Biomedical subjects

M Valdivieso

Publications and source records attributed to M Valdivieso.

At least 19 recordsLinked to original sources

PubMed2001

Chronic oral administration of CI-994: a phase 1 study.

OBJECTIVES: CI-994 (N-acetyl dinaline, PD 123654) is a novel oral agent active in a broad variety of murine and human tumor xenografts. While cytotoxic in the Brown Norway (BN) rat leukemia model, growth inhibition in other murine and human tumor xenografts is predominantly cytostatic. Its specific mechanism of action remains unknown. Following CI-994 administration, inhibition of both histone deacetylation and cellular proliferation at the G1 to S transition phase of the cell cycle are observed. This Phase 1 study in patients with solid tumors was carried out to determine a maximum tolerated daily oral dose (MTD) for CI-994 administered on a chronic basis. METHODS: Fifty-three patients received CI-994 daily for treatment durations ranging from 2 to 10 weeks. Dosage escalation proceeded in 2 phases; an Acute Dosing Phase (n = 11) to define the MTD for CI-994 administered over 2 weeks and a Chronic Dosing Phase (n = 29) to define the MTD for daily administration for 8 weeks. Upon completion of the Chronic Dosing Phase, a third cohort of patients (n = 13) received CI-994 at the recommended Phase 2 dose and schedule with 2 additional single doses of drug administered separated by a 1-week washout to assess the effect of food on CI-994 pharmacokinetics. RESULTS: Thrombocytopenia was dose limiting at the MTD of 8 mg/m2/day for 8 weeks. Other toxicities included fatigue and gastrointestinal effects such as nausea, vomiting, diarrhea, constipation and mucositis. Pharmacokinetic studies revealed that peak plasma levels and AUC's generally increased with dose and that food intake did not affect the rate or extent of drug absorption. One patient with heavily pre-treated adenocarcinoma of the lung achieved a Partial Response (PR) lasting over 2 years and 3 additional patients achieved Stable Disease (SD), 1 each with non-small cell lung, colorectal, and renal cancer. CONCLUSIONS: The recommended Phase 2 starting dose is 8 mg/m2/day for 8 weeks repeated after a 2-week drug-free interval.

Administration, Oral↗

PubMed2001

A phase II study of weekly alternating chemotherapy in extensive-stage small cell lung cancer.

Despite the recent development of new chemotherapeutic agents with activity in small cell lung cancer (SCLC), the long-term prognosis of patients with extensive-stage disease remains poor and has not improved in the past 20 years. The present study was designed to evaluate the activity and toxicity of weekly, alternating-regimen chemotherapy in patients with extensive-stage SCLC. Patients with previously untreated extensive-stage SCLC and performance status 0-2 were treated with cyclophosphamide 250 mg/m2, etoposide 100 mg/m2, and cisplatin 50 mg/m2 on day 1; vincristine 1 mg/m2 on day 8; and ifosfamide 1.2 gm/m2 on days 8 and 9 with the entire treatment repeated every 14 days. Eighteen patients received chemotherapy for a median of 14 weeks (range, 1-35 weeks). Seventeen patients (94%) required dose delays and 16 patients (89%) required at least one dose reduction due to toxicity. Twelve patients (67%) exhibited an objective response (1 complete response, 11 partial response) with a median duration of response of 18 weeks (range, 8-32 weeks). Median survival was 33 weeks (range, 1-57 weeks) with a 1-year survival rate of 22%. Toxicity was primarily hematologic, including grade 3-4 leukopenia (82% of patients) and anemia (53% of patients). Only 2 patients developed grade 3 peripheral neuropathy and none exhibited grade 3-4 renal insufficiency. This regimen of weekly alternating combination chemotherapy resulted in tolerable toxicity as well as response and survival rates comparable to those achieved with standard chemotherapy in patients with extensive-stage SCLC. However, weekly chemotherapy regimens for the treatment of SCLC remain investigational.

Adult↗

PubMed2000

A phase II study of mitomycin C, etoposide, and cisplatin in advanced non-small cell lung cancer.

Standard chemotherapeutic regimens, such as cisplatin and etoposide, may improve quality of life and prolong survival in patients with incurable non-small cell lung cancer (NSCLC). This trial was designed to evaluate the activity and toxicity of a regimen combining three of the most active agents against advanced-stage NSCLC: mitomycin C, etoposide, and cisplatin (MEP). Sixty-eight patients with stage IIIB (pleural effusion) or IV NSCLC received cisplatin 80 mg/m2 i.v. on day 1 and etoposide 80 mg/m2 i.v. on days 1, 2, and 3 every 3 weeks along with mitomycin C 10 mg/m2 i.v. on day 1 of the first and third cycles for a median of four cycles (range, 1-11). Median age was 59 years, and nine patients were enrolled after relapse from previously treated early-stage NSCLC. Eighty-eight percent of patients had stage IV disease, and 14 (21%) had brain metastases at diagnosis. Palliative radiotherapy was given to 10 patients (15%) before MEP and to 17 (25%) concurrent with MEP. The major toxicity of MEP was myelosuppression, with grade 3-4 neutropenia in 74% of patients. Sixteen patients (24%) had documented infections, and there were eight (12%) treatment-related deaths. Partial response was observed in 24 patients (35%) with a median duration of 4.4 months, (range 1.4-13 months). Median survival was 8.1 months (range, 1-34 months), and 1-year survival was 32%. The addition of mitomycin C to cisplatin and etoposide resulted in response and survival rates comparable with those achieved with standard regimens in patients with advanced NSCLC but was associated with substantial hematologic toxicity and unacceptable treatment-related mortality.

Adult↗

PubMed1999

Phase I trial of concurrent thoracic radiation and continuous infusion cisplatin and etoposide in stage III non-small cell lung cancer.

OBJECTIVE: Although combined modality therapy appears to be superior to radiotherapy alone for the treatment of locally advanced non-small cell lung cancer (NSCLC), the optimal treatment regimen has not been determined. We designed this trial to determine the maximal tolerated doses (MTD) of continuous intravenous infusion (CI) cisplatin and etoposide that could be administered concurrently with thoracic irradiation. METHODS: 19 patients with stage IIIA or IIIB NSCLC were treated at three different dose levels of CI cisplatin and etoposide with concurrent single daily fraction thoracic radiotherapy to 4500 cGy. This chemoradiotherapy phase of treatment was followed by a 1500-2000 cGy radiotherapy boost and three cycles of standard intermittent bolus cisplatin 80 mg/m2 i.v. on day 1 and etoposide 80 mg/m2 i.v. on days 1, 2 and 3. RESULTS: The MTD of CI chemotherapy was determined to be cisplatin 5 mg/m2/day plus etoposide 18 mg/m2/day for 5 days per week over 5 weeks along with thoracic irradiation. Overall, 37% of patients required breaks in the chemoradiotherapy course and 32% required attenuation of the planned duration of CI chemotherapy. Only 42% of patients received all three planned cycles of bolus chemotherapy and 16% received < 6000 cGy of thoracic irradiation. The major toxicities during concurrent chemoradiotherapy were grade 3-4 esophagitis (42%) and myelosuppression (47%). Subsequent chemotherapy was complicated by grade 3-4 myelosuppression in 38% of patients. An objective response was documented in 58% of patients (CR 11%, PR 47%). Median survival was 18 months with 2- and 5-year survival rates of 42 and 11%, respectively. CONCLUSIONS: These results demonstrate that CI cisplatin and etoposide can be administered safely to patients with locally advanced NSCLC, and that such potentially radiosensitizing strategies deserve further evaluation in this setting.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1999

Etoposide-induced pulmonary toxicity.

After treatment with etoposide, two patients with lung cancer developed interstitial infiltrates and respiratory failure. Of the two, one patient responded rapidly to steroid therapy and developed recurrent symptoms on re-challenge with etoposide. Both patients had histopathologic findings consistent with drug-induced pulmonary toxicity. Etoposide-induced lung disease needs to be considered in patients who develop subacute dyspnea and interstitial infiltrates during treatment with this agent.

Adult↗

PubMed1998

Phase II study of hyperfractionated radiotherapy and concurrent weekly alternating chemotherapy in limited-stage small cell lung cancer.

Despite recent advances in combined modality therapy, long-term survival remains elusive in most patients with limited-stage small cell lung cancer (SCLC). The present study was designed to evaluate the activity and toxicity of concurrent hyperfractionated radiotherapy and weekly, alternating-regimen chemotherapy. Twelve patients with limited-stage SCLC and performance status 0-1 were treated with cyclophosphamide 250 mg/m2, etoposide 100 mg/m2, and cisplatin 50 mg/m2 on day 1 every other week, and vincristine 1 mg/m2 on day 8, and ifosfamide 1.2 mg/m2 on days 8 and 9 every other week. Hyperfractionated thoracic radiotherapy, consisting of three daily doses of 1.1 Gy for 20 days to a total dose of 66 Gy, was started on day 1 of chemotherapy. Ten patients (83%) exhibited an objective response (9 CRs and 1 PR) with a median duration of response of 8.6 months. Two complete responders died at 50 and 53 months without evidence of progression and two remain alive and free of SCLC at 73 and 87 months. Median survival was 19.8 months with 2- and 5-year survival rates of 50 and 17%, respectively. Severe toxicity, including grade 3-4 esophagitis (67%) and granulocytopenia (83%), as well as debilitating fatigue and pneumonitis, prompted early termination of the trial. Hyperfractionated radiotherapy and concurrent weekly alternating-regimen chemotherapy resulted in promising response and survival rates, but induced excessive toxicity, in patients with limited-stage SCLC.

Aged↗

PubMed1996

Evaluation of multimodality treatment of locoregional esophageal carcinoma by Southwest Oncology Group 9060.

BACKGROUND: Continuous infusion 5-fluorouracil (CI5-FU) has been utilized concurrently with radiotherapy to improve tumor control. In this pilot trial, cisplatin, CI5FU, and radiotherapy were utilized for the treatment of locoregional esophageal carcinoma. It was postulated that the combination would be well tolerated and associated with high response rate and survival duration. METHODS: Thirty-two eligible patients with locoregional squamous cell carcinoma and adenocarcinoma of the esophagus received a regimen consisting of the following: radiotherapy, 50 Gray (Gy) (30 Gy anteroposterior/posteroanterior regional with 20 Gy AP/LPO/RPO boost) over 5 weeks, with CI5-FU 250 mg/m2/d for the duration of radiotherapy and cisplatin 25 mg/m2/day on Days 1-3 during Weeks 1 and 4 of the radiotherapy cycle. Upon completion of radiotherapy, two additional course, of cisplatin 75 mg/m2 on Days 1 and 29 and CI5-FU 300 mg/m2/day on Days 1-21 and 29-50 were delivered. Following imaging and endoscopic reassessment, patients with no evidence of disease received more chemotherapy. Surgery was suggested only for patients with residual local disease. RESULTS: Complete response was demonstrated in 44% of patients, clinically in 12 patients, and during surgery in 2 others. The median survival was 20 months, and the 1-year survival rate was 59%. Toxicity was severe, comprised of esophagitis, infection, and gastrointestinal complications. Dose delays and reductions occurred in the majority of patients. Four early deaths were noted. CONCLUSIONS: The regimen that was the focus of this trial has been active in the treatment of esophageal carcinoma. However, compared with existing regimens, its complexity and toxicity preclude its future use without modifications.

Adenocarcinoma↗

PubMed1996

Phase I trial of Adozelesin using the treatment schedule of daily x5 every 3 weeks.

CC-1065 is a unique alkylating agent that preferentially binds in the minor groove of double-stranded DNA at adenine-thymine-rich sites. Although it has broad antitumor activity in preclinical models its development was discontinued because of deaths observed during preclinical toxicology studies. Adozelesin is a potent synthetic analog that was chosen for clinical development because it had a similar preclinical antitumor spectrum, but did not produce deaths similar to CC-1065 at therapeutic doses. Phase I evaluations using a variety of Adozelesin treatment schedules have been conducted. This report describes our experience using a multiple dose treatment schedule. Endpoints including antitumor response, maximum tolerated dose, dose limiting toxicity as well as other toxicities and the recommended Phase II starting dose were determined. Adozelesin was given as a 10 minute IV infusion for 5 consecutive days every 21 days or upon recovery from toxicity. The dose range evaluated was 6-30 mcg/m2/day. All patients had refractory solid tumors and had received prior cytotoxic treatment. Thirty-three patients (22 men: 11 women) were entered onto the study and 87 courses were initiated. Dose limiting toxicity was cumulative myelosuppression (leucopenia, thrombocytopenia). The maximum tolerated dose was 30 mcg/m2/day. The only other significant toxicity was an anaphylactoid syndrome that occurred in 2 patients. A partial response was observed in a patient with refractory soft tissue sarcoma. The recommended Phase II starting dose of Adozelesin using a 10 minute IV infusion for 5 consecutive days is 25 mcg/m2/day to be repeated every 4-6 weeks to allow recovery from myelotoxicity, based on our experience. Additional Phase I and II studies with Adozelesin are recommended.

Adult↗

PubMed1995

Phase I study of monoclonal antibody-ricin A chain immunoconjugate Xomazyme-791 in patients with metastatic colon cancer.

The immunoconjugate XMMCO-791/RTA consists of ricin A chain bound to a murine monoclonal antibody MoAb 791T. This monoclonal antibody (MoAb) binds to a glycoprotein of 72 kD, which is expressed on human colorectal carcinoma, ovarian carcinoma, and osteogenic sarcoma. XMMCO-791/RTA was tested in a Phase I trial with proposed dose escalation steps of 0.02, 0.04, 0.15, and 0.2 mg/kg per day. Twelve patients with metastatic colorectal carcinoma were treated at 0.02, 0.03, and 0.04 mg/kg per day dose levels administered over 1 hour on days 1-5. Study-related toxicities were hypotension (6 patients); greater than 10% weight gain (6 patients); peripheral edema (9 patients); fever (4 patients); confusion (3 patients); diarrhea (3 patients); proteinuria, as identified by dipstick (3 patients), greater than 0.6 mg/dl decrease in serum albumin (11 patients); greater than 25% decrease in oncotic pressure (10 patients), and a decrease in ionized calcium (8 patients). Six patients received a second course of treatment. HAMA levels developed in 9 patients and titers increased with number of courses administered. Decreased overall toxicity, in comparison to the first course, was noted, but one patient had an allergic-type response (hypotension, crushing chest pain, diaphoresis) after the test dose of the second course (HAMA level > 10,000 IgG). Life-threatening toxicity in the form of fluid shift, resulting in noncardiac pulmonary edema and third-spacing occurred after course 1 in 1 of 3 patients at the 0.04 mg/kg per day level. No further dose escalation was attempted and no antitumor activity was seen.

Adenocarcinoma↗

PubMed1995

A universal method for the mutational analysis of K-ras and p53 gene in non-small-cell lung cancer using formalin-fixed paraffin-embedded tissue.

The p53 tumor suppressor gene has been found to be altered in almost all human solid tumors, whereas K-ras gene mutations have been observed in a limited number of human cancers (adenocarcinoma of colon, pancreas, and lung). Studies of mutational inactivation for both genes in the same patient's sample on non-small-cell lung cancer have been limited. In an effort to perform such an analysis, we developed and compared methods (for the mutational detection of p53 and K-ras gene) that represent a modified and universal protocol, in terms of DNA extraction, polymerase chain reaction (PCR) amplification, and nonradioisotopic PCR-single-strand conformation polymorphism (PCR-SSCP) analysis, which is readily applicable to either formalin-fixed, paraffin-embedded tissues or frozen tumor specimens. We applied this method to the evaluation of p53 (exons 5-8) and K-ras (codon 12 and 13) gene mutations in 55 cases of non-small-cell lung cancer. The mutational status in the p53 gene was evaluated by radioisotopic PCR-SSCP and compared with PCR-SSCP utilizing our standardized nonradioisotopic detection system using a single 6-microns tissue section. The mutational patterns observed by PCR-SSCP were subsequently confirmed by PCR-DNA sequencing. The mutational status in the K-ras gene was similarly evaluated by PCR-SSCP, and the specific mutation was confirmed by Southern slot-blot hybridization using 32P-labeled sequence-specific oligonucleotide probes for codons 12 and 13. Mutational changes in K-ras (codon 12) were found in 10 of 55 (18%) of non-small-cell lung cancers. Whereas adenocarcinoma showed K-ras mutation in 33% of the cases at codon 12, only one mutation was found at codon 13. As expected, squamous cell carcinoma samples (25 cases) did not show K-ras mutations. Mutations at exons 5-8 of the p53 gene were documented in 19 of 55 (34.5%) cases. Ten of the 19 mutations were single nucleotide point mutations, leading to amino acid substitution. Six showed insertional mutation, and three showed deletion mutations. Only three samples showed mutations of both K-ras and p53 genes. We conclude that although K-ras and p53 gene mutations are frequent in non-small-cell lung cancer, mutations of both genes in the same patient's samples are not common. We also conclude that this universal nonradioisotopic method is superior to other similar methods and is readily applicable to the rapid screening of large numbers of formalin-fixed, paraffin-embedded or frozen samples for the mutational analysis of multiple genes.

Base Sequence↗

PubMed1995

Phase I clinical trial of pyrazoloacridine NSC366140 (PD115934).

The pyrazoloacridine (PZA) analogue NSC366140 (PD115934) entered clinical trial based on unique preclinical characteristics including solid tumor selectivity in vitro, marked antitumor activity in vivo against murine solid tumors, selectivity against noncycling cells, and activity against multidrug-resistant tumor cells. After identification of the pre-clinical efficacy and an acceptable toxicity profile, a Phase I study of PZA was carried out. A total of 28 patients was entered and received a total of 67 treatment courses. The drug was administered via a 1-h infusion every 21 days. The starting dose was 30 mg/m2 with 2-fold dose escalations through 480 mg/m2. The next dose escalation was 50%, to 720 mg/m2. Grade I through grade IV toxicities were observed. Since no dose-limiting toxicities were observed at 480 mg/m2, and up to grade IV toxicities were observed at 720 mg/m2, an intermediate dose, 600 mg/m2, was evaluated. Dose-limiting toxicities at 720 mg/m2 were hematological (grade III and IV neutropenia) in four of six patients and neurological (up to grade III cerebral toxicities, including restlessness, dizziness, agitation/anxiety, personality changes, and nightmares, as well as myoclonus) in three of six patients treated. The pharmacokinetic parameters which helped predict these toxicities included area under the curve and peak plasma level. Pharmacokinetic studies showed interpatient variations in all parameters studied. The mean area under the curve levels of PZA at the highest two dose levels in patients were near the level detected in mice at their maximum tolerated total dose. The recommended starting dose for Phase II trials using this schedule is 600 mg/m2.

Acridines↗

PubMed1994

Effects of rhG-CSF, 5-fluorouracil and extramedullary irradiation on murine megakaryocytopoiesis in vivo.

The aim of this study was to systematically characterize possible rhG-CSF effects on the murine megakaryocyte-platelet system (untreated and recovering from chemotherapy or extramedullary irradiation). In untreated, splenectomized male B6D2F1 mice, rhG-CSF treatment (50 micrograms/kg/d for up to 8 d) markedly decreased femoral megakaryocytopoiesis. CFU-Meg, small acetylcholinesterase-positive (SAChE) cells, and megakaryocytes were significantly reduced to 35-70%; platelets, however, were not affected. Peripheral CFU-Meg and CFU-GM increased up to 200-fold. Following a single injection of 5-FU (150 mg/kg) on day 0, rhG-CSF (50 micrograms/kg/d) on days 1-8 suppressed the megakaryocytopoietic recovery as indicated by significantly lower platelet numbers on day 9. Granulopoietic recovery was accelerated by rhG-CSF. When rhG-CSF treatment was started on day 5, no beneficial effect on granulopoietic recovery was observed, but again platelet levels were significantly lower on day 9, indicating that within the first 4 d of rhG-CSF application, recruitment or lineage competition was not a critical event. To test for the effects of extramedullary irradiation on circulating progenitors, mice pretreated with 50 micrograms/kg/d of rhG-CSF for 8 d received irradiation to the chest with 500 cGy resulting in a substantial kill of circulating CFU-Meg and CFU-GM of up to 99%. However, this striking decrease of blood progenitors did not significantly affect their total body contents. This study indicates that rhG-CSF treatment can impair bone marrow megakaryocytopoiesis, which might be an important consideration for those clinical situations that carry a high potential for treatment-induced thrombocytopenia.

Animals↗

PubMed1993

A phase II study of dacarbazine and cisplatin in combination with outpatient administered interleukin-2 in metastatic malignant melanoma.

BACKGROUND: Based on prior experience with dacarbazine (DTIC) and an outpatient interleukin-2 (IL-2) regimen, the current study was conducted to improve the antitumor efficacy and assess the immunologic interactions between chemotherapy and IL-2. METHODS: Thirty-two patients were registered onto a treatment program, which included DTIC 750 mg/m2 with cisplatin 100 mg/m2, each by intravenous bolus on day 1. Recombinant IL-2 was administered on an outpatient basis intravenously by 15-30-minute infusion (24.0 x 10(6) IU/m2) daily on days 12-16 and 19-23 of a 28-day cycle for three cycles and then every 42 days for responding patients. RESULTS: There were responses in 13 of the 32 registered patients (41% response rate), including five complete and eight partial remissions. Responses in the liver, lung, spleen, lymph nodes, and soft tissue sites were noted. The median duration of response was 8.0 months (range, 3.0-20.0+ months), and the overall median survival duration was 10.2 months. Three patients (9%) are alive, free of disease, without any treatment at 32.0+, 36.0+, and 42.0+ months after initiation of treatment. Only minor nephrotoxicity was observed, and treatment delays were rare. CONCLUSIONS: Additional chemotherapeutic, hormonal, or biologic agents may be added to enhance efficacy further if they have toxicities that do not overlap.

Adolescent↗

PubMed1992

Difluorodeoxycytidine (dFdC)--gemcitabine: a phase I study.

Difluorodeoxycytidine (dFdC) demonstrated broad spectrum activity in preclinical models. A phase 1 study utilizing twice weekly injections was conducted in 50 eligible and evaluable patients. Twenty-nine patients received drug by 30 minute infusion at doses of 5-90 mg/m2 and 22, by 5 minute bolus at 30-150 mg/m2. The primary dose limiting toxicities were marrow suppression and flu-like symptomatology. Thrombocytopenia was dose limiting at 75 mg/m2 on the infusion schedule and 150 mg/m2 on the 5 minute schedule. Flu-like symptoms with fever, rigors and malaise occurred the day of injection in many patients. One patient with renal cell carcinoma attained a partial response. Evaluation of the drug's efficacy and schedule dependency continue.

Adult↗

PubMed1992

Effect of calcium replacement on the hemodynamic changes associated with high dose interleukin-2 therapy.

Administration of high-dose IL-2 results in hemodynamic changes that are similar to those seen in septic shock. These include a decrease in systemic vascular resistance (SVR) with a resultant drop in mean arterial pressure (MAP). Hypocalcemia is seen in septic shock and with IL-2 administration. Calcium replacement in septic shock has been reported to result in hemodynamic improvement; we therefore administered calcium to patients receiving high dose IL-2 to correct ionized hypocalcemia. Five consecutive patients underwent invasive hemodynamic monitoring before and during IL-2 administration. Calcium chloride was administered to correct ionized hypocalcemia, and hemodynamic parameters were monitored before and after calcium administration. Ionized hypocalcemia was associated with an elevation in parathyroid hormone levels. There was no toxicity related to the administration of calcium. An improvement in the MAP and SVR was seen early and late (after a dose of IL-2 was held) in the IL-2 treatment cycle; there were minimal effects at other points. Because of the potential hemodynamic benefit of calcium replacement, we recommend that ionized hypocalcemia be corrected in patients receiving high-dose IL-2.

Adult↗

PubMed1992

Phase I trial of recombinant macrophage colony-stimulating factor by rapid intravenous infusion in patients with cancer.

Fourteen patients were entered into a phase I dose-escalation trial of macrophage colony-stimulating factor (M-CSF). M-CSF was administered to inpatients by rapid 15 min i.v. infusion every 8 h x 5 days, repeated after a 9-day rest. Dose levels evaluated were 20, 40, 80, 330, and 1,100 micrograms/m2. Monitoring of patients every 4 h included vital signs, daily complete blood count (CBC), and serum chemistries (SGOT, creatinine, and bilirubin) while receiving M-CSF. No clinical or laboratory evidence of toxicity was seen. The average serum t1/2 varied with dose level. At 330 and 1,100 micrograms/m2, the serum t1/2 was 25 and 84 min, respectively, implying a saturable mechanism of clearance. After 5 days of treatment, the t1/2 decreased by twofold, consistent with enhancement of the saturable mechanism. Monocyte cytotoxicity against the A375 melanoma cell line was evaluated pretreatment and day 5 of each cycle. No consistent enhancement of monocyte cytotoxicity was seen. No effect on peripheral blood monocyte number was seen until the 1,100 micrograms/m2 dose level. At this dose level, the mean monocyte number on day 5 was increased compared to baseline (1,300 mm3 vs. 300/mm3). Clinical activity was seen in two patients with previously progressive leiomyosarcoma metastatic to the liver. A partial response (PR) lasting 7 months occurred at the 330 micrograms/m2 dose level while a patient treated at 1,100 micrograms/m2 has had stable disease for 20+ months. The maximum tolerated dose (MTD) of M-CSF was not determined. Based on clinical responses, a phase II trial is warranted in patients with metastatic soft tissue sarcoma.

Antineoplastic Agents↗

PubMed1991

5-Fluorouracil, etoposide, and cisplatin in the management of metastatic non-small cell lung cancer.

Encouraging response rates have been reported in Stage III non-small cell lung cancer when 5-fluorouracil (5-FU), etoposide (VP-16), and cisplatin (FED) have been combined with radiation therapy (RT) or RT and surgery. The current study evaluated the effectiveness of FED chemotherapy in 32 patients with metastatic non-small cell lung cancer. Treatment consisted of 5-FU (800 mg/m2/d) on days 1 to 4 by continuous infusion, intravenous (IV) VP-16 (60 mg/m2) over 1 hour on days 1 to 4, and IV cisplatin (60 mg/m2) over 1 hour on day 1. Treatment cycles were repeated every 28 days as toxicity permitted. Partial responses occurred in 7 of 32 patients (22%; 95% confidence limit [CL] 0.09, 0.40), including 6 of 19 patients (32%) with performance status of 0 or 1, and 1 of 13 patients (8%) with performance status of 2 or 3. The median response duration was 5.0 months. Although toxicity was modest and consisted of primarily hematologic and gastrointestinal side effects, this combination does not appear to provide an advantage over other cisplatin combinations in Stage IV non-small cell lung cancer.

Adult↗

PubMed1990

Antitumor efficacy of interleukin-2 alone and in combination with adriamycin and dacarbazine in murine solid tumor systems.

Recombinant interleukin-2 (IL-2)/chemotherapy combinations have recently entered clinical trial. The rationale for sequencing has primarily been empiric or based on in vitro data. To establish in vivo models for chemoimmunotherapy trials, we investigated IL-2 alone and in combination with dacarbazine (DTIC) and adriamycin. IL-2 (as a single agent given i.v. at 1-3 x 10(5) Cetus units once daily for 5 days, repeated 7-10 days later), was highly active against an immunogenic line of colon adenocarcinoma no. 11/A [tumor growth inhibition (T/C) = 0% with cures]. It was modestly active against colon adenocarcinoma no. 38 (T/C = 39%), mammary adenocarcinoma no. 16/C (T/C = 18%), and B16 melanoma (T/C = 21%). IL-2 was inactive against colon adenocarcinoma no. 7/A (T/C = 83%). Combination trials were done using DTIC and IL-2 against colon no. 7/A and upstaged colon no. 11/A. The combination of adriamycin and IL-2 was tested against mammary adenocarcinoma no. 16/C. In the DTIC/IL-2 combination trials, the combination was superior over either agent used alone. In the IL-2/adriamycin trials, the combination was no better than adriamycin alone at optimum dosages.

Adenocarcinoma↗