RESUMEN
BACKGROUND: Liposomal doxorubicin (Caelyx, Doxil) delivers doxorubicin to a tumor, but has a vastly altered pharmacology and attenuated acute and chronic toxicities. Therefore, its efficacy in soft tissue sarcomas is worth exploring. PATIENTS AND METHODS: Sixteen patients with recurrent or metastatic soft tissue sarcomas who had not failed prior doxorubicin were accrued into this phase II study. Patients were treated with Doxil at a dose of 50 mg/m2 every four weeks. RESULTS: No responses were seen but three patients were removed from study after only one cycle of treatment. Moreover, leiomyosarcoma was the most common histology and most patients had low grade, and bulky, disseminated tumors. Treatment was well tolerated with no episodes of grade 4 toxicity and only five episodes of grade 3 toxicities: two episodes of neutropenia and one each of stomatitis, dermatologic toxicity and nausea and vomiting. CONCLUSIONS: Doxil's lack of activity in this study of patients with adult soft tissue sarcoma may be related to the poor prognostic features of our population. We confirm its favorable toxicity profile and suggest that additional studies be done in patients with other characteristics.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Doxorrubicina/uso terapéutico , Sarcoma/tratamiento farmacológico , Adulto , Anciano , Humanos , Persona de Mediana Edad , Pronóstico , Sarcoma/secundario , Resultado del TratamientoRESUMEN
BACKGROUND: Ewing's sarcomas, osteosarcomas, and rhabdomyosarcomas are significantly more responsive to chemotherapy than other sarcomas. Adjuvant chemotherapy is used routinely based on data from randomized trials. Although a percentage of children with locally advanced or metastatic tumors remain curable, few data exist regarding the tumor's natural history or response and survival in adults. METHODS: This Phase II study evaluated doxorubicin, dacarbazine, ifosfamide, and mesna (MAID) in adults with inoperable or metastatic Ewing's sarcoma, rhabdomyosarcoma, or osteosarcoma. RESULTS: Between 1987-1991, 81 patients were entered; 69 patients were eligible. One patient died of neutropenic infection. Ten patients (14%) responded completely and 34 patients (49%) had a complete or partial response. Response rates were significantly higher for patients with Ewing's sarcoma and rhabdomyosarcoma than for those with osteosarcoma (77%, 64%, and 26%, respectively; P < 0.005). Although there were no significant differences in progression free survival by histology, survival for patients with Ewing's sarcoma was significantly longer than for patients with osteosarcoma (P = 0.004.) At the time of last follow-up, 7 patients (10%) were alive without progression: 3 with Ewing's sarcoma, 1 with osteosarcoma, and 3 with rhabdomyosarcoma. CONCLUSIONS: MAID chemotherapy is an active regimen in adults with advanced or metastatic Ewing's sarcoma and rhabdomyosarcoma. Although there was no direct comparison with a doxorubicin and cisplatin-based regimen, the response rate and survival in patients with osteosarcoma suggest that doxorubicin and cisplatin-based chemotherapy would remain the accepted initial chemotherapy regimen. For patients with rhabdomyosarcoma and Ewing's sarcoma, 10-20% of patients remained disease free at 5 years.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Osteosarcoma/tratamiento farmacológico , Rabdomiosarcoma/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dacarbazina/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Masculino , Mesna/administración & dosificación , Persona de Mediana Edad , Osteosarcoma/mortalidad , Rabdomiosarcoma/mortalidad , Sarcoma de Ewing/mortalidad , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
The authors report three patients with features of the Carney complex: cardiac myxomas (n = 2), multicentric (n = 1) or recurrent (n = 1); pigmented skin lesions (n = 2); cutaneous myxomas (n = 2); melanotic schwannoma (n = 2); and sonographic evidence of multicentric, large cell, calcifying Sertoli cell tumors of the testes (n = 1). The initial component of the complex was cutaneous myxoma (n = 1), cardiac myxoma (n = 1), or psammomatous melanotic schwannoma (n = 1). Two patients died of metastatic schwannoma.
Asunto(s)
Neoplasias Cardíacas/diagnóstico , Mixoma/diagnóstico , Neoplasias Primarias Múltiples/diagnóstico , Neurilemoma/diagnóstico , Neoplasias Cutáneas/diagnóstico , Adulto , Diagnóstico por Imagen , Femenino , Atrios Cardíacos , Ventrículos Cardíacos , Humanos , Masculino , Trastornos de la Pigmentación/diagnóstico , Tumor de Células de Sertoli/diagnóstico , Síndrome , Neoplasias Testiculares/diagnósticoAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/patología , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Humanos , Factores de Riesgo , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patologíaRESUMEN
Thirteen patients with metastatic renal cancer were treated in a phase II trial with interleukin-2, 21.6 million IU/m2 intravenously daily for five days on two consecutive weeks, starting 3 days after the administration of low dose cyclophosphamide 350 mg/m2 intravenously. Treatment cycles were repeated every 21 days. No responses were seen (95% Confidence Interval: 0-22%). The most common toxicities were fever, fatigue, hypotension, nausea/emesis, and myalgia/arthralgia. There were 11 episodes of Grade III toxicity including Grade III hypotension in 7 patients. Because of the significant toxicity and the lack of observed response, the study was discontinued. Cyclophosphamide and interleukin-2 at the dose and schedule used in this study has considerable toxicity and is unlikely to improve on response rates previously seen with other IL-2 based regimens in metastatic renal cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Interleucina-2/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Femenino , Humanos , Inyecciones Intravenosas , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Metástasis de la NeoplasiaRESUMEN
Preoperative therapy has been tested as part of limb salvage therapy for localized bone and soft tissue sarcoma of the extremities. The activity of cisplatin (CDDP) by intraarterial (IA) infusion was evaluated in 40 cases of which 36 were evaluable for response. All patients had high-grade sarcomas. All but 3 patients received 3 or 4 courses (24 patients received 4 courses) of CDDP at a dosage of 120 to 150 mg/m2 given over 6 hours every 2 weeks by IA infusion. Patients younger than 18 years of age received the higher dose of CDDP. Treatment was well tolerated with combination antiemetics. One patient experienced severe hearing loss with the first cycle of the higher CDDP dose. Pathologic evaluation of resected osteosarcoma showed a favorable response (90% or greater necrosis) in 8 of 20 evaluable cases and in 3 of 4 patients with malignant fibrous histiocytoma (MFH) of bone (without osteoid). In soft tissue sarcomas, minimal (50% to 89%) necrosis was seen in two of nine cases and none had 90% or greater necrosis. Patients received postoperative chemotherapy based on pathologic response, but the value of this postoperative adjuvant therapy requires further follow-up and is uncertain in this small study. IA CDDP can often cause significant tumor necrosis in patients with bone sarcomas, whereas soft tissue sarcomas are less sensitive to this therapy.
Asunto(s)
Neoplasias Óseas/terapia , Cisplatino/uso terapéutico , Extremidades/cirugía , Sarcoma/terapia , Neoplasias de los Tejidos Blandos/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/mortalidad , Neoplasias Óseas/patología , Niño , Cisplatino/efectos adversos , Terapia Combinada , Evaluación de Medicamentos , Humanos , Infusiones Intraarteriales , Persona de Mediana Edad , Necrosis , Sarcoma/mortalidad , Sarcoma/patología , Neoplasias de los Tejidos Blandos/mortalidad , Neoplasias de los Tejidos Blandos/patología , Tasa de SupervivenciaRESUMEN
Twenty-seven evaluable patients with advanced malignant melanoma received fludarabine phosphate in a daily x 5 injection. Initial dosing was based on the presence of previous radiation therapy. There was no response seen in these patients despite appropriate dose escalation. Myelosuppression occurred without significant sequelae.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Melanoma/tratamiento farmacológico , Fosfato de Vidarabina/análogos & derivados , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Relación Dosis-Respuesta a Droga , Evaluación de Medicamentos , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Fosfato de Vidarabina/administración & dosificación , Fosfato de Vidarabina/efectos adversos , Fosfato de Vidarabina/uso terapéuticoRESUMEN
Twenty-five patients with metastatic melanoma were treated with a therapeutic vaccine ("theraccine") consisting of allogeneic melanoma lysates and a novel adjuvant, DETOX (Ribi ImmunoChem Research, Inc, Hamilton, MT). Each patient received 200 antigenic units (20 x 10(6) tumor cell equivalents) subcutaneously on weeks 1, 2, 3, 4, and 6. Clinical responses included one complete remission, three partial remissions, and a long-term (17-month) stability. Two other patients had mixed responses, with partial remissions of numerous subcutaneous nodules. Sites of responsive disease included primarily the skin, but ileal, breast, and a liver metastasis also responded. Removal of residual lesions in patients with partial remissions, whose other lesions had disappeared during treatment, led to long disease-free survivals. The median duration of remission was 17 months, with four of the five responders alive for at least 24 months after treatment. An increase in precursors of cytolytic T cells (CTLs) correlated with clinical outcome, when complete, partial, and mixed responses and long-term stability were considered. The CTLs recognized melanoma-associated antigens on many cell lines, but not other types of tumor or normal lymphocytes. Skin-test reactivity to melanoma antigens and serum antibodies against the melanoma cells was unrelated to clinical response. Toxicity was minimal, restricted largely to minor soreness at the site of injection. Only five patients, four of whom were treated with repeated courses, developed severe granulomas. These results confirm that active-specific immunization with allogeneic lysates of melanoma administered with the adjuvant DETOX can induce immunity to melanoma, and can induce regressions of disease in a proportion of patients with metastatic disease with little toxicity.
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Inmunoterapia , Melanoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antineoplásicos/biosíntesis , Antígenos de Neoplasias/análisis , Esqueleto de la Pared Celular , Citotoxicidad Inmunológica , Femenino , Humanos , Hipersensibilidad Tardía/inmunología , Recuento de Leucocitos , Lípido A/análogos & derivados , Lípido A/uso terapéutico , Masculino , Melanoma/inmunología , Melanoma/mortalidad , Persona de Mediana Edad , Mucoproteínas/uso terapéutico , Ácidos Micólicos/uso terapéutico , Inducción de Remisión , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/terapia , Pruebas Cutáneas , Tasa de Supervivencia , Linfocitos T Citotóxicos/inmunologíaRESUMEN
A 19-year-old man with telangiectatic osteosarcoma of the left proximal femur was started on a course of neoadjuvant chemotherapy consisting of intraarterial administration of cis-platinum. Within 72 hours of receiving the first intraarterial dose, the patient developed signs and symptoms of fat embolism syndrome (FES). A physical examination revealed cyanosis, tachycardia, and seizure activity. Laboratory studies demonstrated a pO2 of less than 65 mmHg, lipuria, and a drop in hematocrit of three percentage points. There was no clinical or roentgenographic evidence of pathologic fracture. Tumor necrosis secondary to intraarterial cis-platinum therapy in this patient with osteosarcoma may have caused a sudden release of free fatty acids and embolization of fat macroglobules that precipitated this episode of FES. FES in association with the intraarterial administration of cis-platinum seems not to have been previously reported.
Asunto(s)
Cisplatino/efectos adversos , Embolia Grasa/etiología , Neoplasias Femorales/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Adulto , Cisplatino/administración & dosificación , Humanos , Bombas de Infusión , Inyecciones Intraarteriales , Masculino , SíndromeRESUMEN
We report 2 patients with transient, focal, repetitive, stereotyped episodes of neurologic deficits during treatment with interleukin-2. One patient had recurrent monocular blindness, while the 2nd had recurrent homonymous quadrantanopia. We suggest that these attacks are provoked by endothelial cell activation induced by interleukin-2.
Asunto(s)
Interleucina-2/uso terapéutico , Trastornos de la Visión/etiología , Ceguera/etiología , Femenino , Humanos , Inmunoterapia , Masculino , Persona de Mediana Edad , Neoplasias/terapiaRESUMEN
We have performed a comparative evaluation of systemic (i.v.) and intraarterial (i.a.) cisplatin by using a trace dose of the radiolabeled form of this drug [( 195mPt]cisplatin) to monitor the drug's biodistribution by dynamic scintigraphic imaging. We have analyzed the drug's metabolism using a compartmental model both following i.a. and i.v. administration in patients with gliomas. Significantly larger amounts of radioactivity (up to 10 times higher than in the uninvolved brain) were measured in tumors following i.a. administration, whereas the differential localization following i.v. drug administration was, at best, only twofold that of the uninvolved brain. On the other hand, no significant differences could be detected in the pharmacokinetics of either free cisplatin or platinated proteins in blood. The washout slope in tumors following i.a. administration may be an indicator of the higher local concentration of free cisplatin; no such washout could be observed in tumors following i.v. administration. The present noninvasive methods may help document the amount and the rate of (active) drug deposition at the desired target site. They may also assist in monitoring, prospectively and/or, on line, the probable effect of chemotherapy in an individual patient. In turn it may lead to novel methods for optimizing chemotherapeutic effectiveness at specific tumor-bearing sites and in defined treatment protocols.
Asunto(s)
Cisplatino/farmacocinética , Neoplasias/metabolismo , Platino (Metal) , Radioisótopos , Cisplatino/administración & dosificación , Femenino , Humanos , Inyecciones Intraarteriales , Masculino , Modelos Biológicos , Monitoreo Fisiológico , Neoplasias/tratamiento farmacológico , Distribución TisularRESUMEN
We have studied the effects of low-dose recombinant interleukin-2 preceded by low-dose cyclophosphamide on malignant melanoma. Thirty eight outpatients aged from 25 to 75 years were treated with interleukin-2, 3.6 million Cetus units/m2 i.v. daily for five days on two successive weeks beginning three days after 350 mg/m2 of intravenous cyclophosphamide. This schedule was repeated at least twice more with a one-week interval between cycles, usually at the same dosage level. Ten of the 38 patients (26.3%) had clinically significant remissions: two complete (5.3%), seven partial (18.4%), and one ongoing, long-term (greater than 18 mo) "minor" response (2.6%). Four others (10.5%) had shorter minor responses and four (10.5%) a mixed response. One patient with disease restricted to the skin had a complete remission, while the other patient with a complete remission had had three lung nodules and an enlarged hilar lymph node. It was gratifying that one of the major sites of disease responding to treatment was the liver. Two complete and two partial remissions (i.e., greater than 50% regressions for greater than four weeks at this site) were obtained in 10 patients with liver involvement. Lung metastases also responded in four of 16 patients (one complete and three partial remissions). Subcutaneous nodules responded in seven of 21 patients (two complete, five partial remissions), while lymph node metastases diminished significantly in four of 14 patients (one complete, three partial remissions). The median duration of response was nine months (range, 1.5-20 months), with four patients treated for more than one year. Toxicity was moderate and controllable, and only two patients required hospitalization, both overnight. Lymphokine activated killer cell activation was induced in 24 of 38 patients, including all nine of the major responders. Conversely, none of 14 patients without lymphokine activated killer cell activation had a significant clinical remission. This regimen appeared to be as effective in melanoma as those involving ex vivo activation of lymphokine activated killer cells, and was more tolerable than therapy with high doses of interleukin-2.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Indometacina/farmacología , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Células Asesinas Naturales/inmunología , Activación de Linfocitos/efectos de los fármacos , Masculino , Melanoma/inmunología , Persona de Mediana Edad , Monitorización Inmunológica , Neoplasias/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunologíaRESUMEN
A Phase I trial of active specific immunotherapy for melanoma was performed to measure the toxicity and immunological effects of the therapy. A mixture of mechanical lysates (homogenates) of two melanoma cell lines was injected together with a novel adjuvant, DETOX, into 22 patients. Several types of cell-mediated and humoral immunity to melanoma-associated antigens were measured serially. In the 17 patients with measurable disease, the sizes of lesions were also noted serially. At least six patients per group were injected s.c. with either 100, 200, or 400 antigenic units (approximately 10, 20, and 40 million tumor cell-equivalents) of the lysates mixed with 0.25 ml of DETOX s.c. on weeks 1, 2, 3, 4, and 6. Three patients at each dose level also received 300 mg/m2 of cyclophosphamide i.v. 4 days before the start of immunization. Evidence for successful immunization was obtained in 13 of the 22 patients. An increase in the frequency of peripheral blood cytolytic lymphocyte precursors reacting against melanoma cells occurred in 12 patients, as measured by a limiting dilution assay involving in vitro re-exposure to irradiated melanoma cells for 9-10 days. Eight of the 12 patients had received cyclophosphamide. By cold-target competition assays, these cytolytic lymphocytes appeared to be atypical T-cells, which recognized melanoma-associated antigens on several allogeneic lines without apparent major histocompatibility complex restriction. An increase in antibody titers against melanoma-associated antigens, measured by enzyme immunoassay, was found in five of 22 patients, and a change in delayed hypersensitivity against the melanoma lysate, in three patients. Responses were found at all three dosage levels of lysate, without an obvious dose optimum. No toxicity except minor local soreness was noted. Therefore, no maximum tolerable dose was defined. Five of 17 patients with measurable lesions had a remission of their melanoma, two complete and three partial, with three additional minor responses. A patient whose complete remission lasted 5.5 months, has no evidence of disease 22+ months after entry onto the study, with the aid of surgical resection of small s.c. recurrences on two separate occasions. Sites of regression included s.c. nodules, lymph nodes, and pulmonary nodules, with no responses in liver, adrenal gland, or bone. The patients who had an increase in cytolytic lymphocyte precursors comprised all eight with a clinical remission (five major, three minor). In contrast, none of the seven patients lacking an increase in cytotoxic lymphocytes had a clinical response.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Inmunización Pasiva , Melanoma/terapia , Adulto , Evaluación de Medicamentos , Femenino , Humanos , Hipersensibilidad Tardía , Metástasis Linfática , Masculino , Melanoma/inmunología , Melanoma/patología , Persona de Mediana Edad , Linfocitos T Citotóxicos/análisis , Linfocitos T Citotóxicos/inmunologíaRESUMEN
We studied the effects on melanoma of low-dose recombinant interleukin-2 (IL-2) preceded by low-dose cyclophosphamide (CYC). Twenty-seven outpatients, aged 25 to 75 years, were treated with IL-2, 3.6 million U/m2 intravenously (IV), daily for five days on 2 successive weeks beginning three days after 350 mg/m2 of IV CYC. This schedule was repeated at least twice more at 1-week intervals. Six of 24 patients (25%) who received more than one 2-week cycle of treatment had a remission, one complete and five partial, with minor responses in eight others (33.3%). Three patients with rapidly progressive disease, who received only one cycle, were excluded from the analysis of response. The responses comprised remissions of liver metastases in two patients, one of them complete, two complete and two partial regressions of subcutaneous metastases, partial remission of lymph node metastases, and a partial remission of lung nodules. The mean duration of response exceeded 5 months, with two patients treated for greater than 1 year. Toxicity was moderate and controllable and only two patients required hospitalization, both overnight. Lymphokine-activated killer (LAK) cell activation was induced in 17 of the 24 patients, including all six responders, while none of seven patients without LAK activation had a remission. This regimen appeared to be as effective in melanoma as those involving ex vivo activation of LAK cells, and was generally tolerable to patients in all age groups.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Interleucina-2/administración & dosificación , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Eosinofilia/etiología , Femenino , Humanos , Interleucina-2/farmacocinética , Células Asesinas Naturales/inmunología , Masculino , Melanoma/inmunología , Persona de Mediana Edad , Neoplasias Cutáneas/inmunología , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
Ninety-seven patients with recurrent or metastatic renal cell carcinoma were randomized to receive recombinant interferon (IFN) alfa-2b (Intron A; Schering-Plough, Kenilworth, NJ) by either the subcutaneous (SC) or intravenous (IV) route. The SC dosage was 2 X 10(6) IU/m2 three times weekly, and the IV dose 30 X 10(6) IU/m2 for five consecutive days every 3 weeks. Dose escalation to a maximum of 10 X 10(6) IU/m2 SC and 50 X 10(6) IU/m2 IV was allowed for patients with minimal or absent toxicity. Five of 51 of the SC-treated patients (10%) and three of 46 of the IV-treated patients (7%) had a partial response (PR) or complete response (CR). Patients with prior nephrectomy, no prior treatment, and lack of bone metastases were most likely to respond, and a retrospective analysis of this subgroup revealed a 23% response rate. Achievement of response took from 3 weeks to 11 months, while response duration lasted from 3 to 31+ months. All responders had prior nephrectomy; six of eight had no prior chemotherapy or hormonal therapy; five had lung metastases, and none had bone metastases. Regardless of route, almost all patients developed a flu-like syndrome; however, grade 3 or greater toxicity was much more common for IV-treated patients. This trial demonstrates modest, but definite antitumor activity for recombinant interferon in advanced renal cell carcinoma. SC administration with lower dose and toxicity is as effective as treatment administered IV.
Asunto(s)
Carcinoma de Células Renales/terapia , Interferón Tipo I/uso terapéutico , Neoplasias Renales/terapia , Adulto , Anciano , Ensayos Clínicos como Asunto , Femenino , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Interferón Tipo I/administración & dosificación , Masculino , Persona de Mediana Edad , Distribución Aleatoria , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Factores de TiempoRESUMEN
Twelve patients with advanced malignant disease were entered onto a Phase I study of escalating doses of beta-interferon serine given by 4-h i.v. infusion twice a wk. Three patients each were entered at starting doses of 0.01, 1, 10, and 30 million units (MU)/m2. Doses escalation within individual patients was allowed to a maximum dose of 400 MU/m2. Fever, chills, fatigue, and acral cyanosis were commonly seen and increased in frequency at higher doses. Myalgia, nausea, diarrhea, headache, and confusion were seen at lesser frequencies. Mild leukopenia, paresthesia, infusion site erythema, and hypotension were each seen in one patient. No conventional maximal tolerated dose could be defined, since several patients underwent escalation to the highest allowable dose and seemed to develop tolerance to acute toxicities. However, a maximal starting dose of 10 MU/m2 was identified, such that those begun at this level or below tolerated semiweekly dose escalation, while those begun at 30 MU/m2 could not tolerate continued therapy. Detectable serum interferon levels were noted during treatment at 10 and 30 MU/m2, the levels at which significant toxicity also first appeared. A maximal starting dose of 10 MU/m2, with gradual escalation as tolerance to side effects develops, is suggested if therapy with high-dose beta-interferon serine is given by 4-h infusion.
Asunto(s)
Interferón Tipo I/uso terapéutico , Interferón beta , Proteínas Recombinantes/uso terapéutico , Adulto , Evaluación de Medicamentos , Femenino , Humanos , Interferón Tipo I/administración & dosificación , Interferón Tipo I/toxicidad , Interferón beta-1a , Interferon beta-1b , Cinética , Masculino , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/toxicidad , Factores de TiempoRESUMEN
To analyze the humoral immune response to melanoma, human-mouse hybridomas were generated by the fusions of regional lymph node lymphocytes of patients with the mouse myeloma cell line M5. Six stable hybridomas were cloned from six separate lymphocyte parents obtained from three patients. Ascites were obtained from nude mice after i.p. injection with cultured hybridoma cells. The monoclonal antibodies, four immunoglobulin Gs and two pentameric immunoglobulin Ms, were partially purified to remove mouse immunoglobulin and then conjugated to biotin for immunocytochemical and immunohistochemical studies. With the avidin:biotin:peroxidase complex method to detect and amplify binding by the biotin-conjugated human monoclonal antibodies, we found the six antibodies to be reactive against cytoplasmic determinants in five short-term melanoma cultures and formalin-fixed paraffin-embedded melanoma tumors from four patients. The antigenic target of the antibodies identified was not carcinoembryonic antigen. Two antibodies, 2-139-1 and 6-26-3, were studied in more detail. Each stained 25 of 25 specimens of melanomas. Little or no reactivity was detected against fixed sections of normal skin, which included tissues such as epidermis, dermis, monocytes, lymphocytes, and vascular endothelium. More striking was the absence of binding to melanocytes in the basal layer of the skin or to pigmented nevus cells. Both antibodies showed cross-reactivity against other tumors, in particular colonic and prostatic carcinomas. In the normal colon, reactivity was restricted to the surface of the columnar epithelium; no reactivity was detected against normal prostatic epithelium. Reactivity was also not observed against liver and lung. However, the epithelia of the renal tubules, pancreatic ducts, and salivary ducts were all reactive. These human monoclonal antibodies identify cytoplasmic melanoma-associated tumor antigens that appear different from the membrane antigens defined by serological approaches and by most mouse monoclonal antibodies.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Antígenos de Neoplasias/inmunología , Melanoma/inmunología , Especificidad de Anticuerpos , Antígeno Carcinoembrionario/inmunología , Membrana Celular/inmunología , Citoplasma/inmunología , Humanos , Ganglios Linfáticos/inmunologíaRESUMEN
Human monoclonal antibodies were generated by fusing a nonsecretory variant of murine myeloma cells with lymphocytes obtained from the lymph nodes of patients with metastatic cutaneous malignant melanoma. Two human IgG monoclonal antibodies, designated 2-139-1 and 6-26-3, were extensively studied for their patterns of binding to cells in 64 specimens of formalin-fixed, paraffin-embedded tissue sections. These comprised: 23 cutaneous and 2 ocular melanomas; 4 specimens of lentigo maligna; 27 benign nevi; 2 basal and 2 squamous cell neoplasms of the skin; and 4 specimens of normal skin. A direct avidin-biotin-immunoperoxidase staining method was used. Under these conditions, the antibodies reacted with variable intensity to all 18 primary cutaneous malignant melanomas, 5 metastatic cutaneous melanomas, and both ocular melanomas. Antibody 2-139-1 reacted with 1 of 4 specimens and 6-26-3 with 3 of 4 specimens of lentigo maligna. Two of 5 dysplastic nevi reacted with both antibodies, each with a smaller proportion of cells than with melanomas. There was no reactivity with the 22 other nevi representing a spectrum of histologic types or with normal melanocytes. Basal cell and squamous cell carcinomas of the skin also were not stained. These human monoclonal antibodies appear to be useful in distinguishing malignant melanomas from benign nevi, with the exception of dysplastic nevi, and from basal and squamous cancers of the skin in routinely prepared tissue sections. They may also help to identify the cytoplasmic antigens that are immunogenic in humans.
Asunto(s)
Anticuerpos Monoclonales/inmunología , Melanoma/inmunología , Nevo Pigmentado/inmunología , Neoplasias Cutáneas/inmunología , Antígenos de Neoplasias , Diagnóstico Diferencial , Histocitoquímica , Humanos , Técnicas para Inmunoenzimas , Melanoma/diagnóstico , Antígenos Específicos del Melanoma , Proteínas de Neoplasias/análisis , Nevo Pigmentado/diagnóstico , Neoplasias Cutáneas/diagnósticoRESUMEN
Because two of five patients with renal cell carcinoma in a Phase I study had partial response to recombinant alpha-2 interferon (IFN), we treated 26 patients with advanced renal cell carcinoma with a 3-month regimen of IFN. Patients were randomized to receive IFN either subcutaneously (2 X 10(6) IU/m2 3 times a week) or intravenously (3 X 10(7) IU/m2 for 5 consecutive days every 2-3 weeks). Patients whose disease was responding or stable were treated further, while those with progressive disease on subcutaneous treatment were offered intravenous therapy. Sites of metastasis included lung (14 patients), bone (7 patients), soft tissue (7 patients) and liver (2 patients). Twenty patients were evaluable for response. One patient had a partial response at the end of the third course of intravenous IFN and subsequently had complete disappearance of a 12 X 7 cm subcutaneous mass after the seventh course of treatment. The disease was stable in 13 patients including two minor responses, and six patients had progressive disease (5 with subcutaneous treatment; 1 with intravenous treatment) including one mixed response. All patients experienced early flu-like symptoms of fever, chills, and rigors during the first few days of treatment and most had mild to moderate fatigue. Three patients left the study because of fatigue, and one had an urticarial rash. From these results and our previous experience, it appears that IFN has activity against renal cell carcinoma with acceptable toxicity.