RESUMEN
BACKGROUND: Stage IV hormone-sensitive breast cancer is often treated with aromatase inhibitors (anastrozole, letrozole, exemestane), which block the conversion of dehydroepiandrosterone (DHEA) to estrone and estradiol. This is intended to obviate the need for steroid replacement and antiquate adrenalectomy. METHODS: Patients who underwent oophorectomy and were being treated with new aromatase inhibitor therapy received serial measurements of serum estrone, estradiol, and DHEA-sulfate (DHEA-S). Steroid values during responsive and progressive phases of disease were compared. In vitro, human breast cancer cell lines T-47D (estrogen-receptor and progesterone-receptor positive) and HCC 1937 (estrogen-receptor and progesterone-receptor negative) were treated with DHEA-S. Proliferation rates were measured by colorimetric assay. RESULTS: Disease in 12 of the 19 patients progressed. DHEA-S was less than 89 microg/dL in patients during the responsive phase and more than or equal to 89 microg/dL during disease progression, with 1 exception (P < .0005). Estrone and estradiol remained suppressed. After disease progression, the condition of 9 patients stabilized with aminoglutethimide therapy (n = 8) or adrenalectomy (n = 1), and their DHEA-S levels were reduced to less than 89 microg/dL. In vitro, elevated DHEA-S induced cell proliferation in T-47D cells. CONCLUSIONS: DHEA-S levels more than or equal to 89 microg/dL predicted disease progression in states of low estrogen. Tissue culture results supported the role of DHEA-S as an estrogenic agent. Oophorectomies with either aminoglutethimide therapy or adrenalectomy were effective remedies for breast cancer progression due to high DHEA-S.
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Adrenalectomía , Aminoglutetimida/uso terapéutico , Inhibidores de la Aromatasa , Neoplasias de la Mama/terapia , Sulfato de Deshidroepiandrosterona/sangre , Inhibidores Enzimáticos/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , División Celular/efectos de los fármacos , Femenino , Humanos , Persona de Mediana Edad , Células Tumorales CultivadasRESUMEN
BACKGROUND: The exact role of lymphoscintigraphy (LS) in the evaluation of sentinel lymph nodes (SLNs) in melanoma is controversial. METHODS: We reviewed our experience with preoperative LS for the determination of the lymph node drainage pattern of clinically node negative primary melanomas, with attention to the rate of ambiguous drainage and the effect of previous wide local excision (WLE). RESULTS: The scans of 87 patients who underwent LS at our institution for evaluation of their primary melanomas from 1995 to the present were reviewed. Fourteen of the primary tumor sites were in the head and neck region, 41 were truncal, and 32 were in the extremities. The average tumor thickness was 2.6 mm. Nine of 14 (64%) head/neck lesions and 12 of 41 (29%) truncal lesions displayed ambiguous drainage, as compared with only 2 of 32 (6%) extremity lesions (P <0.05). Forty-one of the 87 patients (47%) had undergone previous WLE of their primary lesion prior to their LS. The number of draining basins for the WLE and the non-WLE groups were not significantly different, and at least one SLN was found for all WLE cases. CONCLUSIONS: Preoperative LS is important for the treatment planning of SLN biopsy for head/neck and truncal melanomas, but adds little additional information for extremity lesions. Lymph node drainage scans and subsequent SLN biopsies are not contraindicated in the presence of a prior WLE.
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Ganglios Linfáticos/diagnóstico por imagen , Metástasis Linfática/diagnóstico por imagen , Melanoma/patología , Neoplasias Cutáneas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Planificación de Atención al Paciente , Cuidados Preoperatorios , Cintigrafía , Estudios Retrospectivos , Biopsia del Ganglio Linfático CentinelaRESUMEN
Malignant melanoma is a neuroendocrine tumor that contains somatostatin receptors (SSTRs). Adjuvant therapy for melanoma is limited. Because melanomas arise from neural crest cells, we sought to evaluate the distribution of SSTR subtypes found in these tumors and their functional significance by imaging with 111In-pentetreotide scintigraphy (OctreoScan). Octreotide binds with greatest affinity to SSTR2 and SSTR5. Studying the expression of SSTRs in melanoma may demonstrate a potential role for octreotide in the treatment of melanoma. A series of 23 melanomas from 17 patients who underwent resection of regional or distant metastases were evaluated for the presence of SSTRs by the reverse transcriptase-polymerase chain reaction (RT-PCR) using primers specific for SSTR1 through SSTR5. Identity of RT-PCR products was confirmed by Southern blot analysis. Sixteen patients underwent preoperative OctreoScan. SSTR1 was expressed in 96% of tumors, SSTR2 in 83%, SSTR3 in 61%, SSTR4 in 57%, and SSTR5 in 9%. OctreoScan imaged 63% of tumors. There was no correlation between SSTR subtype expression and OctreoScan result. Most of the melanomas expressed mRNA for SSTR1 and SSTR2, with approximately half expressing SSTR3 and SSTR4. The SSTR mRNA for SSTR2 appears to be transcribed into functional protein that binds 111In-pentetreotide in more than half of these patients. Although OctreoScan has limited sensitivity for localizing melanomas, tumors that can be imaged by OctreoScan may be amenable to adjuvant therapy with octreotide or targeted therapy with high-energy radioisotope-labeled octreotide. These studies clearly define melanoma as a neuroendocrine tumor, which may open new avenues for tumor control.
Asunto(s)
Melanoma/metabolismo , Tumores Neuroendocrinos/metabolismo , Receptores de Somatostatina/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/uso terapéutico , Femenino , Humanos , Radioisótopos de Indio , Masculino , Melanoma/diagnóstico por imagen , Persona de Mediana Edad , Tumores Neuroendocrinos/diagnóstico por imagen , Octreótido/uso terapéutico , Cintigrafía , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Rates of response to systemic chemotherapy among patients with advanced colorectal carcinoma rarely exceed 25- 30%, and complete responses are rare. The liver is the most common site of metastasis; however, regional therapies have not improved survival rates. The Southwest Oncology Group designed a clinical trial combining hepatic arterial chemoembolization with systemic infusion of 5-fluorouracil chemotherapy in an attempt to increase the complete response rate and prolong the time to disease progression. METHODS: Patients with documented liver metastasis from colorectal carcinoma were treated with two or three cycles of chemoembolization using a collagen suspension with doxorubicin, mitomycin C, and cisplatin. Subsequently, systemic chemotherapy with continuous infusion of 5-fluorouracil and weekly leucovorin was initiated. Patients were assessed for response at 12-week intervals, with treatment continuing until disease progression. RESULTS: Thirty-one eligible, evaluable patients were treated. One complete and 8 partial responses were observed, for an overall response rate of 29%. Fifty-eight percent of patients survived 1 year, and the median survival for the whole cohort was 14 months. The median time to progression was 8 months. Seven patients (23%) experienced Grade 4 toxicity and 21 patients (67%) had Grade 3 toxicity. CONCLUSIONS: The response rate in this trial was comparable to that achieved with systemic chemotherapy consisting of a fluorinated pyrimidine-based regimen for patients with this disease. No improvement in complete response rate or time to progression was observed compared with the Southwest Oncology Group's experience with systemic therapy. The authors are not planning to study this regimen further as a treatment for patients with metastatic colorectal carcinoma.
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Quimioembolización Terapéutica , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Fluorouracilo/uso terapéutico , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/terapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Terapia Combinada , Doxorrubicina/administración & dosificación , Estudios de Factibilidad , Femenino , Fluorouracilo/administración & dosificación , Arteria Hepática , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Leucovorina/uso terapéutico , Neoplasias Hepáticas/irrigación sanguínea , Masculino , Persona de Mediana Edad , Mitomicina/administración & dosificación , Proyectos Piloto , Análisis de SupervivenciaRESUMEN
The therapeutic benefit of adding interferon alpha (IFNalpha) to established single-agent and combination chemotherapy regimens for the treatment of metastatic melanoma has not been proven. We designed the present study to estimate the response rate of IFNalpha, dacarbazine, cisplatin and tamoxifen in patients who had not been treated with systemic therapy for advanced disease. Using a schedule similar to that which had previously been shown to favor IFNalpha plus dacarbazine over dacarbazine alone, we treated patients with an "induction" regimen of IFNalpha, 15 mU m(-2) day(-1) intravenously 5 days/week for 3 weeks. Following induction, schedules of IFNalpha, 5 mU m(-2) day(-1) subcutaneously three times a week, and tamoxifen, 10 mg orally twice a day, were begun. Dacarbazine, 250 mg m(-2) day(-1) and cisplatin 33 mg m(-2) day(-1) for 3 consecutive days were repeated every 4 weeks, and subcutaneous IFNalpha and oral tamoxifen were continued until the discontinuation of chemotherapy. We treated 25 patients (18 men and 7 women, median age 52 years) and observed only 1 objective response (response rate 4%, 95% confidence interval 0.1%-20%). The toxicities of the regimen consisted of moderate myelosuppression and constitutional side-effects. On the basis of the low antitumor activity of this regimen, we do not recommend it for further study or for use as standard therapy of metastatic melanoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/secundario , Adolescente , Adulto , Anciano , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Dacarbazina/administración & dosificación , Esquema de Medicación , Femenino , Humanos , Interferón-alfa/administración & dosificación , Masculino , Persona de Mediana Edad , Sudoeste de Estados Unidos , Tamoxifeno/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Interferon alfa has modest but definite activity in the treatment of metastatic melanoma and is the only agent currently available for adjuvant therapy of high-risk resected disease. A variety of retinoic acid derivatives have been shown to be synergistic with interferon alfa in vitro and in vivo, with nonoverlapping toxicities. If promising combinations of interferon alfa and retinoids could be developed for melanoma patients, they would have clinical relevance for the treatment of advanced as well as localized disease. PURPOSE: To determine the efficacy and toxicity of a combination of interferon alfa-2a and all-trans-retinoic acid in patients with measurable metastatic melanoma, the South-west Oncology Group conducted a phase II clinical trial. PATIENTS AND METHODS: Fifty-seven patients with measurable metastatic melanoma (American Joint Committee on Cancer stage IV) were entered; five patients were unevaluable. Treatment consisted of oral all-trans-retinoic acid (37.5 to 75 mg/m2 orally twice daily for 21 days followed by 7 days' rest) plus subcutaneously administered interferon alfa-2a (6 MU/m2 three times a week). RESULTS: Two complete and three partial responses were observed among 52 evaluable patients, for an objective response rate of 10% (95% confidence interval 3% to 21%). Responses were seen only in patients with pulmonary, nodal, or subcutaneous metastases, and lasted from 4 to 23+ months. Median survival for the 52 patients was 8 months. Side effects were tolerable but significant, with one case of grade IV anemia and 92% of patients experiencing at least grade II toxicity. Flu-like symptoms were the most commonly reported side effects. There was one case of grade III hyperlipidemia. CONCLUSION: The combination of recombinant human interferon alfa-2a with all-trans-retinoic acid did not result in a greater percentage of objective responses or a longer overall survival than that associated with interferon alfa alone. This combination cannot be recommended for further evaluation in melanoma in either the advanced disease or the adjuvant settings.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Interferón-alfa/efectos adversos , Masculino , Melanoma/patología , Melanoma/secundario , Persona de Mediana Edad , Estadificación de Neoplasias , Proteínas Recombinantes , Tretinoina/administración & dosificación , Tretinoina/efectos adversosRESUMEN
BACKGROUND: Patients with hepatic metastases often develop obstruction of the intrahepatic inferior vena cava (IVC), known as IVC syndrome. This obstruction is debilitating due to the development of ascites and anasarca. OBJECTIVES: To update our experience in the diagnosis and treatment of IVC syndrome and to evaluate the efficacy of expandable stents in the treatment of IVC syndrome. DESIGN: Retrospective review. SETTING: University hospital. PATIENTS: Twenty-eight patients with hepatic metastases diagnosed as having IVC syndrome. INTERVENTION: Patients underwent transfemoral placement of Gianturco-Rosch self-expandable Z metallic stents in the intrahepatic IVC. One patient was treated with a Wallstent. Stents were 15 to 25 mm in diameter and 60 to 140 mm in length. Pressure gradients across the IVC were measured before and after stent placement in all patients. MAIN OUTCOME MEASURES: Change in pressure gradient, relief of ascites and anasarca, loss of weight, patency of the primary stent, and survival after stent placement. RESULTS: Pressure gradients were reduced in all patients, which was followed by rapid reduction of ascites and anasarca with a median weight loss of 5.85 kg. Survival after stent placement varied from 1 to 99 days, with a mean of 34 days. Stent patency remained until death in all patients. CONCLUSION: The debilitation of IVC syndrome due to ascites and anasarca can be considerably palliated by placement of transfemoral percutaneous stents.
Asunto(s)
Células Neoplásicas Circulantes , Stents , Vena Cava Inferior/cirugía , Anciano , Anciano de 80 o más Años , Ascitis/etiología , Ascitis/cirugía , Femenino , Humanos , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Presión , Estudios Retrospectivos , Síndrome , Enfermedades Vasculares/etiología , Enfermedades Vasculares/cirugíaRESUMEN
PURPOSE: A phase II study was conducted by the Southwest Oncology Group (SWOG) to assess the efficacy and toxicity of concurrent carboplatin, etoposide, and thoracic radiation (XRT) in a defined population of poor-risk patients with stage III non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage III NSCLC were eligible if they were excluded from cisplatin-based protocols because of poor pulmonary or renal function, history of congestive heart failure, hearing loss, peripheral neuropathy, or weight loss. Carboplatin 200 mg/m2 daily intravenously days 1, 3, 29, and 31 and etoposide 50 mg/m2 daily intravenously days 1 through 4 and 29 through 32 were administered. Beginning day 1, XRT was delivered at 1.8 to 2.0 Gy daily to a total dose of 61 Gy. RESULTS: Within a period of 1 year, 63 patients were registered and 60 were eligible. Patient characteristics were age 47 to 79 years, performance status 0 to 1 (82%) and 2 (18%), and stages IIIA (60%) and IIIB (40%) NSCLC. The most common grades 3 and 4 toxicities included leukopenia (50%), thrombocytopenia (23%), and esophagitis (15%). There were no treatment-related deaths. The overall confirmed response rate was 29%, and median overall survival was 13 months (95% confidence interval, 11 to 14 months). The 2-year survival rate was 21%. CONCLUSION: This chemoradiotherapy regimen is well tolerated in poor-risk patients and yields a median survival similar to that of good-risk patients who received cisplatin-based chemoradiotherapy. This chemoradiotherapy regimen will be compared with XRT alone in poor-risk patients with stage III NSCLC in a randomized phase III trial.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Anciano , Carboplatino/administración & dosificación , Terapia Combinada , Etopósido/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
BACKGROUND: The survival of patients with metastatic melanoma is poor. The response rates for chemotherapy and immunotherapy have been low, with no real improvement in survival. We reviewed the results of surgical resection. METHODS: We performed a retrospective review of the medical records of all patients who underwent resection of metastases from melanoma from 1979 to 1994. RESULTS: There were 77 patients (44 men, 33 women, mean age 51 years). Metastases were resected from soft tissue (n = 28), abdominal viscera (n = 22), lung (n = 15), and brain (n = 12). Forty-four patients had complete resections, and 33 had incomplete resections. Sixty-five patients had solitary lesions and 12 had multiple lesions resected. The overall 5-year survival rate was 10%. Patients with solitary lesions had a 5-year survival rate of 12%, compared with 0% for patients with multiple lesions (P = 0.01). Patients with complete resection had a 5-year survival rate of 15%, compared with 4% for patients with incomplete resection (P < 0.001). Patients with complete resection of solitary lesions had a 5-year survival of 18%. There was no difference in survival between synchronous and metachronous resection. Gender, primary site, disease-free interval, and metastatic site had no impact on survival rates. CONCLUSIONS: We conclude that patients with metastatic melanoma should be resected for (1) relief of symptoms such as obstruction and bleeding, (2) solitary lesions that can be completely resected, (3) serial lesions that can be completely resected, and (4) selected cases that can be rendered macroscopically free of disease. Surgical resection is superior to any other available therapy for metastatic melanoma.
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Melanoma/cirugía , Neoplasias Cutáneas/cirugía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/cirugía , Oregon/epidemiología , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Tasa de Supervivencia , Factores de TiempoRESUMEN
PURPOSE: The combination of carmustine (BCNU), dacarbazine (DTIC), cisplatin (DDP), and tamoxifen (Tam) has been reported in small series to provide a response rate of 50%, but with significant myelosuppression and risk of thromboembolic complications. We performed this phase II study to assess the antitumor activity and important toxicities of this combination in the cooperative group setting. PATIENTS AND METHODS: Seventy-nine eligible patients were treated with BCNU 150 mg/m2/d, every 6 weeks, DTIC 220 mg/m2/d on days 1 to 3 every 3 weeks, DDP 25 mg/m2/d on days 1 to 3 every 3 weeks, and Tam 20 mg orally daily throughout treatment. Treatment cycles were repeated every 6 weeks in responding or stable patients for a maximum duration of 1 year. RESULTS: Twelve objective responses were achieved (response rate 15%, 95% confidence interval 8%-25%). Five responses were complete (CR) and seven were partial (PR). The median response duration was 8+ (range, 4-19+) months, (16+ [4-19+] for CR and 8+ [4-11] for PR), and the median survival of the entire group was 9 months. The toxicities were predominantly neutropenia and thrombocytopenia. Four patients developed thromboembolic events. Two patients died while on protocol therapy, one with complications of neutropenia, and the other with disease progression. CONCLUSION: The activity of this regimen is in the range reported for single agents or DTIC plus DDP, and the addition of BCNU and Tam appears to increase toxicity. We do not recommend this combination for routine treatment of advanced melanoma or as the control arm in randomized studies of combination therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Dacarbazina/administración & dosificación , Dacarbazina/efectos adversos , Femenino , Humanos , Masculino , Melanoma/secundario , Persona de Mediana Edad , Neoplasias Cutáneas/patología , Tamoxifeno/efectos adversos , Tamoxifeno/análisisRESUMEN
BACKGROUND: Tamoxifen is considered an antiestrogen against breast cancer, yet it has known estrogenic side effects. We hypothesized that long-term administration of tamoxifen may significantly increase circulating estrogen levels in women with breast cancer. METHODS: Serum dehydroepiandrosterone (DHEA), estrone (E1), and estradiol (E2) levels were prospectively measured in 47 breast cancer patients before and during tamoxifen therapy for 2 years. Differences in baseline and peak hormone levels during treatment were compared, and significance was determined by paired Student's t test. RESULTS: Mean DHEA levels increased by 133% from 61 mg/L to 142 mg/L (P <0.001) and mean E2 levels increased by 239% from 28 pg/mL to 95 pg/mL (P <0.05). Mean E1 levels increased by 264% from 42 pg/mL to 153 pg/mL (P = 0.06). CONCLUSIONS: Long-term tamoxifen therapy can be associated with increased serum levels of DHEA, E1, and E2. Elevated serum estrogens may explain tamoxifen's estrogenic effects and may represent a mechanism for the development of drug resistance.
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Neoplasias de la Mama/tratamiento farmacológico , Estrógenos/sangre , Tamoxifeno/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/sangre , Deshidroepiandrosterona/sangre , Estradiol/sangre , Estrona/sangre , Femenino , Humanos , Menopausia/sangre , Persona de Mediana Edad , Estudios Prospectivos , Tamoxifeno/sangreRESUMEN
On the basis that melanomas are of neural crest origin and might contain somatostatin receptors, the authors utilized 111In Pentetreotide (OctreoScan) to image 16 melanoma patients with known sites of disease. Twelve of 16 patients were positive with 38 percent imaging all sites. No lesion less than 1.5 cm imaged nor did one ocular and one amelanotic melanoma. Of the five described somatostatin receptors, OctreoScan binds only 2 and 5 suggesting that not all melanomas contain those receptors. It is concluded that melanomas contain somatostatin receptors and that this property might be used for imaging, tumor suppression with Octreotide, and/or as a target for Octreotide labelled with therapeutic agents such as immune complexes, chemotherapeutic agents or high energy radioisotopes.
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Melanoma/diagnóstico por imagen , Receptores de Somatostatina/análisis , Somatostatina/análogos & derivados , Humanos , Radioisótopos de Indio , Melanoma/metabolismo , Melanoma/patología , Cintigrafía , Receptores de Somatostatina/metabolismoRESUMEN
OBJECTIVE: The objective of this study was to analyze the effect of dimethylsulfoxide (DMSO) on skin flap viability. BACKGROUND: Dimethylsulfoxide has been shown to decrease necrosis of random skin flaps in the rat model, but no human studies have been performed. The authors performed a randomized, prospective study on the effect of DMSO on skin flap viability in patients undergoing mastectomy and inguinal lymphadenectomy. METHODS: Twenty-four patients had topical 60% DMSO applied to their flaps every 4 hours x 10 days after operation and 27 patients had operation alone. The maximum area of flap ischemia was traced by a masked observer and measured by cut and weigh technique. Significance of differences between the treatment and control group was determined by Student's test. RESULTS: The mean area of ischemia for the DMSO group was 16.33 U versus 44.93 U for the control group. This difference was statistically significant (p = 0.01). CONCLUSIONS: The authors conclude that topical application of DMSO reduces skin flap ischemia in humans and recommend its use after operation in which skin flaps are created.
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Dimetilsulfóxido/administración & dosificación , Supervivencia de Injerto/efectos de los fármacos , Colgajos Quirúrgicos , Administración Tópica , Dimetilsulfóxido/efectos adversos , Ingle/cirugía , Humanos , Isquemia/etiología , Isquemia/prevención & control , Escisión del Ganglio Linfático , Mastectomía , Persona de Mediana Edad , Complicaciones Posoperatorias/prevención & control , Piel/irrigación sanguíneaRESUMEN
Based on the reports of substantial improvement in the response rate w ith the addition of tamoxifen to a multiagent chemotherapy regimen for metastatic melanoma, Southwest Oncology Group (SWOG)-8921 was initiated. A prior regimen (SWOG-8804) of dacarbazine (DTIC) 750 mg/m(2) i.v. day 1 and cisplatin 100 mg/m(2) day 1 repeated every 3 weeks produced a 13% response rate in patients with metastatic melanoma without brain metastasis. SWOG-8921 using identical chemotherapy and schedule added tamoxifen 10 mg twice daily. There were 55 eligible patients registered, median age 52, with 37 men and 18 women. Fifty (91%) patients had evidence of visceral metastasis at registration. There were 10 responders (2 complete and 8 partial responses) for an 18% response rate (95% CI, 9-31%). The response rate in women was 28% (95% CI, 10-53%; in men, 14% (95% CI, 5-29%). Tamoxifen has produced a small increase in the response rate when added to the present combination and schedule of chemotherapy. Further Phase III trials will be necessary to assess whether there is a statistical advantage to the use of tamoxifen when combined with chemotherapy and whether there are statistical differences between men and women.
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Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cisplatino/administración & dosificación , Dacarbazina/administración & dosificación , Antagonistas de Estrógenos/administración & dosificación , Melanoma/tratamiento farmacológico , Melanoma/secundario , Tamoxifeno/administración & dosificación , Adulto , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/efectos adversos , Dacarbazina/efectos adversos , Esquema de Medicación , Antagonistas de Estrógenos/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Factores Sexuales , Tamoxifeno/efectos adversosRESUMEN
Previous data in rat conductance vessels indicated that cellular mevalonate contributes to vascular tone and systemic blood pressure control. Using exogenous mevalonate (M) or lovastatin, a 3-hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitor (L), we characterized the role of mevalonate availability in resistance artery function, both in experimental animals and humans. Rat mesenteric artery resistance vessels (MARV, n = 9) were incubated for 48 h with either L, M, L + M, or vehicle (V) and tested for reactivity to NE, serotonin, acetylcholine, atrial natriuretic peptide, and sodium nitroprusside (SNP). Lovastatin increased sensitivity to NE (P < 0.03) and serotonin (P < 0.003), and significantly impaired the response to all three vasodilators. These effects were reversed by co-incubation with mevalonate. Mevalonate alone had no effect. In separate experiments, intravascular free Ca2+ concentration (ivfCa2+) was determined in fura-2AM loaded MARV. Basal ivfCa2+ was increased after a 48-h exposure to L (52.7 +/- 4.6 nM, L, vs. 29.7 +/- 2.4 nM, V, n = 12, P < 0.003), as were ivfCa2+ levels following stimulation with low (100 nM) NE concentrations. Similar ivfCa2+ concentrations were achieved during maximum contraction with NE (10 mM) in both groups. Human resistance arteries of human adipose tissue were also studied. Lovastatin increased the sensitivity to NE (ED50 = 372 +/- 56 nM, V, and 99 +/- 33 nM, L, P < 0.001) and significantly decreased the relaxation to acetylcholine and SNP of human vessels. We conclude that mevalonate availability directly contribute to resistance vessel function and vascular signal transduction systems in both experimental animals and humans. The study calls for the identification of non-sterol, mevalonate-derived vasoactive metabolites, and suggests that disorders of the mevalonate pathway can alter vascular tone and cause hypertension.
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Vasos Sanguíneos/efectos de los fármacos , Ácido Mevalónico/farmacología , Adulto , Anciano , Animales , Vasos Sanguíneos/fisiología , Calcio/metabolismo , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Lovastatina/farmacología , Masculino , Arterias Mesentéricas/efectos de los fármacos , Persona de Mediana Edad , Ratas , Ratas Wistar , Vasoconstricción/efectos de los fármacosRESUMEN
BACKGROUND: Overall survival and quality of life in patients with metastatic carcinoid tumors depend on control of tumor growth and suppression of amine-induced symptoms. METHODS: We report on a series of 10 patients with carcinoid tumors metastatic to the liver who were treated with long-term octreotide acetate therapy (100 to 500 micrograms three times a day), sequential intra-arterial 5-fluorouracil (5-FU) infusions, and hepatic tumor chemoembolization. RESULTS: All 10 patients remained asymptomatic or had extremely mild symptoms after combined modality therapy (mean follow-up duration of 51.5 months). Sixty percent of the patients had a > 50% reduction of their tumor size (mean duration 42 months). An additional 30% experienced stabilization of tumor growth for 6 months or longer. Five of the 10 patients are currently alive. The mean group survival is 58 months since diagnosis (range 33 to 115) and 40 months since starting therapy (range 12 to 65). CONCLUSIONS: Combining octreotide acetate, intra-arterial 5-FU, and tumor chemoembolization effectively retards tumor growth while providing excellent symptom control.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Tumor Carcinoide/terapia , Quimioembolización Terapéutica/métodos , Fluorouracilo/administración & dosificación , Neoplasias del Íleon/terapia , Neoplasias Hepáticas/terapia , Octreótido/administración & dosificación , Anciano , Tumor Carcinoide/diagnóstico por imagen , Tumor Carcinoide/mortalidad , Tumor Carcinoide/secundario , Quimioembolización Terapéutica/efectos adversos , Terapia Combinada , Femenino , Estudios de Seguimiento , Arteria Hepática , Humanos , Neoplasias del Íleon/diagnóstico por imagen , Neoplasias del Íleon/mortalidad , Neoplasias del Íleon/patología , Infusiones Intraarteriales , Inyecciones Subcutáneas , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Inducción de Remisión , Tasa de Supervivencia , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
We hypothesized that megestrol acetate (MA) may work on breast carcinoma by inducing changes in serum sex steroid levels. We prospectively measured levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), dehydroepiandrosterone (DHEA), estrone (E1), and estradiol (E2) in 18 postmenopausal women before and during megestrol acetate therapy. MA significantly suppressed serum FSH, LH, DHEA and E1 levels. However, this was accompanied by a marked increase in serum E2 levels as measured by radioimmunoassay performed on whole serum. MA did not cross-react with the anti-E2 antibodies used in the assay. Elevated E2 levels also occurred in oophorectomized and/or adrenalectomized patients indicating the ovary and adrenal are not the source of the elevated E2 levels. We conclude that MA may be metabolized to oestrogenic compounds that crossreact with antibodies to E2, explaining the elevated E2 levels observed. The effects of these oestrogenic metabolites on breast carcinoma are unknown.
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Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Hormonas/sangre , Megestrol/análogos & derivados , Adrenalectomía , Anciano , Anticuerpos/análisis , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Reacciones Cruzadas , Deshidroepiandrosterona/sangre , Estradiol/sangre , Estradiol/inmunología , Estrona/sangre , Femenino , Hormona Folículo Estimulante/sangre , Humanos , Hormona Luteinizante/sangre , Megestrol/farmacología , Megestrol/uso terapéutico , Acetato de Megestrol , Persona de Mediana Edad , Estadificación de Neoplasias , Ovariectomía , Posmenopausia , Estudios Prospectivos , RadioinmunoensayoRESUMEN
PURPOSE: A national cooperative group trial was conducted in patients with early-stage cutaneous malignant melanoma to determine if oral vitamin A can increase disease-free survival or survival. PATIENTS AND METHODS: Two hundred forty-eight patients with completely resected melanoma of Breslow's thickness greater than 0.75 mm and clinically negative lymph nodes were randomized to oral vitamin A (100,000 IU/d) for 18 months or to observation. Patients were stratified by Breslow's thickness of primary lesion (0.76 to 1.50 mm, 1.51 to 3.00 mm, or > 3.00 mm), sex, and type of therapy (excision, excision plus node dissection, excision plus perfusion, or excision plus both). The median duration of follow-up observation of living patients is greater than 8 years. The relative risk (RR) in disease-free survival and overall survival in the treatment compared with the observation group was calculated using Cox proportional hazards models. RESULTS: Overall, there was no difference in disease-free survival or overall survival between the two groups. Examination of treatment by stratification interactions and subset analysis did not show any treatment-effect differences based on sex or type of therapy. There was also no difference between groups in disease-free survival based on Breslow's thickness of the primary lesion. Overall, 12% of patients who received vitamin A experienced grade 3 or 4 toxicities. CONCLUSION: Based on the lack of overall survival benefit, further evaluation of vitamin A as adjuvant therapy for melanoma does not appear warranted.
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Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Vitamina A/uso terapéutico , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Terapia Combinada , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melanoma/mortalidad , Melanoma/cirugía , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de Riesgo , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/cirugía , Tasa de Supervivencia , Estados Unidos , Vitamina A/administración & dosificación , Vitamina A/efectos adversosRESUMEN
Controversy still exists regarding the features and prognosis of colorectal cancer in young patients. We reviewed the records of 62 patients 40 years of age and younger with adenocarcinoma of the colon and rectum, treated and followed at our institution between 1968 and 1991. These patients represented 3.1 per cent of our total colorectal patient population during that time period. Their mean age was 34.5 years old, with the youngest patient being 18 years of age. Modified Dukes stages at presentation were 8 per cent A, 20 per cent B, 23 per cent C, and 48 per cent D. Underlying inflammatory bowel disease was present in 21 per cent of patients and was proportionately distributed between high (C and D) and low (A and B) stages. Half of the stage D patients had high grade lesions, compared with only 20 per cent of lower stage patients (P = 0.037). All but two patients had operative exploration; 36 (60%) had complete resection of all gross disease. With a mean follow-up of 98.2 months, the 5-year overall survival for stage A disease was 100 per cent, but dropped to 85, 40, and 7 per cent for stages B, C and D, respectively. Compared to published figures for the general population, younger patients with colon and rectal cancer tend to present at a more advanced stage, but have similar stage-related survival.
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Adenocarcinoma/epidemiología , Neoplasias del Colon/epidemiología , Neoplasias del Recto/epidemiología , Adenocarcinoma/patología , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Adenocarcinoma Mucinoso/epidemiología , Adenocarcinoma Mucinoso/patología , Adolescente , Adulto , Factores de Edad , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Femenino , Estudios de Seguimiento , Hemorragia Gastrointestinal/epidemiología , Humanos , Enfermedades Inflamatorias del Intestino/epidemiología , Masculino , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Oregon/epidemiología , Dolor , Pronóstico , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Factores de Riesgo , Tasa de Supervivencia , Pérdida de PesoRESUMEN
BACKGROUND: We analyzed prospectively collected data on 145 cis-platin hyperthermic isolation limb perfusion (HILPs) for melanoma and soft-tissue sarcoma to determine the pharmacokinetics and maximum tolerable dose of cis-platin. There were 70 melanoma and 75 sarcoma patients. Dosages ranged from 26 to 265 mg/m2. Perfusate and systemic cis-platin levels were measured in patients perfused at doses of 190-200 mg/m2. Tissue levels were measured in patients perfused at 123-209 mg/m2. METHODS: Cis-platin HILP was well tolerated up to doses of 250 mg/m2 for lower extremities. Higher doses produced toxicities of rhabdomyolysis, myoglobinuria, hyponatremia, and neuropathy. Systemic levels of cis-platin were equivalent to those of routine intravenous administration, while perfusate levels were 33 times higher. Tissue levels of cis-platin were five to six times higher than effective intravenous levels. RESULTS: Six melanoma patients have developed local recurrences. All were perfused at doses < 120 mg/m2. However, regional nodal recurrences have occurred in six other patients perfused at doses < or = 200 mg/m2. Four sarcomas have recurred locally, but three of them were present at the time of perfusion. CONCLUSIONS: We conclude that 250 mg/m2 is the maximum tolerable dose of cis-platin for lower-extremity HILPs. Neoadjuvant cis-platin HILP may improve local control rates for sarcomas. However, no tolerable dose of cis-platin provides control of nodal metastases from melanoma.