The importance of added albumin during continuous intravenous infusion of interleukin-2 with alpha-interferon

We treated 14 patients (4 malignant melanoma/10 renal carcinoma) with a combination of continuous infusion interleukin-2 (IL-2) and subcutaneous alpha-interferon. Variable concentrations of albumin were added to the infusion of IL-2. The toxicity of this regimen seems to be related to the percentage of albumin added to the IL-2 infusion. Partial responses were observed in 3 cases. Interestingly, 1 patient's response appeared dependent on the addition of human serum albumin. The mechanism of these effects is unknown, but the use of albumin with IL-2 should be carefully investigated in future studies.     

持续与间歇静脉输注脱氧氟尿苷的毒副作用比较

目的探讨胃肠癌术后持续静脉输注脱氧氟尿苷（FUDR）后出现以口腔炎为主的毒副反应的原因。方法选择2004年1月至2007年12月间的80例胃肠癌手术后病人,随机分为两组,每组40例,治疗组在静滴顺铂和表阿霉素的基础上持续静脉输注FUDR500mg／24h,持续72h;对照组在上述化疗基础上间歇静滴FUDR500mg／d,2～3h／次,d1～d5。化疗期间及结束后,查血常规、肝肾功能,观察毒副反应。结果治疗组仅29例完成化疗,均在化疗后3d出现逐渐加重的口腔炎,重者无法进食,饮水;对照组40例全部完成化疗,仅2例发生以口腔炎为主的毒副反应,且程度轻,不影响进食,饮水;两组病人肝肾功能及造血功能无明显改变。结论持续静脉输注FUDR可导致较为严重的、以口腔炎为主的化疗毒副反应。     

High-dose continuous infusion plus pulse interleukin-2 and famotidine in melanoma

High-dose, continuous infusion interleukin-2 (IL-2) regimens generate greater Lymphokine Activated Killer cell (LAK) cytotoxicity in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 then subsequently pulsed with IL-2 have increased cytotoxicity against cancer cells. Famotidine may enhance the lysis of tumors by cytotoxic lymphocytes. Fourteen patients with melanoma were treated with famotidine 20 mg intravenously twice per day and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes for 1 dose (12 patients) or daily for 3 doses (2 patients). Most common toxicities were fever, nausea/emesis, hypophosphatemia, hypomagnesemia, and rigors. Nine partial responses (64% response rate; 95% Confidence Interval: 39%-84%) have been seen. Median survival has not been reached at greater than 10 months. Two patients responding to therapy showed an increase in detectable CD 56(+) cells in serial subcutaneous or lymph node biopsies, while 1 patient undergoing progression of disease had no such infiltrate. High-dose, 72-hour continuous infusion plus pulse interleukin-2 with famotidine has activity in melanoma. CD 56(+) cells may play a role in responding patients.     

Interleukin 2 and lymphokine-activated killer cell therapy: analysis of a bolus interleukin 2 and a continuous infusion interleukin 2 regimen

Several groups have described the efficacy of interleukin 2 (IL-2) plus lymphokine-activated killer (LAK) cells in the treatment of cancer patients with significant response rates noted in patients with renal cell cancer and malignant melanoma; however, the optimum regimen remains undefined. The Biological Response Modifiers Program of the National Cancer Institute conducted two consecutive Phase I/II studies evaluating the toxicity and clinical efficacy of different methods of IL-2 and LAK cell therapy. In the first trial, we modified the standard Rosenberg regimen by decreasing the duration of priming in an attempt to reduce the toxicity related to this phase of the therapy and thereby administer more IL-2 doses with the LAK cells. In the second trial, we used a continuous i.v. infusion IL-2 regimen and altered both the leukapheresis procedure and the LAK cell culture techniques based on our in vitro and preclinical studies suggesting that 2-day LAK cells were superior. Thirty cancer patients received i.v. bolus IL-2 at 100,000 units/kg every 8 h for 3 days during priming and for 5 days during LAK cell administration. A second group of 22 cancer patients received IL-2 by continuous i.v. infusion at 3 x 10(6) units/m2 for 5 days during priming and an additional 5 days of IL-2 with the LAK cell phase of the treatment. The timing of the start of the leukapheresis procedures, their duration and number, and the LAK cell culture techniques differed in the two trials. Overall, 52 patients with various cancers were treated. The toxicities associated with each regimen were similar to those seen in other IL-2 plus LAK cell trials. Four patients (one each with melanoma and diffuse large cell lymphoma and two with renal cell cancer) exhibited partial responses lasting 2, 4, 10, and 15+ mo. Serial tumor biopsies from treated patients demonstrated that therapy can produce a marked mononuclear cell infiltrate and an increase in HLA-DR expression on tumor cells. There was no difference in the overall response rate between the two regimens, but toxicity was less with continuous i.v. infusion IL-2. The 5-day continuous i.v. infusion regimen resulted in significantly higher rebound lymphocytosis, cell yield from leukapheresis, and number of LAK cells harvested from culture.     

High-dose continuous infusion plus pulse interleukin-2 and famotidine in metastatic kidney cancer

High-dose continuous infusion interleukin-2 (IL-2) regimens generate a higher degree of lymphokine activated killer cell (LAK) cytotoxicity when tested against tumor cells in vitro and a higher rebound lymphocytosis in vivo than do bolus IL-2 regimens. Lymphocytes initially activated by continuous infusion IL-2 have increased cytotoxicity against cancer cells when they are subsequently pulsed with additional IL-2. Famotidine may enhance LAK cytolytic ability. Six patients with kidney cancer have been treated with a combination of famotidine 20 mg intravenous bid and continuous infusion IL-2 (18 MIU/sq m/24 hours) for 72 hours, followed by a 24-hour rest, then IL-2 18 MIU/sq m over 15-30 minutes. The most common metastatic sites were the lung, lymph node, and bone. Median number of cycles received = 5 (range, 3-8). The most common toxicities were fever, rigors, nausea/emesis, hypophosphatemia, hypotension, elevated creatinine, and metabolic acidosis. There were no treatment-related deaths, and no patients required intensive care admission. Two partial responses (33% response rate) have been seen. Median survival has not been reached at greater than 8 months. The combination of high-dose continuous infusion plus pulse IL-2 and famotidine is active in metastatic kidney cancer. An accrual of additional patients is needed to better assess the response rate.     

Continuous intravenous infusion of high dose recombinant interleukin 2 for advanced lymphomas--a phase II study

The prognosis of patients with advanced refractory lymphoma remains poor. We have carried out a Phase II study of continuous high dose intravenous recombinant interleukin 2 alone without LAK cells in this group of patients. Eight patients have so far been treated, 4 with non-Hodgkins lymphoma and 4 with Hodgkins disease. Of the 7 evaluable patients, the maximum response observed was stable disease in 2 patients (1 with NHL and 1 with HD). The other patients' diseases progressed in the face of immune activation following the rIL-2 infusion. Adverse reactions were common but no life-threatening occurred. These results are disappointing. Whether or not lymphokine-activated killer (LAK) cells are needed to improve response rate deserve further investigations.     

Prolonged continuous intravenous infusion interleukin-2 and lymphokine-activated killer-cell therapy for metastatic renal cell carcinoma.

PURPOSE: Two consecutive protocols of continuous intravenous (CIV) infusion interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells were carried out in patients with metastatic renal cell carcinoma (RCC) to determine the response rate and toxicity. PATIENTS AND METHODS: In both protocols, patients received induction IL-2 at 6 x 10(6) U/m2/d on days 1 to 5, and underwent leukapheresis on days 7 to 9 at the peak of rebound lymphocytosis. LAK cells were generated by a 5-day incubation with IL-2 at 1,000 U/mL, and were infused on days 12 to 14. For the first 20 patients (protocol A), maintenance IL-2 was administered at 6 x 10(6) U/m2/d on days 12 to 16. On the assumption that less IL-2 might be required to maintain rather than to induce LAK activity, and that a longer duration of maintenance IL-2 might enhance LAK survival and function in vivo, the protocol for the subsequent 22 patients (protocol B) was altered so that the maintenance phase consisted of a lower dose of IL-2 (2 x 10(6) U/m2/d) administered for a longer period of time (days 10 to 20). RESULTS: In protocol A, there were two complete responses (CRs) and three partial responses (PRs), for a total response rate of 25%. One PR was surgically converted into a CR. The durations of the CRs are 36+, 18+, and 18+ months. Hypotension and capillary leak were most severe during maintenance, which limited the median duration of maintenance IL-2 to 4 days. In protocol B, no patient experienced severe hypotension, and the median duration of maintenance IL-2 was 9 days. Two patients exhibited a CR and seven a PR, for a total response rate of 41%. Two PRs were surgically converted to CRs. The durations of CR are 14+, 9+, 6+, and 5+ months. In both protocols, the CIV induction regimen resulted in marked rebound lymphocytosis (mean, 11,097/microL) and LAK-cell yield (mean, 18.1 x 10(10)). The cumulative response rate was 14 of 42 patients, or 33% (95% confidence interval, 19% to 47%). CONCLUSION: These results demonstrate that both protocols of CIV IL-2 plus LAK cells have substantial antitumor activity, and that a longer maintenance phase of IL-2 at a lower dose is associated with significantly less toxicity without a loss of therapeutic efficacy.     

Etoposide plus carboplatin admixture. Phase I study of five- or seven-day continuous infusion.

Thirty-five patients were entered in a Phase I trial of an admixture infusion of etoposide (VP-16) and carboplatin (CBDCA) administered continuously for 5 or 7 days. Because of the compatibility and solubility of the two agents, the treatment program could be administered on an outpatient basis. The dose rate of VP-16 was fixed at 30 mg/m2/day (total dose 150 mg/m2 for 5 days or 210 mg/m2 for seven days) for each cycle. Carboplatin was evaluated at three dose rates: 50, 60, and 75 mg/m2/day on the 5-day infusion and 40, 50, and 60 mg/m2/day on the 7-day infusion with cycles repeated at 28 to 42 days. The dose limiting toxicity was hematologic and followed a pattern typical for carboplatin, that is, delayed neutropenia and/or thrombocytopenia with a protracted leukocyte recovery. Renal toxicity was observed in three patients. The optimum total dose for the infusional carboplatin component was 300 mg/m2 (5-day) and 420 mg/m2 (7-day). The total etoposide dose was 150 mg/M2 and 210 mg/M2, which did not appear to contribute to the hematologic toxicity. Delivery of the admixture of VP-16 and CBDCA was feasible, although cumbersome, as a result of the portable delivery system. Extending the duration of infusion increases the total cumulative dose of carboplatin and etoposide that can be administered without increasing adverse effects.     

Metabolic changes following the intravenous infusion of Corynebacterium parvum in man.

The acute changes in concentrations of key blood metabolites and liver function tests were measured following intravenous infusion of Corynebacterium parvum in 9 healthy patients who had recently undergone resection of a colorectal cancer. The following results were obtained: 1) Blood glucose, lactate and ketone body concentrations significantly increased over a 5 hour study period; 2) blood alanine fell during the same period; 3) plasma bilirubin, GOT and urea were significantly elevated 24 hours after C. parvum 4) plasma albumin and cholesterol concentrations were significantly lower 24 hours after C. parvum. These changes are similar to the alterations in hepatic metabolism previously described in clinical bacterial infections, and indicate parenchymal cell damage and reduced synthetic activity. They are potentially important in relation to the treatment of cancer with combined modalities where drug metabolism or excretion may be affected.     

Vinblastine plus bleomycin continuous infusion chemotherapy of stage III testicular carcinomas

Thirty-four consecutive patients with stage III testicular carcinomas were treated with vinblastine, 8 mg/m2 given in 2 fractions on day 1 and 2, followed by continuous intravenous administration of bleomycin, 15 mg/m2 in 1000 cc of 5% glucose and distilled water over a 24-hour period for 5 successive days beginning on day 2. This cycle was repeated every 28-35 days as toxicity permitted. Complete remission occurred in 18% and complete plus partial remission in 79%. Only 2 of 22 patients with advanced abdominal disease achieved a complete remission. After cytoreductive surgery the complete remission rate was increased to 39%. Median survival of complete responders at 3 years has not been reached, and it has been shown to be significantly superior to that of partial (p less than 0.01) and nonresponders (p less than 0.01). Toxic effects consisted mainly in severe leukopenia, stomatitis, adynamic ileum and osteoarticular pain. One drug-related death due to sepsis with agranulocytopenic fever was observed. Probably because of different patient selection, this report could not reproduce the results reported by Samuels et al. with equivalent drug dosage, but it was confirmed that this regimen is able to achieve a high overall response rate and a prolonged median survival in complete responders. The consistent success of this aggressive combination in inducing a high percentage of partial responses has opened the way for a better definition of the role of surgery for the treatment of advanced testicular carcinoma at out Institute.     

Cerebral vasomotor responses after recombinant interleukin 2 infusion

The effects of systemic human recombinant interleukin 2 (rIL-2) infusion upon both the vasoconstrictor effect of hypocapnia and the endothelium-dependent vasodilator effect of acetylcholine (Ach) were examined in anesthetized rats equipped with cranial windows. Prior to the functional studies, each of six animals received an i.v. infusion of rIL-2 (6 x 10(5) IU/kg) every 8 h for 3 days. At the same time, six control animals received infusions of equivalent volumes of sterile water. Eight h after the final infusion, each animal was anesthetized and equipped with a cranial window for the observation of pial arterioles overlying the left frontoparietal cortex. Pial arteriolar diameters were measured before and after the topical application of Ach which in normal cerebral arterioles elicits the release of endothelium-dependent relaxing factor, causing vasodilation. When arteriolar diameters returned to base line, they were measured again both before and during hyperventilation-induced hypocapnia. Following functional assessments, these same pial vessels were processed for study by transmission electron microscopy to determine if any observed functional changes correlated with morphological abnormality. Results of the statistical analyses suggested that normal Ach-induced endothelium-dependent vasodilation was absent in the rIL-2-infused group. Additionally, these animals exhibited reduced reactivity to the vasoconstrictive effects of arterial hypocapnia. The control group exhibited normal responsiveness to both Ach and hyperventilation. Ultrastructural studies revealed occasional morphological alterations of both vascular smooth muscle and endothelial cells in some vessels of rIL-2-infused animals but not in controls. These data suggest that repeated systemic rIL-2 infusion results in altered vasomotor responsiveness within the cerebral microcirculation. The data also suggest that the observed vasomotor changes are not always accompanied by overt morphological alterations of either endothelial or smooth muscle cells.     

Successful treatment of a pretreated elderly case of small-cell lung carcinoma with continuous five-day intravenous infusion of cisplatin plus etoposide]

A 78-year-old man was admitted to our hospital with dyspnea in June 1988, and diagnosed as having small-cell lung carcinoma by cytological findings of pleural effusion. He was treated three times with CAV (cyclophosphamide, doxorubicin, vincristine) therapy and a partial response was achieved. In March 1989, he was again admitted complaining of right dull hypochondralgia accompanied by enlargement of primary tumor in the right lower lobe of the lung and metastases to mediastinal and intraabdominal lymph nodes. Because it was an aged and recurrent case, he was treated with continuous five-day infusion of etoposide, 30 mg/m2/day and CDDP, 18.5 mg/m2/day. After the second course, subjective symptoms clearly disappeared and swelling of mediastinal and intraabdominal lymph nodes was markedly reduced on computed tomography. No severe side effects except for moderate myelosuppression, alopecia and nausea were observed. This regimen appears useful in the treatment of small-cell lung carcinoma in elderly patients.     

Low-dose continuous intravenous infusion of 5-fluorouracil for metastatic breast cancer

BACKGROUND:: Third-line chemotherapies for advanced breast cancer are difficultto tailor to the individual patient because of reduced toleranceand significant toxicity. Treatment with a continuous intravenousinfusion of low-dose 5-fluorouracil (FU-LDCI) is generally welltolerated and thus, a reasonable option for heavily pretreatedpatients. PATIENTS AND METHODS:: From 1989 to 1995,106 consecutive patients with advanced breastcancer were treated with FU-LDCI. 5-Fluorouracil was given atan initial daily dose of 250 mg/m² administered continuouslywith the aid of an elastomer, non-electronic pump through apermanent central venous line for 21 days followed by a 7-dayrest. The median age was 56 years (range, 30–82), themedian ECOG Performance Status was 1 (range 0–4) and themedian number of metastatic sites was 2 (range 1–4). Sixty-onepercent of the patients had previously received more than 2chemotherapy regimens which in 81% included adriamycin, andin 90% 5-fluorouracil. RESULTS:: Eighty patients were evaluable for objective response: 17 ofthem had partial responses (21%, 95% CI: 14%–31%) and23 stable disease (29%, 95% CI: 20%–40%). One-hundredfive patients were evaluable for subjective response, with 46reporting improvement (44%,95% CI: 35%–54%). Previoustreatments with either 5-fluorouracil or adriamycin did notpredict response to FU-LDCI. Median time to progression forpatients with a partial response or stable disease was 259 days(range 82–737). The overall survival for the populationsas a whole was 274 days (range 13–2264), and the mediandose received was 1904 mg/week (range 753–4329). The maintoxic effects were grades I and II mucositis, and nausea andvomiting (observed in 31% and 28%, respectively). Grade IIItoxicities were uncommon: mucositis in 3%, nausea and vomitingin 3%, anemia, thrombocytopenia and hepatitis in 2%, and skintoxicity (hand-foot syndrome) in 1%. Catheter-related thrombosiswas observed in 2% of the patients, and there were no pump failures.A questionnaire concerning the impact of the treatment uponquality of life was completed by all of the 13 patients whowere alive at the time of evaluation of the results, and allof them rated FU-LDCI as easy to tolerate. The monthly costof FU-LDCI (USS1,051.00 in Switzerland) was lower than the costof weekly low-dose adriamycin (USS1,483.00 in Switzerland),a treatment which is often used as a palliative regimen in similarcircumstances. CONCLUSIONS:: FU-LDCI is a useful, cost-effective third-line treatment forpatients with metastatic breast cancer who need palliation withcytotoxic drugs. advanced breast cancer, chemotherapy, 5-fluorouracil infusion, financial costs, low-dose continuous, palliative therapy, quality of life     

Clinical reevaluation of continuous intravenous infusion of 5-fluorouracil--plasma concentrations and clinical dose by continuous intravenous and 60-min infusions

Daily and intermittent continuous intravenous infusions [by gravity drip, (IVG) or infusion pump, (IVP)] and intermittent short-time intravenous drip infusion of 5-FU were carried out on advanced cancer patients. The MTD and dose-limiting toxicity were investigated in relation to the plasma concentrations of 5-FU determined by HPLC. Responses in eleven patients receiving IVG administration daily at 8-21 mg/kg/day were NC, but those given 5-FU alone showed no adverse reactions. Plasma concentrations were too low to be determined. In 9 patients receiving IVG or IVP administration weekly at 60 mg/kg for 24 hr, 1 of the 5 evaluable patients showed reduced hepatic metastatic lesions. One of 4 patients receiving IVP administration weekly at 120 mg/kg for 48 hr showed a disappearance of metastatic lesions in the skeletal muscle, but bone marrow suppression was observed as dose-limiting toxicity. Pharmacokinetics were more stable in IVP than in IVG with less individual difference in the plasma concentrations. Among the outpatients receiving short-time iv, IVG administration once or twice a week, 2 patients given weekly administrations at 20 mg/kg for 60 min showed slight adverse reactions. In 6 patients given high-dose administrations, bone marrow suppression was observed. When pharmacokinetics in the patients given 5-FU for 60 min were compared between the IVG and IVP groups, there were individual differences in plasma concentrations, but the differences were not significant. It was concluded from above results that the following practical dose schedules would be recommendable: 60 mg/kg for 24hr/week by IVP for inpatients and 20 mg/kg for 60 min/week by IVG for outpatients.     

Alterations in polyamine metabolism during continuous intravenous infusion of alpha-difluoromethylornithine showing correlation of thrombocytopenia with alpha-difluoromethylornithine plasma levels

Polyamine biosynthesis is important for cell proliferation and growth. The purpose of this study was to determine the biochemical and pharmacological parameters associated with host toxicity from a continuous infusion of alpha-difluoromethylornithine (DFMO). Twenty-five patients with metastatic carcinoma of the colon or rectum received continuous infusion of DFMO at a median dose of 8 g/m2/day (range, 6-14) for 28 days. DFMO plasma levels, RBC, plasma putrescine, spermidine, and spermine levels, and patient toxicities were evaluated. There was a significant decrease in RBC and plasma levels of putrescine, spermidine, and spermine following DFMO administration compared with the baseline RBC and plasma levels. Pearson correlation coefficient comparing nadir platelet count and steady-state DFMO level was statistically significant (n = 37; P less than 0.01; r = -0.53). Sustained suppression of circulating polyamine levels was also achieved with continuous DFMO infusion. The correlation between steady-state plasma DFMO levels and lowering of platelet count warrants prospective evaluation to determine its clinical usefulness.