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1.
Cancer J ; 7(2): 140-8, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11324767

RESUMEN

PURPOSE: Locoregionally advanced oropharyngeal cancer has been conventionally treated with either surgery and adjuvant radiotherapy or radiotherapy alone, and clinical and functional outcomes have been poor. Chemoradiotherapy has been demonstrated to improve functional outcome and disease control over conventional treatment in recent randomized head and neck trials. Herein, we report overall survival, progression-free survival, and patterns of failure in locoregionally advanced oropharyngeal cancer treated with induction chemotherapy with or without conservative surgery followed by concomitant chemoradiation. MATERIALS AND METHODS: Three cycles of induction chemotherapy consisting of cisplatin, 5-fluorouracil, leucovorin, and interferon alpha-2b (PFL-IFN) were followed by conservative, organ-sparing surgery for residual disease. All patients then proceeded to concomitant chemoradiation consisting of seven or eight cycles of 5-fluorouracil, hydroxyurea, and a total radiotherapy dose of roughly 7,000 cGy. RESULTS: Sixty-one patients with predominantly stage IV disease were treated. Clinical complete response was observed in 65% of patients after induction therapy. The median follow-up was 68.0 months for survivors and 39.0 months for all patients. At 5 years, overall survival is 51%, progression-free survival is 64%, locoregional control is 70%, and distant control is 89%. Locoregional recurrence accounted for 80% of all initial failures. Only five radical surgeries (none were total glossectomy) were performed for initial disease control. Treatment-related toxicity accounted for four deaths. CONCLUSION: PFL-IFN given with 5-fluorouracil, hydroxyurea, and radiotherapy produces a high rate of cures with organ preservation in a disease group that has traditionally fared poorly. Local and distant disease control and survival rates exceed those observed with more standard treatment approaches involving surgery and radiotherapy. Further investigation into chemoradiotherapy as a curative modality for this disease is warranted.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Terapia Neoadyuvante , Neoplasias Orofaríngeas/tratamiento farmacológico , Neoplasias Orofaríngeas/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/secundario , Carcinoma de Células Escamosas/cirugía , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Hidroxiurea/administración & dosificación , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/mortalidad , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/cirugía , Proteínas Recombinantes , Análisis de Supervivencia , Resultado del Tratamiento
2.
J Clin Oncol ; 18(8): 1652-61, 2000 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-10764425

RESUMEN

PURPOSE: To achieve locoregional control of head and neck cancer, survival, and organ preservation using intensive concomitant chemoradiotherapy. PATIENTS AND METHODS: This study was a phase II trial of chemoradiotherapy with cisplatin 100 mg/m(2) every 28 days, infusional fluorouracil 800 mg/m(2)/d for 5 days, hydroxyurea 1 g orally every 12 hours for 11 doses, and radiotherapy twice daily at 1.5 Gy/fraction on days 1 through 5 (total dose, 15 Gy). Five days of treatment were followed by 9 days of rest, during which time patients received granulocyte colony-stimulating factor. Five cycles (three with cisplatin) were administered over 10 weeks (total radiotherapy dose, locoregional). Surgery after concomitant chemoradiotherapy is feasible. Compliance with adjuvant chemoprevention is poor. Identification of less toxic regimens and improved distant disease control emerge as important future research goals.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Terapia Combinada , Progresión de la Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Hidroxiurea/administración & dosificación , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Masculino , Calidad de Vida , Radioterapia/efectos adversos , Dosificación Radioterapéutica , Proteínas Recombinantes , Tasa de Supervivencia , Tretinoina/administración & dosificación
3.
Cancer Res ; 57(19): 4340-7, 1997 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-9331096

RESUMEN

Approximately 30% of cancer deaths result from the failure to control local and regional tumors. The goal of radiotherapy is to maximize local and regional tumor cell killing while minimizing normal tissue destruction. Attempts to enhance radiation-mediated tumor cell killing using halogenated pyrimidines, antimetabolites, and other DNA-damaging agents or sensitizers of hypoxic tumor cells have met with only modest clinical success. In an unique strategy to modify tumor radiosensitivity, we used an inhibitor of the protein kinase C group A and B isoforms, chelerythrine chloride (chelerythrine), to enhance the killing effects of ionizing radiation (IR). Protein kinase C activity plays a central role in cellular proliferation, differentiation, and apoptosis. Chelerythrine increases sphingomyelinase activity and enhances IR-mediated cell killing through induction of apoptotic tumor cell death in a radioresistant tumor model both in vitro and in vivo. Although previous reports have suggested that IR-mediated apoptosis correlates with tumor volume reduction, we demonstrate for the first time that lowering the apoptotic threshold increases tumor cell killing in vivo.


Asunto(s)
Apoptosis/efectos de los fármacos , Carcinoma de Células Escamosas/radioterapia , Traumatismos Craneocerebrales/radioterapia , Inhibidores Enzimáticos/farmacología , Isoenzimas/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Fenantridinas/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Esfingomielina Fosfodiesterasa/metabolismo , Alcaloides , Animales , Benzofenantridinas , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/enzimología , Ceramidas/farmacología , Quimioterapia Adyuvante , Terapia Combinada , Traumatismos Craneocerebrales/tratamiento farmacológico , Traumatismos Craneocerebrales/enzimología , Endopeptidasas/metabolismo , Activación Enzimática/efectos de los fármacos , Isoenzimas/metabolismo , Ratones , Ratones Desnudos , Proteínas de Neoplasias/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Fármacos Sensibilizantes a Radiaciones/farmacología , Trasplante Heterólogo
4.
J Natl Cancer Inst ; 89(4): 308-13, 1997 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-9048835

RESUMEN

BACKGROUND: Thymidylate synthase (TS), an essential enzyme in DNA synthesis, is a target for the fluoropyrimidines, an important group of antineoplastic agents used widely in the treatment of head and neck cancer. PURPOSE: We evaluated relationships between the level and/or pattern of tumor TS expression and response to fluorouracil (5-FU)-based neoadjuvant chemotherapy in patients with advanced head and neck cancer. METHODS: Tumor specimens from 86 patients were available for this retrospective analysis. The patients were enrolled in four consecutive phase II studies that tested combinations of 5-FU, leucovorin, and cisplatin with or without added methotrexate plus piritrexim or interferon alfa-2b (IFN alpha-2b). TS protein expression in the tumors was assessed by use of the TS 106 monoclonal antibody and standard immunohistochemical staining techniques. TS immunostaining was classified according to its level of intensity (TS 0-1 = low, TS 2 = intermediate, and TS 3 = high) and according to its extent (focal pattern = less than 25% of tumor cells positive; diffuse pattern = greater than or equal to 25% of tumor cells positive). Data from 79 patients were available for an analysis of tumor TS expression and patient/tumor characteristics; 70 patients were assessable for their response to neoadjuvant chemotherapy. RESULTS: There was a statistically significant association between the level of tumor TS expression and the degree of tumor differentiation; a higher proportion of patients whose tumors exhibited TS 0-1 immunostaining had undifferentiated or poorly differentiated tumors than patients whose tumors exhibited TS 2 or TS 3 immunostaining (P = .04, Jonckheere-Terpstra trend test). Among the 70 patients who were assessable for response to neoadjuvant chemotherapy, TS 3 tumor immunostaining was associated with a lower rate of complete response (i.e., complete disappearance of clinically detectable disease for a minimum of 4 weeks from time of initial determination) than was TS 2 or TS 0-1 immunostaining, but this association was not statistically significant (P = .09, exact trend test); among the 39 patients who were treated with regimens that included 5-FU, leucovorin, cisplatin, and IFN alpha-2b, this inverse association between TS immunostaining intensity and response was statistically significant (P = .02, exact trend test). Tumor TS immunostaining intensity and overall survival were not found to be associated. Patients with tumors exhibiting a focal pattern of TS immunostaining have experienced significantly longer survival than patients with tumors exhibiting a diffuse pattern; for the 53 patients with diffuse tumor TS immunostaining, the median survival was 24.7 months, whereas the median survival has not yet been reached for the 22 patients with focal tumor TS immunostaining (P = .04, two-tailed logrank test). However, the survival advantage for the focal versus diffuse TS immunostaining pattern was limited to patients whose tumors also exhibited a TS 3 level of immunostaining intensity. CONCLUSIONS AND IMPLICATIONS: Characterization of tumor TS expression may be of value in identifying patients with advanced head and neck cancer who would benefit from fluoropyrimidine-based neoadjuvant chemotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/enzimología , Timidilato Sintasa/biosíntesis , Antimetabolitos Antineoplásicos/administración & dosificación , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Dihidrouracilo Deshidrogenasa (NADP) , Fluorouracilo/administración & dosificación , Fluorouracilo/sangre , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunohistoquímica , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Leucovorina/administración & dosificación , Oxidorreductasas/sangre , Valor Predictivo de las Pruebas , Proteínas Recombinantes , Inducción de Remisión , Estudios Retrospectivos , Timidilato Sintasa/efectos de los fármacos , Resultado del Tratamiento
5.
Semin Oncol ; 22(5 Suppl 12): 8-12, 1995 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-7481866

RESUMEN

Current chemotherapeutic approaches to recurrent head and neck cancer have routinely yielded response rates of 10% to 30% (for single agents) and 30% to 50% (for combination chemotherapy). However, median survival times for patients with metastatic and/or recurrent disease have stagnated at around 6 months since the 1970s. The investigation of new drugs and treatment approaches thus continues to be a high priority. One such agent, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ), has shown good single-agent activity and is also believed to potentiate the effects of radiation therapy in patients with head and neck cancer. We have focused on the addition of paclitaxel to the previously established combination of 5-fluorouracil, hydroxyurea, and radiation therapy. The study goals are to establish the maximum tolerated dose and dose-limiting toxicity of paclitaxel when added to this combination as a 5-day continuous infusion on a biweekly schedule. Preliminary results of this ongoing study have demonstrated activity in patients with poor-prognosis head and neck cancer. Major dose-limiting toxicities have consisted of neutropenia and mucositis, and definition of a recommended phase II dose is in progress.


Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Paclitaxel/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Cisplatino/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Hidroxiurea/administración & dosificación , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Paclitaxel/efectos adversos , Radioterapia Adyuvante , Células Tumorales Cultivadas
6.
Int J Radiat Oncol Biol Phys ; 30(1): 151-60, 1994 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-8083108

RESUMEN

PURPOSE: To determine the pattern of failure and outcome of patients achieving a complete response following high-dose chemotherapy and autologous bone marrow transplantation for metastatic breast cancer, and to evaluate the use of involved field radiation therapy in this setting. METHODS AND MATERIALS: Thirty-one patients with metastatic breast cancer treated on three successive high-dose chemotherapy and autologous bone marrow transplantation trials between January 1987 and March 1992 who achieved a complete response were evaluated. Twenty-three patients (74.2%) had initially Stage I-II disease. Initial therapy consisted of mastectomy in 19 (74.2%), adjuvant chemotherapy in 19 (61.3%), and adjuvant radiation therapy in 11 (35.5%). All patients underwent induction chemotherapy prior to high-dose intensification. High-dose chemotherapy consisted of cytoxan, thiotepa +/- carmustine. Fourteen patients received radiation therapy prior to (7) or following the high-dose chemotherapy (7) with either the intent to palliate a symptomatic disease site (4) or to attain/maintain a complete response (10). The four palliatively treated sites received 30 Gy in 3.0 Gy fractions, the sites treated definitively received a mean dose of 43.9 Gy (range, 18-64.8 Gy) in 1.5-2.0 Gy fractions. Seventy-two disease sites were present in the 31 patients. The most common sites involved were nodal (23), bone (14), and chest wall/breast (11). Nineteen sites were bulky (> 2 cm in size). Twenty-three sites were irradiated (19 definitively, 4 palliatively). Median follow-up was 18 months (range, 2-49 months). RESULTS: Twenty (64.5%) of the 31 patients relapsed. Eleven of the 17 patients not receiving radiation failed. Seven (63.6%) failed first solely in sites of previous disease involvement and four (36.4%) failed in new sites. This failure pattern was reversed in the patients receiving radiation therapy. Nine of the 14 (64.3%) patients relapsed. Two (22.2%) failed solely in old sites and six (66.7%) solely in new sites. One patient (11.1%) failed simultaneously in both old and new sites. Patients receiving radiation therapy had a similar 2-year actuarial disease-free survival compared to those not treated with radiation (28.3% vs. 32.1%) (p = 0.14). However, patients with less than three sites of disease had a better disease-free survival at 2 years with the addition of radiation therapy (30.0% vs. 17.6%) (p = 0.03). Patients with locoregional disease only had a lower rate of local failure (one out of four vs. three out of five) and a longer mean time to any failure (4.0 months vs. 17.5 months) with the addition of radiation therapy. Of the 72 sites identified, 59 (81.9%) were amenable to radiation therapy either prior to or following the transplant. The use of radiation therapy resulted in a borderline significant improvement in 2-year actuarial control of all sites (82.4% vs. 64.3%) (p = 0.09) as well as of bulky sites (80.0% vs. 51.4%) (p = 0.08). Excluding the four sites treated with palliative intent only, the 2-year actuarial local control of the irradiated sites was 92.8%. None of the 14 treated patients experienced untoward sequelae. CONCLUSION: The predominant site of initial failure in patients with metastatic breast cancer achieving a complete response following high-dose chemotherapy and autologous bone marrow transplantation is in sites of previous disease involvement. Radiation therapy given in conjunction with the high-dose chemotherapy is capable of improving the control of these sites, the majority of which are amenable to treatment with radiation therapy. Our data suggests that patients with less than three sites of disease, bulky disease, and locoregional disease only should be considered for radiation therapy in addition to high-dose chemotherapy.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea , Neoplasias de la Mama/terapia , Adulto , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Cisplatino/administración & dosificación , Terapia Combinada , Ciclofosfamida/administración & dosificación , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Metotrexato/administración & dosificación , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Metástasis de la Neoplasia , Insuficiencia del Tratamiento , Vincristina/administración & dosificación
7.
Int J Radiat Oncol Biol Phys ; 29(4): 777-80, 1994 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-8040024

RESUMEN

PURPOSE: Previous work has demonstrated that inhibitors of phospholipase A2 attenuate ionizing radiation induced arachidonic acid production, protein kinase C activation and prevent subsequent induction of the tumor necrosis factor gene. Because arachidonic acid contributes to radiation-induced tumor necrosis factor expression, we analyzed the effects of agents which alter arachidonate metabolism on the regulation of this gene. METHODS AND MATERIALS: Phospholipase A2 inhibitors quinicrine, bromphenyl bromide, and pentoxyfylline or the inhibitor of lipoxygenase (ketoconazole) or the inhibitor of cyclooxygenase (indomethacin) were added to cell culture 1 h prior to irradiation. RESULTS: Radiation-induced tumor necrosis factor gene expression was attenuated by each of the phospholipase A2 inhibitors (quinicrine, bromphenyl bromide, and pentoxyfylline). Furthermore, ketoconazole attenuated X ray induced tumor necrosis factor gene expression. Conversely, indomethacin enhanced tumor necrosis factor expression following irradiation. CONCLUSION: The finding that radiation-induced tumor necrosis factor gene expression was attenuated by ketoconazole suggests that the lipoxygenase pathway participates in signal transduction preceding tumor necrosis factor induction. Enhancement of tumor necrosis factor expression by indomethacin following irradiation suggests that prostaglandins produced by cyclooxygenase act as negative regulators of tumor necrosis factor expression. Inhibitors of tumor necrosis factor induction ameliorate acute and subacute sequelae of radiotherapy. We propose therefore, that ketoconazole may reduce acute radiation sequelae such as mucositis and esophagitis through a reduction in tumor necrosis factor induction or inhibition of phospholipase A2 in addition to its antifungal activity.


Asunto(s)
Regulación Leucémica de la Expresión Génica/efectos de la radiación , Cetoconazol/farmacología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genética , Ácido Araquidónico/metabolismo , Northern Blotting , Inhibidores de la Ciclooxigenasa/farmacología , ADN Complementario/genética , Expresión Génica/efectos de los fármacos , Expresión Génica/efectos de la radiación , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Genes jun/efectos de la radiación , Humanos , Leucemia Mieloide/genética , Leucemia Mieloide/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Fosfolipasas A/antagonistas & inhibidores , Fosfolipasas A2 , Transducción de Señal/fisiología , Transducción de Señal/efectos de la radiación , Células Tumorales Cultivadas/efectos de la radiación
8.
Semin Oncol ; 19(3 Suppl 9): 53-8, 1992 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-1641658

RESUMEN

Hydroxyurea is an active single agent in squamous cell cancer of the head and neck. It has been used clinically, most frequently as a radiation-enhancing agent with concomitant radiotherapy. Pilot trials testing hydroxyurea in this setting reported encouraging results. Two randomized trials have been conducted with inconclusive results, possibly relating to study cohort size and short period of follow-up. More recently, hydroxyurea has been investigated with 5-fluorouracil and concomitant radiotherapy. A sound theoretic rationale can be made for this approach and data derived from a phase I/II study are presented. These support the further investigation of this regimen.


Asunto(s)
Carcinoma de Células Escamosas/radioterapia , Fluorouracilo/uso terapéutico , Neoplasias de Cabeza y Cuello/radioterapia , Hidroxiurea/uso terapéutico , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Administración Oral , Médula Ósea/efectos de los fármacos , Médula Ósea/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/secundario , Quimioterapia Adyuvante , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/efectos adversos , Infusiones Intravenosas , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/radioterapia , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/efectos adversos , Dosificación Radioterapéutica , Inducción de Remisión , Estomatitis/inducido químicamente , Tasa de Supervivencia
9.
Laryngoscope ; 102(6): 630-6, 1992 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-1602911

RESUMEN

Based on encouraging results with 5-fluorouracil (5-FU), hydroxyurea, and concomitant radiotherapy in patients with advanced or recurrent head and neck cancer, an attempt was made to modulate the regimen by the addition of cisplatin as a third active agent. A cohort of 26 patients with head and neck cancer of all histologies were entered into a broad phase I study investigating simultaneous radiation therapy, 5-FU (with or without leucovorin), HU, and infusional cisplatin administered on an alternate-week schedule. Eleven patients (group 1) had failed prior curative local therapy and 15 patients (group 2) were considered to have a poor prognosis with standard therapy. The median follow-up was 30 months. The response rate for all evaluable patients was 82% (14/17), and the complete response rate was 65% (11/17). Patients in group 1 demonstrated a high failure rate (9/11), while few group 2 patients failed after treatment (2/15). The median time to progression was 4.4 months in group 1 and has not been reached in group 2. Patients in group 1 failed locally (7/11), while no local failures were observed in group 2. Acute and cumulative hematologic toxicity was encountered at all dose levels and schedules tested and prevented escalation of the cisplatin dose beyond the desired level of 100 mg/m2 per months. Mucositis was a second significant toxicity in patients with head and neck cancer and was more pronounced during cycles containing leucovorin. A detailed analysis of survival, time to progression, and site of failure is presented.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Hidroxiurea/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante , Cisplatino/efectos adversos , Terapia Combinada , Fluorouracilo/efectos adversos , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Hidroxiurea/efectos adversos , Persona de Mediana Edad , Pronóstico , Inducción de Remisión , Terapia Recuperativa , Tasa de Supervivencia , Resultado del Tratamiento
10.
J Clin Oncol ; 9(8): 1376-84, 1991 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-2072141

RESUMEN

Fifty-one patients with locally advanced head and neck cancer were treated with three cycles of cisplatin at 100 mg/m2 followed by 5-day continuous infusion fluorouracil (5-FU) at 1,000 mg/m2/d as induction chemotherapy. Subsequent local therapy consisted of surgery for patients with resectable disease and/or radiotherapy. Three cycles of adjuvant chemotherapy were administered to patients with partial response (PR) or complete response (CR) to induction chemotherapy. Twenty-two patients (43%) had a clinical CR that was pathologically confirmed in 12 patients (24%), and 24 patients (47%) had a PR for an overall response rate of 90%. Local therapy included surgery in 24 patients (47%) and radiotherapy alone in 22 patients (43%). Adjuvant chemotherapy was administered to 32 patients (63%) frequently at great dose reduction. At a median follow-up of 90 months, the median survival is 22 months (95% confidence interval, 15 to 36 months), and the 5-year survival is 25%, with only five patients known to be alive and disease-free at this time. The median time to progression is 14 months, with 29 patients (57%) having documented progression of their head and neck cancer and eight (16%) having progression of a second neoplasm. Seven patients died of intervening medical events. This high incidence of second malignancies supports the continued investigation of chemoprevention for patients in CR. Despite the known high response rates achieved with cisplatin and 5-FU induction chemotherapy, the overall poor survival data reported here should lead to a thorough reexamination of the frequent administration of this regimen in the community.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Terapia Combinada , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Inducción de Remisión , Tasa de Supervivencia , Factores de Tiempo
11.
Cancer Res ; 51(2): 521-7, 1991 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-1845955

RESUMEN

Several mechanisms of drug resistance have been defined using cell lines selected for resistance in vitro. However, the relevance of these to tumor cell resistance in vivo remains unclear. We established tumor cell lines from biopsies of human sarcomas before and after doxorubicin therapy. One pretreatment sarcoma line, STSAR90, was 6-fold less sensitive to doxorubicin than was a normal fibroblast line, AG1522. The sensitivities of six other sarcoma lines were similar to that of AG1522. STSAR90 cells did not overexpress P-glycoprotein mRNA, by Northern analysis with the pCHP1 complementary DNA fragment. Photoaffinity labeling with the vinblastine analogue N-(p-azido-3-125I-salicyl)-N'-beta-aminoethylvindesine did not show increased P-glycoprotein concentrations. Accumulation of [3H]daunomycin was not decreased in STSAR90 compared with a less resistant sarcoma line, STSAR11, nor was the doxorubicin sensitivity of STSAR90 increased by coincubation with verapamil. Glutathione levels were twice as high in STSAR90 as in STSAR11, and glutathione peroxidase activity was 3.5- to 6-fold higher. This was due mostly to an increase in selenium-dependent peroxidase activity. After exposure to doxorubicin, STSAR90 cells formed only half as much measurable hydroxyl radical as STSAR11, as detected by electron spin resonance spectrometry. Doxorubicin sensitivity was increased in STSAR90 cells when intracellular glutathione levels were reduced by buthionine sulfoximine. These results indicate that multidrug resistance due to P-glycoprotein-mediated drug efflux is not the only mechanism of doxorubicin resistance that occurs in sarcomas and that glutathione peroxidase-dependent detoxification of doxorubicin-induced oxygen radicals may contribute to clinical doxorubicin resistance.


Asunto(s)
Doxorrubicina/farmacología , Glutatión Peroxidasa/metabolismo , Sarcoma/enzimología , Adolescente , Adulto , Biotransformación , Western Blotting , Línea Celular , Supervivencia Celular/efectos de los fármacos , Niño , Doxorrubicina/metabolismo , Doxorrubicina/uso terapéutico , Resistencia a Medicamentos , Espectroscopía de Resonancia por Spin del Electrón , Femenino , Humanos , Isoenzimas/aislamiento & purificación , Isoenzimas/metabolismo , Cinética , Masculino , Sarcoma/tratamiento farmacológico
12.
Cancer ; 66(2): 206-13, 1990 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-2196107

RESUMEN

Two regimens of neoadjuvant chemotherapy for previously untreated patients with locally advanced head and neck cancer were compared with the goal of identifying a regimen with a greater than 50% complete response (CR) rate. Patients with a performance status of 0 to 2 and normal end-organ function were randomized to receive either four cycles of neoadjuvant methotrexate, cisplatin, and continuous infusion 5-fluorouracil (5-FU) (MPF) (arm A), or four cycles of bleomycin, cisplatin, and methotrexate (PBM) alternating with cisplatin and 5-FU (PF) (arm B). Patients with a performance status of greater than 2 or a carbon monoxide diffusion capacity of less than 50% of the predicted value were assigned to the arm A regimen but were analyzed separately (arm C). Local therapy consisted of surgery (for patients with resectable disease) or radiation therapy followed by two cycles of adjuvant chemotherapy with the regimen that was administered initially. Of the 42 patients who were evaluated, 16 were randomized to arm A, 13 to arm B, and 13 to arm C. The clinical CR rate was 19% on arm A (95% confidence interval, 0% to 38%), 39% on arm B (95% confidence interval, 12% to 66%) (P = 0.41), and 54% on arm C (95% confidence interval, 27% to 81%). At a median follow-up time of 35 months, the 2-year actuarial survival rate was 61% on arm A, 69% on arm B (the P value was not significant), and 38% on arm C. The 2-year survival rate for all 42 patients who were treated was 57% and the median survival time was 31 months. Toxicities of neoadjuvant chemotherapy on all arms consisted of mild to moderate myelosuppression and renal toxicity. The incidence of moderate to severe mucositis was significantly higher on arm A than arm B (P = 0.02). Two cycles of adjuvant chemotherapy were administered to only 11 of 42 patients due to patient refusal or cumulative toxicity. In conclusion, both neoadjuvant chemotherapy regimens resulted in similar response and survival rates, but mucositis was more severe with arm A. However, since neither regimen was likely to cause a CR rate of greater than 50%, this study was closed to further patient accrual.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Adulto , Anciano , Cisplatino/administración & dosificación , Terapia Combinada , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Estadificación de Neoplasias , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Análisis de Supervivencia
13.
J Clin Oncol ; 8(2): 241-7, 1990 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-1688926

RESUMEN

Both cisplatin and leucovorin (LV) interact with fluorouracil (5-FU) by increasing intracellular reduced folate levels and thereby the inhibition of thymidylate synthase. Therefore, the addition of LV to cisplatin and 5-FU (PFL) may increase the activity of that combination in head and neck cancer. We treated 31 patients with locally advanced head and neck cancer with two cycles of neoadjuvant PFL consisting of 100 mg/m2 of cisplatin on day 1 followed by a 5-day continuous infusion of 5-FU at 1,000 mg/m2/day and oral LV at 100 mg administered every 4 hours during the entire duration of chemotherapy infusion. Two patients died during neoadjuvant chemotherapy of sudden death and sepsis, respectively, and were not evaluated for response. Of 29 evaluable patients, nine had a complete response (CR), 17 had a partial response (PR), and three had stable disease. Toxicities consisted of mild to moderate myelosuppression and moderate to severe mucositis, necessitating reduction of 5-FU on cycle 2 to less than or equal to 80% of the intended dose in 22 of 29 patients. Administration of LV by repeated oral dosing resulted in total reduced folate plasma concentrations of 5.3 (+/- 2.9) and 6.7 (+/- 3.4) mumol on days 2 and 4 of the 5-FU infusion. The sum of 1-LV and its metabolite 5-CH3-tetrahydrofolate exceeded the concentration of d-LV, consistent with selective absorption of the biologically active 1-stereoisomer from the gastrointestinal tract.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Leucovorina/administración & dosificación , Adulto , Anciano , Bleomicina/administración & dosificación , Femenino , Humanos , Leucovorina/sangre , Leucovorina/metabolismo , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Inducción de Remisión , Estereoisomerismo
14.
J Clin Oncol ; 7(7): 838-45, 1989 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-2661732

RESUMEN

To increase the complete response (CR) rate of patients with locally advanced head and neck cancer after three cycles of neoadjuvant chemotherapy, we added sequential methotrexate to the combination of cisplatin and continuous infusion fluorouracil (5-FU). We also evaluated the feasibility of administering three additional cycles of the same regimen as adjuvant chemotherapy. Thirty-eight patients were treated; the median age was 53 years and 36 patients had stage IV disease. Chemotherapy consisted of methotrexate 120 mg/m2 followed 24 hours later by cisplatin 100 mg/m2 and a five-day continuous infusion of 5-FU at 1,000 mg/m2/d. Of 34 patients evaluable for response to neoadjuvant chemotherapy, nine had a CR, 21 a partial response (PR), two a minimal response (MR), and one patient each stable disease (SD) and no response (NR). Of 31 patients who received local therapy, 15 were treated with surgery and radiotherapy and 16 with radiotherapy alone. Of 25 patients eligible to receive adjuvant chemotherapy only ten received all three intended cycles, while 15 received less or no adjuvant chemotherapy because of patient refusal, cumulative toxicity, or early disease progression. With a median follow-up time of 39 months, the median survival is estimated to be 20 months. Of eight patients with nasopharyngeal or paranasal sinus cancer, none has had disease recurrence. Patients with good initial performance status and low N-stage also had a significant survival advantage. Chemotherapy-related toxicities consisted mainly of mucositis, requiring 5-FU dose reduction in the majority of patients; similar toxicities were exacerbated in the adjuvant setting. The addition of methotrexate did not increase the CR rate over what has been reported for the combination of cisplatin and 5-FU alone. Certain subsets of patients appear to have a good prognosis when treated in this fashion. The administration of adequate adjuvant chemotherapy in patients with head and neck cancer remains difficult due to toxicity and poor patient compliance.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Ensayos Clínicos como Asunto , Terapia Combinada , Femenino , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad
15.
Cancer ; 63(6 Suppl): 1048-53, 1989 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-2783881

RESUMEN

Both cisplatin and leucovorin may increase the activity of 5-fluorouracil (5-FU) by increasing the intracellular concentration of reduced folates. Therefore, a Phase I study was conducted in patients with recurrent or metastatic head and neck cancer in which high doses of oral leucovorin were added to the combination of cisplatin and 5-FU. Patients received intravenous cisplatin 100 mg/m2 on day 1, followed by a continuous intravenous infusion of 5-FU at 600 mg/m2/day for 5 days. Leucovorin 50 mg/m2 orally was administered from the start of the cisplatin infusion and then every 6 hours throughout the 5-FU infusion. The dose of 5-FU was increased to 800 mg/m2/day and 1 g/m2/day according to observed toxicity. In a second phase of the study, the dose of leucovorin was increased to 50 mg/m2 orally every 4 hours. Twenty-five patients were registered: 23 had recurrent head and neck cancer after extensive treatment; two had newly diagnosed metastatic disease. The maximum tolerated dose of 5-FU was 800 mg/m2/day with leucovorin administered every 6 hours. Toxicities at that level included mild-to-moderate myelosuppression. Mucositis in the previously irradiated field prevented the further increase of the 5-FU dose to 1 g/m2/day. Identical toxicities were observed when administering 5-FU at 800 mg/m2/day with 50 mg/m2 of leucovorin every 4 hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who had previously received cisplatin and 5-FU as induction chemotherapy). Eight patients did not respond. The median survival for all 25 patients was 6.5 months. It was concluded that the combination of cisplatin, 5-FU, and leucovorin is active in the treatment of recurrent head and neck cancer. The maximum tolerated dose of 5-FU in previously treated patients is 800 mg/m2/day, with mucositis being the dose-limiting toxicity. Further investigation of this regimen as neoadjuvant chemotherapy in previously untreated patients with locally advanced head and neck cancer is in progress.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas/secundario , Cisplatino/administración & dosificación , Esquema de Medicación , Evaluación de Medicamentos , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia
16.
J Clin Oncol ; 6(4): 618-26, 1988 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-3258629

RESUMEN

We added high-dose oral leucovorin to the combination of cisplatin and fluorouracil (5-FU) to assess the efficacy of this regimen in the treatment of patients with head and neck cancer. Cisplatin, 100 mg/m2, was followed by a 5-FU continuous infusion at 600 mg/m2/d for five days. Leucovorin, 50 mg/m2, was administered at the start of cisplatin and every six hours throughout the duration of the 5-FU infusion. The dose of 5-FU was escalated to 800 mg/m2 and 1,000 mg/m2 according to observed toxicity. In a second phase of the study, the dose of leucovorin was escalated to 50 mg/m2 every four hours. A total of 25 patients were registered: 23 had recurrent disease after extensive prior treatment; and two had newly diagnosed metastatic disease. The maximally tolerated dose of 5-FU was 800 mg/m2/d with leucovorin administered every six hours. Toxicities at that level included mild to moderate myelosuppression and dose-limiting mucositis in the previously irradiated field. Identical toxicities were observed when administering 800 mg/m2/d of 5-FU with leucovorin every four hours. Eighteen patients were evaluated for response: one had a pathologic complete response; nine had a partial response (including four who received prior cisplatin and 5-FU as induction chemotherapy); and eight patients failed to respond. The mean peak and trough plasma leucovorin concentrations were 2.61 (+/- 1.07) mumol/L and 2.46 (+/- 0.95) mumol/L with administration of the drug every six hours, and 2.75 (+/- 2.15) mumol/L and 2.52 (+/- 1.48) mumol/L with administration every four hours. We conclude that the combination of cisplatin, 5-FU, and leucovorin has activity in the treatment of recurrent head and neck cancer. The maximally tolerated dose of 5-FU in this study was 800 mg/m2/d, with mucositis in previously irradiated sites being dose-limiting. Plasma leucovorin concentrations exceeding 1 mumol/L are achieved following oral administration of this drug.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Adulto , Anciano , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Femenino , Fluorouracilo/administración & dosificación , Neoplasias de Cabeza y Cuello/patología , Humanos , Leucovorina/administración & dosificación , Leucovorina/sangre , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia
17.
J Clin Oncol ; 5(1): 10-20, 1987 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-2433406

RESUMEN

This study examines the role of combination chemotherapy with surgery and/or radiotherapy in the initial treatment of patients with advanced stage III and IV squamous-cell carcinoma of the head and neck (SCCHN). Two courses of initial (induction) cisplatin, bleomycin, and methotrexate with oral calcium leucovorin (PBM) were used with the principal intent of increasing the effectiveness of subsequent surgery and/or radiotherapy. Following induction chemotherapy and local treatment, disease-free patients who had responded to initial chemotherapy were entered into a randomized trial of adjuvant PBM. The response rates to induction PBM chemotherapy were a complete response (CR) rate of 26% and a partial response (PR) rate of 52%, for an overall response rate of 78%. A response to induction PBM was highly correlated with failure-free survival (P less than .0001). A Cox multistep regression analysis of potential prognostic factors was performed. After adjusting for the significant prognostic factors of performance status, initial tumor size, and primary tumor site, a response to induction chemotherapy remained independently associated with improved survival (P = .0002). The randomized trial of adjuvant chemotherapy demonstrated that such treatment significantly improved failure-free survival by decreasing local-regional failures. The benefit of adjuvant chemotherapy was particularly evident in patients who had a PR to induction chemotherapy (P = .01). The toxicity of this multidisciplinary approach was predictable and acceptable. Surgery and radiotherapy were not compromised by induction or adjuvant chemotherapy. Definitive evidence that chemotherapy can favorably influence survival awaits confirmation of these results by a randomized trial using a control arm of patients treated with conventional surgery and/or radiotherapy alone.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeza y Cuello/terapia , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina/administración & dosificación , Carcinoma de Células Escamosas/patología , Cisplatino/administración & dosificación , Terapia Combinada , Esquema de Medicación , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Leucovorina/administración & dosificación , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Distribución Aleatoria , Estadística como Asunto
18.
Arch Otolaryngol ; 109(12): 792-6, 1983 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-6357165

RESUMEN

Hypoxic cell sensitizers, particle therapy, hyperthermia, and combinations of chemotherapy and radiotherapy have potential to increase the therapeutic ratio in future clinical radiotherapy treatment regimens. The biologic bases of these investigations are beginning to appear as avenues of clinical investigation.


Asunto(s)
Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Hipertermia Inducida , Oxígeno , Aceleradores de Partículas , Radiación Ionizante , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Radiobiología
20.
Cancer ; 40(1): 78-83, 1977 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-406980

RESUMEN

Ten patients with metastatic osteosarcoma were treated at the Joint Center for Radiation Therapy, the Sidney Farber Cancer Institute, and the Children's Hospital Medical Center from 1973 to 1976. Patients were treated with an aggressive multimodality approach with included surgery, chemotherapy, and radiation therapy. Three of 10 patients are alive with no evidence of disease, five are alive, with disease, and two are dead of disease. The median survival is 12+ months. Local control data for radiation combined with high dose methotrexate in metastatic osteosarcoma is shown.


Asunto(s)
Neoplasias Pulmonares/terapia , Metotrexato/uso terapéutico , Osteosarcoma/terapia , Adolescente , Adulto , Femenino , Humanos , Leucovorina/uso terapéutico , Neoplasias Pulmonares/mortalidad , Masculino , Metástasis de la Neoplasia , Osteosarcoma/mortalidad , Pronóstico , Radioterapia de Alta Energía
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