RESUMEN
AIM: To evaluate the expression and prognostic value of the epidermal growth factor receptor HER3 in patients with primary colorectal cancer (CRC) and corresponding lymph node metastases. PATIENT AND METHODS: HER3 expression was analysed immunohistochemically (IHC) in primary tumours and in corresponding lymph node metastases from 236 patients with stage II and III CRC. In 58 primary tumours, fluorescence in situ hybridisation (FISH) detection was performed. RESULTS: HER3 was detected at high frequency in the cell membrane. Seventy percent of the primary tumours had a high HER3 expression compared to 75% in the lymph node metastases. HER3 expression in the primary tumour was an independent prognostic factor for overall survival in the entire group of patients (p=0.026) and in the subgroup of patients with colon cancer stage II (p=0.030). A high HER3 expression in the primary tumour was associated with worse clinical outcome. The expression of HER3 was homogenous within the primary tumour (r=0.9, p<0.0001) and correlated with the HER3 expression in corresponding lymph node metastases (r=0.6, p<0.0001). No gene amplification with respect to HER3 was seen in primary tumours using FISH analysis. CONCLUSION: A high HER3 expression was found in 70% of the primary CRC tumours and in 75% of the corresponding lymph node metastases. HER3 expression in the tumour was an independent prognostic factor, where a high HER3 expression was associated with worse clinical outcome. There was a correlation in HER3 expression between primary tumour and corresponding lymph node metastases.
Asunto(s)
Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/patología , Receptor ErbB-3/biosíntesis , Anciano , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Ganglios Linfáticos/enzimología , Ganglios Linfáticos/patología , Metástasis Linfática , Masculino , Pronóstico , Receptor ErbB-3/genética , Análisis de SupervivenciaRESUMEN
AIM: To investigate thymidylate synthase (TS) expression in primary colorectal cancer (CRC) as a prognostic and predictive marker of benefit for adjuvant chemotherapy. PATIENTS AND METHODS: TS expression was immuno0-histochemically (IHC) assessed on tumors from 1,389 patients with stage II and III CRC randomly assigned to either surgery alone or surgery plus 5-fluorouracil (5-FU)-based adjuvant chemotherapy. RESULTS: In the subgroup treated with surgery alone (n=708), TS expression was prognostic using the classification of TS 0-1 versus 2-3 (p=0.045) as well as TS classified as 0-2 versus 3 (p=0.002). A high TS expression was associated with a shorter overall survival. Among patients with TS grade 3 (n=460), the subgroup treated with adjuvant chemotherapy had a significant longer OS (p=0.005). CONCLUSION: In this study TS, immunohistochemically assessed, is a prognostic factor in CRC patients treated with surgery alone. Patients with the highest level of TS expression (grade 3) had an improved clinical outcome following adjuvant 5-FU-based chemotherapy.
Asunto(s)
Neoplasias Colorrectales/enzimología , Timidilato Sintasa/metabolismo , Adulto , Anciano , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Cytokines may enhance the effect of therapeutic monoclonal antibodies (mAb). Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) have been shown to increase ADCC levels. GM-CSF may augment the induction of an idiotypic network response (anti-tumour immunity). The clinical anti-tumour effect of a combination of mouse mAb17-1A-1A [anti-colorectal carcinoma (CRC)], and GM-CSF was, however, not enhanced by the addition of IL-2. In the present study, some immune functions considered to be involved in mAb-mediated tumour cell killing were analysed in patients receiving GM-CSF and GM-CSF/IL-2 respectively together with the mAb17-1A-1A. Ten patients received mAb17-1A and GM-CSF, and ten patients mAb17-1A with GM-CSF and IL-2. During a 10- day cytokine treatment period, a significantly higher increase in white blood cell counts was noted in the GM-CSF/IL-2 treatment group as compared to GM-CSF-treated patients. In the GM-CSF/IL-2 group, significantly higher serum concentrations of neopterin and soluble IL-2 receptor (sIL-2R) respectively were induced as compared to GM-CSF-treated patients. However, the ADCC of peripheral blood mononuclear cells (PBMC) against a CRC cell line was significantly higher in the GM-CSF group than in the GM-CSF/IL-2 group. The frequencies of patients developing human anti-mouse antibodies (HAMA) and anti-idiotypic antibodies were the same in both groups, while serum concentrations were significantly lower in the GM-CSF/IL-2 group as compared to the GM-CSF group. GM-CSF/IL-2 therapy seems to induce an immune suppressive stage compared to GM-CSF alone affecting cytotoxic mononuclear cells and B cells, which might be mediated through the neopterin metabolic pathway or other inducible immune suppressive factors such as reactive oxygen and nitrogen intermediates.
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Carcinoma/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Interleucina-2/farmacología , Neopterin/sangre , Receptores de Interleucina-2/sangre , Adulto , Anciano , Animales , Anticuerpos Monoclonales/metabolismo , Femenino , Humanos , Macrófagos/metabolismo , Masculino , Ratones , Persona de Mediana Edad , Monocitos/metabolismo , Metástasis de la Neoplasia , Proteínas Recombinantes/farmacología , Factores de Tiempo , Células Tumorales CultivadasRESUMEN
This report by The Swedish Council on Technology Assessment in Health Care (SBU) reviews, classifies, and grades the scientific literature on cancer chemotherapy in some major tumour types, describes the practice of chemotherapy in Sweden, compares practice with scientific knowledge, and analyses the costs and cost-effectiveness of chemotherapy. The report is intended primarily for decision-makers at various levels, both practitioners and administrators. It is also of interest for the medical profession. The extensive body of scientific literature was reviewed according to strict criteria that reflected the scientific weight of the literature. Sixteen experts representing different disciplines (oncology, surgery, internal medicine, health economy and quality of life research) participated in the literature review. Each section was discussed within the project group and was reviewed by at least one, but usually two international researchers. Additional input was provided by national experts representing different scientific disciplines. For the final evaluation to be as close to the objective truth as possible, a concerted effort was made to guarantee objectivity and thorough assessment of current knowledge about the effects of chemotherapy on the selected cancers. The tumour types selected for this assessment include firstly those types where three investigations had shown an increased use of chemotherapy in Sweden during the latest decade. These were non-small cell lung cancer (NSCLC), gastric cancer, pancreatic cancer, colorectal cancer and urinary bladder cancer. Secondly, the two tumour types comprising the greatest number of patients treated with chemotherapy in Sweden, breast cancer and haematological malignancies, were included. Among the haematological malignancies, the most prevalent ones, acute myeloid leukaemia (AML), chronic lymphocytic leukaemia (CLL), Hodgkin's disease (HD), aggressive non-Hodgkin's lymphoma (NHL) of the large B-cell type and indolent NHL of follicular type were evaluated. These constitute about 75%, of all haematological malignancies. Thirdly, ovarian cancer was included since chemotherapy has been extensively used and since, at the time of the planning of this overview, a group of very expensive drugs, the taxanes, had preliminarily shown promising results. A wealth of scientific literature has been published on cancer therapy. The review presented in this report is limited to scientific studies judged to be important for evaluating chemotherapy efficacy. Assessments of the content and quality of these studies, and a critical summary of the results in all stages of the selected tumours, have never before been attempted in this way. However, similar comprehensive overviews of certain stages of the tumours have previously been made. These overviews were also critically evaluated. Totally 1,496 studies involving 558,743 patients were reviewed. The survey of practice of chemotherapy use involved all departments of surgery, urology, gynaecology, internal medicine including haematologic units, pulmonary medicine and general and gynaecologic oncology at 16 hospitals in two health care regions in Sweden, covering 39% of the Swedish population. During the 4 weeks of the survey, all patients with the diagnoses concerned who received chemotherapy were registered. The study included 1,590 patients. The working group's general conclusions are summarised in the following points: The literature on the effects of chemotherapy is extensive. Chemotherapy has a well-documented role in the curative and palliative treatment of patients with several types of cancer. The use of chemotherapy is of utmost importance for the possibility of cure in certain tumour types. In other tumours, chemotherapy increases the possibility of cure when added to local and regional treatments, particularly surgery. In the instances of no possibility of cure, chemotherapy may to a variable extent improve both patient survival and well-being. In Sweden chemotherapy is largely used in accordance with that documented in the scientific literature. The extent of both over- and under-treatment seems to be limited but cannot be excluded at the individual patient level. The literature-based knowledge is scientifically of lower quality in the most chemotherapy sensitive tumours than in tumours showing more limited sensitivity. In the more sensitive tumours, positive effects on a symptomatic stage and survival were seen several decades ago. In those days, clinical treatment studies did not fulfil the current high quality requirements. Small life-prolonging effects of chemotherapy are sometimes very well documented in large, high quality scientific studies. Some of these s
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Evaluación de la Tecnología Biomédica , Antineoplásicos/economía , Análisis Costo-Beneficio , Toma de Decisiones , Costos de los Medicamentos , Medicina Basada en la Evidencia , Humanos , SueciaRESUMEN
A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on adjuvant and palliative therapy with cytostatics for colorectal cancer is based on 208 scientific articles, including eight meta-analyses and 162 randomised studies. These studies involve approximately 126,800 patients. The conclusions reached can be summarized into the following points: The benefit of postoperative adjuvant chemotherapy with fluorouracil and levamisole in patients with colon cancer stage Dukes' C was demonstrated more than ten years ago in two phase III trials. There was a reduction of recurrence from 56% to 39% and reduction of death from 51% to 40% after more than five years of follow-up. Although this combination has been widely accepted as standard adjuvant treatments for stage Dukes' C colon cancer, there is still debate on whether adjuvant treatment with fluorouracil alone would be equally efficacious. Several phase III trials with postoperative adjuvant chemotherapy with fluorouracil and leucovorin in patients with colon cancer stage Dukes' C have demonstrated a similar statistically significant improvement in disease-free and overall survival in comparison with a control arm. Six months of treatment with fluorouracil and leucovorin is as efficient as twelve months of fluorouracil and levamisole. This treatment is, thus, recommended for routine use. No convincing benefit from adjuvant chemotherapy is proven in colon cancer stage Dukes' B although some randomised trials have shown the same relative survival gain as seen in stage Dukes' C. There is less knowledge on survival benefits from adjuvant chemotherapy for Dukes' stage B and C rectal cancer. In small randomised trials, postoperative radiochemotherapy has, however, improved survival to the same extent as chemotherapy in colon cancer Dukes' stage C. A meta-analysis of nine randomised trials revealed a small but statistically significant benefit in five-year survival and a reduction in the risk of death for the patients receiving immediate postoperative portal vein infusion compared with controls. At present, however, the use of portal vein infusion or intraperitoneal therapy outside of a research trial cannot be recommended in the light of the limited effects. This conclusion is further supported by similarly limited effects in two recently reported very large European multicentre trials. In advanced colorectal cancer, chemotherapy may prolong survival, decrease tumour-related symptoms, improve general well-being or maintain it at a high level for a longer time period compared with best supportive care. These effects have been seen using systemic chemotherapy and using regional chemotherapy in patients with metastases limited to the liver. Subjective responses and quality of life improvements are seen more frequently than objective tumour remissions. Although the impact on overall survival is modest, i.e. an improvement in median survival of five to six months, treatment is recommended also outside clinical trials. High-dose infusional regimens with modulated fluorouracil may turn out to be superior to conventional bolus regimens, since they result in more tumour regressions, longer times to disease progression and possibly longer survival. A plateau seems, however, to have been reached with fluorouracil, giving objective response rates of up to 30% to 40% with a variety of modulators. Randomised studies of regional therapy, mostly hepatic arterial infusions, of liver metastases in colorectal patients have demonstrated significantly higher response rates than systemic fluorouracil therapy alone without impact on overall survival. The importance of the higher response rates for patient benefit in the predominantly asymptomatic patients with isolated liver metastasis remains to be elucidated. Regional therapy in advanced disease cannot be recommended outside of clinical trials. New cytotoxic agents are emerging with antitumour activity similar to fluorouracil-based chemotherapy. The addition of oxaliplatin or irinotecan to existing fluorouracil regimens improves response rates and duration of response, and possibly overall survival. Based upon the results of two randomised studies, there is a role for irinotecan as second line therapy for selected patients who have failed first-line therapy with fluorouracil plus leucovorin. The role of these agents, alone or in combinations, in clinical routine remains, however, to be determined due to more pronounced toxicity than caused b
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Adyuvantes Inmunológicos/administración & dosificación , Quimioterapia Adyuvante , Neoplasias Colorrectales/cirugía , Relación Dosis-Respuesta a Droga , Fluorouracilo/administración & dosificación , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Levamisol/administración & dosificación , Estadificación de Neoplasias , Cuidados Paliativos , Vena Porta , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for urothelial bladder cancer is based on 234 scientific reports including two meta-analyses, 75 randomised studies and 143 other prospective studies, and totally comprising 31,974 patients. The conclusions reached can be summarised into the following points: Intravesical chemotherapy administered in an adjuvant setting to transurethral resection (TUR-B) of superficial tumour reduces short-term (one to three years) recurrence rate by approximately 20%. After a median follow-up of eight years, 8%, fewer recurrences were seen after intravesical chemotherapy. Long-term maintenance instillation chemotherapy ( > 1 year) does not further increase the recurrence-free interval nor the long-term recurrence rate when compared with immediate postoperative short-term intravesical chemotherapy. The majority of studies on intravesical Bacillus Calmette-Guerin (BCG) vs intravesical chemotherapy show superior protection from tumour recurrence for BCG. Despite prolongation of the disease-free survival, adjuvant intravesical chemotherapy has, in the majority of studies, no apparent long-term impact on the evolution of superficial into muscle invasive bladder cancer. There are no data showing a survival benefit from adjuvant intravesical chemotherapy. Chemotherapy with cisplatin-based regimens induce objective tumour response in at least 50% of patients with metastatic disease. A prolonged disease-free and overall survival (median two to three months) is seen in patients treated with cisplatin-based polychemotherapy compared with patients treated with cisplatin alone or less intensive chemotherapy. With the exception of one randomised study, there are no conclusive data on possible survival benefit for patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy prior to cystectomy or radiotherapy. Although the results from use of adjuvant chemotherapy after surgery or curative radiotherapy obtained are promising, the small studies performed lack statistical power and, hence, there is insufficient data to make any conclusion regarding a possible survival benefit from adjuvant chemotherapy. A growing body of data indicate that bladder preservation can be achieved by multi-modality approach in selected patients and that survival in these is similar to that seen after radical cystectomy, but randomised trials are still lacking.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Administración Intravesical , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Vacuna BCG/uso terapéutico , Quimioterapia Adyuvante , Cisplatino/administración & dosificación , Terapia Combinada , Cistectomía , Supervivencia sin Enfermedad , Humanos , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Pronóstico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
A prospective study on total utilisation of cytotoxic drugs for selected cancers was carried out in two Swedish health service regions, during four weeks in the autumn of 1997. The study included 1,590 patients; 1,169 with solid tumours and 421 with haematological malignancies. The majority of patients (75% to 80%) were treated at university/regional hospitals, often at oncology or haematology departments, and most received treatment as outpatients. Furthermore, most were treated according to recommendations in regional or national clinical guidelines, so-called care programmes, although the percentage varied by diagnosis. Only 10% were participants in a clinical trial. In approximately 40% of the patients, treatment was aimed at cure. However, this percentage varied between 0% and 94% depending on tumour type. At the population level, a comparison of the scientific evidence according to a literature review (Acta Oncol, this issue) with the survey showed that treatment with cytotoxic drugs in Sweden was largely evidence-based. A high percentage of patients received cytotoxic drugs for diseases where recommendations to treat were strong, i.e. outcomes were well-documented in the literature. A low percentage of patients received chemotherapy in disease settings with little or no scientific documentation. The percentage of patients treated was also limited in cases where the effects of chemotherapy are relatively small, although scientifically well-documented. For methodological reasons, one cannot exclude the possibility that cytotoxic drugs may be overutilised at the individual level for palliative purposes, e.g. by not discontinuing treatment despite the absence of clinical benefits. Likewise, one cannot exclude the possibility of underutilisation, e.g. by patients declining treatment because they were not informed about the potential benefits.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Medicina Basada en la Evidencia , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Anciano , Atención a la Salud/estadística & datos numéricos , Quimioterapia/estadística & datos numéricos , Femenino , Hospitales Comunitarios , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Cuidados Paliativos , Estudios Prospectivos , SueciaRESUMEN
In this study, we have assessed the development of neutralizing and non-neutralizing interleukin 2 (IL-2) antibodies in metastatic colorectal carcinoma patients receiving a colon carcinoma reactive monoclonal antibody (17-1A) in combination with granulocyte macrophage colony-stimulating factor and IL-2 therapy. Before treatment, no IL-2 antibodies were detected in any of the patients. After therapy, 10 of the 19 patients tested developed antibodies that bound to the IL-2 product used for therapy, but only one developed antibodies that neutralized the biological activity of IL-2 as assessed using an in vitro bioassay. We found that the induction of IL-2 antibodies in some patients irrespective of their neutralizing potential had a significant impact on IL-2 pharmacokinetics. A significant reduction of the area under the concentration-time curve and maximum concentration (C(max)) and increased IL-2 distribution and clearance were observed in IL-2 antibody-positive patients in comparison with IL-2 antibody-negative patients. A significant decrease in IL-2-mediated expansion of lymphocytes was also evident in patients positive for IL-2 antibodies in comparison with those negative for these antibodies. Further characterization of sera from patients with antibodies showed that, in most cases, the antibodies recognized different IL-2 preparations. Results also showed that serum IL-2 concentration at initiation of therapy in patients was significantly higher relative to healthy control donors. The endogenous production of IL-2 gradually increased during the treatment cycles. To conclude, induction of neutralizing and non-neutralizing antibodies in cytokine-treated patients should be carefully monitored in terms of their clinical significance.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos/análisis , Neoplasias Colorrectales/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Interleucina-2/farmacocinética , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/inmunología , Quimioterapia Combinada , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Interleucina-2/sangre , Interleucina-2/inmunología , Interleucina-2/uso terapéutico , Leucocitos/efectos de los fármacos , Masculino , Persona de Mediana EdadRESUMEN
We have assessed the immunogenicity profile of GM-CSF in patients with either colorectal carcinoma (CRC) at different stages of disease or with multiple myeloma who were given recombinant human GM-CSF (Escherichia coli-derived) combination therapy. Metastatic CRC patients received a colon carcinoma-reactive antibody and high doses of GM-CSF (425--500 microg/day for 10 days), while other CRC patients and those with myeloma received low doses of GM-CSF (75--80 microg/day for 4 days) as an adjuvant along with appropriate tumor antigens. We found that 55% of the patients (11/20) given high doses of GM-CSF developed GM-CSF-reactive antibodies in comparison with an incidence of only 16% (4/25) in patients given low doses of GM-CSF. None of the patients developed neutralizing antibodies and so the biological effects of GM-CSF were not compromised. A majority of patients (80%) (36/45) also developed antibodies to E. coli proteins that were present as trace contaminants in the GM-CSF product. Treatment with recombinant GM-CSF products, therefore, may induce antibodies against this cytokine depending on the regimen and the amounts used. In this study, multiple immunizations with low doses of GM-CSF was associated with a low incidence of GM-CSF antibodies, which did not neutralize the effect of the cytokine. This therapeutic strategy was effective in inducing adjuvant-type effects and needs to be explored in further clinical trials with this cytokine.
Asunto(s)
Anticuerpos/sangre , Neoplasias Colorrectales/terapia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Mieloma Múltiple/terapia , Vacunas Sintéticas/inmunología , Neoplasias Colorrectales/inmunología , Humanos , Inmunización , Immunoblotting , Mieloma Múltiple/inmunologíaRESUMEN
GA733/EpCAM is an oncofetal antigen abundantly expressed in colorectal carcinoma. This antigen can spontaneously induce a humoral and cellular antitumor immunity and may therefore be a suitable target structure for immunotherapy. Patients with advanced colorectal carcinoma have been treated with monoclonal antibodies (MAb17-1A) against this structure. The data indicate that the chimeric variant was not superior to the original mouse MAb. Addition of cytokines and chemotherapeutics may improve the therapeutic effect of the MAb. A particularly interesting regimen is a combination of MAb17-1A/GM-CSF/alpha-IFN/5-Fu. The GA733 protein antigen can also be used as a vaccine. Patients with colorectal carcinoma stages B and C were vaccinated with this protein antigen in combination with GM-CSF as an adjuvant cytokine. A strong type I T cell response was induced that seemed to be MHC class I as well as class II restricted. No systemic side effects were noted.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Antígenos de Neoplasias/inmunología , Moléculas de Adhesión Celular/inmunología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/inmunología , Inmunoterapia , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Antineoplásicos/inmunología , Neoplasias Colorrectales/fisiopatología , Molécula de Adhesión Celular Epitelial , Humanos , Ratones , Análisis de SupervivenciaRESUMEN
Several studies have suggested that the intratumoral level of thymidylate synthase (TS) in colorectal tumors correlates with survival. We have studied the correlation between TS expression in primary rectal cancer and locoregional recurrence, distant metastases, and survival. TS enzyme levels were evaluated immunohistochemically using the specific monoclonal antibody TS 106 in paraffin-embedded tumors from 243 patients who had undergone primary surgery for rectal cancer during the years 1980-1993. All patients were included in prospective randomized trials aimed at determining the clinical value of a short preoperative course of local radiation therapy (five doses of 5 Gy each). With a median follow-up of 94 months (range, 43-202 months), it was observed by multivariate analysis that Dukes' stage and TS expression were independent prognostic markers of locoregional recurrence (P < 0.001 and P = 0.038, respectively) distant metastasis (P < 0.001 and P = 0.011, respectively) disease-free survival (P < 0.001 and 0.014, respectively), and overall survival (P < 0.001 and 0.020, respectively). By multivariate analysis, preoperative irradiation therapy showed a borderline improvement in locoregional recurrence (P = 0.051). No other factors, such as age, sex, differentiation of the tumor, or p53 expression, were noted to be independent prognostic factors for clinical outcome in these patients. We concluded that the intratumoral expression of TS in primary rectal cancer is an independent prognostic factor for locoregional recurrence, distant metastases, disease-free survival, and overall survival. Patients with low intratumoral TS expression had a significantly better outcome than those with high TS expression.
Asunto(s)
Adenocarcinoma/enzimología , Neoplasias del Recto/enzimología , Timidilato Sintasa/biosíntesis , Adenocarcinoma/radioterapia , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia , Pronóstico , Estudios Prospectivos , Neoplasias del Recto/radioterapia , Neoplasias del Recto/cirugía , Análisis de Supervivencia , Tasa de Supervivencia , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/biosíntesisRESUMEN
Intratumoral thymidylate synthase (TS) expression and M(r) 53,000 phosphoprotein (p53) overexpression were studied immunohistochemically in sections from stored paraffin-embedded primary colorectal cancers in 70 patients who had undergone surgery during the years 1987-1990. These cancers were classified according to Dukes' stage A-D, using monoclonal antibodies TS 106 and DO-7. In patients with Dukes' stage A-C tumors, univariate analyses showed that there was a significant correlation (P = 0.048) between disease-free survival and TS expression and between TS expression and time to death with colorectal cancer (P = 0.038). In patients with Dukes' stage A-D tumors, overall survival was correlated to TS expression (P = 0.015), Dukes' stage (P < 0.001), and level of tumor differentiation (P = 0.044) but not to p53 overexpression. Patients with low intratumoral TS expression survived significantly longer than patients with high expression. Cox multivariate analysis showed that Dukes' stage (P < 0.001) and TS expression (P = 0.043) could independently serve as prognostic factors for time to death with colorectal cancer in patients with Dukes' stage A-D tumors.
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Biomarcadores de Tumor/análisis , Neoplasias del Colon/patología , Neoplasias Colorrectales/patología , Neoplasias del Recto/patología , Timidilato Sintasa/análisis , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/enzimología , Neoplasias del Colon/mortalidad , Neoplasias del Colon/cirugía , Neoplasias Colorrectales/enzimología , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Neoplasias del Recto/enzimología , Neoplasias del Recto/mortalidad , Neoplasias del Recto/cirugía , Tasa de Supervivencia , Factores de Tiempo , Proteína p53 Supresora de Tumor/análisisRESUMEN
Granulocyte/macrophage-colony-stimulating factor (GM-CSF) has previously been indicated to enhance the therapeutic effect of the anti-colorectal carcinoma mAb17-1A as well as to augment in vivo immune effector functions. In vitro interleukin-2 (IL-2) augmented GM-CSF-induced antibody-dependent cellular cytotoxicity, a mechanism considered to be of significance for the therapeutic effect of mAb. A treatment regimen was elaborated that combined mAb17-1A (400 mg at day 3 of a 10-day treatment cycle) with the simultaneous administration of GM-CSF (250 microgram/m(2) once daily) and IL-2 (2.4 x 10(6) U/m(2) twice daily) for 10 days. The treatment cycle was repeated once a month. Twenty patients with advanced colorectal carcinoma were included in the study. One patient obtained a partial remission and 2 patients stable disease for 7 and 4 months respectively. The median survival time from the start of mAb therapy was 8 months. Owing to allergic reactions, the planned mAb17-1A dose had to be reduced by repeated infusions. At the fourth treatment cycle only 25% received the planned mAb dose. In 3 patients the GM-CSF and IL-2 dose was reduced because of side-effects. The subjective tolerability of the treatment was considered good or acceptable in more than 80% of the patients. The increment in white blood cell subsets induced by the cytokines decreased by increasing number of courses. This particular regimen did not augment the therapeutic effect of mAb17-1A anticipated from in vitro data but rather hampered the clinical effect of the antibody. The reason for this is not clear but a possibility might be the induction of immune suppression in vivo resulting from an impaired human anti-(mouse Ab) and anti-idiotypic antibody response as well as antibody-dependent cellular cytotoxicity, on the basis of a comparison of mAb17-1A/GM-CSF/IL-2- and mAb17-1A/GM-CSF-treated patients.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/terapia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Interleucina-2/uso terapéutico , Adulto , Anciano , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales de Origen Murino , Recuento de Células Sanguíneas/efectos de los fármacos , Calcio/sangre , Neoplasias Colorrectales/inmunología , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Humanos , Inmunoterapia , Interleucina-2/efectos adversos , Masculino , Ratones , Persona de Mediana Edad , Albúmina Sérica/metabolismo , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
In this study, we have assessed the development of neutralizing and nonneutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) antibodies in two groups of patients with metastatic colorectal carcinoma receiving two different GM-CSF products. Three clinical trials were carried out, and a combination of GM-CSF and a colon carcinoma-reactive antibody was used in the absence of any concomitant chemotherapy. Two different GM-CSF products, both rDNA-derived and produced in Escherichia coli, were used. Patients in Trial 1 received product X, and those in Trials 2 and 3 received product Y. Patients in Trial 2 also received interleukin 2 in an attempt to potentiate immune responses. After the first cycle of treatment, no GM-CSF antibodies were detected, but on subsequent therapy, 28 of the 38 patients tested receiving product Y (Trials 2 and 3) developed antibodies that bound to the GM-CSF product used for therapy. However, none of the patients developed antibodies that neutralized the biological activity of GM-CSF, as assessed using an in vitro bioassay. Furthermore, there was no in vivo impairment in GM-CSF-induced expansion of leukocytes, neutrophils, and eosinophils in the patients. In contrast, 19 of the 20 patients given product X (Trial 1) developed GM-CSF binding antibodies, and 9 of these patients were shown to develop antibodies that neutralized the biological activity of GM-CSF. The presence of the latter was associated with a significant reduction in GM-CSF-induced expansion of leukocytes, neutrophils, and eosinophils in patients. Therefore, product X appears to be more immunogenic than product Y. Immunochemical characterization confirmed that the specificity of the antibody responses varied depending on the product used for therapy. Whereas sera from Trial 1 patients treated with product X showed the presence of antibodies with strong recognition of GM-CSF proteins, sera from patients treated with product Y showed varied recognition of GM-CSF ranging from fairly strong to very weak but bound predominantly to two E. coli-derived, non-GM-CSF-related proteins of Mr approximately 20,000 and Mr approximately 30,000. Therefore, in sera from patients receiving product Y, the antibody specificity appeared to be directed not only against GM-CSF but also against non-product-related host cell contaminants. This study shows that GM-CSF products used for therapy are potentially immunogenic and generate antibodies to GM-CSF and/or other non-product-related contaminants. However, only antibodies that neutralize the biological activity of GM-CSF compromise therapeutic efficacy of the cytokine.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/terapia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Adulto , Anciano , Anticuerpos/sangre , Anticuerpos/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Especificidad de Anticuerpos , Unión Competitiva/inmunología , Humanos , Immunoblotting , Interleucina-2/inmunología , Interleucina-2/uso terapéutico , Recuento de Leucocitos/efectos de los fármacos , Persona de Mediana Edad , Proteínas RecombinantesRESUMEN
Granulocyte-macrophage colony-stimulating factor is by far the most widely used hematopoietic growth factor to augment immune responses. At present, the best secured effect is as an adjuvant cytokine for vaccination. Granulocyte-macrophage colony-stimulating factor can be delivered as gene-transduced tumor cells, as plasmid DNA, or as the soluble free granulocyte-macrophage colony-stimulating factor protein. Granulocyte-macrophage colony-stimulating factor must be present at the same site as the vaccine component. Granulocyte-macrophage colony-stimulating factor may also augment the effect of therapeutic monoclonal antibodies by enhancing various effector functions such as antibody-dependent cellular cytotoxicity and amplifying an idiotypic network response (i.e., antitumor immunity). It may also be advantageous to combine granulocyte colony-stimulating factor with monoclonal antibodies (neutrophil and monocyte antibody-dependent cellular cytotoxicity) for tumor therapy. However, these growth factors might also induce immune suppression, which may hamper the contemplated effect of the growth factor. It is urgently warranted to better understand these dual effects on the immune system so that we can find optimal uses for the growth factors in various clinical settings.
Asunto(s)
Formación de Anticuerpos/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/fisiología , Factores de Crecimiento de Célula Hematopoyética/fisiología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Factores de Crecimiento de Célula Hematopoyética/inmunología , Humanos , Tolerancia Inmunológica/efectos de los fármacosRESUMEN
Twenty patients with metastatic colorectal carcinoma were treated with a single infusion (400 mg) of a mouse monoclonal antibody (IgG2a) against the tumor-associated antigen CO 17-1A and with a daily injection of granulocyte macrophage colony-stimulating factor (GM-CSF) for 10 days. The cycle was repeated every month. Metastases from 5 of the 20 patients biopsied on days 1 and 10 of the first two treatment cycles were studied by immunohistochemistry. During treatment, neutrophils, monocytes, and T lymphocytes increased concordantly in the tumor as in the blood of the individual patient. Macrophages (CD68) and CD8+ T cells infiltrated the tumor glands and displayed TIA-1-reactive cytotoxic granules. Neutrophils were seen mainly in areas of necrosis. Activated (HLA-DR+) CD4+ T cells were usually abundant in the stroma. During treatment, few natural killer cells were found in the tumor, contrary to the marked increase seen in blood. Our observations indicate that GM-CSF markedly recruited activated, tumor-infiltrating leukocytes, possibly representing antibody-dependent cellular cytotoxicity and cytotoxic T effector cells. The notion that combined antibody and GM-CSF therapy may also promote a T-cell antitumor response is further supported and advocated by our findings. The study lends further support to combining GM-CSF with monoclonal antibody-based therapy.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/terapia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Anciano , Antígenos de Neoplasias/análisis , Antígenos de Neoplasias/inmunología , Biopsia , Neoplasias Colorrectales/tratamiento farmacológico , Proteínas del Sistema Complemento , Antígenos de Histocompatibilidad Clase I/análisis , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/análisis , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunoglobulina G/análisis , Inmunohistoquímica , Inmunoterapia , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Recuento de Leucocitos , Linfocitos Infiltrantes de Tumor/citología , Linfocitos Infiltrantes de Tumor/inmunología , Macrófagos/citología , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neutrófilos/citología , Neutrófilos/inmunología , Linfocitos T/citología , Linfocitos T/inmunologíaRESUMEN
With the aid of specific monoclonal antibodies, an immunohistochemical technique has recently been developed for the detection of intratumoral thymidylate synthase (TS). This technique can be applied to paraffin-embedded material suitable for retrospective studies. In order to examine this technique further, the TS enzyme activity of lysates from frozen-stored colorectal cancer (CRC) specimens were compared with their immunohistochemical TS staining intensity (arbitrarily graded from 0 to 3). A statistically significant correlation between these two methods on a total of 25 tumour specimens (P < 0.001) was observed. The staining intensity in different areas of 48 paraffin-embedded CRCs was examined. Sixty-seven per cent of the tumours were homogeneously stained (either grades 0-1 or 2-3), 33% showed a heterogeneity in TS staining. Increased TS expression correlated with more advanced Dukes' stage (P < 0.001). It is concluded that TS immunostaining intensity reflects TS enzyme activity in colorectal tumours and is well suited for paraffin-embedded material. The TS immunostaining pattern is heterogeneous in up to one-third of the tumours.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias del Colon/enzimología , Neoplasias del Recto/enzimología , Timidilato Sintasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias del Colon/patología , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Adhesión en Parafina , Neoplasias del Recto/patología , Estudios RetrospectivosRESUMEN
There is a high risk of developing neutralizing and non-neutralizing antibodies when GM-CSF is used as an immunomodulatory agent in non-immune compromised patients and not in combination with chemotherapy. The presence of neutralizing antibodies may seriously hamper the clinical response of the patients this must be taken into account when designing protocols if the biological activity of the exogenously administered GM-CSF is not to be impaired and the endogenous production of GM-CSF is not to be inactivated. Assessment of production of neutralising antibodies during cytokine therapy is important for predicting the clinical response to progressive therapy.
Asunto(s)
Formación de Anticuerpos , Neoplasias Colorrectales/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Animales , Quimioterapia Combinada , Factor Estimulante de Colonias de Granulocitos y Macrófagos/biosíntesis , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Humanos , Pruebas de Neutralización , Proteínas RecombinantesRESUMEN
Cytotoxicity is an important function of the immune system that results in destruction of cellular targets by humoral and cellular mechanisms. The functional capacity of granulocytes, lymphocytes and macrophages are of significance for cancer patients because of the ability of these cells to exhibit anti-tumor activity. The hallmark of immune cytotoxicity is the recognition and destruction of selected targets by humoral and cellular effects that distinguish between targets and normal cells. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine with potential to be an anti-neoplastic cytokine. GM-CSF induces: (1) differentiation of monocytes to large macrophage like cells; (2) augmentation of MHC class II antigen expression on monocytes; (3) enhancement in vitro of macrophage and granulocyte natural cytotoxicity and ADCC; and (4) increased expression of adhesion molecules and granulocytes and monocytes. GM-CSF also cooperates with other cytokines in the expansion of specific T cells. Several experimental and clinical studies have demonstrated the anti-neoplastic effects of GM-CSF alone or in combination with cytokines or/and monoclonal antibody. Interestingly, the future might see the combination of GM-CSF and mouse monoclonal antibody MAb17-1A in the adjuvant setting in colon- and/or rectal carcinoma patients.