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.

High-dose continuous intravenous infusion of interleukin-2 therapy for metastatic renal cell carcinoma: the University of Chicago experience.

OBJECTIVES: Treatment of patients with metastatic renal cell carcinoma with high-dose interleukin-2 (IL-2) administered as continuous intravenous (CIV) infusion or as bolus injection results in response rates of 15% to 30%; however, toxicities with these regimens have been severe. A trial in which CIV IL-2 was administered at high doses during days 1 to 5 and at reduced doses during days 10 to 20 reported less toxicity without a decrease in response rates. We treated a series of patients with this regimen and our experience is presented. METHODS: Seventeen patients with metastatic renal cell carcinoma were treated with IL-2 by CIV at a dose of 18 x 10(6) IU/m2/day for 5 days followed by 4 to 6 days of rest followed by 10 days of CIV IL-2 at a dose of 6 x 10(6) IU/m2/day. Five patients also received CT-1501R, a pentoxifylline derivative. RESULTS: There was 1 partial responder (PR) and there were no complete responses. The patient with the PR had a 14 x 9 cm(2) renal tumor with metastases to lung, pancreas, and liver. A surgical resection induced a CR, but he relapsed 9 months later. Severe toxicities included hyponatremia (serum sodium of less than 123 mmol/L) (n=3), biopsy-proven cardiomyopathy (n=1), creatinine more than 4.5 mg/dL (n=7), and sudden death (n=1). CONCLUSIONS: We conclude that high-dose CIV IL-2 therapy of renal cell carcinoma results in severe toxicity and cannot be recommended for general use. Alternatives need to be developed.

Metastatic colorectal cancer.

Despite advances in screening procedures and the use of adjuvant therapy, approximately 50% of patients with colorectal cancer eventually will develop metastatic disease. Long-term disease-free survival can be achieved in 25% to 40% of selected patients who undergo resection of liver or lung metastases. For all other patients, treatment is palliative. For decades, 5-fluorouracil was the only available drug for colorectal cancer; hence, numerous trials were performed that used various administration schedules and modulating agents to improve therapeutic efficacy. The addition of leucovorin to 5-FU improves response but not survival. Infusion schedules alter the toxicity profile but have a negligible impact on survival. Irinotecan was the first new drug to demonstrate activity in colorectal cancer. It was used initially in the second-line setting, where it was shown to improve quality of life and survival over best supportive care or infusional 5-FU. Recently, irinotecan has been incorporated into the front-line treatment of metastatic colorectal cancer in combination with 5-FU and leucovorin; this combination improves survival by approximately 3 months. Careful patient selection and adherence to strict dose adjustments are essential to prevent significant toxicity when patients are treated on this regimen. The oral fluoropyrimidine capecitabine recently has been approved for the front-line treatment of patients with colorectal cancer who are not appropriate candidates for combination therapy. Oxaliplatin, a novel DACH (diaminocyclohexane) platinum with definite activity in colorectal cancer, is approved for this disease in Europe and is undergoing phase III clinical trials in the United States. Other drugs with potential activity in colorectal cancer include raltitrexed, pemetrexed disodium, and the epothilone analog BMS-247550 (Bristol-Myers Squibb, New York, NY). Novel cytostatics with promising activity in colorectal cancer are being evaluated in clinical trials, including epidermal growth factor receptor inhibitors, such as IMC-C225 (Imclone Systems, New York, NY) and ZD1839 (AstraZeneca, London, UK), angiogenesis inhibitors such as bevacizumab and SU5416 (Sugen, San Francisco, CA), and vaccines such as CEAVac (Titan Pharmaceuticals, San Francisco, CA). For those patients whose disease is localized to the liver, there also is an emerging role for local therapies, including cryosurgery, radiofrequency ablation, and hepatic artery infusional chemotherapy, and resection. The emergence of these new drugs and new interventional modalities has allowed physicians who treat colorectal cancer to move beyond 5-FU.

Adverse reactions to intravenous contrast media in patients treated with interleukin-2.

Seventy patients consecutively admitted to a single institution were treated with high-dose interleukin-2 (IL-2) and analyzed for determining the incidence and risk factors associated with reactions to i.v. contrast media. Patients with metastatic renal cancer (n = 44) or melanoma (n = 26) received 74 cycles of IL-2 administered at 2 to 6 x 10(6) U/m2/d for 10-21 days either alone or with lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TILs). Seventy-four computed tomography (CT) scans were performed before administration of IL-2; and 74, 59, and 35 CT scans were performed, respectively, 2, 6, and 10 weeks after administration of IL-2. Of the 168 scans performed after therapy with IL-2, non-ionic media were used in 110 and ionic media were used in 58. There were no reactions before administration of IL-2, but there were nine reactions after therapy with IL-2. Reactions to contrast media occurred 1-4 hours after media infusion and included fever, chills, emesis, diarrhea, rash, wheezing, hypotension, edema, and oliguria. Hospitalization was required in seven cases, including intensive care unit support in four, but all patients recovered fully. Contrast reactions were more frequent 2 weeks after therapy with IL-2 (eight of 74 scans, 11%) compared with 6 weeks after IL-2 (one of 59 scans, 1.7%), but the difference was not statistically significant (McNemar's test). Six patients who reacted to contrast 2 weeks after IL-2 treatment received contrast 4 weeks later: five had no reaction and only one experienced a reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

CI-980 in advanced melanoma and hormone refractory prostate cancer.

INTRODUCTION: CI-980 is a novel chemotherapeutic agent that inhibits polymerization of tubulin. Preclinical studies have indicated a high level activity of this agent against various tumor cell lines. METHODS: 13 malignant melanoma patients who had failed prior chemotherapy and/or immunotherapy and 13 hormone refractory prostate cancer patients, including 4 who had received prior chemotherapy, were treated in 2 separate NCI-supported clinical trials. Subjects received a recommended phase II dose of CI-980 of 4.5 mg/m2/day by continuous infusion for 72 hours every 3 weeks. RESULTS: No activity was seen in either study. Toxicity was tolerable with neutropenia being the most common, significant toxicity. Among the melanoma patients, 15% and 31% developed grade 3 and grade 4 neutropenia, while 7% and 38% of the prostate patients developed grade 3 and grade 4 neutropenia, respectively. CONCLUSIONS: CI-980 at this dose and schedule is ineffective against malignant melanoma and hormone refractory prostate cancer.

Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced pancreatic carcinoma: a University of Chicago phase II consortium study.

BACKGROUND/OBJECTIVES: Uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) has broad anti-tumor activity for cancers arising from the gastrointestinal tract. However, there are no published data regarding the efficacy of leucovorin-modulated UFT in patients with pancreatic cancer. The objective of this trial was to determine the activity and evaluate the toxicity of UFT plus oral calcium leucovorin in patients with advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Fourteen patients with advanced measurable adenocarcinoma of the pancreas were enrolled onto the trial. Patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided doses every eight hours for 28 days repeated every 35 days. Objective tumor response was evaluated after two courses of therapy. RESULTS: Fourteen patients were evaluable for response and toxicity. No objective responses were seen. The median (range) time to progression and survival were 14 (1.6-37), and 15 (1.9-62) weeks, respectively. Toxicity was mild with severe (grade 3 or 4) hyperbilirubinemia, pain, diarrhea, transaminitis, venous thrombus, weakness, renal failure, confusion, and edema/ascites seen in three (21%), one (7%), two (14%), one (7%), one (7%), one (7%), one (7%), one (7%), and two (14%) patients, respectively. CONCLUSION: In the 14 patients evaluable, UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate anti-tumor activity against advanced pancreatic adenocarcinoma; however, this oral regimen was well tolerated and devoid of neutropenia, significant oral mucositis or diarrhea.

Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced hepatocellular carcinoma.

UNLABELLED: Although UFT 300 mg/m2/day and leucovorin 90 mg/day administered orally in divided doses administered every 8 hours for 28 days repeated every 35 days could be administered safely to patients with advanced hepatomas and good performance status, this combination and schedule has limited activity in treating advanced hepatoma. BACKGROUND/PURPOSE: Biochemical modulation of 5-fluorouracil has yielded higher response rates in hepatoma when compared to treatment with 5-fluorouracil as a single agent, although the impact on survival has been negligible. This study was conducted to determine the activity and evaluate the toxicity of uracil and tegafur in a 4:1 molar concentration ratio (UFT; Bristol-Myers Squibb, Wallingford, CT) plus oral calcium leucovorin in the treatment of patients with advanced hepatocellular carcinoma (hepatoma). PATIENTS AND METHODS: Sixteen patients with advanced measurable hepatocellular carcinoma were enrolled onto the trial. All patients had a Karnofski performance status > or = 60%, platelet count > or = 75,000/micro L, total bilirubin < or = 2.0 x institutional upper limit of normal but otherwise normal liver and kidney function profile and bidimensionally measurable disease by CT or ultrasound examination. None of these patients received prior cytotoxic chemotherapy or radiation therapy for advanced disease. Fourteen patients received 300 mg/m2/d UFT plus 90 mg/d leucovorin administered orally in divided daily doses every 8 hours for 28 days repeated every 35 days. Two patients registered for the trial but did not receive study medication. Objective tumor response, the primary purpose of this trial, was evaluated after two courses of therapy. Other end-points included toxicity, time to progression, and overall survival. RESULTS: Fourteen patients were evaluable for response and toxicity, respectively. No complete or partial responders were observed in this trial. Three patients had stable disease lasting 17 to 22 weeks. Toxicity was mild with severe (grade 3 or 4) liver pain, diarrhea, anorexia/nausea, fatigue, dyspnea, hyperbilirubinemia, anemia, and edema seen in 3 (21%), 2 (14%), 3 (21%), 2 (14%), 1 (7%), 1 (7%), 1 (7%) and 1 (7%) patients, respectively. The most frequent grade I and 2 toxic effects included fever of unknown origin, dyspnea, nausea, vomiting and diarrhea. CONCLUSION: UFT 300 mg/m2/d plus oral leucovorin 90 mg/d administered for 28 days did not demonstrate antitumor activity against advanced hepatomas. Further treatment using this regimen is not recommended for this disease.