modulated radiation therapy, which resulted in decreased rectal dose and toxicity and less decline in bowel quality of life (QOL). A secondary analysis was performed to correlate penile bulb dose and sexual QOL. METHODS AND MATERIALS: Sexual QOL was measured with the Expanded Prostate Cancer Index Composite (EPIC) by mean scores, the proportion of patients with a minimal clinically important difference (MID), and analyses of the different items composing the sexual domain. RESULTS: A total of 222 men enrolled with median follow-up of 37 months. Hydrogel reduced penile bulb mean dose, maximum dose, and percentage of penile bulb receiving 10 to 30 Gy (all P < .05) with mean dose indirectly correlated with erections sufficient for intercourse at 15 months (P = .03). Baseline EPIC was low (53 [standard deviation ± 24]) with no difference between arms (P > .1). A total of 41% (88/222) of men had adequate baseline sexual QOL (EPIC >60 (mean, 77 [± 8.3]). This subgroup at 3 years had better sexual function (P = .03) with a spacer with a smaller difference in sexual bother (P = .1), which resulted in a higher EPIC summary on the spacer arm (58 [±24.1] vs control 45 [± 24.4]) meeting threshold for MID without statistical significance (P = .07). There were statistically nonsignificant differences favoring spacer for the proportion of men with MID and 2× MID declines in sexual QOL with 53% vs 75% having an 11-point decline (P = .064) and 41% vs 60% with a 22-point decline (P = .11). At 3 years, more men potent at baseline and treated with spacer had "erections sufficient for intercourse" (control 37.5% vs spacer 66.7%, P = .046) as well as statistically higher scores on 7 of 13 items in the sexual domain (all P < .05). CONCLUSIONS: The use of a hydrogel spacer decreased dose to the penile bulb, which was associated with improved erectile function compared with the control group based on patient-reported sexual QOL.
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Neoplasias de la Próstata/radioterapia , Calidad de Vida/psicología , Radioterapia de Intensidad Modulada/psicología , Conducta Sexual/psicología , Humanos , Masculino , Radioterapia de Intensidad Modulada/métodosRESUMEN
PURPOSE: SpaceOAR, a Food and Drug Administration-approved hydrogel intended to create a rectal-prostate space, was evaluated in a single-blind phase III trial of image guided intensity modulated radiation therapy. A total of 222 men were randomized 2:1 to the spacer or control group and received 79.2 Gy in 1.8-Gy fractions to the prostate with or without the seminal vesicles. The present study reports the final results with a median follow-up period of 3 years. METHODS AND MATERIALS: Cumulative (Common Terminology Criteria for Adverse Events, version 4.0) toxicity was evaluated using the log-rank test. Quality of life (QOL) was examined using the Expanded Prostate Cancer Index Composite (EPIC), and the mean changes from baseline in the EPIC domains were tested using repeated measures models. The proportions of men with minimally important differences (MIDs) in each domain were tested using repeated measures logistic models with prespecified thresholds. RESULTS: The 3-year incidence of grade ≥1 (9.2% vs 2.0%; P=.028) and grade ≥2 (5.7% vs 0%; P=.012) rectal toxicity favored the spacer arm. Grade ≥1 urinary incontinence was also lower in the spacer arm (15% vs 4%; P=.046), with no difference in grade ≥2 urinary toxicity (7% vs 7%; P=0.7). From 6 months onward, bowel QOL consistently favored the spacer group (P=.002), with the difference at 3 years (5.8 points; P<.05) meeting the threshold for a MID. The control group had a 3.9-point greater decline in urinary QOL compared with the spacer group at 3 years (P<.05), but the difference did not meet the MID threshold. At 3 years, more men in the control group than in the spacer group had experienced a MID decline in bowel QOL (41% vs 14%; P=.002) and urinary QOL (30% vs 17%; P=.04). Furthermore, the control group were also more likely to have experienced large declines (twice the MID) in bowel QOL (21% vs 5%; P=.02) and urinary QOL (23% vs 8%; P=.02). CONCLUSIONS: The benefit of a hydrogel spacer in reducing the rectal dose, toxicity, and QOL declines after image guided intensity modulated radiation therapy for prostate cancer was maintained or increased with a longer follow-up period, providing stronger evidence for the benefit of hydrogel spacer use in prostate radiation therapy.
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Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/radioterapia , Traumatismos por Radiación/epidemiología , Traumatismos por Radiación/prevención & control , Protección Radiológica/estadística & datos numéricos , Enfermedades del Recto/epidemiología , Enfermedades del Recto/prevención & control , Adulto , Anciano , Causalidad , Fraccionamiento de la Dosis de Radiación , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Órganos en Riesgo/efectos de la radiación , Prevalencia , Neoplasias de la Próstata/psicología , Calidad de Vida/psicología , Traumatismos por Radiación/psicología , Protección Radiológica/instrumentación , Radioterapia Conformacional/métodos , Radioterapia Conformacional/psicología , Radioterapia Conformacional/estadística & datos numéricos , Radioterapia Guiada por Imagen/psicología , Radioterapia Guiada por Imagen/estadística & datos numéricos , Enfermedades del Recto/psicología , Factores de Riesgo , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
PURPOSE: Perirectal spacing, whereby biomaterials are placed between the prostate and rectum, shows promise in reducing rectal dose during prostate cancer radiation therapy. A prospective multicenter randomized controlled pivotal trial was performed to assess outcomes following absorbable spacer (SpaceOAR system) implantation. METHODS AND MATERIALS: Overall, 222 patients with clinical stage T1 or T2 prostate cancer underwent computed tomography (CT) and magnetic resonance imaging (MRI) scans for treatment planning, followed with fiducial marker placement, and were randomized to receive spacer injection or no injection (control). Patients received postprocedure CT and MRI planning scans and underwent image guided intensity modulated radiation therapy (79.2 Gy in 1.8-Gy fractions). Spacer safety and impact on rectal irradiation, toxicity, and quality of life were assessed throughout 15 months. RESULTS: Spacer application was rated as "easy" or "very easy" 98.7% of the time, with a 99% hydrogel placement success rate. Perirectal spaces were 12.6 ± 3.9 mm and 1.6 ± 2.0 mm in the spacer and control groups, respectively. There were no device-related adverse events, rectal perforations, serious bleeding, or infections within either group. Pre-to postspacer plans had a significant reduction in mean rectal V70 (12.4% to 3.3%, P<.0001). Overall acute rectal adverse event rates were similar between groups, with fewer spacer patients experiencing rectal pain (P=.02). A significant reduction in late (3-15 months) rectal toxicity severity in the spacer group was observed (P=.04), with a 2.0% and 7.0% late rectal toxicity incidence in the spacer and control groups, respectively. There was no late rectal toxicity greater than grade 1 in the spacer group. At 15 months 11.6% and 21.4% of spacer and control patients, respectively, experienced 10-point declines in bowel quality of life. MRI scans at 12 months verified spacer absorption. CONCLUSIONS: Spacer application was well tolerated. Increased perirectal space reduced rectal irradiation, reduced rectal toxicity severity, and decreased rates of patients experiencing declines in bowel quality of life. The spacer appears to be an effective tool, potentially enabling advanced prostate RT protocols.
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Hidrogel de Polietilenoglicol-Dimetacrilato/administración & dosificación , Órganos en Riesgo/efectos de la radiación , Neoplasias de la Próstata/radioterapia , Traumatismos por Radiación/prevención & control , Protección Radiológica/instrumentación , Radioterapia Guiada por Imagen/instrumentación , Radioterapia de Intensidad Modulada/instrumentación , Recto/efectos de la radiación , Anciano , Marcadores Fiduciales , Humanos , Masculino , Estudios Prospectivos , Próstata , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Calidad de Vida , Dosis de Radiación , Radiografía , Dosificación Radioterapéutica , Radioterapia Guiada por Imagen/métodos , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Sistema Urinario/efectos de la radiaciónRESUMEN
PURPOSE: To measure the benefits of intensity-modulated radiotherapy (IMRT) compared with three-dimensional conformal radiotherapy (3D-CRT) when used in combination with brachytherapy for the treatment of prostate cancer. METHODS AND MATERIALS: We conducted a retrospective review of all patients with localized prostate cancer who received external-beam radiotherapy (EBRT) in combination with brachytherapy with at least 1 year follow-up (n = 812). Combination therapy consisted of (103)Pd or (125)I implant, followed by a course of EBRT. From 1993 to March 2003 521 patients were treated with 3D-CRT, and from April 2003 to March 2009 291 patients were treated with IMRT. Urinary symptoms were prospectively measured with the International Prostate Symptom Score questionnaire with a single quality of life (QOL) question; rectal bleeding was assessed per the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer Late Radiation Morbidity Scoring Schema. The Pearson χ(2) test was used to compare toxicities experienced by patients who were treated with either IMRT or 3D-CRT. Logistic regression analyses were also performed to rule out possible confounding factors. RESULTS: Within the first 3 months after treatment, patients treated with 3D-CRT scored their urinary symptoms as follows: 19% mild, 44% moderate, and 37% severe; patients treated with IMRT scored their urinary symptoms as follows: 36% mild, 47% moderate, and 17% severe (p < 0.001). The 3D-CRT patients rated their QOL as follows: 35% positive, 20% neutral, and 45% negative; IMRT patients rated their QOL as follows: 51% positive, 18% neutral, and 31% negative (p < 0.001). After 1 year of follow-up there was no longer any difference in urinary morbidity between the two groups. Logistic regression confirmed the differences in International Prostate Symptom Score and QOL in the acute setting (p < 0.001 for both). Grade ≥ 2 rectal bleeding was reported by 11% of 3D-CRT patients and 7% of IMRT patients (p = 0.046); logistic regression analysis also confirmed this observation (p = 0.040). CONCLUSIONS: When used in combination with brachytherapy, IMRT offers less Grade ≥ 2 rectal bleeding, less acute urinary toxicities, and is associated with a higher QOL compared with 3D-CRT.
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Braquiterapia/efectos adversos , Hemorragia Gastrointestinal/etiología , Neoplasias de la Próstata/radioterapia , Radioterapia Conformacional/efectos adversos , Radioterapia de Intensidad Modulada/efectos adversos , Enfermedades del Recto/etiología , Trastornos Urinarios/etiología , Anciano , Anciano de 80 o más Años , Braquiterapia/métodos , Distribución de Chi-Cuadrado , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Estudios de Seguimiento , Hemorragia Gastrointestinal/diagnóstico , Humanos , Radioisótopos de Yodo/uso terapéutico , Masculino , Persona de Mediana Edad , Paladio/uso terapéutico , Neoplasias de la Próstata/patología , Calidad de Vida , Radioisótopos/uso terapéutico , Dosificación Radioterapéutica , Radioterapia Conformacional/métodos , Radioterapia de Intensidad Modulada/métodos , Enfermedades del Recto/diagnóstico , Análisis de Regresión , Estudios Retrospectivos , Encuestas y Cuestionarios , Trastornos Urinarios/clasificaciónRESUMEN
PURPOSE: To identify predictors of metastatic disease after brachytherapy treatment for prostate cancer. METHODS AND MATERIALS: All patients who received either brachytherapy alone (implant) or brachytherapy in combination with external beam radiation therapy for treatment of localized prostate cancer at The Mount Sinai Hospital between June 1990 and March 2007 with a minimum follow-up of 2 years were included. Univariate and multivariable analyses were performed on the following variables: risk group, Gleason score (GS), clinical T stage, pretreatment prostate-specific antigen level, post-treatment prostate-specific antigen doubling time (PSA-DT), treatment type (implant vs. implant plus external beam radiation therapy), treatment era, total biological effective dose, use of androgen deprivation therapy, age at diagnosis, and race. PSA-DT was analyzed in the following ordinate groups: 0 to 90 days, 91 to 180 days, 180 to 360 days, and greater than 360 days. RESULTS: We included 1,887 patients in this study. Metastases developed in 47 of these patients. The 10-year freedom from distant metastasis (FFDM) rate for the entire population was 95.1%. Median follow-up was 6 years (range, 2-15 years). The only two significant predictors of metastatic disease by multivariable analyses were GS and PSA-DT (p < 0.001 for both variables). Estimated 10-year FFDM rates for GS of 6 or less, GS of 7, and GS of 8 or greater were 97.9%, 94.3%, and 76.1%, respectively (p < 0.001). Estimated FFDM rates for PSA-DT of 0 to 90 days, 91 to 180 days, 181 to 360 days, and greater than 360 days were 17.5%, 67.9%, 74%, and 94.8%, respectively (p < 0.001). Estimated 10-year FFDM rates for the low-, intermediate-, and high-risk groups were 98.6%, 96.2%, and 86.7%, respectively. A demographic shift to patients presenting with higher-grade disease in more recent years was observed. CONCLUSIONS: GS and post-treatment PSA-DT are both statistically significant independent predictors of metastatic disease. Patients with a high GS and/or short PSA-DT have a higher likelihood of developing metastatic disease and should be considered for systemic therapy.
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Braquiterapia/métodos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/radioterapia , Análisis de Varianza , Antagonistas de Andrógenos/uso terapéutico , Terapia Combinada/métodos , Estudios de Seguimiento , Humanos , Radioisótopos de Yodo/uso terapéutico , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Paladio/uso terapéutico , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Radioisótopos/uso terapéutico , Estudios RetrospectivosRESUMEN
OBJECTIVE: To assess the efficacy of prophylactic swallowing exercises on swallowing function in patients undergoing chemoradiation therapy (CRT) for head and neck cancer. DESIGN: Randomized controlled trial. SETTING: Tertiary care, academic medical center. PATIENTS: Twenty-six patients with head and neck cancer receiving CRT. INTERVENTION: Patients performed 5 targeted swallowing exercises throughout their CRT and participated in weekly swallowing therapy sessions to promote adherence and accurate technique. Controls had no prophylactic exercises and were referred for swallowing treatment after completion of CRT if indicated. MAIN OUTCOME MEASURES: Swallowing function was assessed with the Functional Oral Intake Scale (FOIS) and the Performance Status Scale for Head and Neck Cancer Patients (PSS-H&N) at baseline, immediately after CRT, and at 3, 6, 9, and 12 months after CRT. RESULTS: There were no statistically significant differences in FOIS scores between intervention and control patients immediately after CRT (immediately after CRT: intervention group median score, 3 [range, 1-7], vs median control score, 4 [range, 1-6] (P = .88). However, intervention patients had significantly better scores at months 3 and 6 (median 3-month intervention score, 7 [range, 5-7], vs median control score, 5 [range, 3-7] [P = .03]; median 6-month intervention score, 7 [range, 6-7], vs median control score, 6 [range, 3-7] [P = .009]). There was no significant difference in scores at months 9 and 12 (P = .24 and P = .93, respectively). The same pattern between intervention and control patients was observed for scores on the PSS-H&N. CONCLUSIONS: Patients who performed prophylactic swallowing exercises had improved swallowing function at 3 and 6 months after CRT but not immediately after CRT or at 9 and 12 months after CRT. The small sample size may have limited our ability to detect significant differences beyond 6 months of observation as well as additional significant differences in our study.
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Quimioradioterapia , Trastornos de Deglución/prevención & control , Trastornos de Deglución/fisiopatología , Deglución/fisiología , Terapia por Ejercicio/métodos , Neoplasias de Cabeza y Cuello/fisiopatología , Neoplasias de Cabeza y Cuello/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
A phase II trial was conducted to evaluate the tolerability and efficacy of incorporating cetuximab and simultaneous integrated boost intensity-modulated radiation therapy (SIB-IMRT) into a well-described 5-fluorouracil (5-FU) and hydroxyurea (HU)-based chemoradiation regimen. Patients with stage IVa-IVb or high-risk stage III squamous cell carcinomas were enrolled. Prior organ-conserving surgery or induction chemotherapy was allowed. IMRT was administered in 1.5 Gy fractions twice daily on days 1-5 of weeks 1, 3, 5, 7±9 for a total dose of 60-73.5 Gy. Concurrent systemic therapy consisted of 5-FU (600 mg/m2), HU (500 mg BID) and cetuximab (250 mg/m2). p16INK4A expression was assessed by immunohistochemistry. From January 2007 to January 2010, 65 patients (61 with stage IV disease; 31 with oropharyngeal primaries) were enrolled. At a median follow-up of 28 months, 2-year locoregional control, distant control, progression-free survival, event-free survival and overall survival were 79, 83, 72, 63 and 80%, respectively. In 48 patients with available pre-treatment tissue, p16 overexpression was associated with significantly increased distant control (p=0.03), progression-free survival (p=0.02), event-free survival (p=0.007) and overall survival (p=0.03). The most common grade 3-4 toxicities were mucositis (46%), leukopenia (18%), anemia (18%) and dermatitis (17%). Concurrent 5-FU, HU, cetuximab and SIB-IMRT is a highly active regimen, particularly in patients with p16-positive disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/terapia , Radioterapia de Intensidad Modulada , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cetuximab , Terapia Combinada , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Hidroxiurea/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Radioterapia de Intensidad Modulada/efectos adversos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Preclinical data suggest that sunitinib enhances the efficacy of radiotherapy. We tested the combination of sunitinib and hypofractionated image-guided radiotherapy (IGRT) in a cohort of patients with historically incurable distant metastases. METHODS: Twenty five patients with oligometastases, defined as 1-5 sites of active disease on whole body imaging, were enrolled in a phase II trial from 2/08 to 9/10. The most common tumor types treated were head and neck, liver, lung, kidney and prostate cancers. Patients were treated with the recommended phase II dose of 37.5 mg daily sunitinib (days 1-28) and IGRT 50 Gy (days 8-12 and 15-19). Maintenance sunitinib was used in 33% of patients. Median follow up was 17.5 months (range, 0.7 to 37.4 months). RESULTS: The 18-month local control, distant control, progression-free survival (PFS) and overall survival (OS) were 75%, 52%, 56% and 71%, respectively. At last follow-up, 11 (44%) patients were alive without evidence of disease, 7 (28%) were alive with distant metastases, 3 (12%) were dead from distant metastases, 3 (12%) were dead from comorbid illness, and 1 (4%) was dead from treatment-related toxicities. The incidence of acute grade ≥ 3 toxicities was 28%, most commonly myelosuppression, bleeding and abnormal liver function tests. CONCLUSIONS: Concurrent sunitinib and IGRT achieves major clinical responses in a subset of patients with oligometastases. TRIAL REGISTRATION: ClinicalTrials.gov NCT00463060.
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Antineoplásicos/uso terapéutico , Quimioradioterapia , Indoles/uso terapéutico , Neoplasias/terapia , Pirroles/uso terapéutico , Radioterapia Guiada por Imagen , Anciano , Anciano de 80 o más Años , Fraccionamiento de la Dosis de Radiación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias/patología , Pronóstico , Sunitinib , Tasa de SupervivenciaRESUMEN
PURPOSE: To evaluate the efficacy of multimodality therapy consisting of hormone therapy (HT), brachytherapy (BT), and external beam radiotherapy (EBRT) in extraprostatic prostate cancer and identify factors with predictive value. METHODS AND MATERIALS: Between June 1992 and October 2006, 97 patients with extraprostatic prostate cancer received permanent seed implant BT. Extraprostatic disease was defined by one or more of the following: positive seminal vesicle biopsy (n=56), positive lymph node dissection (n=8), or a clinical tumor stage of T3 (n=48). Treatment consisted of BT alone with (103)Pd or (125)I (n=4); HT and BT (n=3); BT and EBRT (n=2); or trimodality therapy with HT, BT, and EBRT (n=88). Median followup was 69 (range, 23-182) months. Freedom from biochemical failure (FBF) rates were calculated using the Phoenix criteria. RESULTS: The 7-year actuarial FBF, freedom from distant metastases, disease-specific survival, and overall survival rates were 67%, 82%, 96%, and 81%, respectively. Biologically effective dose (BED) was the only variable significantly impacting FBF rates. FBF at 7 years was 60% vs. 74% for BED below 200 and 200 or above, respectively (p=0.048). Trends toward worse outcomes were noted with increasing Gleason score, with 7-year FBF rates of 86% vs. 71% vs. 55% for scores of 6 or less, 7, and 8-10, respectively (p=0.090). BED was the only significant predictor of FBF in multivariate analysis (p=0.032). None of the predictors were significant in multivariable analyses for the other outcomes studied. CONCLUSIONS: Trimodality approach achieves durable biochemical control in most patients with historically poor prognosis T3 prostate cancer. BED above 200Gy was associated with superior FBF.
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Braquiterapia/métodos , Hormonas/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Anciano , Anciano de 80 o más Años , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Invasividad Neoplásica , Neoplasias de la Próstata/patología , Dosificación Radioterapéutica , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate retrospectively the biochemical outcomes of young men treated with low-dose-rate brachytherapy for prostate cancer. METHODS AND MATERIALS: From 1990 to 2005, 1,665 men with clinically localized prostate cancer were treated with low-dose-rate brachytherapy +/- hormone therapy (HT) +/- external beam radiotherapy and underwent > or = 2 years of follow-up. Patients were stratified on the basis of age: < or = 60 (n = 378) and >60 years (n = 1,287). Biochemical failure was defined as a prostate-specific antigen (PSA) nadir plus 2 ng/mL. Univariate and multivariate analyses were used to determine the association of variables with freedom from biochemical failure (FFbF). RESULTS: Median follow-up was 68 months (range, 24-180) for men < or = 60 years and 66 months (range, 24-200) for men >60. For the entire group, the actuarial 5- and 8-year FFbF rates were 94% and 88%, respectively. Men < or = 60 demonstrated similar 5- and 8-year FFbF (95% and 92%) compared with men >60 (93% and 87%; p = 0.071). A larger percent of young patients presented with low-risk disease; lower clinical stage, Gleason score (GS), and pretreatment PSA values; were treated after 1997; did not receive any HT; and had a high biologic effective dose (BED) of radiation (all ps <0.001). On multivariate analysis, PSA (p = 0.001), GS (p = 0.005), and BED (p < 0.001) were significantly associated with FFbF, but age was not (p = 0.665). CONCLUSION: Young men achieve excellent 5- and 8-year biochemical control rates that are comparable to those of older men after prostate brachytherapy. Young age should not be a deterrent when considering brachytherapy as a primary treatment option for clinically localized prostate cancer.
Asunto(s)
Braquiterapia/métodos , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/radioterapia , Factores de Edad , Análisis de Varianza , Estudios de Seguimiento , Humanos , Radioisótopos de Yodo/uso terapéutico , Masculino , Persona de Mediana Edad , Paladio/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Radioisótopos/uso terapéutico , Dosificación Radioterapéutica , Análisis de Regresión , Efectividad Biológica Relativa , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Safety concerns surrounding the use of recombinant human erythropoietin (Epo) to treat anemia in cancer patients were raised after 2 recent clinical studies reported a worse survival outcome in patients who received epoetin alpha or epoetin beta compared with patients who received placebo. Although those findings contrasted with previous clinical studies, which demonstrated no difference in survival for cancer patients who received erythropoiesis-stimulating agents (ESAs), some investigators have suggested a potential role for ESAs in promoting tumor growth through 1) stimulation of Epo receptors (EpoR) expressed in tumors, 2) stimulation and formation of tumor vessels, and/or 3) enhanced tumor oxygenation. The first and second hypotheses appeared to be supported by some EpoR expression and ESA in vitro studies. However, these conclusions have been challenged because of poor specificity of EpoR-detection methodologies, conflicting data from different groups, and the lack of correlation between in vitro data and in vivo findings in animal tumor models. For this report, the authors reviewed the biology of EpoR in erythropoiesis and compared and contrasted the reported findings on the role of ESAs and EpoR in tumors.
Asunto(s)
Hematínicos/uso terapéutico , Neoplasias/metabolismo , Receptores de Eritropoyetina/fisiología , Animales , Proliferación Celular , Supervivencia Celular , Modelos Animales de Enfermedad , Eritropoyesis , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
The t(9;22) chromosomal translocation results in expression of P210(BCR-ABL), a fusion protein necessary for the development of chronic myelogenous leukemia (CML). The constitutive activation of the P210(BCR-ABL) tyrosine kinase results in phosphorylation of multiple signaling pathways leading to the transformed phenotype. Additionally, extracellular interactions between P210(BCR-ABL)-expressing progenitor cells and bone marrow stroma may provide external signals that facilitate CML development. In contrast to the intracellular signaling pathways involved in CML, little is known about how P210(BCR-ABL) expression modifies cell-cell and cell-substratum interactions. To investigate the role of P210(BCR-ABL) in modulating cellular adhesion, we used a highly sensitive and quantitative cell detachment apparatus that measures the strength of association between a population of cells and an adhesive matrix. Our findings show that P210(BCR-ABL) expression increased adhesion nearly 2-fold between the myeloblastic cell line, 32D, and fibronectin compared to a control vector. We then investigated whether abnormal adhesion due to P210(BCR-ABL) expression was caused by its tyrosine kinase activity. A quantitative analysis of cell-fibronectin adhesion found that neither expression of a kinase-inactive P210(BCR-ABL) mutant in 32D cells or attenuation of kinase activity by STI571 (imatinib mesylate) in 32D cells transduced with wild-type P210(BCR-ABL) could correct the nearly 2-fold increase in cell-fibronectin adhesion. Similarly, STI571 treatment of Meg-01 cells, a P210(BCR-ABL)-expressing cell line derived from a patient in blast crisis, failed to inhibit adhesion to fibronectin. Together, our results indicate that changes in adhesion induced by P210(BCR-ABL) are independent of its tyrosine kinase activity.