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1.
《Cryobiology》1996,33(6):600-606
Cryosurgery of hepatic metastases from colorectal carcinoma is a form of local therapy for unresectable disease. After curative resection, failures occur in the liver, and at extrahepatic sites. This pilot study evaluated the toxicity and tolerance to cryotherapy and intraoperative chemotherapy for unresectable hepatic metastases from colorectal cancer. If after exploratory celiotomy for potential curative resection of hepatic metastases the patient was deemed unresectable because of location and/or number of lesions, cryosurgery and intraoperative chemotherapy with systemic 5-fluorouracil 600 mg/m2and leucovorin 500 mg/m2was performed. Four patients were treated with cryochemotherapy. All patients developed toxicity. Two patients developed grade III leukopenia on Postoperative Days 2 and 12, and grades II and III diarrhea on Postoperative Days 5 and 7, respectively. Grade III hyperbilirubinemia and thrombocytopenia occurred in one patient on Postoperative Days 3 and 7. Acute respiratory distress syndrome, postoperative ileus, and grade II mucositis occurred in one patient each. All patients had delays and dose reductions on their subsequent chemotherapy treatments secondary to toxicity. Two patients had disease progression, one had stable disease, and one is “disease free.” Combining the tumoricidal effects of chemotherapy and cryosurgery is in theory a good concept. However, the toxicity of 5-FU and leucovorin is enhanced by this approach.  相似文献   

2.
Tumour infiltrating lymphocytes (TIL) were isolated and expanded from biopsy samples of 4 patients with metastatic melanoma. The patients were treated with autologous expanded TIL and continuous or bolus infusion of Interleukin 2 (IL-2) at a dose of 18 × 106 International Units/m2/day for 5 days starting 36–48 hours after administration of cyclophosphamide at a dose of 1 g/m2. The number of TIL infused ranged from 1010 to 5,56 × 1010 cells. Two patients had stable disease (SD) lasting for 2 1/2 and 4 months respectively and they died 24 and 13 months after therapy. One patient died during therapy due to a pseudomonas septicaemia and another patient developed progressive disease (PD). He died 3 months after the start of therapy. The side effects were substantial but most of them were reversible upon cessation of the treatment.The majority of the expanded TIL of all patients were of the CD8+ phenotype. Cutaneous metastases from two patients, removed after treatment with IL-2 and TIL, showed moderate lymphocytic infiltration also mainly of CD8+ T cells.The treatment with IL-2 and TIL is feasible, but further investigations should continue in an attempt to improve the efficacy of the therapy, to reduce toxicity and to diminish the costs and labour of the culture methods.  相似文献   

3.
The National Biotherapy Study Group (NBSG) conducted a broad phase II trial using interleukin-2 (IL-2) by continuous infusion and alpha interferon (IFN) subcutaneously in 267 patients with a variety of advanced cancers, including 29 with breast cancer, 89 with renal cancer, and 69 with melanoma. IL-2 [18 million international units (MIU)/m2] was given by continuous infusion for 108 hours with 3 mu/m2 subcutaneous IFN every other day during the IL-2 infusion. The patients were treated for 1 week followed by a 2-week rest. After two cycles of treatment, patients were evaluated for response. Of the 237 patients evaluable for response, 20 (8%) had a complete or partial response and 128 (54%) were stable. Therefore, 62% of the evaluable patients were nonprogressive during the first 90 days of IL-2/IFN therapy. The objective response rate was 11% in melanoma, 7% in renal cancer, 14% in breast cancer, and 3% in patients with a variety of malignancies for an overall response rate of 7% in these patients with advanced cancer. The patients were treated on a general medical ward and tolerated treatment well with fatigue and fever being nearly universal. Dyspnea, pruritus, chills, and elevated creatinines were frequent but less common. This combination biotherapy regimen has minimal activity in a variety of advanced cancers and must be compared with the best existing chemotherapy for each cancer type in randomized, prospective trials.  相似文献   

4.
Modified vaccinia Ankara (MVA) encoding the tumor antigen 5T4 (TroVax) has been evaluated in an open label phase II study in metastatic colorectal cancer patients. The primary objective was to assess the safety and immunogenicity of TroVax injected before, during and after treatment with 5-fluorouracil, leukovorin and irinotecan. TroVax was administered to 19 patients with metastatic colorectal cancer. Twelve patients had blood samples taken following each of the six injections and were considered to be evaluable for assessment of immunological responses. Both antibody and cellular responses specific for the tumor antigen 5T4 and the viral vector MVA were monitored throughout the study. Administration of TroVax alongside chemotherapy was safe and well tolerated with no SAEs attributed to the vaccine and no enhancement of chemo-related toxicity. Of the 12 patients who were evaluable for assessment of immune responses, ten mounted 5T4-specific antibody responses with titers ranging from 10 to > 5,000. IFNgamma ELISPOT responses specific for 5T4 were detected in 11 patients with frequencies exceeding one in 1,000 PBMCs in five patients. Eight patients presented with elevated circulating CEA concentrations, six of whom showed decreases in excess of 50% during chemotherapy and four had CEA levels which remained stable for > 1 month following completion of chemotherapy. Of the 19 intention to treat (ITT) patients, one had a CR, six had PRs and five had SD. Potent 5T4-specific cellular and/or humoral immune responses were induced in all 12 evaluable patients and were detectable in most patients during the period in which chemotherapy was administered. These data demonstrate that TroVax can be layered on top of chemotherapy regimens without any evidence of enhanced toxicity or reduced immunological or therapeutic efficacy.  相似文献   

5.
We have used chemo-immunotherapy with 5-fluorouracil (5-FU), thymosin α1 (Tα1) and interleukin-2 (IL-2) to treat multiple liver metastases from colorectal cancer induced by DHD/K12 cells in syngeneic BDIX rats, comparing one and two cycles of treatment, and different treatment combinations. 5-FU was delivered loco-regionally as a continuous infusion via an intraperitoneal (i.p.) catheter from a subcutaneously implanted mini-pump, a method we developed for this study. We show here that two cycles of a triple chemo-immunotherapy regimen significantly increased the average survival time compared to one cycle, and compared to untreated controls or those treated with two cycles of 5-FU alone. At 150 days, two rats treated with two cycles of triple therapy were cured, showing no signs of cancer at autopsy; all the other rats died before this time. Triple chemo-immunotherapy resulted in significantly fewer extra-hepatic metastases than in the controls and in those treated with 5-FU only. Further, we found that two cycles of triple treatment significantly increased the absolute number of peripheral T cells expressing IL-2 receptor, CD4 and CD8 compared to controls. We conclude that two cycles of chemo-immunotherapy with 5-FU, Tα1 and IL-2 were superior to one cycle of treatment and to other treatments tested. Our results suggest that the triple therapy acts by increasing numbers of effector T cells. This method shows promise for the use of multi-cycle chemo-immunotherapy in the treatment of unresectable metastases of colorectal cancer in humans. Received: 1 October 1998 / Accepted: 9 April 1999  相似文献   

6.
INTRODUCTION: Experimental results reported in the literature have suggested that CEA might inhibit host defense mechanisms and that immunotolerance to CEA could play an important role in the development of metastases in colorectal carcinoma. It might therefore be assumed that negative CEA values during metastatic disease represent a favorable prognostic factor. Surprisingly, there are very few data available about negative CEA. The aim of this study was to determine the significance of negative initial CEA values in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS: Initial CEA values were determined in 114 patients with metastatic colorectal carcinoma. The patients were divided into three groups according to these values: I (n=22) <5 ng/mL; II (n=33) 5-100 ng/mL; III (n=59) >100 ng/mL. RESULTS: Seven/114 complete responses (CR), 22/114 partial responses (PR), 45/114 instances of stable disease (SD) and 38/114 of progressive disease (PD) were registered, while two patients were not evaluable. There were six long-lasting CRs (median 24 months, range 10-37 months) in the CEA-negative patient subset, while in the CEA-positive subset there was only one CR, in a patient with an initial CEA level of 18 ng/mL. The mean initial CEA values in the different response categories were: CR: 4.0 ng/mL; PR: 436 ng/mL; SD: 1442 ng/mL; PD: 6071 ng/mL. The likelihood of response, in particular CR, was highly dependent upon CEA levels (Fisher's exact test, 0.00001). The median survival decreased significantly with increased values of CEA (p=0.006). CONCLUSION: Negative CEA in metastatic disease was the main characteristic of the patient subset capable of attaining CR. When relapsing, all patients but one became CEA positive.  相似文献   

7.
Anthracyclin-based chemotherapy is the most efficient chemotherapy for advanced or metastatic soft tissue sarcoma (STS). Development of anthracyclin chemoresistance has been widely documented. In a previous clinical trial, we evaluated a possible reversal of anthracyclin chemoresistance after exposure to subcutaneous IL-2. The current phase II clinical study entered 17 proven metastatic STS patients, refractory to anthracyclin chemotherapy, who received IL-2, and subsequent anthracyclin-based chemotherapy. Subcutaneous IL-2 was administered at 18 million Units/day, 5 days a week for two consecutive weeks. Treatment was administered safely at the full dose for 16 out of 17 patients, and toxicity was mild. One patient had treatment stopped because of rapidly progressive disease. As soon as patients met biological and clinical criteria, chemotherapy was administered. The median delay was 12 days (2-23) from the end of IL-2 administration. Only 13 patients received anthracyclin chemotherapy after IL-2. The other 4 patients did not receive chemotherapy for progressive disease. One partial response was observed out of 13 evaluable patients (7.7% overall response, 95% confidence interval: 0.2 to 36). The overall response rate was 5.9% (95% CI: 0.15 to 29), so the study was stopped due to lack of efficacy. In previous and current studies, a few patients have developed restored anthracyclin chemosensitivity following exposure to IL-2. No conclusive evidence of IL-2 chemoresistance reversal was obtained from this study. Further investigations need to be performed with perhaps a larger group of more carefully selected patients using a different schedule and sequence of combined cytokines and chemotherapy.  相似文献   

8.
Previous clinical studies have demonstrated a dose-response relationship between enhancement of certain immune parameters and interleukin-2 (IL-2) dose in trials with low dosages of the cytokine. This has not been demonstrated for high-dose (greater than 18×106 IU/m2 per day) IL-2. We completed phase II trials of sustained administration of indomethacin and ranitidine with IL-2 given as a continuous infusion over 5 days for three courses. Peripheral blood mononuclear cells, both fresh and cultured in vitro with IL-2 or IL-2 and indomethacin, were tested for tumoricidal function against K562 and Daudi targets; these results were then correlated with actual delivered dose and mean infusion rate per course. Similar correlations were calculated between delivered dose or infusion rate and absolute and proportional counts of lymphocyte subsets as determined by flow cytometry. No enhancement of in vitro tumoricidal function with either increasing delivered dose or increasing infusion rate was seen. No consistent pattern of correlation was found between the absolute counts of lymphocyte subsets after each course of IL-2 with delivered dose or infusion rate. The percent rise in absolute counts of selected T- and NK-cell subsets at the end of course 1 compared with baseline values correlated positively with infusion rate; however, a similar correlation between the infusion rate and an increase in lymphocyte tumoricidal function was lacking. Little evidence was found for improved tumoricidal function of mononuclear cells or consistent enhancement of lymphocyte subset counts in patients able to tolerate doses of IL-2 beyond 18×106 IU/m2 per day in a 5-day continuous infusion schedule.Presented in part at the Twenty-eighth Annual Meeting of the American Society of Clinical Oncology, May 17–19, 1992, San Diego, Calif.  相似文献   

9.
 Cells of the monocyte/macrophage lineage have shown antitumor activity in vitro and in murine models after activation with interferon (IFN) γ. In vitro data suggest an additional effect on macrophage antitumor activity when IFNγ is combined with endotoxin (lipopolysaccharides; LPS). In this study we treated nine cancer patients with a total of 62 MAK infusion cycles with autologous macrophages given intravenously (i.v.) after in vitro activation with IFNγ and LPS. Low-grade fever (WHO I/II) was the commonest side-effect. Chills, nausea, and headache were noted when the number of transfused macrophages exceeded 2×108. One WHO IV toxicity occurred, consisting of hypotension after transfer of 3×108 cells, defining this dose as the maximum cell number tolerated. After pretreatment with ibuprofen, however, the maximum cell number could be increased without reaching dose-limiting toxicity. The highest number of cells reinfused was 15×108. Circulating interleukin(IL)-6 increased in a dose-dependent manner as did IL-1 receptor antagonist (IL-1RA) and IL-8. Tumor response consisted of one case of stable disease (12 weeks) in a patient with formerly progressing colorectal cancer and progressive diseases in eight patients. This study indicates that reinfusion of autologous LPS-activated macrophages upon pretreatment with ibuprofen is feasible and tolerated without major side-effects. Received: 22 May 1997 / Accepted: 2 October 1997  相似文献   

10.
Interleukin-2 (IL-2) and sodium butyrate allow rats to be cured of peritoneal carcinomatosis from colon cancer. We performed a phase I trial of IL-2 and high-dose arginine butyrate (ArgB) in patients with advanced metastatic colorectal cancer. Patients and methods: From April to July 1997, six patients were included in the trail; they had a median age of 52 years, four had a performance status of 0, two had a performance status of 1 with normal biological functions. All patients had received at least two prior lines of chemotherapy. A fixed dose of 18 MIU/m2 IL-2,was administered by subcutaneous injection and ArgB was delivered via continuous intravenous infusion on days 1–6 with escalating doses starting at 2 g kg−1 day−1. Results: The planned dose escalation was not possible because of toxicities. A daily ArgB dose of 2 g/kg was delivered for nine cycles. Level 2 (4 g/kg) could not be delivered in three of the six patients because of liver toxicity. The dose-limiting toxicities were fatigue and liver function disturbances. The maximum tolerated dose for ArgB was 3 g kg−1 day−1, in combination with IL-2 at 12 MIU m2 day−1. No clinical response was seen. Pharmacokinetic analysis showed large intra- and interindividual variations. Conclusion: This schedule with a high dose of ArgB proved to be highly toxic with liver insufficiency. We will be running another trial with lower doses of ArgB calculated from the schedule used in the experimental model, starting at a dose of 20 mg kg−1 day−1 for ArgB and 200 000 UI kg−1 day−1 IL-2, every 8 h. Received: 13 May 1999 / Accepted: 28 October 1999  相似文献   

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