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IMPORTANCE: Radiation therapy to the head and neck has traditionally been associated with adverse effects that can affect oral health and physical functioning. Although intensity-modulated radiotherapy (IMRT) has been widely adopted as a means of decreasing toxic effects, limited clinical data exist on its potential effect on long-term quality of life. OBJECTIVE: To analyze quality of life among long-term survivors of head and neck cancer treated with IMRT. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional analysis studied 50 consecutive long-term survivors of head and neck cancer from a comprehensive cancer center who had previously undergone IMRT that required bilateral neck irradiation for locally advanced disease. All patients were clinically without evidence of recurrent disease and had at least 5 years of follow-up. MAIN OUTCOMES AND MEASURES: The University of Washington Quality of Life (UW-QOL) scores were reviewed for all study participants. The UW-QOL questionnaire consists of 12 domains that pertain to the degree of quality of life in the categories of pain, appearance, activity, recreation, swallowing, chewing, speech, shoulder function, taste, saliva, mood, and anxiety. RESULTS: Five years after completion of IMRT, 42 patients (84%) reported that their health-related quality of life was "much better" or "somewhat better" than at the time of cancer diagnosis. With respect to recent health-related quality of life during the preceding 7 days at the time of completing the UW-QOL questionnaire, 40 patients (80%) treated with IMRT reported "outstanding" or "very good" levels of functioning. Five years after completion of treatment, 41 (82%) rated their overall quality of life as "outstanding" or "very good." The lowest domain score on the UW-QOL questionnaire at 5 years pertained to salivary dysfunction. However, 42 patients (84%) reported saliva "of normal consistency" or "less saliva than normal but enough" compared with 8 (16%) reporting "too little saliva." No patient reported having "no saliva." CONCLUSIONS AND RELEVANCE: Our findings add to the body of literature that supports the acceptance of IMRT as standard treatment for head and neck cancer. The fact that most 5-year survivors were satisfied with their quality of lives points to the ability of IMRT to preserve long-term functioning.
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Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Calidad de Vida , Radioterapia de Intensidad Modulada/métodos , Sobrevivientes/psicología , Adulto , Anciano , Análisis de Varianza , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Estudios Transversales , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Disección del Cuello/métodos , Disección del Cuello/mortalidad , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Satisfacción del Paciente/estadística & datos numéricos , Dosificación Radioterapéutica , Radioterapia de Intensidad Modulada/efectos adversos , Medición de Riesgo , Estadísticas no Paramétricas , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
BACKGROUND: Despite advances in targeted therapies, there is an ongoing need to develop new and effective cytotoxic drug combinations in non-small cell lung cancer (NSCLC). Based on preclinical demonstration of additive cytotoxicity, we evaluated the safety and efficacy of combining pemetrexed and nanoparticle albumin bound (nab) paclitaxel with a focus on NSCLC for phase II expansion. METHODS: A 3 + 3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Three dose levels were tested: pemetrexed 500 mg/m(2) day 1 and nab-paclitaxel day 1 at 180, 220, & 260 mg/m(2) every 21 days. Phase II eligibility included advanced NSCLC, ≤2 line prior therapy, PS 0-1, adequate organ function. Primary endpoint for further study was response rate (RR) ≥ 25%. RESULTS: Planned dose escalation was completed without reaching the MTD. The RP2D was pemetrexed 500 mg/m(2) and nab-paclitaxel 260 mg/m(2). The phase II portion accrued 37 pts before early closure due to increasing first-line pemetrexed/platinum doublet use in non-squamous NSCLC. In 31 assessable phase II patients there were 5 partial responses, 12 stable disease, 14 progressive disease. The median overall survival was 8.8 months; progressive disease 4.4 months and disease control 15.6 months. CONCLUSIONS: Pemetrexed 500 mg/m(2) day 1 with nab-paclitaxel 260 mg/m(2) was feasible and well tolerated. The phase II component demonstrated activity in second/third-line therapy of advanced NSCLC; response rate 14% and disease control rate 46%. Treatment practice patterns of advanced NSCLC have evolved; further trials of this regimen are not planned.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Anciano , Albúminas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Esquema de Medicación , Femenino , Glutamatos/administración & dosificación , Guanina/administración & dosificación , Guanina/análogos & derivados , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Paclitaxel/administración & dosificación , PemetrexedRESUMEN
PURPOSE: Stage III non-small cell lung cancer (NSCLC) patients with poor performance status (PS) or co-morbidities are often not candidates for standard chemoradiotherapy (chemoRT) due to poor tolerance to treatments. A pilot study for poor-risk stage III NSCLC patients was conducted combining cetuximab, a chimeric monoclonal antibody targeting epidermal growth factor receptor (EGFR), with chest radiation (RT). METHODS: Stage III NSCLC patients with Zubrod PS 2, or Zubrod PS 0-1 with poor pulmonary function and co-morbidities prohibiting chemoRT were eligible. A loading dose of cetuximab (400 mg/m(2)) was delivered week 1, followed by weekly cetuximab (250 mg/m(2))/RT to 64.8 Gy in 1.8 Gy daily fractions, and maintenance weekly cetuximab (250 mg/m(2)) for 2 years or until disease progression. H-score for EGFR protein expression was conducted in available tumors. RESULTS: Twenty-four patients were enrolled. Twenty-two were assessed for outcome and toxicity. Median survival was 14 months and median progression-free survival was 8 months. The response rate was 47% and disease control rate was 74%. Toxicity assessment revealed 22.7% overall ≥Grade 3 non-hematologic toxicities. Grade 3 esophagitis was observed in one patient (5%). The skin reactions were mostly Grade 1 or 2 except two of 22 (9%) had Grade 3 acne and one of 22 (5%) had Grade 3 radiation skin burn. Grade 3-4 hypomagnesemia was seen in four (18%) patients. One patient (5%) had elevated cardiac troponin and pulmonary emboli. H-score did not reveal prognostic significance. An initially planned second cohort of the study did not commence due to slow accrual, which would have added weekly docetaxel to cetuximab/RT after completion of the first cohort of patients. CONCLUSION: Concurrent weekly cetuximab/chest RT followed by maintenance cetuximab for poor-risk stage III NSCLC was well tolerated. Further studies with larger sample sizes will be useful to establish the optimal therapeutic ratio of this regimen.
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OBJECTIVES: Although concurrent chemoradiation is increasingly used for patients with locally advanced head and neck cancer, many elderly patients receive radiation alone due to toxicity concerns. We evaluate acute and late toxicity among patients age ≥ 65 who received concurrent chemoradiation for head and neck cancer. DESIGN: Retrospective review. SETTING: Tertiary care center. PARTICIPANTS: Between 6/2003 and 8/2011, 40 consecutive patients age ≥ 65 underwent combined chemoradiation for head and neck cancer. Ten patients were treated in the postoperative setting and 30 underwent definitive chemoradiation. Twenty-eight patients received concurrent platinum-based chemotherapy and 12 received concurrent weekly paclitaxel. Treatment plans were designed to provide a dose of 66-72 Gy at 2-2.12 Gy/fraction to >95% of the gross tumor volume in the definitive setting or for positive margins and 60-66 Gy at 2 Gy/fraction post-operatively. Median follow-up was 23.2 months (range: 0-94.4 months). MAIN OUTCOMES MEASURES: Acute skin and mucosal toxicity, unplanned treatment interruptions, and chronic treatment related toxicity including gastrostomy tube dependence as graded by the CTCAE v3.0. RESULTS: Eight patients (20%) required a radiation treatment break of ≥ 3 days. Thirteen (33%) required unplanned hospitalization during or immediately following treatment. No grade 4+ skin or mucosal toxicity was noted. Five patients remained PEG tube dependent at >1 year. One patient developed non-healing mandibular osteoradionecrosis >3 years following chemoradiation. The 2-year Kaplan-Meier estimate of overall survival was 55%. CONCLUSION: Higher-than-expected rates of in-patient hospitalization with significant acute toxicity were noted in this cohort with a correspondingly high rate of radiation treatment breaks. Late toxicity rates were similar to those observed in historical controls with younger patients. Careful patient selection criteria should be employed for elderly patients considering concurrent chemoradiation for head and neck cancer.
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Quimioradioterapia/efectos adversos , Neoplasias de Cabeza y Cuello/terapia , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/terapia , Cetuximab , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Dermatitis/clasificación , Dermatitis/etiología , Utilización de Medicamentos , Endoscopía Gastrointestinal/estadística & datos numéricos , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Gastrostomía/estadística & datos numéricos , Neoplasias de Cabeza y Cuello/mortalidad , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Enfermedades Mandibulares/etiología , Mucositis/clasificación , Mucositis/etiología , Narcóticos/uso terapéutico , Osteorradionecrosis/clasificación , Osteorradionecrosis/etiología , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Dosificación Radioterapéutica , Estudios Retrospectivos , Pérdida de PesoRESUMEN
BACKGROUND: Pemetrexed, a multitargeted antifolate drug, is an active agent in non-small-cell lung cancer (NSCLC), especially adenocarcinomas. Based on preclinical data supporting the relevance of alpha-folate receptors in adenocarcinoma of the bronchioloalveolar carcinoma (BAC) subtype, this trial was designed to assess pemetrexed in patients with this pathologic subtype of lung adenocarcinoma. PATIENTS AND METHODS: Patients with histologically confirmed stage IIIB (with malignant pleural effusion) or stage IV adenocarcinoma with BAC features or pure BAC were eligible. Treatment consisted of pemetrexed, 500 mg/m(2), administered intravenously every 21 days. RESULTS: Of 27 patients enrolled, 24 were eligible and assessable for adverse events: Toxicity was primarily hematologic, consisting of leukopenia/neutropenia, thrombocytopenia, and anemia. The median follow-up among patients still alive (n = 8) was 35 months (range, 26-47 months). Among 17 patients with measurable disease, the response rate was 23% (all partial responses; 95% confidence interval [CI], 10%-56%). The median progression-free survival (PFS) and overall survival (OS) were 6 and 25 months, respectively. CONCLUSION: Pemetrexed is active and well tolerated and, in patients with adenocarcinoma BAC subtypes, likely related to its underlying mechanism of action as a multitargeted antifolate drug.
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Adenocarcinoma Bronquioloalveolar/tratamiento farmacológico , Adenocarcinoma/tratamiento farmacológico , Antimetabolitos Antineoplásicos/uso terapéutico , Glutamatos/uso terapéutico , Guanina/análogos & derivados , Neoplasias Pulmonares/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adenocarcinoma Bronquioloalveolar/mortalidad , Adenocarcinoma Bronquioloalveolar/patología , Administración Oral , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Guanina/uso terapéutico , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pemetrexed , Pronóstico , Tasa de SupervivenciaRESUMEN
OBJECTIVES/HYPOTHESIS: To evaluate the responsiveness of human papillomavirus (HPV) -positive and HPV-negative oropharyngeal cancer to intensity-modulated radiotherapy (IMRT), using axial imaging obtained daily during the course of image-guided radiotherapy (IGRT). STUDY DESIGN: Observational cohort study with matched-pair analysis of patients irradiated for HPV-positive and HPV-negative oropharygeal cancer. METHODS AND MATERIALS: Ten patients treated by IMRT to 70 Gy for locally advanced, HPV-positive squamous cell carcinoma of the oropharynx were matched to one HPV-negative control subject by age, gender, performance status, T-category, tumor location, and the use of concurrent chemotherapy. The gross tumor volume (GTV) was delineated on daily IGRT scans obtained via kilovoltage cone-beam computed tomography (CBCT). Mathematical modeling using fitted mixed-effects repeated measure analysis was performed to quantitatively and descriptively assess the trajectory of tumor regression. RESULTS: Patients with HPV-positive tumors experienced a more rapid rate of tumor regression between day 1 of IMRT and the beginning of week 2 (-33% Δ GTV) compared to their counterparts with HPV-negative tumors (-10% Δ GTV), which was statistically significant (p<0.001). During this initial period, the average absolute change in GTV was -22.9 cc/week for HPV-positive tumors and -5.9 cc/week for HPV-negative tumors (p<0.001). After week 2 of IMRT, the rates of GTV regression were comparable between the two groups. CONCLUSIONS: HPV-positive oropharyngeal cancers exhibited an enhanced response to radiation, characterized by a dramatically more rapid initial regression than those with HPV-negative tumors. Implications for treatment de-intensification in the context of future clinical trials and the possible mechanisms underlying this increased radiosensitivity will be discussed.
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Carcinoma de Células Escamosas/radioterapia , Neoplasias Orofaríngeas/radioterapia , Papillomaviridae , Infecciones por Papillomavirus/diagnóstico por imagen , Radioterapia de Intensidad Modulada/métodos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/virología , Estudios de Cohortes , Tomografía Computarizada de Haz Cónico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/patología , Radioterapia Guiada por Imagen , Resultado del TratamientoRESUMEN
PURPOSE: To identify clinical and treatment-related predictors of brachial plexus-associated neuropathies after radiation therapy for head-and-neck cancer. METHODS AND MATERIALS: Three hundred thirty patients who had previously completed radiation therapy for head-and-neck cancer were prospectively screened using a standardized instrument for symptoms of neuropathy thought to be related to brachial plexus injury. All patients were disease-free at the time of screening. The median time from completion of radiation therapy was 56 months (range, 6-135 months). One-hundred fifty-five patients (47%) were treated by definitive radiation therapy, and 175 (53%) were treated postoperatively. Radiation doses ranged from 50 to 74 Gy (median, 66 Gy). Intensity-modulated radiation therapy was used in 62% of cases, and 133 patients (40%) received concurrent chemotherapy. RESULTS: Forty patients (12%) reported neuropathic symptoms, with the most common being ipsilateral pain (50%), numbness/tingling (40%), motor weakness, and/or muscle atrophy (25%). When patients with <5 years of follow-up were excluded, the rate of positive symptoms increased to 22%. On univariate analysis, the following factors were significantly associated with brachial plexus symptoms: prior neck dissection (p = 0.01), concurrent chemotherapy (p = 0.01), and radiation maximum dose (p < 0.001). Cox regression analysis confirmed that both neck dissection (p < 0.001) and radiation maximum dose (p < 0.001) were independently predictive of symptoms. CONCLUSION: The incidence of brachial plexus-associated neuropathies after radiation therapy for head-and-neck cancer may be underreported. In view of the dose-response relationship identified, limiting radiation dose to the brachial plexus should be considered when possible.
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Neuropatías del Plexo Braquial/etiología , Plexo Braquial/efectos de la radiación , Neoplasias de Cabeza y Cuello/radioterapia , Traumatismos por Radiación/complicaciones , Radioterapia de Intensidad Modulada/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Neuropatías del Plexo Braquial/diagnóstico , Quimioradioterapia/efectos adversos , Quimioradioterapia/estadística & datos numéricos , Relación Dosis-Respuesta en la Radiación , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Masculino , Persona de Mediana Edad , Disección del Cuello/efectos adversos , Estadificación de Neoplasias/clasificación , Órganos en Riesgo/efectos de la radiación , Estudios Prospectivos , Radioterapia de Intensidad Modulada/estadística & datos numéricos , Análisis de Regresión , Factores de RiesgoRESUMEN
PURPOSE: To compare the long-term quality of life among patients treated with and without intensity-modulated radiotherapy (IMRT) for head-and-neck cancer. METHODS AND MATERIALS: The University of Washington Quality of Life instrument scores were reviewed for 155 patients previously treated with radiation therapy for locally advanced head-and-neck cancer. All patients were disease free and had at least 2 years of follow-up. Eighty-four patients (54%) were treated with IMRT. The remaining 71 patients (46%) were treated with three-dimensional conformal radiotherapy (3D CRT) by use of initial opposed lateral fields matched to a low anterior neck field. RESULTS: The mean global quality of life scores were 67.5 and 80.1 for the IMRT patients at 1 and 2 years, respectively, compared with 55.4 and 57.0 for the 3D CRT patients, respectively (p < 0.001). At 1 year after the completion of radiation therapy, the proportion of patients who rated their global quality of life as "very good" or "outstanding" was 51% and 41% among patients treated by IMRT and 3DCRT, respectively (p = 0.11). At 2 years, the corresponding percentages increased to 73% and 49%, respectively (p < 0.001). On multivariate analysis accounting for sex, age, radiation intent (definitive vs. postoperative), radiation dose, T stage, primary site, use of concurrent chemotherapy, and neck dissection, the use of IMRT was the only variable independently associated with improved quality of life (p = 0.01). CONCLUSION: The early quality of life improvements associated with IMRT not only are maintained but apparently become more magnified over time. These data provide powerful evidence attesting to the long-term benefits of IMRT for head-and-neck cancer.
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Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Calidad de Vida , Radioterapia de Intensidad Modulada/normas , Sobrevivientes , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estado de Salud , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Mejoramiento de la Calidad/normas , Radioterapia Conformacional/normas , Adulto JovenRESUMEN
BACKGROUND: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors. METHODS: Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated. RESULTS: Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route. CONCLUSIONS: Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.
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Antineoplásicos/farmacocinética , Neoplasias/tratamiento farmacológico , Piridinas/farmacocinética , Tiosemicarbazonas/farmacocinética , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Disponibilidad Biológica , California , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/patología , Piridinas/administración & dosificación , Piridinas/efectos adversos , Piridinas/uso terapéutico , Tiosemicarbazonas/administración & dosificación , Tiosemicarbazonas/efectos adversos , Tiosemicarbazonas/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: To determine if intra-patient dose escalation of the multi-targeted kinase inhibitor sorafenib is feasible in patients with advanced pretreated solid malignancies. METHODS: An intra-patient dose escalation scheme starting at 400 mg BID was employed in this prospective trial. Doses were escalated to 600 mg BID for the second cycle and to 800 mg BID for the third cycle in the absence of grade 3+ adverse events. In the event of grade 3+ adverse events during cycle 1, doses were reduced to 400 mg daily through cycle 2. Dose re-escalation for cycle 3 was allowed in the absence of grade 3+ adverse events during cycle 2. Further dose escalation was prohibited. The primary endpoint was the overall percentage of patients tolerating dose escalation to 600 mg BID through cycle 2 or tolerating re-escalation to 400 mg BID through cycle 3. RESULTS: Fifty eligible patients with various solid tumors and a median of 3 prior therapies were enrolled. Eleven patients (22%) tolerated primary dose escalation or re-escalation. Only 14 patients (28%) completed cycle 1 without dose modification or discontinuing treatment. Seven of 13 patients tolerated primary dose escalation through cycle 2. Four of 5 patients tolerated dose re-escalation through cycle 3. Reasons for escalation failure included tumor progression (42%) and adverse events (26%). Common grade 3+ adverse events included hand-foot skin reaction, hypertension, and hypophosphatemia. CONCLUSIONS: Intra-patient dose escalation and/or re-escalation of sorafenib were not feasible in pretreated solid tumor patients. Sorafenib dose escalation remains an investigational approach.
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Neoplasias/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Estudios de Factibilidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Niacinamida/administración & dosificación , Niacinamida/efectos adversos , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , SorafenibRESUMEN
BACKGROUND: The purpose of this study was to analyze voice quality among patients treated by definitive radiotherapy for laryngeal cancer. METHODS: Ten patients with laryngeal cancer who had completed radiotherapy were involved in this pilot study. A standardized protocol was administered assessing: (1) sustained vowel production following maximal inspiration, (2) sustained vowel production for a 7-second duration repeated 5 times, and (3) spontaneous speech for 10 seconds. RESULTS: The acoustic parameters among patients with early-stage cancer were not statistically different from healthy age-corresponding controls, except for shimmer (0.20 vs 0.16 dB, ρ = 0.01) and maximum phonation duration (24.37 vs 30.10 seconds, ρ = 0.04). For patients with locally advanced cancer, differences with controls were observed with shimmer (2.29 vs 0.16 dB, ρ = 0.01), jitter (7.49% vs 1.04%, ρ = 0.01), harmonics-to-noise ratio (2.67 vs 9.22, ρ = 0.01), and maximum phonation duration (14.12 vs 30.10 seconds, ρ = 0.01). CONCLUSIONS: Despite the subtle differences in voice quality that existed, radiotherapy as a curative treatment for laryngeal cancer allows maintenance of a functional voice.
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Carcinoma de Células Escamosas/radioterapia , Neoplasias Laríngeas/radioterapia , Calidad de la Voz/efectos de la radiación , Anciano , Anciano de 80 o más Años , Humanos , Masculino , Persona de Mediana Edad , Fonación , Proyectos Piloto , Calidad de Vida , Resultado del Tratamiento , Pliegues Vocales/efectos de la radiaciónRESUMEN
INTRODUCTION: Epidermal growth factor receptor tyrosine kinase inhibitors given concurrently with chemotherapy do not improve patient outcomes compared with chemotherapy alone in advanced non-small cell lung cancer (NSCLC). On the basis of preclinical models, we hypothesized pharmacodynamic separation, achieved by intermittent delivery of epidermal growth factor receptor tyrosine kinase inhibitors intercalated with chemotherapy, as a reasonable strategy to deliver combination therapy. METHODS: A phase I dose-escalating trial using two scheduling strategies (arms A and B) was conducted in patients with advanced solid tumors to determine the feasibility of intermittent erlotinib and docetaxel. Phase II efficacy evaluation was conducted in an expanded cohort of patients with previously treated advanced NSCLC using arm B scheduling. Docetaxel was given every 21 days (70-75 mg/m intravenously) in both arms. In arm A, erlotinib was administered on days 2, 9, and 16 (600-1000 mg); in arm B, erlotinib was delivered on days 2 through 16 (150-300 mg). Patients without progression or unacceptable toxicity after six cycles continued erlotinib alone. RESULTS: Eighty-one patients were enrolled in this study (17 arm A; 25 arm B; and 39 at phase II dose). Phase I patients had advanced solid tumors and 22 with NSCLC (10 and 12 patients for arms A and B, respectively). Treatment was well tolerated for both arms, with dose-limiting toxicities including grade 3 infection and febrile neutropenia in arm A (maximum tolerated dose [MTD] of erlotinib 600 mg/docetaxel 70 mg/m) and grade 4 rash, febrile neutropenia, grade 3 mucositis, and grade 3 diarrhea in arm B (MTD of erlotinib 200 mg/docetaxel 70 mg/m). The MTD for arm B was chosen for phase II evaluation given the feasibility of administration, number of responses (one complete response and three partial responses), and achievement of pharmacodynamic separation. The response rate for patients treated at the phase II dose was 28.2%, and the disease control rate was 64.1%. Median progression-free and overall survival were 4.1 and 18.2 months, respectively. Common grade ≥3 toxicities were neutropenia (36%) and diarrhea (18%). CONCLUSIONS: Pharmacodynamic separation using intercalated schedules of erlotinib delivered on an intermittent basis together with docetaxel chemotherapy is feasible and tolerable. Further studies using this approach together with interrogation of relevant molecular pathways are ongoing.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Diarrea/inducido químicamente , Supervivencia sin Enfermedad , Docetaxel , Clorhidrato de Erlotinib , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mucositis/inducido químicamente , Neutropenia/inducido químicamente , Quinazolinas/administración & dosificación , Taxoides/administración & dosificaciónRESUMEN
BACKGROUND: The proteasome inhibitor bortezomib sensitizes tumor cells to chemotherapy-induced apoptosis. In preclinical non-small-cell lung cancer (NSCLC) models, p53-dependent growth arrest after bortezomib treatment resulted in reduced cytotoxicity if bortezomib preceded docetaxel. The reverse sequence of docetaxel before bortezomib was associated with increased apoptosis, cleavage of caspase-3 and PARP (poly [ADP-ribose] polymerase), and reduction in Bcl-2. A prospective randomized phase II trial of concurrent versus sequential docetaxel and bortezomib was conducted to assess whether administration sequence resulted in measurable clinical differences. PATIENTS AND METHODS: Previously treated patients with advanced NSCLC were randomized to concurrent (CON) or sequential (SEQ) docetaxel (75 mg/m² intravenous [I.V.]) followed by bortezomib, every 3 weeks. In the CON arm, bortezomib (1.6 mg/m² I.V.) was given on days 1 and 8, and in the SEQ arm, it was given on days 2 and 8. Previous erlotinib as well as treated or controlled brain metastases were allowed. The primary endpoint was objective response rate (RR); progression-free (PFS) and overall survival (OS) were secondary endpoints. RESULTS: Eighty-one patients were randomized (40 CON and 41 SEQ). Grade 3+ toxicities were mostly due to myelosuppression. One patient each had grade 4 hyponatremia and syncope. Toxicities were similar between the arms. There was 1 treatment-related death in the SEQ arm. There were 8 partial responders, 4 in each arm, for an overall RR of 10%. Disease control rate was similar in both arms (50% vs. 49%). Median PFS was 12 weeks in the CON arm and 11 weeks in the SEQ arm. Median OS times in the CON and SEQ arms were 13.3 and 10.5 months, respectively. CONCLUSION: Docetaxel plus bortezomib given sequentially or concurrently has similar RR and PFS. Median survival in the SEQ arm exceeds published survival estimates for either agent alone or in combination. Any further studies in this population would require molecular characterization of a phenotype most likely to benefit from proteasome inhibitor therapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácidos Borónicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Pirazinas/uso terapéutico , Taxoides/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ácidos Borónicos/administración & dosificación , Ácidos Borónicos/efectos adversos , Bortezomib , California , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Supervivencia sin Enfermedad , Docetaxel , Femenino , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Taxoides/administración & dosificación , Taxoides/efectos adversosRESUMEN
PURPOSE: To determine how the addition of cisplatin-based concurrent chemotherapy to radiation therapy influences outcomes among a cohort of patients treated for head-and-neck cancer of unknown primary origin. METHODS AND MATERIALS: The medical records of 60 consecutive patients treated by radiation therapy for squamous cell carcinoma of the head and neck presenting as cervical lymph node metastasis of occult primary origin were reviewed. Thirty-two patients (53%) were treated by concurrent chemoradiation, and 28 patients (47%) were treated by radiation therapy alone. Forty-five patients (75%) received radiation therapy after surgical resection, and 15 patients (25%) received primary radiation therapy. Thirty-five patients (58%) were treated by intensity-modulated radiotherapy. RESULTS: The 2-year estimates of overall survival, local-regional control, and progression-free survival were 89%, 89%, and 79%, respectively, among patients treated by chemoradiation, compared to 90%, 92%, and 83%, respectively, among patients treated by radiation therapy alone (p > 0.05, for all). Exploratory analysis failed to identify any subset of patients who benefited from the addition of concurrent chemotherapy to radiation therapy. The use of concurrent chemotherapy was associated with a significantly increased incidence of Grade 3+ acute and late toxicity (p < 0.001, for both). CONCLUSIONS: Concurrent chemoradiation is associated with significant toxicity without a clear advantage to overall survival, local-regional control, and progression-free survival in the treatment of head-and-neck cancer of unknown primary origin. Although selection bias cannot be ignored, prospective data are needed to further address this question.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Neoplasias Primarias Desconocidas/radioterapia , Antineoplásicos/administración & dosificación , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/cirugía , Cisplatino/administración & dosificación , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/secundario , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Escisión del Ganglio Linfático/métodos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Cuello , Neoplasias Primarias Desconocidas/mortalidad , Radioterapia de Intensidad Modulada/métodos , Resultado del Tratamiento , Carga TumoralRESUMEN
BACKGROUND: Cetuximab is a chimeric monoclonal antibody targeting the epidermal growth factor receptor (EGFR). The recommended dosage is an initial load of 400 mg/m² intravenously (IV) followed by a weekly maintenance dose of 250 mg/m². It has been reported retrospectively that cetuximab efficacy was correlated with dose-related severity of skin rash. This study was prospectively designed to examine the safety and feasibility of escalating weekly doses of cetuximab, testing the hypothesis of the relationship of dose-dependent skin toxicity and efficacy. Methods Four dose levels were tested: Cetuximab 400 mg/m² IV loading dose and 250, 300, 350, 400 mg/m² weekly IV maintenance. There was no intra-patient dose escalation. Standard dose limiting toxicity criteria were used. Rash was evaluated using two additional validated dermatology methods: global acne grading scale (GAGS) and acne lesion counting (ALC). Tumor specimens and blood samples were obtained for correlative analyses. RESULTS: Twenty seven patients with solid tumors were enrolled: five head and neck, three pancreas, four gall bladder, two each of prostate, breast, colorectal, lung, and esophagus, and five others. Planned dose escalation was completed without reaching dose-limiting toxicity (DLT) or the maximum tolerated dose (MTD). The highest dose level was expanded to a total of 17 patients. Gr 3/4 toxicities included: lymphopenia (2), fatigue (2), and hypomagnesemia (2). One patient experienced a grade 3 rash (350 mg/m²). Sixty five percent of pts had a ≥ Gr 2 rash that was not dose dependent. In 22 evaluable patients, there was one partial response (PR) in a patient with cholangiocarcinoma (400 mg/m²) and seven patients had stable disease (SD). ALC and GAGS demonstrated no correlation with dose or response. Correlative studies evaluating k-ras, EGFR FISH status and immunologic correlatives were conducted on available tumor samples. CONCLUSIONS: Cetuximab administered at 400 mg/m² IV as a loading dose with weekly maintenance dose of 400 mg/m² is feasible and well tolerated. There was no direct correlation of the grade of rash with dose in this group of patients with heterogenous solid tumors.
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Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Piel/efectos de los fármacos , Acné Vulgar/inducido químicamente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Cetuximab , Quimiocinas/sangre , Demografía , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Piel/patología , Resultado del TratamientoRESUMEN
PURPOSE: To analyze outcomes after radiation therapy for head-and-neck cancer among a cohort of patients with human immunodeficiency virus (HIV). METHODS AND MATERIALS: The medical records of 12 patients with serologic evidence of HIV who subsequently underwent radiation therapy to a median dose of 68 Gy (range, 64-72 Gy) for newly diagnosed squamous cell carcinoma of the head and neck were reviewed. Six patients (50%) received concurrent chemotherapy. Intensity-modulated radiotherapy was used in 6 cases (50%). All patients had a Karnofsky performance status of 80 or 90. Nine patients (75%) were receiving antiretroviral therapies at the time of treatment, and the median CD4 count was 460 (range, 266-800). Toxicity was graded according to the Radiation Therapy Oncology Group / European Organization for the Treatment of Cancer toxicity criteria. RESULTS: The 3-year estimates of overall survival and local-regional control were 78% and 92%, respectively. Acute Grade 3+ toxicity occurred in 7 patients (58%), the most common being confluent mucositis (5 patients) and moist skin desquamation (4 patients). Two patients experienced greater than 10% weight loss, and none experienced more than 15% weight loss from baseline. Five patients (42%) experienced treatment breaks in excess of 10 cumulative days, although none required hospitalization. There were no treatment-related fatalities. CONCLUSIONS: Radiation therapy for head-and-neck cancer seems to be relatively well tolerated among appropriately selected patients with HIV. The observed rates of toxicity were comparable to historical controls without HIV.
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Carcinoma de Células Escamosas/radioterapia , Infecciones por VIH/complicaciones , Neoplasias de Cabeza y Cuello/radioterapia , Huésped Inmunocomprometido , Radioterapia de Intensidad Modulada , Fármacos Anti-VIH/uso terapéutico , Recuento de Linfocito CD4 , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Terapia Combinada/métodos , Infecciones por VIH/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Estado de Ejecución de Karnofsky , Mucositis/etiología , Mucositis/patología , Radiodermatitis/etiología , Radiodermatitis/patología , Pérdida de PesoRESUMEN
PURPOSE: To evaluate the effect of continued cigarette smoking among patients undergoing radiation therapy for head-and-neck cancer by comparing the clinical outcomes among active smokers and quitters. METHODS AND MATERIALS: A review of medical records identified 101 patients with newly diagnosed squamous cell carcinoma of the head and neck who continued to smoke during radiation therapy. Each active smoker was matched to a control patient who had quit smoking before initiation of radiation therapy. Matching was based on tobacco history (pack-years), primary site, age, sex, Karnofsky Performance Status, disease stage, radiation dose, chemotherapy use, year of treatment, and whether surgical resection was performed. Outcomes were compared by use of Kaplan-Meier analysis. Normal tissue effects were graded according to the Radiation Therapy Oncology Group/European Organization for the Treatment of Cancer toxicity criteria. RESULTS: With a median follow-up of 49 months, active smokers had significantly inferior 5-year overall survival (23% vs. 55%), locoregional control (58% vs. 69%), and disease-free survival (42% vs. 65%) compared with the former smokers who had quit before radiation therapy (p < 0.05 for all). These differences remained statistically significant when patients treated by postoperative or definitive radiation therapy were analyzed separately. The incidence of Grade 3 or greater late complications was also significantly increased among active smokers compared with former smokers (49% vs. 31%, p = 0.01). CONCLUSIONS: Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcomes. Further studies analyzing the biologic and molecular reasons underlying these differences are planned.
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Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Fumar/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Estudios de Casos y Controles , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Primarias Secundarias/epidemiología , Estudios Retrospectivos , Fumar/mortalidad , Resultado del TratamientoRESUMEN
PURPOSE: To determine the effect of prophylactic gastrostomy tube (GT) placement on acute and long-term outcome for patients treated with definitive chemoradiotherapy for locally advanced head and neck cancer. METHODS AND MATERIALS: One hundred twenty consecutive patients were treated with chemoradiotherapy for Stage III/IV head and neck cancer to a median dose of 70 Gy (range, 64-74 Gy). The most common primary site was the oropharynx (66 patients). Sixty-seven patients (56%) were treated using intensity-modulated radiotherapy (IMRT). Seventy patients (58%) received prophylactic GT placement at the discretion of the physician before initiation of chemoradiotherapy. RESULTS: Prophylactic GT placement significantly reduced weight loss during radiation therapy from 43 pounds (range, 0 to 76 pounds) to 19 pounds (range, 0 to 51 pounds), which corresponded to a net change of -14% (range, 0% to -30%) and -8% (range, +1% to -22%) from baseline, respectively (p < 0.001). However, the proportion of patients who were GT-dependent at 6- and 12-months after treatment was 41% and 21%, respectively, compared with 8% and 0%, respectively, for those with and without prophylactic GT (p < 0.001). Additionally, prophylactic GT was associated with a significantly higher incidence of late esophageal stricture compared with those who did not have prophylactic GT (30% vs. 6%, p < 0.001). CONCLUSIONS: Although prophylactic GT placement was effective at preventing acute weight loss and the need for intravenous hydration, it was also associated with significantly higher rates of late esophageal toxicity. The benefits of this strategy must be balanced with the risks.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Gastrostomía/métodos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Pérdida de Peso , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/mortalidad , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Trastornos de Deglución/etiología , Femenino , Estudios de Seguimiento , Gastrostomía/instrumentación , Gastrostomía/mortalidad , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Masculino , Desnutrición/prevención & control , Persona de Mediana Edad , Dosificación Radioterapéutica , Radioterapia de Intensidad Modulada/efectos adversos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: The aim of this study was to determine the incidence of esophageal toxicity after radiation therapy for head and neck cancer. METHODS: The records of 211 patients treated by radiation therapy for head and neck cancer were reviewed to identify those with dysphagia lasting more than 90 days after therapy. Late toxicity criteria established by the Radiation Therapy Oncology Group were used to score the symptoms. RESULTS: The incidence of grade 3+ esophageal toxicity at 3 and 6 months was 30% and 19%, respectively. The rate of gastrotomy-tube dependence at 3 and 6 months was 20% and 11%, respectively. Hypopharyngeal and unknown primary site (p = .01, for both), T4 disease (p = .01), and the use of concurrent chemotherapy (p = .001) were associated with grade 3+ esophageal toxicity and stricture formation. CONCLUSION: A significant proportion of patients exhibit symptoms of esophageal toxicity after radiation therapy for head and neck cancer. Therefore, preventive strategies need further investigation.
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Carcinoma de Células Escamosas/radioterapia , Trastornos de Deglución/etiología , Neoplasias de Cabeza y Cuello/radioterapia , Radioterapia/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Quimioterapia Adyuvante/efectos adversos , Trastornos de Deglución/clasificación , Fraccionamiento de la Dosis de Radiación , Estenosis Esofágica/etiología , Estenosis Esofágica/patología , Esófago/efectos de la radiación , Femenino , Gastrostomía , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Primarias Desconocidas , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Pérdida de PesoRESUMEN
PURPOSE: To investigate the association between dose to various anatomical structures and dysphagia among patients with head and neck cancer treated by definitive intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy. METHODS AND MATERIALS: Thirty-nine patients with squamous cancer of the head and neck were treated by definitive concurrent chemotherapy and IMRT to a median dose of 70 Gy (range, 68 to 72). In each patient, a gastrostomy tube (GT) was prophylacticly placed prior to starting treatment. Prolonged GT dependence was defined as exceeding the median GT duration of 192 days. Dysphagia was scored using standardized quality-of-life instruments. Dose-volume histogram (DVH) data incorporating the superior/middle pharyngeal constrictors (SMPC), inferior pharyngeal constrictor (IPC), cricoid pharyngeal inlet (CPI), and cervical esophagus (CE) were analyzed in relation to prolonged GT dependence, dysphagia, and weight loss. RESULTS: At 3 months and 6 months after treatment, 87% and 44% of patients, respectively, were GT dependent. Spearman's rho analysis identified statistical correlations (p < 0.05) between prolonged GT dependence or high grade dysphagia with IPC V65, IPC V60, IPC Dmean, and CPI Dmax. Logistic regression model showed that IPC V65 > 30%, IPC V60 > 60%, IPC Dmean > 60 Gy, and CPI Dmax > 62 Gy predicted for greater than 50% probability of prolonged GT dependence. CONCLUSION: Our analysis suggests that adhering to the following parameters may decrease the risk of prolonged GT dependence and dysphagia: IPC V65 < 15%, IPC V60 < 40%, IPC Dmean < 55 Gy, and CPI Dmax < 60 Gy.