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.     

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.     

A phase II trial of interleukin-2 and interferon-alpha in the treatment of metastatic colorectal carcinoma

A total of 29 patients with stage IV colorectal cancer were entered into a phase II trial of bolus interleukin-2 (IL-2) and interferon-alpha (IFN alpha) (3 x 10(6) U/m2 of each cytokine given i.v. q8h x 15 doses and repeated in 2 weeks). Immunologic parameters measured on isolated peripheral blood lymphocytes revealed increased activated T cells with upregulated natural killer and lymphokine-activated killer activity. Among 24 evaluable patients, there were 4 partial responses (17%) of short duration ( < or = 6 months). Three of the responding patients had been refractory to prior chemotherapy. Overall median survival in the 24 evaluable patients was 18.5 months. Therapy necessitated an inpatient setting, with the most common toxicities being hypotension, hepatic insufficiency, fever, hypocalcemia, nausea/vomiting, and renal insufficiency. There were two treatment-related deaths. Because neither IL-2 nor IFN alpha alone has significant activity against colorectal cancer, the responses observed in this study suggest a potential synergistic effect between the two cytokines. However, the toxicity and short duration of response without survival benefit do not support the routine use of this regimen as a therapeutic modality for this tumor histology.     

Continuous venous infusion 5-fluorouracil and interferon-alpha in pancreatic carcinoma

Blood flow via an aberrant internal carotid artery within the tympanic cavity is a rare pathogenic embryonic variation causing pulsatile tintinus and a vascularized tympanum. CT-scan provides the diagnosis. MRI and 3D time-of-flight MRA appear ideal for exploring aberrant flow both for diagnostic purposes and to establish the vascular morphology.     

Phase II trials of 5-fluorouracil and leucovorin in patients with metastatic gastric or pancreatic carcinoma

BACKGROUND: Previous trials in patients with colorectal carcinoma have indicated that enhancement of 5-fluorouracil (5-FU) by leucovorin (LV) can result in an improved response rate and increased survival. METHODS: Phase II trials were performed with patients who had either gastric or papcreatic adenocarcinoma with inetastases. Forty-one gastric carcinoma patients and 31 pancreatic carcinoma patients with measurable disease were treated with 5-FU, 425 mg/m2 intraveneosly (i.v.) on Days 1-5 plus LV, 20 mg/m2 i.v., on Days 1-5, reported at 4 and 8 weeks, and then every 5 weeks thereafter. RESULTS: The patients with metastatic gastric carcinoma had a median survival of 4.8 months. There was a 22% objective response rate, including a 4.9% complete response rate and a 17.1% partial response rate. Among the 31 patients with pancreatic carcinoma, there was a median survival of 5.7 months. No patients in this group showed a response. CONCLUSIONS: The response rate for patients with metastatic gastric adenocarcinoma was modest and this regimen may provide temporary palliation for some patients. However, 5-FU and LV treatment is ineffective against metastatic pancreatic carcinoma.     

Subcutaneous interleukin-2, interferon alfa-2a, and continuous infusion of fluorouracil in metastatic renal cell carcinoma: a multicenter phase II trial. Groupe Fran?ais d'Immunothérapie

PURPOSE: A phase II trial was designed to determine the efficacy and the tolerance of interleukin-2 (IL-2), interferon alfa-2a (IFNalpha), and fluorouracil (5-FU) in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: One hundred eleven patients were included. Patients received subcutaneous IL-2 9 x 10(6) IU daily for 6 days and IFNalpha 6 x 10(6) IU on days 1, 3, and 5 every other week for 8 weeks. 5-FU was administered through a continuous infusion at 600 mg/m2 for 5 consecutive days for 1 week every 4 weeks. RESULTS: The response rate was 1.8% (95% confidence interval [CI], 0% to 4.3%) with only two partial responses (PRs). Toxicity was moderate with 3.6% grade 4 events and two deaths related to treatment. CONCLUSION: This regimen of IL-2, IFNalpha, and 5-FU in patients with metastatic renal cell carcinoma was ineffective. The results raise the question of the dose and schedule of subcutaneous cytokines that must be used in metastatic renal carcinoma.     

Phase II trial of 9-aminocamptothecin administered as a 72-hour continuous infusion in metastatic colorectal carcinoma

PURPOSE: The camptothecin derivative irinotecan has demonstrated clinical activity in metastatic colorectal carcinoma in both chemotherapy-naive and fluorouracil-refractory patients. 9-Aminocamptothecin (9-AC; NSC 603071), another camptothecin derivative, was selected for clinical development based on preclinical activity, including cures in human tumor xenografts resistant to standard anticancer agents. We report a phase II trial of 9-AC in patients with previously untreated metastatic colorectal carcinoma. PATIENTS AND METHODS: Colorectal cancer patients with measurable disease, a performance status of 0 to 2 (Zubrod), and no prior chemotherapy for metastatic disease received 9-AC. A cycle of therapy was 35 microg/m2/h for 72 consecutive hours (840 microg/m2/d for 3 days) and rest on days 4 to 14; a course of therapy was defined as two cycles (28 days). Patients were assessed for response after two courses. RESULTS: Seventeen patients with metastatic colorectal cancer were entered onto this trial. No complete or partial responses were noted. Treatment was well tolerated; toxic effects consisted mainly of neutropenia, nausea, vomiting, stomatitis, fatigue, and anemia. Grade 3 to 4 toxicity was limited to neutropenia (grade 3 in four patients and grade 4 in six), anemia (grade 3 in two patients), and vomiting (grade 3 in two patients). No grade 3 or 4 diarrhea occurred. Only two patients had their 9-AC dose reduced to 30 microg/m2/h. The median nadir absolute granulocyte count (AGC) was 1,500/microL. The median number of courses given was two and the median time to disease progression was 8 weeks. CONCLUSION: At the dose and schedule used in this trial, 9-AC lacked antitumor activity in metastatic colorectal cancer. 9-AC infusion schedules of longer duration are currently being investigated in this disease.     

Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma

Patients with advanced renal cell carcinoma were treated in a Phase I trial with escalating doses of recombinant human interleukin-12 (rHuIL-12) given on days 1, 8, and 15 of each 28-day cycle. Treatment in the initial dose scheme consisted of a fixed dose with dose levels of 0.1, 0.5, and 1.0 microg/kg given to cohorts composed of three or six patients. On the basis of the toxicity profile, a second scheme (up-titration) was undertaken wherein rHuIL-12 was escalated for each patient from week 1 to week 2, to a target dose given week 3 and thereafter; cohort target dose levels were 0.5, 0.75, 1.0, 1.25, and 1.5 microg/kg. Fifty-one patients were treated: 32 (63%) had prior cytokine therapy and 19 (37%) had received no prior systemic therapy. The maximum tolerated dose for the fixed dose scheme was 1.0 microg/kg. Dose-limiting toxicities included increase in transaminase concentration, pulmonary toxicity, and leukopenia. The most severe toxicities occurred with the first injection and were milder upon further treatment. With the up-titration dose scheme, the maximum tolerated dose was reached at 1.5 microg/kg, and dose-limiting toxicity consisted of an increase in serum transaminase levels. At the maximum tolerated dose of 1.5 microg/kg, serum IL-12 levels increased to a mean peak level of 706 pg/ml. Serum levels of IFN-gamma increased to a mean peak level of about 200 pg/ml at 24 h after the first maintenance dose of 1.5 microg/kg. The best responses were as follows: one patient had complete response, 34 patients were stable, 14 patients showed progression, and 1 patient was inevaluable. In conclusion, rHuIL-12 was relatively well tolerated when administered by s.c. injection. The recommended dose according to the up-titration schedule of rHuIL-12 (microg/kg) for Phase II trials was as follows: cycle 1, 0.1 (day 1), 0.5 (day 8), 1.25 (day 15); cycle 2 onwards, 1.25. Phase II trials of rHuIL-12 were initiated in previously untreated patients with renal cell carcinoma and in patients with melanoma.     

Concurrent radiotherapy and chemotherapy with protracted continuous infusion of 5-fluorouracil in inoperable esophageal squamous cell carcinoma

PURPOSE: The feasibility of a concurrent chemoradiotherapeutic protocol for patients with inoperable esophageal squamous cell carcinoma was tested. METHODS AND MATERIALS: Concurrent chemoradiotherapy using protracted low-dose continuous infusions of five-fluorouracil (5-FU; 250-300 mg/m2/24 h) and standard external beam irradiation was given to 28 patients with inoperable esophageal squamous cell carcinoma between November 1991 and June 1993. RESULTS: For 25 patients receiving a total dose of > or = 60 Gy and concurrent 5-FU infusion for more than 5 weeks, the complete response rate was 52%. Local progression-free rate in this chemoradiotherapy group was significantly higher than the historical controls treated by radiotherapy alone (p < 0.05). A multivariate analysis revealed the treatment scheme (concomitant chemoradiotherapy vs. radiotherapy alone) to be a significant factor in local control (p < 0.01). Swallowing pain (39%), anorexia (39%), and nausea (32%) were the most frequent early reactions. Serious late radiation complications have not been observed. CONCLUSION: The concurrent chemoradiotherapy using protracted low-dose continuous infusion of 5-FU and standard radiotherapy is an effective and safe method to obtain a local control in inoperable esophageal squamous cell carcinoma.     

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.     

Myositis associated with interleukin-2 therapy in a patient with metastatic renal cell carcinoma

BACKGROUND: Interleukin-2 (IL-2) has been used successfully in the treatment of some patients with metastatic renal cell carcinoma and melanoma, with a partial response rate of 15%-20%. It produces a well documented spectrum of side effects. Autoimmune diseases have been associated with IL-2 immunotherapy and the development of autoimmune thyroiditis may correlate with antitumor clinical response. METHODS: A patient with metastatic renal cell carcinoma is described who developed a polymyositis-like myopathy after an autologous tumor vaccine and IL-2 therapy. RESULTS: The patient had a delayed response for 15 months after developing this previously unreported toxicity. CONCLUSIONS: To the authors' knowledge, this represents the first reported case of necrotizing myositis in association with IL-2 therapy. Subsequent continuous partial response of the advanced malignancy was observed for 15 months. In this case, IL-2 may have broken tolerance to both normal muscle cells and tumor cells.     

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.     

A phase II trial of 5-fluorouracil, leucovorin, and carboplatin in patients with unresectable biliary tree carcinoma

BACKGROUND: Unresectable adenocarcinoma of the biliary tree are associated with a very poor prognosis. 5-fluorouracil (5-FU) combination regimens have produced objective response rates in approximately 10-20% of patients. Leucovorin increases the selective cytotoxicity of 5-FU. There also are encouraging reports of carboplatin in combination with 5-FU in other gastrointestinal tract malignancies. METHODS: Fourteen consecutive eligible patients were treated with a combination of carboplatin, 300 mg/m2, intravenously (i.v.) on Day 1 only and 5-FU, 400 mg/m2, i.v. with leucovorin, 25 mg/m2, i.v. on Days 1-4. All patients were required to have a histologically confirmed diagnosis and measurable disease. Patients were evaluated for response, survival, and toxicity. RESULTS: A total of 48 cycles of therapy were delivered. The median survival was 5 months. One patient achieved complete remission and two others partial remission, for a total response rate of 21.4%. Four additional patients had stable disease for a median duration of 4 months. The therapy was well tolerated, with moderate myelosuppression as the main dose-limiting toxicity. CONCLUSIONS: The current combination regimen of leucovorin-modulated 5-FU with carboplatin is well tolerated with appropriate supportive care, produces significant objective responses in 21% of patients with biliary tree carcinoma, and should be considered for the treatment of this disease.     

Phase I trial of a 5-day infusion of L-leucovorin plus daily bolus 5-fluorouracil in patients with advanced gastrointestinal malignancies

Increased Na+/H+ exchanger activity is associated with cellular hyperplasia. Cellular hyperplasia is an adaptive response to small-intestinal resection. Therefore, we hypothesized that the small-intestinal Na+/H+ exchanger activity increases in response to small-intestinal resection. Twenty-one-d-old, male Sprague-Dawley rats were randomly divided to receive either a 70% small intestinal resection (n = 59), or a mid-small intestinal transection (n = 49). Seven d postoperatively, the animals were killed and the Na+/H+ exchanger activity of the intestinal remnants was studied by a well validated brush border membrane vesicle technique. The initial rate of Na+ uptake in the presence of an outwardly directed pH gradient and the Vmax of the amiloride-sensitive Na+ uptake were significantly increased (p < 0.01 and p < 0.001, respectively) in the resection as compared with the transection remnants and to a greater magnitude in the distal as compared with the proximal remnants. Km values were not significantly different. The amiloride-sensitive Na+ uptake in the setting of various intravesicular pH was significantly greater (p < 0.001) in the distal resection as compared with the distal transection remnants, with points of enhanced Na+/H+ exchanger activity of intravesicular pH 6.62 and 6.87, respectively. The presence and activation of the Na+/H+ exchanger's internal modifier site was confirmed by demonstrating the effect of intravesicular pH on Na+ efflux. The present study demonstrates an up-regulation of intestinal Na+/H+ exchange activity in a small-bowel resection model in the weanling rat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2''-tetrahydrofuryl)-5-fluorouracil

In order to examine the relationship between long-term potentiation (LTP) and phosphoinositide (PI) turnover, we evaluated these throughout anesthetized rat brain using carbon-11-labeled diacylglycerol (11C-DAG). High-frequency tetanic stimulation (400 pulses at 400 Hz) to the perforant pathway induced LTP in rat dentate gyrus. In autoradiograms of rat brains, LTP was associated with the occurrence of multiple highly radioactive spots in many regions distant from the stimulated site. Following i.v. administration of an NMDA receptor antagonist prior to stimulation, however, no high-density spots were found. These findings directly demonstrate that potentiation of phosphoinositide-derived signaling was induced during LTP, and the finding of multiple location suggests the occurrence of polysynaptic neurotransmission through neural networks pertaining to learning and memory.     

Biologic and clinical effects of continuous infusion interleukin-2 in patients with non-small cell lung cancer

BACKGROUND: Interleukin-2 (IL-2) has shown antitumor activity in some neoplasms, such as melanoma and renal carcinoma, but toxicity derived from bolus administration is significant, particularly at the cardiorespiratory level. METHODS: To test feasibility, antitumor activity, pulmonary and systemic immunologic effects, and pulmonary function changes of continuous-infusion recombinant IL-2 given to patients with non-small cell lung cancer, eleven subjects with Stage III-IV disease were treated in a standard pulmonary medicine unit with a dose of 18 million IU/m2/day from day 1 to day 13 with 1-day rest on day 7. A second induction course was given after a 3-week rest. In patients with nonprogressive disease, four maintenance courses of 6 days' duration at the same dose were planned. Immunologic tests, including lymphocyte phenotype analysis and assays for the detection of tumor necrosis factor (TNF) and of anti-IL-2 antibodies, were performed before and after treatment in serum and bronchoalveolar lavage fluid (BAL). Cardiopulmonary function tests, including spirometry, arterial blood gas analysis, diffusion capacity, and echocardiography, were obtained before, during, and after treatment. RESULTS: Twenty-one cycles (15 induction courses plus 6 maintenance courses) were administered. No patient was able to complete the six planned courses, and only 3 patients entered the maintenance phase. Reasons for discontinuation included progressive disease in five cases, toxicity in three cases, and patient request in three cases. The most common side effects were fever, hypotension, oliguria, and elevated serum creatinine and liver enzyme levels. No patient required intubation or intensive care. No objective response was seen, and the median survival time was 10 months. Lymphocytosis and eosinophilia were observed in all patients. Surface marker analysis revealed a statistically significant increase in the percentage of CD3+, CD4+, CD25+ and DR+ cells in peripheral blood. Lymphoid cells derived from BAL disclosed an increased natural killer activity after IL-2 treatment, and TNF was increased in BAL fluid. Pulmonary function tests evidenced an increased alveolar-arterial difference for oxygen allied with a decrease of forced expiratory volume in 1 second, forced vital capacity, and carbon monoxide transfer coefficient consistent with a significant, albeit not clinically relevant, interstitial lung defect. CONCLUSION: Continuous-infusion IL-2 is feasible in patients with advanced lung cancer even outside an intensive care unit, but overall compliance is poor. Although clinical pulmonary toxicity is negligible, small but statistically significant alterations of the pulmonary function are evident. In addition, this regimen produces a significant activation of the immune system at the pulmonary level.     

Phase II trial of edatrexate in patients with metastatic colorectal cancer

Edatrexate is an analog of methotrexate which in vitro demonstrated activity against human colon cancer xenografts grown in nude mice. In a phase II trial, 12 patients with metastatic colorectal cancer and no prior chemotherapy were treated with Edatrexate 80 mg/m2/week for an initial period of 8 weeks. No objective responses were observed. Edatrexate is inactive against colon cancer at the dose and schedule used in this trial.     

The addition of paclitaxel to continuous infusion 5-fluorouracil is an active regimen for metastatic breast cancer

We investigated tissue staining for Bcl-2 and Bax proteins, which regulate apoptosis, as indicators of chemotherapeutic effect in patients with gastric cancer. In 23 patients with gastric carcinoma biopsy specimens were obtained endoscopically prior to chemotherapy and stained immunohistochemically with anti-Bcl-2 and anti-Bax antibodies. Patients then were treated with continuous infusion of 5-FU and cisplatin. No correlation was seen between chemotherapeutic effect and Bcl-2 or Bax alone. However, among the Bax-positive cases, the patients with Bcl-2-positive tumors were significantly more chemoresistant (p = 0.036) and had worse prognoses (p = 0.008) than Bcl-2-negative cases. Therefore, immunohistochemical staining for Bcl-2 protein may predict chemotherapeutic efficacy or guide specific therapeutic choices in treating Bax-positive tumors.     

Phase II study of 5-fluorouracil and adriamycin in transitional cell carcinoma of the urinary tract

A prospective study was carried out to determine the effectiveness and tolerance of the combination of 5-fluorouracil (600 mg/m2) and Adriamycin (50 mg/m2) given iv every 3 weeks to patients with disseminated transitional cell carcinoma of the urinary tract. Twenty-one of 23 patients entered in the study were evaluable for both response and toxicity. Two patients had complete responses and six had partial responses (greater than or equal to 50% reduction), yielding an overall response rate (complete plus partial) of 38%. Leukopenia (72.7%) and thrombocytopenia (54.5%) were common. Toxicity was life-threatening in one patient. Other common side effects were alopecia, nausea and vomiting, and a generalized feeling of weakness. Responders had a median survival time of 29 weeks compared to a median survival time of 9 weeks for nonresponders.     

Intensive regimen of cytokines with interleukin-2 and interferon alfa-2b in selected patients with metastatic renal carcinoma

We conducted a Phase II trial using an intensive regimen combining interleukin-2 (IL2), interferon-alfa-2b (IFN), and lymphokine-activated killer (LAK) cells. The aim of this study was to evaluate the toxicity and the efficacy of this combination in selected patients with metastatic renal cell carcinoma. Thirty-one assessable patients were treated with at least one cycle of a regimen consisting of 20 x 10(6) IU/day s.c. IFN for 5 days, followed 2 days later by i.v. injections of 24 x 10(6) IU/m2/day IL2 every 8 h together with i.v. bolus of 5 x 10(6) IU/m2/day IFN every 8 h during 5 days. After a 6-day break, during which four leukophereses were performed, this i.v. combination was administered along with the LAK cell reinjections for a maximum of 5 days. Twenty-seven patients underwent the two parts of the first course of treatment; respectively, 42% and 46% of the planned dose of IL2 and IFN were administered. Several severe toxicities were observed including two treatment-related deaths. Significant tumor responses were observed in seven patients, including two complete remissions. Two of these patients remain alive without evidence of disease 36 and 40 months after treatment, respectively. This intensive regimen of IL2 together with IFN and LAK cells cannot be recommended even in selected patients with metastatic renal cell carcinoma. In addition, our results argue against the concept of a dose-response relationship in this setting.