Daily Continuous Infusion Research Articles

Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma. A phase II study

Low resectability rate and high locoregional recurrence are major factors contributing to the failure of surgical treatment for localized pancreatic adenocarcinoma. A Phase II study involving preoperative 5-fluorouracil (5-FU) and mitomycin C and radiation therapy was evaluated. Thirty-one patients with biopsy-proven carcinoma (24, head of pancreas; 2, body; 5 duodenum) were treated with preoperative radiation therapy, 5040 cGy (180 cGy/fraction, 5 days/week), concurrent with 5-FU, 1000 mg/m2/day continuous infusion (days 2-5, 28-32) and mitomycin C 10 mg/m2 bolus (day 2). Ten patients had previous laparotomy or bypass surgery and were deemed unresectable; 21 had percutaneous, endoscopic retrograde choleangiopancreatic, or transhepatic stent biopsies. Toxicity included neutropenic fever (2 patients), biliary sepsis (2 patients), and nausea and vomiting requiring total parenteral nutrition. One patient died of biliary sepsis before completion of chemoradiation and 11 patients showed evidence of metastatic disease (clinical or occult). Resectability rate was 38% (10/26) for pancreatic carcinoma and 80% (4/5) for duodenal carcinoma. Pathology of the resected specimens revealed extensive necrosis and hyalinization with clear margins in all cases. Lymph node metastases were found in one case of pancreatic carcinoma. The four resected duodenal carcinomas contained no residual tumor in the specimens. At a median follow-up of 29 months, the median survival time for those with pancreatic carcinoma was not yet reached in the resection group and was 8 months in the nonresection group. The corresponding actuarial 5-year survival rates were 58% and 0%, respectively. Neoadjuvant chemoradiation therapy was given safely to patients with pancreatic and duodenal carcinoma. It facilitated complete resection in 38% of patients with pancreatic carcinoma and 80% of those with duodenal carcinoma. A significant downstaging of positive margins and regional lymph nodes occurs as a result of preoperative chemoradiation.

Reversal of ongoing heart, kidney, and pancreas allograft rejection and suppression of accelerated heart allograft rejection in the rat by rapamycin.

Rapamycin was examined for its effects on reversal of ongoing rejection of heart, kidney, and pancreas allografts and on suppression of accelerated heart allograft rejection in the rat. A 14-day continuous intravenous infusion of RAPA by an osmotic pump at 0.02, 0.08, and 0.8 mg/kg/day to WFu recipients, starting 4 days postoperation, significantly protected the BUF heart allografts with a mean survival time (MST) +/- 1 SD of 33.2 +/- 19.8 (p < 0.001), 48.2 +/- 14.8 (p < 0.001), and 107.0 +/- 86.3 (p < 0.001) days, respectively, as compared with 7.2 +/- 0.8 days in vehicle-treated controls. Combination of low dose RAPA (0.02 mg/kg or 0.08 mg/kg) and low dose CsA (2 mg/kg) achieved significantly longer cardiac allograft survival than RAPA or CsA alone. RAPA's effect in reversing ongoing rejection of renal and pancreatic allografts was also significant. The BUF kidney and pancreas in WFu recipients treated with a 14-day course of RAPA (0.8 mg/kg/day starting 4 days postoperation) had an MST of 44.7 +/- 15.9 (p < 0.001) and 46.4 +/- 12.5 (p < 0.001), while in vehicle-treated controls, the grafts were rejected within 10 days. RAPA could also suppress accelerated cardiac allograft rejection. Hyperimmunized WFu recipients were treated with two 14-day courses of continuous i.v. RAPA at 0.8 mg/kg/day before and after BUF heart allografting. Significantly longer survival of the grafts (25.5 +/- 3.7 days, p < 0.001) was achieved compared with that of the vehicle-treated controls (3.8 +/- 1.0 days). One-course RAPA treatment before or after heart transplantation was considerably less effective. RAPA was also shown to prevent the increase of serum IgG levels and to inhibit the production of specific cytotoxic Ab in the rat receiving repetitive immunizations. Such effects presumably contribute to the inhibition of the accelerated rejection. The results of this study suggest that RAPA is potentially useful in treatment of ongoing as well as accelerated allograft rejection.

Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia.

To determine the toxicities and maximum-tolerated dose of cyclosporine (CsA) administered with daunorubicin as a modulator of multidrug resistance (MDR) in acute leukemia, and to evaluate response to treatment and its relationship to mdr1 gene expression. Patients with poor-risk acute myeloid leukemia (AML) received sequential treatment with cytarabine (3 g/m2/d intravenously [i.v.]) days 1 to 5, and daunorubicin (45 mg/m2/d) plus CsA as a 72-hour continuous infusion (CI) days 6 through 8 in a phase I/II trial. A loading dose of CsA administered over 1 to 2 hours preceded the CI. CsA dose escalations ranged from 1.4 to 6 mg/kg (load) and 1.5 to 20 mg/kg/d (CI). Whole-blood concentrations of CsA were monitored by immunoassay; plasma concentration of daunorubicin and daunorubicinol were determined by high-pressure liquid chromatography (HPLC). Specimens were analyzed for P-glycoprotein expression, and results confirmed by a quantitative RNA polymerase chain reaction (PCR) assay for the mdr1 gene transcript. Forty-two patients are assessable for toxicity and response. P-glycoprotein was detected in 70% of cases. Dose-dependent CsA toxicities included nausea and vomiting (22%), hypomagnesemia (61%), burning dysesthesias (21%), and prolongation of myelosuppression. Transient hyperbilirubinemia developed in 62% of treatment courses and was CsA-dose-dependent. Reversible azotemia occurred in three patients receiving concurrent treatment with potentially nephrotoxic antibiotics. Steady-state blood concentrations of CsA > or = 1,500 ng/mL were achieved in all patients receiving CI doses > or = 16 mg/kg/d. Mean plasma daunorubicin, but not daunorubicinol, levels were significantly elevated in patients who developed hyperbilirubinemia (P = .017). Twenty-six (62%) patients achieved a complete remission (CR) or restored chronic phase and three patients achieved a partial remission (PR) for an overall response rate of 69% (95% confidence interval, 54% to 84%). The response rate was higher in patients who developed hyperbilirubinemia (P = .001), whereas MDR phenotype did not influence response to treatment. Among five patients with MDR-positive leukemia, cellular mdr1 mRNA decreased (n = 1) or was absent from relapsed specimens (n = 4), while mdr1 RNA remained undetectable at relapse in two patients who were MDR-negative before treatment. High doses of CsA, which achieve blood concentrations capable of reversing P-glycoprotein-mediated anthracycline resistance in vitro, can be incorporated into induction regimens with acceptable nonhematologic toxicity. Transient hyperbilirubinemia occurs commonly with CsA administration and may alter daunorubicin pharmacokinetics. Recommended doses of CsA for phase II and III trials are a load of 6 mg/kg and CI of 16 mg/kg/d.

Chemoradiotherapy versus radiotherapy alone for anal cancer: A retrospective comparison

Purpose : To evaluate the effect of adding one cycle of concomitant chemotherapy to curative radiotherapy on tumor control and toxicity in the treatment of anal cancer. Methods and Materials : One hundred twenty-five patients completed curative sphincter-conserving treatment, 57 with radiotherapy alone and 68 with concomitant chemo-radiotherapy. Compared with chemoradiotherapy patients, radiotherapy patients were older (median age 71 vs 63) and had less advanced tumors (T3-4 26% vs 51%). Radiotherapy patients were usually treated with a direct perineal cobalt field (mean dose 31 Gy at 5 cm/10 fractions/3 weeks), complemented in most cases by a sacral arc field, followed (mean dose 31 Gy at 5 cm/10 fractions/3 (mean dose 23 Gy, Paris system). The large majority of chemoradiotherapy patients received antero-posterior opposed 10 MV photon fields, including pelvic and inguinial nodes (mean dose 38 Gy/19 fractions/4 weeks), followed (mean split 42 days) by implant boost (mean dose 18 Gy). In addition, chemo-radiotherapy patients received starting on day 1 an IV bolus of Mitomycin-C, 0.4 mg/kg (maximum 20 mg) and a 5-day continuous infusion of 5-fluorouracil 600–800 mg/m 2/day. Median follow-up was 65 months for radiotherapy and 48 months for chemo-radiotherapy patients. Results : For all 125 patients at 5 years, overall survival was 65.5%, definitive local control 83% and local control with sphincter preservation 68%. Overall and stage for stage, there was no difference in overall, progression-free or cancer-specific survival, nor in local control, local-regional control, or sphincter preservation rates between patients treated with chemoradiotherapy vs. radiotherapy alone. There was no significant difference between the two groups regarding acute or late toxicity. Conclusion : This retrospective analysis does not confirm the efficacy of one course of simultaneous Mitomycin-C and5-fluorouracil, at least in association with full-dose radiotherapy incorporating Iridium-192 boost.

5-Fluorouracil, hydroxyurea and escalating doses of iododeoxyuridine with concomitant radiotherapy for malignant gliomas: A clinical and pharmacologic analysis

Iododeoxyuridine (IUdR) is a known radiation enhancer, and interacts biochemically with 5-fluorouracil (5-FU) and hydroxyurea (HU). IUdR was added to the previously studied regimen of continuous infusion 5-FU at 300 mg/m2/day for 5 days, HU 500 mg every 12 hours for 11 doses and radiotherapy 200 cGy/day for 5 days, all administered for 7 consecutive weeks to patients with malignant glioma. IUdR was administered as 5-day continuous intravenous infusion during weeks 1 and 4. The IUdR dose was changed in cohorts of patients. IUdR plasma concentrations were determined during weeks 1 and 4, and IUdR incorporation into the DNA of granulocytes was measured on weeks 2 and 5. Two patients treated at the initial IUdR dose of 500 mg/m2/day developed grade 3 or 4 myelosuppression and mucositis. Additional dose levels of IUdR tested were 250 mg/m2/day and 125 mg/m2/day; at the latter dose, severe or life-threatening toxicity was seen in only 3 of 8 patients treated. IUdR incorporation into DNA of granulocytes was 10.5(+/- 2.3)% at an IUdR dose of 500 mg/m2/day but decreased to 0.76(+/- 0.3)% at 125 mg/m2/day. Similarly, IUdR plasma concentrations decreased from 436 (+/- 114) ng/ml to 99 (+/- 29) ng/ml. The addition of IUdR to 5-FU and HU results in significant systemic toxicity necessitating limitation of the IUdR dose to 125 mg/m2/day. There is a significant biochemical interaction between IUdR, 5-FU and HU leading to increased IUdR incorporation into DNA and to substantial clinical toxicity. Further clinical studies to exploit this interaction at more feasible schedules may be useful.

The suitability of carboplatin solutions for 14-day continuous infusion by ambulatory pump: an HPLC-dynamic FAB study.

The stability of aqueous carboplatin solutions over 14 days has been studied at 37 and 60 degrees C. High-performance liquid chromatography and dynamic FAB mass spectrometry studies have shown that carboplatin solutions were stable at 37 degrees C but degraded at 60 degrees C. Fluid loss through evaporation was significant at the higher temperature.

Adjuvant Immunotoxin Therapy With Anti-B4-Blocked Ricin After Autologous Bone Marrow Transplantation for Patients With B-Cell Non-Hodgkin's Lymphoma

Anti-B-blocked ricin (anti-B4-bR) combines the specificity of the anti-B4 (CD19) monoclonal antibody with the protein toxin "blocked ricin." In blocked ricin, affinity ligands are attached to the ricin B-chain to attenuate its lectin binding capacity. In a phase I trial, Anti-B4-bR was administered by 7-day continuous infusion to 12 patients in complete remission after autologous bone marrow transplantation (ABMT) for relapsed B-cell non-Hodgkin's lymphoma (NHL). Patients were treated at 20, 40, and 50 micrograms/kg/d for 7 days. Potentially therapeutic serum levels could be sustained for 3 to 4 days. The maximum tolerated dose was 40 micrograms/kg/d for 7 days (total 280 micrograms/kg). The dose-limiting toxicities were reversible grade IV thrombocytopenia and elevation of hepatic transaminases. Mild capillary leak syndrome was manifested by hypoalbuminemia, peripheral edema (4 patients), and dyspnea (1 patient). Anti-immunotoxin antibodies developed in 7 patients. Eleven patients remain in complete remission between 13 and 26 months post-ABMT (median 17 months). These results show that Anti-B4-bR can be administered with tolerable, reversible toxicities to patients with B-cell NHL in complete remission following ABMT.

Adjuvant immunotoxin therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with B-cell non- Hodgkin's lymphoma

Anti-B-blocked ricin (anti-B4-bR) combines the specificity of the anti- B4 (CD19) monoclonal antibody with the protein toxin “blocked ricin.” In blocked ricin, affinity ligands are attached to the ricin B-chain to attenuate its lectin binding capacity. In a phase I trial, Anti-B4-bR was administered by 7-day continuous infusion to 12 patients in complete remission after autologous bone marrow transplantation (ABMT) for relapsed B-cell non-Hodgkin's lymphoma (NHL). Patients were treated at 20, 40, and 50 micrograms/kg/d for 7 days. Potentially therapeutic serum levels could be sustained for 3 to 4 days. The maximum tolerated dose was 40 micrograms/kg/d for 7 days (total 280 micrograms/kg). The dose-limiting toxicities were reversible grade IV thrombocytopenia and elevation of hepatic transaminases. Mild capillary leak syndrome was manifested by hypoalbuminemia, peripheral edema (4 patients), and dyspnea (1 patient). Anti-immunotoxin antibodies developed in 7 patients. Eleven patients remain in complete remission between 13 and 26 months post-ABMT (median 17 months). These results show that Anti-B4- bR can be administered with tolerable, reversible toxicities to patients with B-cell NHL in complete remission following ABMT.

Anti-B4-blocked ricin: a phase I trial of 7-day continuous infusion in patients with B-cell neoplasms.

This phase I trial was undertaken to determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the B-cell-restricted immunotoxin anti-B4-blocked ricin (anti-B4-bR) when it is administered by 7-day continuous infusion. Thirty-four patients with relapsed and refractory B-cell neoplasms (26 non-Hodgkin's lymphoma [NHL], four chronic lymphocytic leukemia [CLL], four acute lymphoblastic leukemia [ALL]) received 7-day continuous infusion anti-B4-bR. Successive cohorts of at least three patients were treated at doses of 10 to 70 micrograms/kg/d for 7 days with the dose increased by 10 micrograms/kg/d for each cohort. The initial three cohorts of patients (10, 20, and 30 micrograms/kg/d x 7 days) also received a bolus infusion of 20 micrograms/kg before beginning the continuous infusion. The MTD was reached at 50 micrograms/kg/d x 7 days. The DLTs were National Cancer Institute Common Toxicity Criteria (NCI CTC) grade IV reversible increases in AST and ALT, and grade IV decreases in platelet counts. Adverse reactions included fevers, nausea, headaches, myalgias, hypoalbuminemia, dyspnea, edema, and capillary leak syndrome. Potentially therapeutic serum levels of anti-B4-bR could be sustained for 4 days in patients treated at the MTD. Two complete responses (CRs), three partial responses (PRs), and 11 transient responses (TRs) were observed. Anti-B4-bR can be administered safely by 7-day continuous infusion with tolerable, reversible toxicities to patients with relapsed B-cell neoplasms. Although occasional responses were seen, future trials will use anti-B4-bR in patients with lower tumor burdens to circumvent the obstacle of immunotoxin delivery to bulk disease.

Immunotoxin Therapy of Small-Cell Lung Cancer: N901-Blocked Ricin for Relapsed Small-Cell Lung Cancer

Despite its initial chemosensitivity, small-cell lung cancer (SCLC) is rarely cured with chemotherapy alone, and fewer than 5% of patients are alive at 5 years. Immunotoxin therapy appears to offer promise in treating the minimal residual disease that remains after induction chemotherapy. We have studied N901-bR in patients with relapsed SCLS. N901-bR consists of the N901 monoclonal antibody (MoAb) and blocked ricin, an altered ricin molecule in which the galactose binding sites of the ricin B-chain which mediate nonspecific binding of the toxin are blocked through the covalent binding of ligands. N901 is an anti-NCAM (CD56) MoAb which binds to SCLC tumors and cell lines, cardiac muscle, natural killer (NK) cells, and peripheral nerve. N901-bR showed a 2.7 log greater in vitro cytotoxicity to the CD56-positive cell line SE-2 than to the antigen-negative Namalwa cell line. Nineteen patients with relapsed antigen-negative Namalwa cell line. Nineteen patients with relapsed and/or refractory SCLC have been entered into a phase I study at doses ranging from 5 to 40 micrograms/kg/day given as a 7-day continuous infusion. The dose-limiting toxicity is capillary leak syndrome observed in two thirds of the patients treated at 40 micrograms/kg/day. One patient at the maximum tolerated dose, 30 micrograms/kg/day x 7 days, has achieved a partial response to N901-bR. No patient has developed clinically significant peripheral or central neuropathy. We plan to begin a phase II study of N901-bR following induction chemotherapy in patients with SCLC.

Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia

The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to-moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.

Phase I Study of Topotecan, A New Topoisomerase I Inhibitor, in Patients With Refractory or Relapsed Acute Leukemia

Abstract The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to- moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.

Phase II evaluation of recombinant alpha-2a-interferon and continuous infusion fluorouracil in previously untreated metastatic colorectal adenocarcinoma

Thirty-nine patients with advanced measurable metastatic colorectal carcinoma were entered in a clinical trial of recombinant alpha-2a-interferon (r alpha-2a-IFN) and continuous-infusion 5-fluorouracil (5-FU). Patients had not been treated previously with chemotherapy and had bidimensionally measurable disease. A course of therapy consisted of a 5-day continuous infusion of 5-FU, 750 mg/m2/day, with r alpha-2a-IFN, 9 x 10(6) IU, subcutaneously, on days 1, 3 and 5 of the 5-FU infusion. A course of therapy was repeated every 15 days, and patients were examined for response after receiving four courses of therapy. One patient had a complete response, and 11 patients experienced partial responses, for an overall response rate of 31% (95% confidence interval [CI], 17-48%). The median duration of response was 7.5 months (range, 2-13 months). Fifty-two percent of the patients entered in this trial are alive at time of this writing, with a median follow-up duration of 12.2 months (range, 6-24 months). Grade 3-4 toxicities included mucositis (nine patients), diarrhea (two patients), granulocytopenia (two patients), and fatigue (three patients). This regimen of 5-FU with r alpha-2a-IFN administration does not appear to be superior to previously published schedules of 5-FU with r alpha-2a-IFN or to other methods that modulate 5-FU.

Recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for non-small cell lung cancer

This study was aimed at preventing of chemotherapy-induced neutropenia and improving the therapeutic result by reducing the cycle length of cisplatin (25 mg/m2/day, 5-day continuous infusion) and vindesine (3 mg/m2, bolus, days 1 and 8) (PiV) through the use of recombinant human granulocyte colony-stimulating factor (rG-CSF) (2-5 micrograms/kg/day, subcutaneous, days 6-21) for non-small cell lung carcinoma (NSCLC). PiV regimen with rG-CSF was repeated every 21 days. 28 out of 33 previously untreated patients, who completed two or more cycles of PiV regimen on schedule, were evaluable for analysis. The absolute neutrophil count in the third week after chemotherapy was 8187 +/- 5376/ml. It became possible to administer PiV therapy at 3-week intervals. The response rate was 74% (23/31). In conclusion, the combined administration of rG-CSF enabled shortening of administration schedule of PiV therapy and increasing the dose intensity.

Circadian rhythm-modulated chemotherapy with high-dose 5-fluorouracil: a pilot study in patients with pancreatic adenocarcinoma

From November 1986 to April 1989, 16 patients with advanced measurable pancreatic carcinoma were involved in a pilot phase I–II study. 5-Fluorouracil was given every 3 weeks by 5-day continuous chronomodulated venous infusion (CMVI) with peak 5-FU delivery at 4 a.m. Intrapatient dose escalation started at 1200 mg/m 2/day up to 1600 mg/m 2/day in the absence of grade III (WHO) toxicity. Mucositis and diarrhoea were dose limiting in the 131 cycles given. Three partial responses (21%) and 5 stable diseases were seen in the 14 patients with measurable disease. Dose intensity after three or after six courses (1800 mg/m 2/week) was significantly correlated with time to progression (Pearson r = 0.64; P < 0.004). These results, although modest, support a multicentre phase II trial with 5-FU CMVI.

Oxaliplatin activity against metastatic colorectal cancer. A phase II study of 5-day continuous venous infusion at circadian rhythm modulated rate

Oxaliplatin (L-OHP) is a non-nephrotoxic third generation platinum complex with proven antitumoral activity and minimal haematological toxicity. Circadian scheduling has allowed significant increases in L-OHP dosage and dose intensity and decreases in its toxicities. This phase II trial has tested the antitumour activity of a 5-day circadian schedule of continuous venous infusion of L-OHP against metastatic colorectal cancer. Initial dose was 150 mg/m 2/course. An intrapatient dose escalation scheme by 25 mg/m 2/course was planned up to 200 mg/m 2/course, according to toxicity criteria. The delivery rate of L-OHP was sinusoidally modulated along the 24-h time scale, and was highest at 1600 h. A programmable-in-time ambulatory pump was used, so that all patients could receive their treatment at home. 29 of 30 patients registered were eligible. 25 had failed previous chemotherapy. Three objective responses were observed (response rate: 10%), in patients progressive while on chemotherapy with 5-fluorouracil and folinic acid. Toxicity was moderate. Dose-limiting toxicities were diarrhoea and peripheral sensitive neuropathy. The latter adverse effect appeared to be cumulative. L-OHP, as delivered under this circadian schedule, exhibits clinical antitumour activity against metastatic colorectal cancer. These results, which await further confirmation, support the place of L-OHP in combination regimens including 5-fluorouracil.

2-Chlorodeoxyadenosine in the treatment of hairy cell leukemia and chronic lymphocytic leukemia.

More than 450 patients with hairy cell leukemia have been treated at the Scripps Clinic. Of 144 patients followed for a median of 14.2 months (range, 8.1-70 months), 123 (85%) obtained complete responses, 17 (12%) partial responses, 3 (2%) did not respond, and 1 patient was unevaluable. So far, 4 patients have relapsed at a median of 36 months (range, 12-48 months). Fever was the principal toxicity occurring in 43% of patients. Five patients resistant (3 patients) or intolerant (2 patients) to deoxycoformycin were also treated. Of these 5 patients, 4 obtained complete responses, including 2 patients resistant to deoxycoformycin, and 1 patient a partial response, suggesting a possible lack of cross-resistance between deoxycoformycin and 2-CdA in hairy cell leukemia. Other single-institution studies have documented similar response rates and toxicities. Ninety patients with advanced chronic lymphocytic leukemia were treated with 2-CdA administered either as a 0.1 mg/kg/day 7-day continuous intravenous infusion or as a 0.028-0.14 mg/kg/day 2-hour bolus for 5 consecutive days. Four patients (4%) obtained complete responses and 36 patients (40%) partial responses, using NCI-sponsored Working Group guidelines. Of the 50 patients who were non-responders, 27 (54%) had a > or = 50% sustained reduction in the absolute lymphocyte count. The ratio of deoxycytidine kinase to cytoplasmic 5'-nucleotidase was predictive of 2-CdA responsiveness. Fourteen patients with fludarabine-failed chronic lymphocytic leukemia were also treated. No responses were achieved and 2 patients had progressive disease. Six patients had a > or = 50% reduction in the absolute lymphocyte count.(ABSTRACT TRUNCATED AT 250 WORDS)

Natriuretic and Vasoactive Hormones and Glomerular Hyperfiltration in Hyperglycaemic Type 2 Diabetic Patients: Effect of Insulin Treatment

Evidence that an increase in plasma atrial natriuretic peptide (ANP) concentrations mediates, at least in part, glomerular hyperfiltration in diabetic rats prompted us to study the relationship between ANP and renal haemodynamics in hyperfiltering type 2 diabetic patients in association with other hormones implicated in the control of glomerular filtration rate (GFR) (catecholamines, vasopressin, renin) and in sodium tubular transport (aldosterone, ouabain-displacing factor, ODF). Since hyperglycaemia is also associated to hyperfiltration, diabetic patients who presented with secondary drug failure were studied both in hyperglycaemic and in normoglycaemic condition. For this purpose, 11 normotensive non-macroproteinuric hyperfiltering patients with type 2 diabetes were treated with an 8-day continuous insulin infusion (days 0-7). Dehydration was prevented or corrected and natriuresis was on day 0 above 100 mmol/day. The following parameters were determined on days 0 and 7: GFR and renal plasma flow (RPF) by 99mTc-DTPA and 131I-hippuran clearances; the extracellular volume, assimilated to the DTPA diffusion volume; urinary ODF by receptor-binding assay and urinary as well as plasma catecholamines by HPLC after extraction on alumin. Plasma ANP and antidiuretic hormone (ADH) were measured by radioimmunoassay after extraction on phenyl-silylsilica (ANP) and with ether (ADH). Unextracted plasma was used for radioimmunological measurement of plasma renin activity and aldosterone. When correcting hyperglycaemia to normoglycaemia GFR decreased from high to normal mean value (138 +/- 27 and 115 +/- 6 ml/min, p < 0.001), RPF followed the same trend, and the DTPA diffusion volume did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

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

The combination of leucovorin [(6d,l)-5-formyl-tetrahydrofolate] and 5-fluorouracil (5-FU) has increased efficacy compared to 5-FU alone as treatment of advanced colorectal cancer. Leucovorin is metabolized to methylene tetrahydrofolate, which potentiates the antitumor actions of 5-FU by forming a ternary complex of thymidylate synthase, fluorodeoxyuridine and methylene tetrahydrofolate. Only l-leucovorin is metabolized to methylene tetrahydrofolate and forms this ternary complex. However, d-leucovorin may not be inert. d-Leucovorin may impair cellular uptake and metabolism of l-leucovorin, thereby inhibiting the actions of l-leucovorin. Because of this possible limitation to the effectiveness of racemic leucovorin, we have begun to explore the effects of the pure, biologically active isomer, l-leucovorin. In this phase I trial, patients with advanced gastrointestinal malignancies were treated with a 5-day continuous infusion of l-leucovorin and daily intravenous boluses of 5-FU at 370 mg/m2. The dose of l-leucovorin was escalated in groups of three patients at four doses, 200 mg/m2 per day, 400 mg/m2 per day, 700 mg/m2 per day and 1000 mg/m2 per day. Treatment was repeated every 28 days. Seventeen patients with advanced gastrointestinal cancers entered the trial. Sixteen patients were evaluable for toxicity. Toxicity was similar to that expected for leucovorin plus 5-FU. The most common severe toxicities (and the number of patents affected) were: diarrhea (2), mucositis (2), nausea/vomiting (1), and abdominal/rectal pain (2). The maximum tolerated dose of l-leucovorin was 700 mg/m2 per day. Twelve patients were evaluable for response. One complete, one partial and one minor response were observed. All responses occurred among the nine patients with colorectal carcinomas. The combination of l-leucovorin and 5-FU is well tolerated by patients and appears active for treatment of advanced colorectal carcinomas. Additional clinical trials are necessary to determine if l-leucovorin is more effective than d,l-leucovorin for modulating the effectiveness of 5-FU.

Effectiveness of an NO-Releasing Pirsidomine Derivative on Coronary Conductance During Long-Term Administration

Nitrovasodilators have long been used in the treatment of myocardial ischemia. One of the limitations of their chronic administration is loss of drug action over time. Nitrovasodilator-induced drug tolerance results from either the loss of cyclic guanosine monophosphate-dependent dilator effects, or from biological counterregulatory processes, usually neurohormonal adaptations. C87-3754, a derivative of pirsidomine, is a new nitric oxide-releasing sydnonimine. Continuous 5-day infusion of C87-3754 in dogs did not result in a substantial loss of drug action. There was long-lasting dilation evident in the large coronary arteries and venous bed, resulting in improved coronary conductance. Administration of C87-3754 was associated with reduction in cardiac preload, wall stress, and subendocardial tissue pressure.