Phase II study of continuous intravenous infusion of recombinant interleukin-2 in patients with advanced renal cell carcinoma

BACKGROUND: The goal of this study was to evaluate the therapeutic efficacy and toxicity of recombinant interleukin-2 (rIL-2) administered by continuous intravenous (CIV) infusion to patients with metastatic renal cell cancer (RCC). PATIENTS AND METHODS: Thirty patients with RCC were given rIL-2 18 MIU/m2/d CIV. The schedule consisted of two induction cycles and four maintenance cycles with a 3-week rest period between cycles. Each induction cycle consisted of two infusion periods lasting 120 and 108 hours, respectively, separated by a 6-day rest period. Each maintenance cycle consisted of a 120-hour infusion period. RESULTS: Among 29 assessable patients, the objective response rate was 14% (95% confidence interval, 2% to 26%); one patient achieved a complete response, and 3 partial responses. Ten patients (34%) had stable disease (SD). Median survival was 11 months. Toxicity was generally manageable. Hypotension was universal, but required dose reduction in only 2 patients. Increase in serum creatinine levels was observed in 20 patients, and returned to normal in all but 4 patients after discontinuation of treatment. CONCLUSION: Results confirm the efficacy of rIL-2 in patients with RCC and the feasibility of the treatment in a normal oncology ward. However, responses are observed in a minority of patients, and treatment-related toxicity, as well as technical problems, may be troublesome to many patients.     

Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies

Guanidines, amidines, S-alkylisothioureas, and other compounds containing the amidine function (-C(=NH)NH2) have been described as inhibitors of the generation of nitric oxide (NO) by NO synthase (NOS). Here we report on the inhibition of the activity of NOS isoforms by compounds in which the amidine function is attached to a nitrogen of 1,2-diazo heterocycles to form N-carboxamidines and related compounds. 1H-Pyrazole-1-carboxamidine HCl (PCA) inhibited the activity of purified inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS) isoforms to a similar extent (IC50 = 0.2 microM). 3-Methyl-PCA and 4-methyl-PCA showed reduced potencies, but a preference for iNOS [IC50 = 5 and 2.4 microM, respectively; cf. N(G)-methyl-L-arginine (NMA) IC50 = 6 microM]. Inhibition of purified iNOS by PCAs could be reversed completely by excess L-arginine, while their inhibition of NO production by stimulated RAW macrophages could be reversed by transfer to a drug-free medium. This suggests a competitive mode of inhibition. PCA caused potent concentration-dependent inhibition of the acetylcholine-induced, endothelium-dependent relaxations of precontracted rat thoracic aorta (IC50 = 30 microM). 4-Methyl-PCA inhibited the relaxations only at > or = 300 microM. In contrast, 4-methyl-PCA was more effective than both PCA and NMA in restoring the ex vivo contractility of aortic rings taken from lipopolysaccharide-treated rats. PCA and NMA, but not 4-methyl-PCA, caused marked increases in mean arterial pressure when administered i.v. to anesthetized rats. In conclusion, PCA and related compounds caused potent inhibition of NOS. Substitution of the pyrazole ring reduced potency, but improved selectivity towards iNOS as exemplified by 4-methyl-PCA.     

A comparison of 2 modes of administration of recombinant interleukin-2: continuous intravenous infusion alone versus subcutaneous administration plus interferon alpha in patients with advanced renal cell carcinoma

PURPOSE: To compare 2 treatment modalities with recombinant Interleukin-2 (rIL-2) for patients with advanced Renal Cell carcinoma (RCC): continuous intravenous infusion (CIV) alone versus subcutaneous (s/c) rIL-2 + Interferon-alpha (IFN-alpha). PATIENTS AND METHODS: Data have been collected on 425 patients with RCC, treated CIV rIL-2 alone, (225 patients), or rIL-2 by the s/c route (200 patients). Patients receiving s/c rIL-2 also received s/c IFN-alpha both drugs being administered on an outpatient basis. Patients receiving CIV rIL-2 were treated as inpatients. Patient eligibility criteria were similar on all studies, and included patients with progressive, advanced disease, but with an ambulatory performance status. RESULTS: The overall response rate for the CIV schedules was not significantly different from the s/c regimens: 15% (95% confidence limits (CL) 10-20%) vs 20% (95%CL 14-26%) with 4% CR in both approaches. Durable responses were seen in both CIV and s/c schedules and there was no evidence of a significant difference in survival in multivariate analysis. There was however an important shift in the toxicity profile. The s/c regimens do not induce a clinically detectable capillary leak syndrome, which is the dose limiting toxicity for CIV regimens. CONCLUSION: Although the introduction of CIV regimens of rIL-2 was a major step forward compared to high-dose bolus, because most patients could be treated in a normal oncology ward, the s/c schedule of rIL-2 + IFN-alpha offers the possibility of outpatient (home) therapy, with no evidence of a reduction in efficacy.     

Phase II trial of 5-fluorouracil, interferon-alpha and continuous infusion interleukin-2 for patients with metastatic renal cell carcinoma

BACKGROUND: This study was designed to evaluate the efficacy and toxicity of the combination of 5-fluorouracil, interferon-alpha, and interleukin-2 for patients with metastatic renal cell carcinoma. METHODS: Previously untreated patients with a Zubrod performance status of < or =2; adequate cardiac, pulmonary, and renal function; and absence of brain metastases were eligible. One course of therapy was 28 days. 5-fluorouracil was administered at a dose of 600 mg/m2/day as a continuous infusions on Days 1-5. Interleukin-2 also was administered as a continuous infusion on Days 1-5 at a dose of 2 million Roche U/m2/day. Interferon-alpha was given as a daily subcutaneous injection of 4 million U/m2/day. RESULTS: Fifty-five patients were enrolled in the trial and 52 were evaluable for response. All patients experienced fever and flu-like symptoms. Grade 3 or 4 nonhematologic toxic effects included hypertension (48%), dermatitis (12%), stomatitis (11%), and altered mental status (9%). There was one toxic death. Four complete responses and 12 partial responses were observed for a total response rate of 31% (95% confidence interval, 18-46%). The survival of responding patients was significantly better than that of nonresponding patients. The improvement in survival was even more significant when comparing patients with at least stable disease with those who progressed through treatment. CONCLUSIONS: The three-drug combination described in this study demonstrates activity. However, it appears to be more toxic than other regimens with similar response rates and cannot be recommended for standard practice. Changing the interleukin-2 route to subcutaneous administration may permit more continuous administration with less toxic effects.     

Phase II study of combined levamisole with recombinant interleukin-2 in patients with advanced malignant melanoma

Adoptive immunotherapy (AI) with interleukin-2 (IL-2) and lymphokine-activated killer cells (LAK) is an antineoplastic modality in which immune-activated cells are administered to a host with advanced cancer in an attempt to mediate tumor regression. Levamisole (LEV), an immune stimulant, has been suggested to have therapeutic effectiveness in a variety of cancers. After a phase I trial of recombinant IL-2 plus LEV, a phase II trial of this combination was conducted in patients with advanced malignant melanoma. Nineteen patients were entered in the trial. They received IL-2 at 3 x 10(6) U/m2 subcutaneously daily x 5 plus LEV 50 mg/ m2 orally three times daily (p.o. t.i.d.) x 5. Patients were reevaluated at four-week intervals. None of the patients achieved a partial or complete regression (PR, CR). The median time to treatment failure (refusal, progression, or off study due to toxicity) was 56 days. Grade IV toxicities included vomiting (3 patients), lethargy (1 patient), and musculoskellar pain (1 patient). This regimen is not recommended for further testing in patients with advanced malignant melanoma.     

Pharmacodynamics of subcutaneous recombinant human interleukin-10 in healthy volunteers

The wound-healing efficacy of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) was studied in a mouse model. Full-thickness wounds were treated with liquid crystalline, emulsion, and niosome vehicles alone and with rhGM-CSF. The control group was non-medicated. Observation of the vehicle groups with and without the rhGM-CSF displayed better healing profiles than the control group. The vehicles were also evaluated among themselves and it was noted that emulsion base and niosome base groups gave significantly better healing profiles and histological results than the liquid crystalline base group. Among the rhGM-CSF containing groups, emulsion formulation displayed a stronger wound-healing effectiveness compared to the other formulations. In vitro release characteristics of the recombinant protein from the three vehicle formulations were demonstrated with diffusion cells. Histological and immunohistochemical evaluation was performed on biopsies taken on the last day of the experiment.     

Phase I trial of temozolomide (NSC 362856) in patients with advanced cancer

Temozolomide (TMZ) is a new imidazotetrazine derivative with early clinical activity in glioma and melanoma. The purpose of this Phase I study is to characterize the toxicity, pharmacokinetics, and antitumor activity of TMZ administered on an oral 5-day schedule to patients with or without prior exposure to nitrosourea (NU). Thirty-six eligible patients received a total of 77 cycles of therapy with TMZ administered p.o. at doses ranging from 50 mg/m2/day to 250 mg/m2/day for 5 days, every 4 weeks. Separate dose escalations were carried out in patients, with or without prior exposure to NU. Pharmacokinetic studies were performed during the first cycle of treatment on days 1 and 5. Dose-limiting toxicity was thrombocytopenia, and the maximally tolerated doses for patients with and without prior exposure to NU were 150 mg/m2/day for 5 days (total dose, 750 mg/m2) and 250 mg/m2/day for 5 days (total dose, 1250 mg/m2), respectively. Significant (grade 3 or higher) thrombocytopenia was observed in six patients during cycle 1. The median times to nadir and recovery were 17 and 15 days, respectively. Nonhematological toxicity was generally manageable and consisted of fatigue, nausea, and vomiting. There were two complete responses (one glioma and one melanoma) in patients without prior NU. No objective responses were seen in patients with prior NU treatment. Pharmacokinetic studies showed rapid absorption with a mean time to peak concentration of 60 min and mean t1/2 of 109 min (range, 80-121 min). The area under the curve and the peak plasma concentrations were linear over the dose range of 50-250 mg/m2/day. The mean apparent oral clearances on day 1 for patients with and without prior NU exposure were 102+/- 27 and 115+/- 22 ml/min/m2, respectively. Apparent oral clearances on days 1 and 5 were found to differ with respect to NU exposure (P = 0.047). Renal clearance of the parent drug and its metabolism to 3-methyl-2, 3-dihydro-4-oxoimidazo[5,1-d]tetrazine-8-carboxylic acid were minor pathways of TMZ elimination. We conclude that TMZ is well tolerated in this oral 5-day schedule with dose-limiting thrombocytopenia and that it has promising activity in glioma and melanoma. The recommended doses for Phase II studies in patients with and without prior NU are 125 mg/m2/day for 5 days and 225 mg/m2/day for 5 days, respectively.     

Phase I/II radioimmunotherapy trial with iodine-131-labeled monoclonal antibody G250 in metastatic renal cell carcinoma

This Phase I/II radioimmunotherapy study was carried out to determine the maximum tolerated dose (MTD) and therapeutic potential of 131I-G250. Thirty-three patients with measurable metastatic renal cell carcinoma were treated. Groups of at least three patients received escalating amounts of 1311I (30, 45, 60, 75, and 90 mCi/m2) labeled to 10 mg of mouse monoclonal antibody G250, administered as a single i.v. infusion. Fifteen patients were studied at the MTD of activity. No patient had received prior significant radiotherapy; one had received prior G250. Whole-body scintigrams and single-photon emission computed tomography images were obtained in all patients. There was targeting of radioactivity to all known tumor sites that were > or =2 cm. Reversible liver function test abnormalities were observed in the majority of patients (27 of 33 patients). There was no correlation between the amount of 131I administered or hepatic absorbed radiation dose (median, 0.073 Gy/mCi) and the extent or nature of hepatic toxicity. Two of the first six patients at 90 mCi/m2 had grade > or =3 thrombocytopenia; the MTD was determined to be 90 mCi/m2 131I. Hematological toxicity was correlated with whole-body absorbed radiation dose. All patients developed human antimouse antibodies within 4 weeks posttherapy; retreatment was, therefore, not possible. Seventeen of 33 evaluable patients had stable disease. There were no major responses. On the basis of external imaging, 131I-labeled mouse monoclonal antibody G250 showed excellent localization to all tumors that were > or =2 cm. Seventeen of 33 patients had stable disease, with tumor shrinkage observed in two patients. Antibody immunogenicity restricted therapy to a single infusion. Studies with a nonimmunogenic G250 antibody are warranted.     

Renal masses simulating primary renal cell carcinoma in patients with advanced malignancies

Most patients who present with a large solid renal mass and evidence of advanced malignancy will have primary renal cell carcinoma but a small subset with similar features have different and more treatable malignancies. We identified 7 patients with clinical and radiological findings suggestive of metastatic renal cell carcinoma who were ultimately diagnosed as have non-Hodgkin's lymphoma (5), germ cell tumor (1) or transitional cell carcinoma (1). Two of these patients presented with abdominal pain, gross hematuria and a flank mass. Computerized tomography was interpreted as showing renal cell carcinoma in all patients, although lymphoma and sarcoma were included in the differential diagnoses in 2. With the correct diagnosis and appropriate therapy, 4 of the 7 patients are currently disease-free. We emphasize the need for histological documentation in such patients in view of curative therapy available for possible underlying neoplasms simulating renal cell carcinoma.     

Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma

PURPOSE: The management of metastatic renal cell carcinoma remains challenging and controversial. There is some evidence of improved response to interleukin-2 (IL-2) based immunotherapy in patients who undergo nephrectomy before systemic treatment. However, recent reports have suggested that surgery prior to immunotherapy may not be an efficient strategy, since many patients will not be able to receive systemic treatment after nephrectomy. We describe our criteria for determining which patients are candidates for nephrectomy before immunotherapy and present our series of patients treated with this approach. MATERIALS AND METHODS: Based on our initial experience with IL-2 based immunotherapy we developed certain inclusion criteria for treatment with initial nephrectomy followed by systemic immunotherapy, including greater than 75% debulking of tumor burden possible, no central nervous system, bone or liver metastases, adequate pulmonary and cardiac function, and Eastern Cooperative Oncology Group performance status of 0 or 1. In addition, patients in whom biopsies show other than predominantly clear cell type histology are excluded. From 1991 through 1996, 28 patients met these criteria and were treated with this approach. Patients were followed to determine the number receiving immunotherapy as well as overall response and survival rates. RESULTS: Radical nephrectomy was performed in all patients. One patient died of respiratory failure from disease progression 1 month after nephrectomy. Another patient had poor pulmonary function and, therefore, was treated with an alternative cytokine therapy. The remaining 26 patients (93%) received at least 1 course of IL-2. Median interval between nephrectomy and initiation of immunotherapy was 1.5 months (range 1 to 3). Overall response rate was 39% with 5 complete (18%) and 6 partial (21%) responses. Actuarial median survival of the entire group was 20.5 months (range 1 to 66) from the initiation of treatment. Currently 13 patients are alive, including 8 who are disease and/or progression-free. CONCLUSIONS: Using these strict criteria nephrectomy can be effectively performed before immunotherapy without compromising the likelihood that patients will receive systemic treatment. The activity of IL-2 in patients treated with this approach is encouraging and justifies its consideration in properly selected patients.     

Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer

PURPOSE: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine. PATIENTS AND METHODS: Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi). RESULTS: At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (Cmax) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t1/2; median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was described by a one-compartment model with a t1/2 of 0.41 hours; peak levels of UFTi were 5.2% +/- 2.5% those of TPTi. CONCLUSION: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.     

Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer

PURPOSE: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies. PATIENTS AND METHODS: Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery. RESULTS: Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs. CONCLUSION: Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.     

Phase I trial of anti-CD3-stimulated CD4+ T cells, infusional interleukin-2, and cyclophosphamide in patients with advanced cancer

PURPOSE: We performed a phase I trial to determine whether in vivo expansion of activated CD4+ T cells was possible in cancer patients. 111Indium labeling was used to observe trafficking patterns of the infused stimulated CD4+ T cells. The influence of cyclophosphamide (CTX) dosing on immunologic outcome was also examined. PATIENTS AND METHODS: Patients with advanced solid tumors or non-Hodgkin's lymphoma received CTX at 300 or 1,000 mg/m2 intravenously (i.v.). Leukapheresis was performed to harvest peripheral-blood mononuclear cells (PBMCs) either just before the CTX dose, or when the patient was either entering or recovering from the leukocyte nadir induced by CTX. An enriched population of CD4+ T cells was obtained by negative selection. The CD4+ T cells were activated ex vivo with anti-CD3, cultured with interleukin-2 (IL-2) for 4 days, and adoptively transferred. After adoptive transfer, patients received IL-2 (9.0 x 10(6) IU/m2/d) by continuous infusion for 7 days. RESULTS: The absolute number of CD4+, CD4+/DR+, and CD4+/CD45RO+ T cells increased in a statistically significant fashion in all cohorts after the first course of therapy. The degree of CD4 expansion was much greater than CD8 expansion, which resulted in a CD4:CD8 ratio that increased in 26 of 31 patients. The greatest in vivo CD4 expansion occurred when cells were harvested as patients entered the CTX-induced nadir. One complete response (CR), two partial responses (PRs), and eight minor responses were observed. Trafficking of 111Indium-labeled CD4 cells to subcutaneous melanoma deposits was also documented. CONCLUSION: CD4+ T cells can be expanded in vivo in cancer patients, which results in increased CD4:CD8 ratios. The timing of pheresis in relation to CTX administration influences the degree of CD4 expansion. Tumor responses with this regimen were observed in a variety of tumors, including melanoma and non-Hodgkin's lymphoma; a high percentage of patients had at least some tumor regression from the regimen that produced the greatest CD4+ T-cell expansion.     

Phase II trial of titanocene dichloride in advanced renal-cell carcinoma

We report on a series of 48 patients, ages 14 to 20 year, with hypophyseal adenomas. Of these, 46 (96%) had secreting tumors, 3 had Cushing's disease, 9 had somatotrophinomas, and 34 (29 females and 5 males) had prolactinomas. Thirty cases were diagnosed as intrasellar adenomas (62%) while the remaining eighteen (38%) presented extrasellar expansion. Of 9 acromegalic patients, 7 had typical clinical and biochemical features 2 were exclusively prognatic with normal basal GH levels, but abnormal dynamic tests. Prolactinomas were noninvasive in women and faster growing and more extensive in men. Forty seven patients underwent surgery. Five of these required craniotomy and the rest approached through the sphenoidal bone (TSE). Remission was achieved in Cushing's disease, acromegaly, and female intrasellar prolactinomas. Larger tumors such as nonsecreting adenomas and male prolactinomas showed poor results after undergoing subtotal resections, with persistence of endocrinological disturbances. From our findings it appears that these tumors are aggressive in youth than in adults. Because there was a close relationship between tumor size, invasiveness, and the patients' final outcome, we conclude that early diagnosis and treatment is essential. Frequent complaints in adolescents such as irregular menses, retarded puberty, and growth disorders should be thoroughly investigated and not merely considered as transient or 'functional'.     

Phase I/II trial of all-trans retinoic acid and tamoxifen in patients with advanced breast cancer

Because tamoxifen and all-trans-retinoic acid (ATRA) have additive antitumor effects in preclinical systems, we performed a Phase I/II clinical trial of this combination in patients with advanced breast cancer. Patients with potentially hormone-responsive advanced breast cancer were enrolled. All received 20 mg of tamoxifen by mouth daily. Consecutive cohorts of 3-6 patients were treated on odd-numbered weeks with ATRA at doses of 70, 110, 150, 190, or 230 mg/m2/day. Twenty-six patients were entered in this trial; 25 were evaluable. A dose of 230 mg/m2 ATRA produced unacceptable headache and dermatological toxicity, but doses < or = 190 mg/m2 were tolerable. Two of 7 patients with measurable disease responded. Seven of 18 patients with evaluable, nonmeasurable disease achieved disease stability for more than 6 months. Plasma AUCs on day 1 of successive weeks of treatment were stable over time. A nonsignificant decrease in serum insulin-like growth factor I levels was noted during treatment, but this trend was similar to that observed in three "control" patients treated with tamoxifen alone. When given with daily tamoxifen, the maximum tolerated dose of ATRA that could be given on alternate weeks was 190 mg/m2/day. This schedule of ATRA resulted in repeated periods of exposure to potentially therapeutic concentrations of ATRA. Declines in the serum insulin-like growth factor I concentrations observed in patients treated with tamoxifen and ATRA were similar to those observed in patients treated with tamoxifen alone. Objective responses were observed, some in patients who had previously progressed while receiving tamoxifen, suggesting that further studies would be of interest.     

A randomized trial of recombinant human interleukin-11 following autologous bone marrow transplantation with peripheral blood progenitor cell support in patients with breast cancer

Complications resulting from advanced atherosclerosis are the most common indication for vascular reconstructive surgery. Atherosclerosis is a systemic disease affecting the entire arterial tree, but lesions involving the coronary, extracranial cerebral, and lower extremity circulations have the most clinical significance for surgeons. The pathogenesis of atherosclerosis involves a complex series of events, similar to a chronic inflammatory process, with the formation of atherosclerotic plaque as the end result. Injury to the endothelial cell of the artery, resulting in endothelial cell dysfunction, is the first step in the process. Activated endothelial cells attract leukocytes and vascular smooth muscle cells (VSMC), which accumulate and proliferate in the arterial wall. These cellular components produce an excessive amount of connective tissue matrix. The ultimate end point is the formation of a mature fibrous plaque. Symptoms occur when advanced lesions are complicated by plaque rupture, hemorrhage into the plaque, emboli, or thrombosis. A thorough understanding of the pathogenesis of atherosclerosis is essential for the development of strategies for the prevention of the disease, and for the development of new and effective treatments.     

A phase II study of interleukin-2 with and without beta-interferon in the treatment of advanced renal cell carcinoma

BACKGROUND: Biologic response modifiers have activity in renal cell carcinoma. The combination of interleukin-2 (IL-2) and beta-interferon (B-IFN) is synergistic in vitro. This trial was initiated to determine the efficacy of IL-2 alone and with B-IFN in advanced RCC. METHODS: Ambulatory patients with advanced RCC were randomly allocated to either IL-2 6 x 10(6) units/M2 intravenously (IV) three days a week for four weeks or IL-2 5 x 10(6) units/M2 IV plus B-IFN 6 x 10(6) units/M2 IV three days a week for 4 weeks. This induction phase was followed by a maintenance phase of the same drugs and doses administered for two weeks out of every four. RESULTS: 84 patients were entered onto this phase II trial with 75 considered eligible for response and survival. Toxicity is reported for the 81 patients on whom data was received, irrespective of eligibility. The overall response rate (RR) was 9.3% (7/75). Of the 3 responses in the IL-2 arm (RR = 8.3%), one was a complete response. 4 patients in the IL-2 + B-IFN arm (RR = 10.3%) achieved a partial response. Median survival was estimated to be 8.4 months for patients given IL-2 and 8.0 months for patients given the IL-2 and B-IFN combination. Multivariate analysis of survival data identified initial performance status, metastases of > 1 site, and weight loss as being important prognostic factors for survival. There were 2 lethal and 3 life threatening toxicities with the IL-2 treatment. While there were no lethal toxicities on the combination arm, there were 4 life threatening toxicities. CONCLUSIONS: The results of this study indicate that further investigation of IL-2 with or without B-IFN at this dose and schedule as treatments for renal cell carcinoma is probably not warranted.     

Pharmacokinetics of recombinant human interferon-alpha 2a combined with 5-fluorouracil in patients with advanced colorectal carcinoma

A cohort study was conducted to estimate the risk of breast cancer recurrence among women diagnosed with ductal carcinoma in situ (DCIS) and to identify tumor or patient characteristics that influence that risk. A population-based cancer registry was used to identify a cohort of 709 female residents of western Washington who were diagnosed with DCIS between January 1980 and June 1992 and were treated with breast-conserving surgery. Information about breast cancer recurrences, treatment, and several patient characteristics and exposures was obtained from postal questionnaires. Recurrences were confirmed using information from the cancer registry or hospital pathology reports. Approximately 15% of women experienced a recurrence within the first 5 years after diagnosis [95% confidence interval (CI), 12-18%]; 31% had a recurrence within 10 years (95% CI, 24-38%). There was a suggestion that risk was slightly elevated for women with larger tumors (> or =1.5 cm) and tumors of comedo subtype. Relative risks (RRs) were elevated for women who were premenopausal at diagnosis of DCIS (RR = 2.3; 95% CI, 1.1-5.0). Women in the upper decile of body mass index were at twice the risk of a recurrence as those women in the lower four deciles (RR = 2.3; 95% CI, 1.1-4.8). There was also a suggestion that women who used menopausal hormones for at least 2 years after their diagnosis of DCIS were at increased risk of recurrence compared to nonusers of menopausal hormones (RR = 1.8; 95% CI, 0.7-5.0). Our results suggest that the risk of recurrence may be related to some tumor characteristics as well as the hormonal milieu of the patient at or after her diagnosis of DCIS. However, larger studies are needed to more clearly document predictors of disease recurrence after DCIS.     

Phase I/II trial of combined 131I anti-CEA monoclonal antibody and hyperthermia in patients with advanced colorectal adenocarcinoma

BACKGROUND: This pilot project was undertaken to evaluate the toxicity of and tumor response to combined 131I anti-carcinoembryonic antigen monoclonal antibody (131I anti-CEA RMoAb) and hyperthermia in patients with metastatic colorectal adenocarcinoma. METHODS: Nine patients who had colorectal carcinoma with liver metastases were enrolled in this study. Intact 131I anti-CEA RMoAb was used (the specific antibody was IMMU-4, provided by Immunomedics, Inc., Morris Plains, NJ). During the diagnostic phase, dosimetry revealed that the tumor site received a higher radiation dose than the surrounding normal tissues in only six patients. These six, who were treated with radioimmunotherapy and hyperthermia, were the basis of this study. The first three patients were treated with 30 mCi/m2 of 131I anti-CEA RMoAb, and the next three received 60 mCi/m2. Pharmacokinetic clearance data were reported for all nine patients. RESULTS: Thermometry data revealed an average T90 of 40.3 (+/- 1.4 degrees C) and T50 of 41.1 (+/- 1.2 degrees C). The average thermal dose equivalent at 42.5 degrees C was 34.5 (+/- 21.5) minutes. The average Tmin, Tmax, and Tmeam were 40 (+/- 1.2 degrees C), 42.4 (+/- 0.7 degrees C), and 41.1 (+/- 1.1 degrees C), respectively. The pharmacokinetic clearance data of antibody showed monoexponential plasma clearances in all patients except one, in whom a biexponential plasma clearance was observed. In general, similar plasma and whole-body clearances as well as similar urinary excretions were observed when diagnostic and therapeutic phases for each patient were compared. Two of the six patients showed a marked improvement in their symptoms; five patients showed a drop in carcinoembryonic antigen levels. A follow-up computed tomography scan one month after treatment showed no change in tumor volume in five patients; one patient showed a partial response. Three patients developed toxicity, two developed moderate thrombocytopenia (39,000 and 58,000), and the other patient developed hematoma resulting from the insertion of a catheter for thermometry. CONCLUSIONS: It is feasible to combine hyperthermia and radiolabeled monoclonal antibodies, and the combination was well tolerated by these patients. The interaction between hyperthermia and low dose rate radioimmunotherapy is complex. Further studies are necessary to explore the use of this combined modality in the management of maligancies.     

Serum interleukin-6 in relation to acute-phase reactants and survival in patients with renal cell carcinoma

Patients with malignancies often present with signs of inflammatory reactions such as elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Since interleukin-6 (IL-6) is a possible regulator of these reactions and has been proposed as a predictor of prognosis, the aim of the study was to analyse its clinical significance in patients with renal cell carcinoma. Serum samples were collected from 196 patients before any treatment. IL-6 was analysed by an enzyme-linked immunoassay and compared with tumour grade, stage, acute-phase reactants and survival. Patients with renal cell carcinoma had significantly higher IL-6 levels (mean 28.1 +/- 63.4 ng/l; median 8.3 ng/l) compared with controls (mean 1.7 +/- 2.6 ng/l; median 0.5 ng/l; P < 0.001). Serum IL-6 levels in patients with distant metastases were significantly higher than for patients with tumours confined to the kidney (P = 0.02). This difference was more pronounced when serum IL-6 levels in patients with poorly differentiated tumours were compared with well-differentiated tumours (P < 0.001). A significant correlation between the acute-phase reactants CRP, ESR and IL-6 levels was found. Survival time was significantly shorter (P = 0.001) for patients with IL-6 levels above the median serum level compared with patients with lower levels. Similar significant prognostic results were obtained in the group of patients with metastatic disease, but not in group of patients with stage I-III. Serum levels of IL-6 correlated to tumour stage, grade and acute-phase reactants. Increased levels were related to the presence of metastases and adverse survival. Serum IL-6 proved univariate prognostic information but this prognostic significance was lost using a multivariate analysis.