RESUMEN
BACKGROUND: A current recommendation for the treatment of patients with locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy (RT) with concurrent cisplatin followed by adjuvant cisplatin and 5-fluorouracil (PF). This randomized NPC-0501 trial evaluated the therapeutic effect of changing to an induction-concurrent sequence or accelerated-fractionation sequence, and/or replacing 5-fluorouracil with capecitabine (X). METHODS: Patients with American Joint Committee on Cancer/International Union Against Cancer stage III to stage IVB NPC initially were randomly allocated to 1 of 6 treatment arms (6-arm full-randomization cohort). The protocol was amended in 2009 to permit centers to opt out of randomization regarding fractionation (3-arm chemotherapy cohort). RESULTS: A total of 803 patients were accrued (1 of whom was nonevaluable) from 2006 to 2012. Based on the overall comparisons, neither changing the chemotherapy sequence nor accelerated fractionation improved treatment outcome. However, secondary analyses demonstrated that when adjusted for RT parameters and other significant factors, the induction-concurrent sequence, especially the induction-PX regimen, achieved significant improvements in progression-free survival (PFS) and overall survival. Efficacy varied among different RT groups: although no impact was observed in the accelerated-fractionation group and the 3-arm chemotherapy cohort, a comparison of the induction-concurrent versus concurrent-adjuvant sequence in the conventional-fractionation group demonstrated a significant benefit in PFS (78% vs 62% at 5 years; P = .015) and a marginal benefit in overall survival (84% vs 72%; P = .042) after adjusting for multiple comparisons. Comparison of the induction-PX versus the adjuvant-PF regimen demonstrated better PFS (78% vs 62%; P = .027) without an increase in overall late toxicity. CONCLUSIONS: For patients irradiated using conventional fractionation, changing the chemotherapy sequence from a concurrent-adjuvant to an induction-concurrent sequence, particularly using induction cisplatin and capecitabine, potentially could improve efficacy without an adverse impact on late toxicity. However, further validation is needed for confirmation of these findings.
Asunto(s)
Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/radioterapia , Adolescente , Adulto , Anciano , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Quimioradioterapia/efectos adversos , Supervivencia sin Enfermedad , Fraccionamiento de la Dosis de Radiación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo/patología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Supervivencia sin Progresión , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: This is an updated combined analysis of 2 randomized studies (NPC-9901 and NPC-9902 trials) to evaluate the 10-year outcome attributed to the addition of concurrent-adjuvant chemotherapy for advanced locoregional nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Eligible patients with stage III-IVB nonkeratinizing NPC were randomly assigned to radiation therapy alone (RT: 218 patients) or chemoradiation therapy (CRT: 223 patients) using 3 cycles of cisplatin (100 mg/m2) concurrent with RT, followed by 3 cycles of cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/day for 4 days). All of the patients were irradiated with conventional fractionation to ≥66 Gy. The median follow-up was 13.9 years. RESULTS: Intention-to-treat analysis confirmed that the CRT group achieved significant improvement in 10-year failure-free rate (FFR: 62% vs 52%, P = .016), progression-free survival rate (PFS: 56% vs 44%, P = .008), and overall survival rate (OS: 60% vs 50%, P = .044). There was no significant increase in overall late toxicity rate (51% vs 48%, P = .34) or noncancer deaths (19% vs 16%, P = .52). Exploratory studies showed no difference in disease control between 2 or 3 cycles of concurrent cisplatin; however, patients given 3 concurrent cycles had a significant increase in hearing impairment (40% vs 24%, P = .017). Only those who continued to receive 2 or more cycles of adjuvant cisplatin-fluorouracil achieved significant improvement in distant control (73% vs 65%, P = .037) and maximal survival gain. CONCLUSION: The addition of concurrent cisplatin plus adjuvant cisplatin-fluorouracil could significantly improve overall survival and disease control without incurring a significant increase in late toxicity or noncancer deaths. Exploratory analyses suggested that both the concurrent and the adjuvant phases contributed to tumor control. Furthermore, the number of concurrent cycles could be reduced from 3 to 2 cycles in order to achieve a similar survival benefit without incurring an excessive increase in hearing impairment. This is a useful hypothesis that warrants further validation.
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Quimioradioterapia Adyuvante/métodos , Quimioradioterapia/métodos , Carcinoma Nasofaríngeo/tratamiento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Adolescente , Adulto , Anciano , Cisplatino/administración & dosificación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Análisis de Regresión , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Concurrent-adjuvant chemoradiotherapy (CRT) became a recommended treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) with the first report of a significant survival benefit from the Intergroup 0099 study. However, data on late toxicities are lacking. Previous reports from the current NPC-9901 trial have raised concerns about a failure to improve overall survival (OS) because of an inadequate impact on distant control and increases in toxicities/noncancer deaths. Validation of the long-term therapeutic ratio is needed. METHODS: In this phase 3, randomized trial, patients with nonkeratinizing NPC (stage T1-4/N2-3/M0) were randomly assigned to radiotherapy alone (176 patients) or to CRT (172 patients) with concurrent cisplatin followed by adjuvant cisplatin plus fluorouracil. RESULTS: The early findings of significant improvements in tumor control were maintained: the CRT group achieved significantly higher 10-year overall failure-free (62% vs 50%; P = .01) and progression-free survival rates (56% vs 42%; P = .006) because of superior locoregional control (87% vs 74%; P = .003), whereas the impact on distant control remained insignificant (68% vs 65%; P = .24). The initial differences in toxicities diminished with longer follow-up: 52% versus 47% at 10 years for late toxicities (P = .20), 4.1% versus 2.8% for deaths due to treatment toxicity, and 15.1% versus 13.1% for deaths due to incidental/unknown causes. The OS rate for the CRT group reached statistical superiority at 10 years (62% vs 49%; P = .047). CONCLUSIONS: Long-term results have confirmed that CRT can significantly improve OS without excessive late toxicities for patients with regionally advanced NPC. However, more potent therapy is needed for improving distant control, especially for patients with stage IVA/B disease. Cancer 2017;123:4147-4157. © 2017 American Cancer Society.
Asunto(s)
Carcinoma/mortalidad , Carcinoma/terapia , Quimioradioterapia Adyuvante/mortalidad , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/patología , Quimioradioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/mortalidad , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Fluorouracilo/administración & dosificación , Humanos , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patología , Radioterapia/efectos adversos , Factores de TiempoRESUMEN
BACKGROUND: A current recommendation for locoregionally advanced nasopharyngeal carcinoma (NPC) is conventional fractionated radiotherapy with concurrent cisplatin plus adjuvant cisplatin and fluorouracil (PF). In this randomized trial, the authors evaluated the potential therapeutic benefit from changing to an induction-concurrent chemotherapy sequence, replacing fluorouracil with oral capecitabine, and/or using accelerated rather than conventional radiotherapy fractionation. METHODS: Patients with stage III through IVB, nonkeratinizing NPC were randomly allocated to 1 of 6 treatment arms. The protocol was amended in 2009 to permit confining randomization to the conventional fractionation arms. The primary endpoint was progression-free survival. Secondary endpoints included overall survival and safety. RESULTS: In total, 803 patients were accrued, and 706 patients were randomly allocated to all 6 treatment arms. Comparisons of induction PF versus adjuvant PF did not indicate a significant improvement. Unadjusted comparisons of induction cisplatin and capecitabine (PX) versus adjuvant PF indicated a favorable trend in progression-free survival for the conventional fractionation arm (P = .045); analyses that were adjusted for other significant factors and fractionation reflected a significant reduction in the hazards of disease progression (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.36-0.80) and death (HR, 0.42; 95% CI, 0.25-0.70). Unadjusted comparisons of induction sequences versus adjuvant sequences did not reach statistical significance, but adjusted comparisons indicated favorable improvements by induction sequence. Comparisons of induction PX versus induction PF revealed fewer toxicities (neutropenia and electrolyte disturbance), unadjusted comparisons of efficacy were statistically insignificant, but adjusted analyses indicated that induction PX had a lower hazard of death (HR, 0.57; 95% CI, 0.34-0.97). Changing the fractionation from conventional to accelerated did not achieve any benefit but incurred higher toxicities (acute mucositis and dehydration). CONCLUSIONS: Preliminary results indicate that the benefit of changing to an induction-concurrent sequence remains uncertain; replacing fluorouracil with oral capecitabine warrants further validation in view of its convenience, favorable toxicity profile, and favorable trends in efficacy; and accelerated fractionation is not recommended for patients with locoregionally advanced NPC who receive chemoradiotherapy.
Asunto(s)
Quimioradioterapia Adyuvante/métodos , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Fluorouracilo/administración & dosificación , Neoplasias Nasofaríngeas/terapia , Recurrencia Local de Neoplasia/terapia , Adulto , Anciano , Capecitabina , Carcinoma , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Fraccionamiento de la Dosis de Radiación , Fluorouracilo/efectos adversos , Humanos , Quimioterapia de Inducción , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patología , Recurrencia Local de Neoplasia/patología , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: The relationship between serum 25-hydroxyvitamin D (25[OH]D) concentrations (nmol/L) and the prevalence of early age-related macular degeneration (AMD) was investigated in participants of the Carotenoids in Age-Related Eye Disease Study. METHODS: Stereoscopic fundus photographs, taken from 2001 to 2004, assessed AMD status. Baseline (1994-1998) serum samples were available for 25(OH)D assays in 1313 women with complete ocular and risk factor data. Odds ratios (ORs) and 95% confidence intervals (CIs) for early AMD (n = 241) of 1287 without advanced disease were estimated with logistic regression and adjusted for age, smoking, iris pigmentation, family history of AMD, cardiovascular disease, diabetes, and hormone therapy use. RESULTS: In multivariate models, no significant relationship was observed between early AMD and 25(OH)D (OR for quintile 5 vs 1, 0.79; 95% CI, 0.50-1.24; P for trend = .47). A significant age interaction (P = .002) suggested selective mortality bias in women aged 75 years and older: serum 25(OH)D was associated with decreased odds of early AMD in women younger than 75 years (n = 968) and increased odds in women aged 75 years or older (n = 319) (OR for quintile 5 vs 1, 0.52; 95% CI, 0.29-0.91; P for trend = .02 and OR, 1.76; 95% CI, 0.77-4.13; P for trend = .05, respectively). Further adjustment for body mass index and recreational physical activity, predictors of 25(OH)D, attenuated the observed association in women younger than 75 years. Additionally, among women younger than 75 years, intake of vitamin D from foods and supplements was related to decreased odds of early AMD in multivariate models; no relationship was observed with self-reported time spent in direct sunlight. CONCLUSIONS: High serum 25(OH)D concentrations may protect against early AMD in women younger than 75 years.
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Degeneración Macular/sangre , Degeneración Macular/prevención & control , Posmenopausia/sangre , Vitamina D/análogos & derivados , Anciano , Dieta , Suplementos Dietéticos , Conducta Alimentaria , Femenino , Humanos , Degeneración Macular/epidemiología , Persona de Mediana Edad , Oportunidad Relativa , Prevalencia , Factores de Riesgo , Luz Solar , Encuestas y Cuestionarios , Vitamina D/sangreRESUMEN
BACKGROUND: The current standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC) was conventional-fractionation radiotherapy plus concurrent-adjuvant chemotherapy as recommended by the Intergroup-0099 Study. This combined analysis of the NPC-9901 and the NPC-9902 Trials aims to provide more comprehensive data to evaluate the efficacy of the Intergroup-0099 regimen and the contributing factors. METHODS: Eligible patients with stage III-IVB non-keratinizing NPC were randomly assigned to radiotherapy-alone (RT(i) group: 218 patients) or chemoradiotherapy (CRT(i) group: 223 patients) using cisplatin (100mg/m(2)) for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg/m(2)/day for 4 days) for three cycles. The median follow-up was 6.1 years. FINDINGS: Comparison by intention-to-treat showed that the CRT(i) group achieved significant improvement in overall failure-free rate (FFR), locoregional-FFR and cancer-specific survival (p ≤ 0.019); but the improvements for distant-FFR and overall survival (OS) were statistically insignificant (p ≥ 0.14). Further exploratory studies based on actual treatment showed that an additional improvement achieved was a significant gain in OS (CRT(a) versus RT(a) group: 72% versus 63% at 5-year, p=0.037). Multivariate analyses showed that the dose of cisplatin during the concurrent phase had significant impact on locoregional-FFR and OS, while that of fluorouracil during the adjuvant phase was significant for distant-FFR. The 5-year locoregional-FFR for patients who received 0-1, 2 and 3 concurrent cycles were 79%, 88% and 88%, respectively; the corresponding distant-FFR by adjuvant cycles were 68%, 78% and 77%, respectively. INTERPRETATION: Our results support the current practice of adding concurrent cisplatin plus adjuvant cisplatin-fluorouracil to radiotherapy for treating patients with locoregionally advanced NPC. The concurrent phase is important for locoregional control and survival, cisplatin 200mg/m(2) in two concurrent cycles might be adequate. Additional chemotherapy using fluorouracil-containing combination contributed to improving distant control.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adolescente , Adulto , Anciano , Carcinoma , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: To evaluate the therapeutic benefits by adding chemotherapy (+C) and/or accelerated-fractionation (AF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma. MATERIALS AND METHODS: From 1999 to 2004, 189 eligible patients were randomized to one of four treatment groups (CF/CF+C/AF/AF+C). The number of fractions/week was 5 for the CF groups and 6 for the AF groups. Patients in the +C groups were given concurrent cisplatin plus adjuvant cisplatin and fluorouracil. RESULTS: The AF+C group achieved significantly higher failure-free rate (88% at 5-year) than the CF group (63%; p=0.013), the AF group (56%; p=0.001) and the CF+C group (65%; p=0.027). As compared with CF alone, the increase in late toxicity was statistically insignificant (36% vs. 20%; p=0.25). Deaths due to cancer progression decreased (7% vs. 33%; p=0.011) but deaths due to incidental causes increased (9% vs. 2%; p=0.62). Improvement in overall survival reached borderline significance (85% vs. 66%; p=0.058). CONCLUSIONS: Concurrent-adjuvant chemotherapy combined with AF significantly reduced failure and cancer-specific deaths. Although the increase in major late toxicity and incidental deaths were statistically insignificant, a subtle increase in non-cancer deaths narrowed the overall survival gain.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Fraccionamiento de la Dosis de Radiación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Terapia Combinada , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/patología , Neoplasias Nasofaríngeas/terapia , Estadificación de Neoplasias , Cooperación del PacienteRESUMEN
BACKGROUND: Current practice of adding concurrent-adjuvant chemotherapy to radiotherapy (CRT) for treating advanced nasopharyngeal carcinoma is based on the Intergroup-0099 Study published in 1998. However, the outcome for the radiotherapy-alone (RT) group in that trial was substantially poorer than those in other trials, and there were no data on late toxicities. Verification of the long-term therapeutic index of this regimen is needed. METHODS: Patients with nonkeratinizing nasopharyngeal carcinoma staged T1-4N2-3M0 were randomly assigned to RT (176 patients) or to CRT (172 patients) using cisplatin (100 mg/m(2)) every 3 weeks for three cycles in concurrence with radiotherapy, followed by cisplatin (80 mg/m(2)) plus fluorouracil (1000 mg per m(2) per day for 4 days) every 4 weeks for three cycles. Primary endpoints included overall failure-free rate (FFR) (the time to first failure at any site) and progression-free survival. Secondary endpoints included overall survival, locoregional FFR, distant FFR, and acute and late toxicity rates. All statistical tests were two-sided. RESULTS: The two treatment groups were well balanced in all patient characteristics, tumor factors, and radiotherapy parameters. Adding chemotherapy statistically significantly improved the 5-year FFR (CRT vs RT: 67% vs 55%; P = .014) and 5-year progression-free survival (CRT vs RT: 62% vs 53%; P = .035). Cumulative incidence of acute toxicity increased with chemotherapy by 30% (CRT vs RT: 83% vs 53%; P < .001), but the 5-year late toxicity rate did not increase statistically significantly (CRT vs RT: 30% vs 24%; P = .30). Deaths because of disease progression were reduced statistically significantly by 14% (CRT vs RT: 38% vs 24%; P = .008), but 5-year overall survival was similar (CRT vs RT: 68% vs 64%; P = .22; hazard ratio of CRT = 0.81, 95% confidence interval = 0.58 to 1.13) because deaths due to toxicity or incidental causes increased by 7% (CRT vs RT: 1.7% vs 0, and 8.1% vs 3.4%, respectively; P = .015). CONCLUSIONS: Adding concurrent-adjuvant chemotherapy statistically significantly reduced failure and cancer-specific deaths when compared with radiotherapy alone. Although there was no statistically significant increase in major late toxicity, increase in noncancer deaths narrowed the resultant gain in overall survival.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Carcinoma/radioterapia , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma/patología , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Hong Kong/epidemiología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/patología , Invasividad Neoplásica , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Oportunidad Relativa , Radioterapia Adyuvante , Suicidio/estadística & datos numéricos , Resultado del TratamientoRESUMEN
PURPOSE: To compare the benefit achieved by concurrent chemoradiotherapy (CRT) and/or accelerated fractionation (AF) vs. radiotherapy (RT) alone with conventional fractionation (CF) for patients with T3-4N0-1M0 nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS: All patients were irradiated with the same RT technique to > or =66 Gy at 2 Gy per fraction, conventional five fractions/week in the CF and CF+C (chemotherapy) arms, and accelerated six fractions/week in the AF and AF+C arms. The CF+C and AF+C patients were given the Intergroup 0099 regimen (concurrent cisplatin plus adjuvant cisplatin and 5-fluorouracil). RESULTS: Between 1999 and April 2004, 189 patients were randomly assigned; the trial was terminated early because of slow accrual. The median follow-up was 2.9 years. When compared with the CF arm, significant improvement in failure-free survival (FFS) was achieved by the AF+C arm (94% vs. 70% at 3 years, p = 0.008), but both the AF arm and the CF+C arm were insignificant (p > or = 0.38). Multivariate analyses showed that CRT was a significant factor: hazard ratio (HR) = 0.52 (0.28-0.97), AF per se was insignificant: HR = 0.68 (0.37-1.25); the interaction of CRT by AF was strongly significant (p = 0.006). Both CRT arms had significant increase in acute toxicities (p < 0.005), and the AF+C arm also incurred borderline increase in late toxicities (34% vs. 14% at 3 years, p = 0.05). CONCLUSIONS: Preliminary results suggest that concurrent chemoradiotherapy with accelerated fractionation could significantly improve tumor control when compared with conventional RT alone; further confirmation of therapeutic ratio is warranted.