Circadian-shaped infusions of floxuridine for progressive metastatic renal cell carcinoma

Sixty-eight unselected patients with progressive metastatic renal cell carcinoma (RCC) were treated between March 1985 and November 1988 with continuous infusion floxuridine (FUDR). Thirty-seven percent of these patients had previously received and failed systemic treatment. Using implantable pumps for automatic drug delivery, FUDR was continuously infused for 14 days at monthly intervals. The starting dose was 0.15 mg/kg/d (intravenous [IV]; n = 61) or 0.25 mg/kg/d (intraarterial [IA]; n = 7); IV doses were increased or decreased in increments of 0.025 mg/kg/d as permitted by toxicity. Diarrhea (with or without mild abdominal cramping) and nausea/vomiting limited the FUDR IV infusion, and hepatic function abnormalities limited FUDR IA infusion. The use of a circadian-modified infusion schedule permitted high FUDR doses to be safely given as compared with a constant rate infusion schedule. Of 63 patients assessable for response, 56 received systemic FUDR infusion. Four complete responses (CRs; 7.1%); and seven partial responses (PRs; 12.5%) were observed (objective response rate, CR plus PR, 19.6 +/- 5.1% [95% confidence limits] ). The median objective response duration was 10.8 months (range, 1 to 18 months; mean, 9.4 +/- 1.6). Four additional patients had minor tumor responses (MRs; 7.1%). In a subgroup of seven assessable patients receiving hepatic arterial FUDR, we observed one CR and three PRs (57.2 +/- 42.8%). Overall, objective response (CR plus PR) was seen in a quarter of assessable patients treated, 15 of 63, while only 15 of the 63 assessable patients (25.4%) have had objective tumor progression. The median follow-up time for all 68 patients was 28 months (range, 1 to 42), and their median survival duration is 15 months (range, 3 to 37 months). Continuous infusion FUDR is an effective outpatient treatment for progressive metastatic RCC, producing durable tumor response and causing little toxicity.     

Continuous intrahepatic infusion of floxuridine and leucovorin through an implantable pump for the treatment of hepatic metastases from colorectal carcinoma

Based on laboratory studies showing enhanced cytotoxicity of floxuridine (FUDR) when used with high doses of leucovorin (LV), a pilot study of FUDR and LV through an implantable pump was initiated for the treatment of hepatic metastases from colorectal cancer. The highest dose of LV that could be administered, taking into account the constraints of the capacity of the pump and the solubility of LV, was 120 mg/m2/d. Due to the possibility of added toxicity, 25% of this dose was initially used. Twenty-four patients were treated at three dose levels. Eight patients were treated with the combination of LV (30 mg/m2/d) and FUDR (0.3 mg/kg/d) for a 14-day infusion through the pump, alternating with 2 weeks of saline. All eight patients had a greater than 50% decrease in measurable disease (PR) and a greater than 50% decrease in carcinoembryonic antigen (CEA) value; however, sclerosing cholangitis developed in two of these patients within 4 months. The next seven patients were treated with a lower dose of FUDR (0.2 mg/kg/d) and the same dose of LV, both for 14 days. Four of seven patients had a PR, and toxicity was decreased with no biliary sclerosis. A third regimen explored the combination of FUDR (0.3 mg/kg/d) and LV (30 mg/m2/d) for 7 days, alternating with 1 week of saline, to evaluate a shorter interval of treatment with the same overall dose intensity. Six of nine patients had a PR and all patients had a greater than 50% decrease in CEA value; sclerosing cholangitis developed in three of these patients. The overall response rate was 72%, with 18 of 25 patients alive after 1 year. The median survival time has not been determined, but it is greater than 27 months. FUDR with LV appeared to be effective in the treatment of hepatic metastases from colorectal carcinoma, but hepatic toxicity appeared to be greater than that previously reported with FUDR alone.     

Regional chemotherapy for hepatic metastases of colorectal carcinoma (continuous intraarterial versus continuous intraarterial/intravenous therapy). Results of a controlled clinical trial

Sixty-four patients with a biopsy diagnosis of colorectal cancer with liver metastases were treated with 5-fluorodeoxyuridine (FUDR) infusions. In a pilot study, the first 20 patients were given hepatic artery infusions of FUDR by implanted pumps. The remaining 44 patients were then randomized prospectively to compare the effectiveness of continuous hepatic artery and intravenous infusion of FUDR (IA/IV group; 21 patients) with hepatic artery infusion alone (IA group; 23 patients). A continuous 14-day infusion regimen of FUDR was applied each month. The dosage was 0.2 mg/kg/d of FUDR for the IA group and 0.3 mg/kg/d for the IA/IV group. The complete and partial response rates were each 50% in the pilot study and 52% and 48% in the IA and IA/IV randomized groups, respectively. Drug toxicities in the 64 patients included gastroenteritis (21%), chemical hepatitis (57%), and biliary sclerosis (25%). There was no difference in the toxicity of FUDR in the two randomized groups (P greater than 0.1). Extrahepatic spread of cancer during therapy was found in 61% (n = 14) of the IA group and 33% (n = 7) of the IA/IV group. There was no difference in survival between the randomized groups. The 64 patients were categorized into the following two groups according to their response to therapy: (1) responders (patients with complete or partial remission [n = 32]) or nonresponders (patients with stable disease or progression of metastases [n = 32]). The median survival time was 31 months for responders and 16 months for nonresponders (P less than 0.0001). Intraarterial FUDR infusion provided control of liver metastases. The combination of intraarterial and intravenous therapy seemed to prevent extrahepatic spread during therapy in most of the patients. Survival appeared to be significantly prolonged in patients with a regression of metastases.     

紫杉醇联合FUDR治疗晚期胃癌的临床观察

为了观察紫杉醇(PTX)联合脱氧氟尿苷(FUDR)/亚叶酸钙(CF)方案治疗晚期胃癌近期疗效及其不良反应,将58例晚期胃癌患者,采用PTX135mg/m2,静脉滴入3h,d1,CF100mg/m2,静脉滴入2h,d1～d5,FUDR425mg/m2,静脉滴入2h,d1,再续滴入FUDR350mg/(m2.d),微量化疗泵24h持续滴入(civ)d1～d5,21d为1个周期,至少完成2个周期。58例晚期胃癌患者,CR3例(5.2%),PR30例(51.7%),SD13例(22.4%),PD12例(20.7%),总有效率(CR PR)达56.9%。主要不良反应为骨髓抑制、脱发和肌肉酸痛,无化疗相关死亡。初步研究结果提示,PTX联合FUDR/CF方案一线治疗晚期胃癌具有较好的疗效和安全性。     

Alternating hepatic arterial infusion and systemic chemotherapy for liver metastases from colorectal cancer: a phase II trial using intermittent percutaneous hepatic arterial access.

PURPOSE: To evaluate the objective response to a short course of hepatic arterial infusion (HAI) using temporary, percutaneously placed catheters alternating with systemic prolonged continuous infusion fluorouracil (ci 5-FU) and daily oral leucovorin (L). PATIENTS AND METHODS: Eligible patients were previously untreated (except for adjuvant therapy) adults with liver-predominant metastases, with Eastern Cooperative Oncology Group performance status of 0 to 2. Treatment regimen included HAI with fluorodeoxyuridine (FUDR) 60 mg/m2/d and L 15 mg/m2/d continuously infused daily for 4 days. After a 1-week rest, ci 5-FU was administered through a central venous access device using a dose of 180 mg/m2/d with a fixed dose of oral L at 5 mg/m2/d for 21 out of 28 days. Cycles were repeated every 6 weeks. After four cycles of therapy, patients were maintained on ci 5-FU and daily oral L until evidence of progression. RESULTS: Forty-three patients were enrolled onto this trial. One patient was ineligible. The objective response rate for all patients (17 partial, zero complete) was 41% (95% confidence interval [CI], 26% to 56%). Five patients were not able to receive at least one complete cycle of HAI. Among patients who received at least one complete cycle of HAI, the response rate was 46% (95% CI, 30% to 62%). Five patients underwent a liver resection after enrolling onto the protocol. At the time of analysis, estimated median time to progression was 6 months, and estimated median overall survival was 13 months. CONCLUSION: The objective response rate was comparable to that achieved with more prolonged and more frequent HAI using FUDR. This approach should be studied as an acceptable alternative to surgically placed hepatic arterial catheters/pumps and may have a role as neoadjuvant therapy for liver metastases that are unresectable, as well as an adjuvant role for patients with resected hepatic metastatic colorectal cancer.     

Circadian-based infusional chrono-chemotherapy controls progressive metastatic renal cell carcinoma

We treated 25 patients with progressive metastatic renal cell carcinoma with continuous infusion of 5-fluoro-2-deoxyuridine (FUDR) by implanted pump. FUDR was infused for 14 days at monthly intervals. Starting dose was 0.15 mg/kg/day intravenous or 0.25 mg/kg/day intra-arterial; intravenous doses were increased or decreased in increments of 0.025 mg/kg/day as permitted by toxicity. Circadian time modification of the infusion shape (sinusoidal with the peak centered around 6 p.m.) significantly lowered serious intravenous infusion-associated toxicity, allowing higher dose intensity. In 24 evaluable patients, two complete responses (8%), six partial responses (25%), and one minor response were seen. One secondary partial response was observed after infusional velban (total objective response rate 37.5%). Previously progressive disease was controlled in greater than 80% of our patients. During a median follow-up period of 8 months (range of 2-26 months), the overall survival for all 25 patients is 75%. Our results indicate that metastatic renal cell cancer responds to infusional chemotherapy and that the circadian shape of infusion markedly affects our ability to deliver effective doses.     

Randomized phase I/II study of troxacitabine combined with cytarabine, idarubicin, or topotecan in patients with refractory myeloid leukemias.

PURPOSE: Troxacitabine has significant single-agent activity. This study was conducted to define the dose-limiting toxicities (DLTs) of its combination with cytarabine (ara-C), idarubicin, or topotecan. PATIENTS AND METHODS: Patients with refractory acute myeloid leukemia (AML), advanced myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP) were initially randomly assigned to receive troxacitabine 5.0 mg/m(2) by intravenous (IV) infusion over 30 minutes on days 1 to 5 with ara-C 1.0 mg/m(2)/d IV over 2 hours on days 1 to 5, idarubicin 12 mg/m(2) by 5 minute IV infusion on days 1 to 3, or topotecan 1.0 mg/m(2) as an continuous IV infusion on days 1 to 5. Doses were then adjusted to define DLT for each combination. RESULTS: Eighty-seven patients (68 AML, eight MDS, 11 CML-BP) were treated. DLTs were hepatic transaminitis, hyperbilirubinemia, and hand foot syndrome (HFS) on the troxacitabine plus ara-C combination. The recommended phase II doses were 6 mg/m(2) once a day for 5 days and 1.0g/m(2) once a day for 5 days, respectively. DLTs were diarrhea, rash, and mucositis on the troxacitabine plus topotecan combination. The recommended phase II doses were 4 mg/m(2) once a day for 5 days and 0.75 mg/m(2) once a day for 5 days, respectively. DLTs were HFS, rash, and mucositis on the troxacitabine plus idarubicin combination. The recommended phase II doses were 4 mg/m(2) once a day for 5 days and 9 mg/m(2) once a day for 3 days, respectively. Among 74 evaluable patients with AML or MDS, 10 (13%) achieved complete remission and four (5%) had hematologic improvement. Two of 11 (18%) evaluable patients with CML-BP returned to chronic phase. CONCLUSION: Troxacitabine-based combinations had significant antileukemic activity.     

Phase I clinical trial of intracarotid bis-chloroethylnitrosourea (BCNU) and 2' dioxy-5-fluorouridine (FUDR) in malignant astrocytomas

Summary Systemic chemotherapy has been of limited benefit in the treatment of intracranial neoplasms, due, in part, to the inability to deliver effective drug doses to the neoplasm without systemic toxicity. We have completed a clinical trial of intracarotid BCNU and FUDR using an implantable pump in patients with unilateral malignant astrocytomas (Grade III and IV) in the hope of obtaining better tumor control with less systemic toxicity. Six patients had in-dwelling catheters placed in the internal carotid artery attached to a percutaneous refillable pump (Infusaid 400). The treatment program consisted of bolus BCNU 400 mg every 6 weeks and FUDR by continuous infusion at dosages ranging from 0.5 mg/24 h to 2.5 mg/24 h. The maximum tolerable dose of FUDR was 1 mg/24 h with ipsilateral mucositis and conjunctivitis being dose limiting factors. Flow studies demonstrated significant perfusion of the ipsilateral eye and surrounding face secondary to ophthalmic artery collaterals. No patient had systemic toxicity and the lowest WBC encountered was 2 400 with normal differential and platelets.     

Sequential hydroxyurea-cytarabine chemotherapy for refractory non-Hodgkin's lymphoma

In experimental systems, hydroxyurea (HU) and cytarabine (ara-C) produce synergistic cytotoxicity to murine and human leukemia cells due to both cytokinetic and biochemical interactions that tend to enhance the effectiveness of ara-C. Therefore, we began a phase II trial of the combination of HU and ara-C to determine the efficacy and toxicity of this combination in treatment of patients with refractory non-Hodgkin's lymphoma. Chemotherapy began with HU 500 mg administered orally every six hours for four doses. Twelve hours following the fourth HU dose, ara-C 100 mg/m2/d was administered by continuous intravenous (IV) infusion for three days. Concomitantly with the three-day ara-C infusion, patients again received HU 500 mg orally every four hours. Cycles of therapy were repeated every 28 days. Twenty-five patients ranging in age from 26 to 70 years were enrolled in the study. Of 21 patients evaluable for response, nine (43%) obtained complete (CR) or partial remissions (PR). Most responding patients had either large-cell or cutaneous T cell lymphoma, and all but two had a performance status of 0 to 1 at entry in the study. The median survival for all responding patients was 13 months compared with 2.5 months for nonresponders. Patients obtaining a CR had a median survival of 27.5 months, and two of the four CRs remain alive and in remission at 10+ and 30+ months from achievement of CR status. The primary toxic effect of this regimen was bone marrow suppression. The median WBC nadir was 2,200 cells/microL, and the median platelet nadir was 80,000/microL. Other toxicities included mild nausea and vomiting and diffuse maculopapular rash. This biochemically rational approach to enhancing ara-C activity may have significant clinical utility and should be further explored in treatment of patients with large-cell and cutaneous T cell lymphomas.     

A dose escalating study of oxaliplatin and high dose weekly leucovorin and 5-Fluorouracil in patients with advanced solid tumors

PURPOSE: To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTD) of L-OHP plus 5-FU and LV in patients with advanced solid malignancies. PATIENTS AND METHODS: Patients received escalated doses of L-OHP (starting dose 50 mg/m2) as a 2-hour IV infusion on Days 1 and 15, and LV (500 mg/m2 as a 2-hour IV infusion) followed by escalated doses of 5FU (starting dose 1,800 mg/m2) as a 22-hour continuous IV infusion on Days 1, 8, 15, 21 every 6 weeks. DLTs were evaluated in the first cycle. RESULTS: Fifty-two patients [median age: 66 years; PS (ECOG) 0-1 in 90 percent] were treated on 12 dose-levels. Five (10 percent) patients had received 2 prior chemotherapy regimens, 24 (46 percent) one, and 23 (44 percent) were chemo-na?ve. The DLT was reached at the dose of LOHP 100 mg/m2 and 5FU 2,200 mg/m2. Dose-limiting events were G3 diarrhea, G3 asthenia, G4 neutropenia, and G4 thrombocytopenia. Grade 3 diarrhea was observed in 6 (12 percent) patients and Grade 3 fatigue in 6 (12 percent). One (2 percent) patient developed Grade 4 neutropenia and another (2 percent) Grade 4 thrombocytopenia. CONCLUSION: The MTD were L-OHP 95 mg/m2 on d1 and d15 and 5FU 2,200 mg/m2/week for 4 consecutive weeks every 6 weeks.     

High-dose, continuous-infusion cyclophosphamide, cytarabine, vincristine, and prednisone for remission induction in refractory adult acute leukemia

Fifteen consecutive patients with refractory adult acute leukemia (RAAL) were treated with a combination of high-dose, continuous-infusion cyclophosphamide, cytarabine, vincristine, and prednisone (Hi-COAP). The initial nine patients received cyclophosphamide 350 mg/m2 as a 24-hour intravenous (IV) infusion over 5 days; cytarabine, 100 mg/m2 IV bolus every 12 hours for ten doses; vincristine, 2.0 mg IV bolus on day 1; and prednisone, 100 mg orally for 7 days. The last six patients had the cyclophosphamide infusion lengthened to 7 days, and the cytarabine increased to 14 doses. All patients were evaluable for toxicity and response. Seven patients (47%) obtained a complete remission and six patients (40%) a partial remission. Median duration of all remissions has been 7.0 months with a range of 1 to 32 months. Toxicity has been limited to primarily myelosuppression with no hemorrhagic cystitis, central nervous system (CNS), hepatic, or pulmonary toxicity noted. Gastrointestinal toxicity was mild, with no effect on nutritional status noted. Median duration of complete responders was 8.5 months. Thus, Hi-COAP demonstrates promising efficacy with minimal toxicity in RAAL and warrants further exploration in multiinstitutional trials.     

Phase I clinical and pharmacokinetic study of flavopiridol administered as a daily 1-hour infusion in patients with advanced neoplasms.

PURPOSE: To define the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol administered as a daily 1-hour infusion every 3 weeks. PATIENTS AND METHODS: Fifty-five patients with advanced neoplasms were treated with flavopiridol at doses of 12, 17, 24, 30, 37.5, and 52.5 mg/m(2)/d for 5 days; doses of 50 and 62.5 mg/m(2)/d for 3 days; and doses of 62.5 and 78 mg/m(2)/d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of flavopiridol with these schedules. RESULTS: Dose-limiting neutropenia developed at doses >/= 52.5 mg/m(2)/d. Nonhematologic toxicities included nausea, vomiting, diarrhea, hypotension, and a proinflammatory syndrome characterized by anorexia, fatigue, fever, and tumor pain. The median peak concentrations of flavopiridol achieved at the MTDs on the 5-day, 3-day, and 1-day schedule were 1.7 micro mol/L (range, 1.3 to 4.2 micro mol/L), 3.2 micro mol/L (range, 1.7 to 4.8 micro mol/L), and 3.9 micro mol/L (1.8 to 5.1 micro mol/L), respectively. Twelve patients had stable disease for >/= 3 months, with a median duration of 6 months (range, 3 to 11 months). CONCLUSION: The recommended phase II doses of flavopiridol as a 1-hour infusion are 37.5 mg/m(2)/d for 5 days, 50 mg/m(2)/d for 3 days, and 62.5 mg/m(2)/d for 1 day. Flavopiridol as a daily 1-hour infusion can be safely administered and can achieve concentrations in the micromolar range, sufficient to inhibit cyclin-dependent kinases in preclinical models. Further studies to determine the optimal schedule of flavopiridol as a single agent and in combination with chemotherapeutic agents are underway.     

Regional chemotherapy of colorectal cancer metastatic to the liver

Ninety-three patients with biopsy-proven colorectal cancer metastatic to the liver were treated with hepatic arterial infusion of 5-fluorodeoxyuridine (FUDR). There were 52 men and 41 women (median age, 60 years). Forty-two patients (45%) had failed prior systemic chemotherapy. Catheters were operatively placed and multiple catheters were used if dictated by hepatic arterial anatomy in order to obtain perfusion of the entire liver. The drug was delivered by a totally implanted INFUSAID model 400 pump and patients received cyclic therapy consisting of 2 weeks of 0.3 mg/kg/d FUDR alternating with 2 weeks of saline. Patients with extrahepatic tumor or patients whose hepatic tumor failed to respond to FUDR were given a 30 minute intraarterial infusion of mitomycin C, 15 mg/m2, every 6 to 8 weeks in addition to FUDR. Fifty of the 93 evaluable patients presented with metastatic tumor confined to the liver. Of these 50 patients, 83% demonstrated a significant reduction in tumor size with a median duration of response of 13 months and a median survival of 25 months from diagnosis of liver metastases. Twenty-four of these 50 patients remain alive. Forty-three patients presented with extrahepatic metastases in addition to their liver tumor, and 74% had a response with a median duration of 6 months and a median survival of 14 months. Only six patients of those presenting with extrahepatic tumor remain alive. None of the 93 patients died solely of uncontrolled liver tumor, and only 9 died as a result of uncontrolled liver metastases and disseminated extrahepatic tumor. The duration of survival for both groups was determined by the uncontrolled progression of extrahepatic tumor. In patients with metastatic colorectal cancer involving only the liver, hepatic arterial FUDR alone and with the addition of mitomycin C provided excellent control of hepatic tumor. Survival appeared to be prolonged in this uncontrolled study.     

Infusional floxuridine-based therapy for patients with metastatic renal cell carcinoma

BACKGROUND: The treatment of patients with metastatic renal cell carcinoma (RCC) continues to pose a major clinical challenge. Previous studies have suggested that infusional floxuridine (FUDR) has antitumor efficacy and is well tolerated. To the authors knowledge the combination of infusional FUDR with biologic response modifiers (BRMs) has not been evaluated extensively in patients with metastatic RCC. METHODS: Thirty-nine previously untreated patients with metastatic RCC were treated with infusional FUDR at 0.075 mg/kg/day for 14 days of a 28-day cycle. Beginning with the second cycle of FUDR, 24 patients received subcutaneous interferon-alpha-2b (3 million U 3 times a week for Weeks 1 and 2) and 15 received subcutaneous interleukin-2 (IL-2) (5 million U/m(2) 5 days a week for 3 weeks, followed by 1 week off). The dose of FUDR was increased by 0.025 mg/kg each cycle until the maximum tolerated dose for each patient was reached. RESULTS: Five patients receiving FUDR plus interferon achieved a partial response and 1 achieved a complete response whereas 3 patients receiving FUDR plus IL-2 achieved a partial response, for an overall response rate of 23%. The median survival for all patients was 21 months, and 8 patients still were alive 6-57+ months after the initiation of therapy. Toxicity was mild to moderate, and was comprised primarily of fatigue, diarrhea, dacryocystitis, and fluid retention (in the IL-2 cohort). CONCLUSIONS: FUDR in conjunction with IL-2 or interferon appears to produce response rates comparable to those observed with other programs utilizing BRMs and generally is well tolerated. FUDR regimens may be useful in the treatment of metastatic RCC in the outpatient community setting.     

Comparative trial of cytarabine and thioguanine in combination with amsacrine or daunorubicin in patients with untreated acute nonlymphocytic leukemia: results of the L-16M protocol

Ninety-six patients with de novo acute nonlymphocytic leukemia (ANLL) were randomized to receive either daunorubicin (50 mg/m2, IV) on days 1-3; cytarabine (Ara-C) (25 mg/m2, IV) bolus, followed by 160 mg/m2 as a continuous IV infusion daily for 5 days and 6-thioguanine (6-TG) (100 mg/m2 po) every 12 hr daily for 5 days (DAT); or amsacrine (190 mg/m2, IV) on days 1-3 with Ara-C and 6-TG at the above doses (AAT). Patients achieving complete remission (CR) then received two courses of consolidation therapy with the same combination that had induced remission but at slightly reduced total doses. Patients less than or equal to age 40 with an HLA-identical sibling donor underwent allogeneic transplantation, usually after consolidation therapy. The remaining patients were then randomized to receive either maintenance therapy (alternating cycles of vincristine/methotrexate, cyclophosphamide/6-TG, daunorubicin/hydroxyurea and Ara-C/6-TG) or no further treatment. Ninety-two patients were evaluable for response. Twenty-five of the 46 patients (54%) who received DAT and 32 of the 46 patients (70%) who received AAT achieved CR (p = 0.13). When patients were stratified by age, however, remission induction advantage with AAT became statistically significant (p = 0.03). Additionally, more patients achieved CR following one course of AAT than following one course of DAT (48% vs 28%, p = 0.03). Overall survival in the AAT group was improved as well (p = 0.01). Too few patients were randomized on the maintenance arm of the protocol to make interpretation meaningful. Non-hematologic toxicity was generally comparable in both arms. In conclusion, patients with de novo ANLL who received AAT had a higher remission incidence and slightly longer survival compared to patients who received DAT. Further investigation of this drug combination in untreated patients with ANLL is warranted.     

Phase II trial of chlorozotocin and fluorouracil in islet cell carcinoma: a Southwest Oncology Group study.

PURPOSE: A phase II trial that used fluorouracil (5-FU) and chlorozotocin (CTZ) was performed in patients with metastatic islet cell carcinoma to determine the response rate and toxicity. PATIENTS AND METHODS: Patients received four cycles of induction chemotherapy. Good-risk patients received 5-FU 800 mg/m2/d days 1 to 4 as a continuous intravenous (IV) infusion (CIV) and CTZ 175 mg/m2 IV on day 1. Poor-risk patients (previous radiation to > or = 25% bone marrow-bearing areas; serum bilirubin > or = 5 mg/dL; creatinine > 1.0 mg/dL) received 5-FU 600 mg/m2/d and CTZ 75 mg/m2 in a similar manner. In responding or stable patients, reduced doses of 5-FU and CTZ were continued as maintenance therapy (maximum, 18 months). RESULTS: Forty-seven of 51 patients were eligible, and 44 received chemotherapy. Fourteen of 44 patients had partial responses, with 13 of 36 (36%; 95% confidence interval [CI], 21.0% to 54.0%) good-risk patients and one of eight (12%; 95% CI, 0.3 to 52.6%) poor-risk patients responding. Median survival of all patients was 25 months, and the median response duration was 11 months. Side effects were moderate to severe and included myelosuppression and gastrointestinal toxicity. Thirteen patients developed renal toxicity, which was severe or life-threatening in five. This seemed to be related to the administration of cumulative doses of CTZ > or = 1,500 mg. CONCLUSION: These results demonstrate that the combination of 5-FU and CTZ has activity in islet cell carcinoma, but the occurrence of renal toxicity secondary to CTZ may limit the use of this agent.     

A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma

Seventy-four previously untreated patients with metastatic colorectal adenocarcinoma were prospectively randomized into one of three treatment regimens: (1) 5-fluorouracil (5-FU) 450 mg/m2 as an intravenous (IV) bolus daily for five days or toxicity, then 200 mg/m2 IV bolus every other day for six doses; (2) methotrexate (MTX) 50 mg/m2 in normal saline by IV infusion over four hours followed by an IV bolus of 5-FU 600 mg/m2. This was administered weekly for 4 weeks and then every 2 weeks. (3) Leucovorin 500 mg/m2 in a two-hour IV infusion of normal saline with 5-FU 600 mg/m2 as an IV bolus one hour after the Leucovorin began every week for 6 weeks. The combined complete and partial response rates in the three regimens were 11%, 5%, and 48%, respectively (P = .0009). The median duration of response in the 5-FU and Leucovorin regimen was 10 months. There was no statistically significant difference between the treatment regimens with respect to survival time (P = .6). Toxicity in the 5-FU and Leucovorin regimen was predominantly diarrhea (13 of 30 patients, 40%). In this regimen, eight of 13 patients (52%) who developed diarrhea not only required a dose reduction of 5-FU, but also hospitalization for IV hydration. The predominant toxicity in the 5-FU alone regimen and the 5-FU and MTX regimen was leukopenia. One drug-related death occurred in each regimen.     

Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer.

PURPOSE: Patients who undergo resection of liver metastases from colorectal cancer have an average 2-year survival of 65%. With hepatic arterial infusion (HAI) plus systemic fluorouracil and leucovorin, 2-year survival increased to 86%. For further improvement in both local and systemic control, combinations of new systemic drugs with HAI are being explored. The purpose of this study was to determine the maximum-tolerated dose (MTD) of systemic irinotecan (CPT-11) and HAI floxuridine (FUDR) plus dexamethasone (DEX) as combination adjuvant therapy after liver resection. PATIENTS AND METHODS: Ninety-six patients who underwent complete resection of liver metastases from colorectal cancer were treated with six monthly cycles of HAI FUDR plus DEX for 14 days of each 4-week cycle plus escalating doses of systemic CPT-11. The primary end points of the phase I/II study were the MTD and efficacy of this regimen. RESULTS: The MTD for combined systemic CPT-11 and HAI FUDR was CPT-11 at 200 mg/m2 every other week and FUDR at 0.12 mg/kg x pump volume / pump flow rate. The dose-limiting toxicities were diarrhea and neutropenia. With a median follow-up time of 26 months, the 2-year survival rate is 89%. All of the 27 patients who were treated at the MTD are alive. CONCLUSION: In patients who undergo resection of liver metastases from colorectal cancer, adding systemic CPT-11 to HAI therapy in an adjuvant regimen is feasible. This regimen seems to have comparable activity to fluorouracil and leucovorin, but further studies are needed to assess whether it improves local control or decreases extrahepatic recurrences.     

Feasibility of using quinine, a potential multidrug resistance-reversing agent, in combination with mitoxantrone and cytarabine for the treatment of acute leukemia.

PURPOSE: We demonstrated previously that sera from quinine-treated patients reversed the multidrug resistance (MDR) of a human leukemic cell line. We now report a phase I and II clinical study that examined the toxicity of the combination of quinine with mitoxantrone and cytarabine (Ara-C). PATIENTS AND METHODS: Fifteen adult patients with relapsed or refractory acute leukemia were treated with quinine formiate (30 mg/kg/d in continuous intravenous (IV) infusion from day 1 through day 5 or 6) associated with Ara-C (1 g/m2 in 3-hour IV infusion twice a day for 5 days) and five increasing doses of mitoxantrone (from 8 mg/m2/d for 4 days to 12 mg/m2/d for 5 days). RESULTS: The main toxicity was severe myelosuppression: the mean times to leukocyte recovery (> 500/microL), granulocytes recovery (> 500/microL), and platelet count recovery (> 50,000/microL) were 23 days (range, 17 to 29 days), 30.6 days (range, 17 to 48 days), and 35.4 days (range, 14 to 75 days), respectively. The nonhematopoietic toxicity of this regimen was acceptable. Nausea and vomiting were common, but severe mucositis was observed in only two patients. Cardiotoxicity was limited to transient episodes of moderate supraventricular tachycardia and a clinically well-tolerated bradycardia. Tinnitus and vertigo were observed in 10 cases (67%), and mild hearing loss and transient increase of serum bilirubin were observed in six patients (40%). Total quinine serum levels reached a steady-state concentration between 6.4 and 18 mg/L in 24 hours. Complete remission (CR) was achieved in eight of 14 (57%) assessable patients, and partial response (PR) was achieved in two additional patients (14%). P-glycoprotein expression was detected on blast cells from five of 13 studied patients before treatment. A response was observed in all P-glycoprotein-positive cases. CONCLUSION: Quinine can be used safely as a potential reversing agent of MDR for the treatment of clinically resistant acute leukemias.     

A randomized trial of continuous intravenous versus hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: the Northern California Oncology Group trial

In 1983, the Northern California Oncology Group (NCOG) instituted a randomized trial of intravenous (IV) versus intraarterial (IA) floxuridine (FUDR) administered via an implantable pump for patients with colorectal cancer metastatic to the liver. The study objectives were to compare the hepatic response rate, time to hepatic progression, and toxicity for the two treatment arms. The study design, which allowed patients failing IV FUDR to crossover to the IA arm, prevents a meaningful comparative analysis of survival. Patients with liver-only metastases (N = 143) were randomized, 76 to the IV arm and 67 to the IA arm, and 115 patients (65 IV, 50 IA) were fully evaluable. Of the 65 patients in the IV arm, 28 crossed over to IA treatment after failing IV FUDR. The dose-limiting toxicity of IV FUDR was diarrhea, whereas biliary toxicity limited both the dose and duration of IA FUDR therapy. Of the first 25 patients treated with IA FUDR at a dose of .3 mg/kg/day, 10 developed radiographically evident biliary strictures, and three developed permanent jaundice. With reduction of the initial IA FUDR dose to .2 mg/kg/day, and adoption of a policy of early dosage reduction, treatment interruption, or termination of therapy for persistent elevations in alkaline phosphatase, only two further cases of serious biliary toxicity occurred. However, 26 of the 50 IA FUDR patients ultimately had therapy terminated because of drug toxicity rather than disease progression. When compared with systemic infusion, infusion into the hepatic artery greatly enhanced the antitumor activity of FUDR against colorectal liver metastases. Although biliary toxicity is the most serious limitation of this form of therapy, biliary stricture and jaundice usually can be averted through careful monitoring of liver enzymes and early dosage reduction.