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V Sinibaldi

Publications and source records attributed to V Sinibaldi.

15 recordsLinked to original sources
PubMed1995

Combined carboplatin plus bleomycin and conventional radiotherapy for advanced carcinomas of the head and neck.

In a previous study, we reported a 72% response rate (CR = 52%) in patients with unresectable head and neck (H&N) carcinomas treated with simultaneous carboplatin (CBDCA) and radiotherapy (RT). Bleomycin (Bleo), a known radiosensitizing agent, has been shown to increase response rates when given together with RT in similar patients. To explore the nonoverlapping toxicities of these two agents, we combined i.v. CBDCA (100 mg/m2/week), Bleo (5 units on day 1 and 4/weekly) and standard doses of RT in patients with unresectable H&N carcinomas. Chemotherapy (CT) was continued until completion of RT. Twenty-three (13 males, 10 females) previously untreated patients with stage IV squamous cell carcinoma of the H&N were treated at the University of Maryland Medical Center: 61% had oropharyngeal cancers; 26%, hypopharynx; 9%, oral cavity; and 4%, an unknown primary. Moderate to severe mucositis developed in 90%, which required RT interruptions of up to 3 weeks. After a median follow-up (FU) of 18 months, 35% achieved a complete response (CR) and 65% died from progressive disease. These preliminary data suggest that the addition of Bleo increases mucosal toxicity substantially and, while a moderate response rate was observed, it is unlikely that the CR rate will be higher than CBDCA/RT, which was also better tolerated and hence more suitable to multimodal approaches.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Approaches to optimal dosing of hexamethylene bisacetamide.

HMBA is a potent differentiating agent capable of causing > 95% morphological differentiation in cell lines in vitro. The induction of differentiation is dependent on both the concentration of and the duration of exposure to HMBA. However, acute toxicities (neurotoxicity and acidosis) have limited the maximal HMBA css value to < 2 mM, which is at the lower limit of effective in vitro concentrations. When HMBA css values have been maintained at 1-2 mM, thrombocytopenia has limited the duration of HMBA infusion to < or = 10 days. The present studies were performed to determine whether exposure to HMBA could be individualized and maximized without resulting in intolerable toxicity to patients and to determine which factors would predispose a patient to the development of acute toxicity during treatment with HMBA. For these investigations, patients were given HMBA at a target css using an adaptive-feedback-control method rather than at a set dose. Because HMBA administration produces large anion gaps, a simple maneuver such as alkalinization might enable the escalation of plasma HMBA css values to > 2 mM. HMBA was given as a 5-day CI to 14 patients (26 courses) at 2 target HMBA css levels near the maximal tolerated value in the presence or absence of concurrent alkalinization with sodium bicarbonate. Symptomatic acidosis occurred in one patient who did not receive bicarbonate. Neurotoxicity proved to be dose-limiting at the target HMBA css value of 1.5-2.0 mM in the absence of concurrent alkalinization and at a css level of > 2 mM, regardless of alkalinization. No neurotoxicity was seen at target HMBA css values of 1.5-2.0 mM in patients who did receive concurrent alkalinization. Alkalinization was not associated with any detectable changes in plasma HMBA metabolites. With the maximal tolerable 5-day HMBA css having thus been defined at 1.5-2.0 mM, we attempted to maximize exposure to HMBA by defining a tolerable duration of infusion. Individualization of the duration of HMBA infusion to a target nadir PLT was performed in patients who had received an initial 5-day CI of HMBA at a css 1.5-2.0 mM along with concurrent alkalinization. The AUC achieved and the thrombocytopenia produced during this first course were used to predict the duration of infusion that each patient would subsequently tolerate (at an HMBA css of 1-2 mM) to achieve a nadir PLT of 75,000-100,000/microliters.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetamides↗
PubMed1992

Phase II trial of 5 day continuous intravenous infusion of 6-thioguanine in patients with recurrent and metastatic squamous cell carcinoma of the head and neck.

Fifteen patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck received a 5 day continuous I.V. infusion of 6-thioguanine repeated every five weeks. Dose limiting toxicity was primarily hematological with grade III/IV leucopenia and thrombocytopenia seen in seven patients. Nausea and vomiting was moderate and well controlled with antiemetics. No complete or partial responses were observed, with a median time to progression of 58 days and a median survival of 227+ days for the entire group. Based on these results we do not recommend I.V. 6-thioguanine for the treatment of this disease.

Adult↗
PubMed1992

Carboplatin in the treatment of squamous cell head and neck cancers.

Cancer of the head and neck, or aerodigestive tract, represents only a small percentage of all cancer cases in the United States, yet its variable presentations have wide-ranging implications that make it one of the most problematic cancers. Recent research has focused on treatment approaches for the patient with advanced disease. Encouraging results have been noted with combination cisplatin/5-fluorouracil (5-FU) and, more recently, with carboplatin/5-FU, particularly in previously untreated patients. The carboplatin-containing regimen has several important advantages over that with cisplatin, including outpatient administration and less severe nausea and vomiting, an important consideration in terms of nutritional support for head and neck cancer patients. The demonstration of possible synergistic activity between platinum compounds and radiation therapy also has prompted considerable interest, as such a combined-modality approach offers the potential for improved quality of life in patients with head and neck cancers. Carboplatin is an excellent agent for the treatment of squamous cell head and neck cancers, with recognized single-agent activity and a high degree of efficacy, when combined with 5-FU. Carboplatin can be combined effectively with concurrent radiotherapy and, with its advantages over cisplatin, is increasingly used as part of initial therapy for head and neck cancers.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Phase I trial using adaptive control dosing of hexamethylene bisacetamide (NSC 95580).

Hexamethylene bisacetamide (HMBA), a potent differentiating agent, was administered to patients with refractory malignant tumors. Thirteen patients received 30 evaluable courses. HMBA was given by continuous i.v. infusion for 5 days. Therapy was repeated every 28 days, if patients had recovered from toxicity. The starting dose was 24 g/m2/day. Because our previous trial had shown wide interpatient variability in HMBA pharmacokinetics and excess toxicity at HMBA plasma concentrations greater than 2 mM (HMBA doses between 24 and 33.6 g/m2/day), we attempted to individualize each patient's dose based on a dosing scheme using an adaptive (feedback) control algorithm, which assumed linear clearance for HMBA. In all courses, a plasma sample was assayed daily and infusion rates were adjusted to achieve an HMBA plasma concentration of 1.5-2.0 mM (300-400 mg/liter). The patients included 12 men and 1 woman with a median age of 56 years (range, 34-76) and median Karnofsky performance status of 90% (range, 60-100). All patients had received prior chemotherapy and 9 patients had also received radiation therapy. The linear adaptive control algorithm was reasonably precise, with a mean absolute error of 0.28 (SE 0.04) mM. However, adjustments in infusion rate systematically overshot the desired change in steady state concentration, probably due to nonlinear clearance of HMBA. For levels within 24 h of a change in infusion rate, this resulted in significant bias, with a mean error of 0.24 (SE 0.09) mM. The mean absolute error was 0.40 (SE 0.06) mM. A second adaptive control algorithm, using a pharmacokinetic model with parallel first-order (renal) clearance and Michaelis-Menten (nonrenal) clearance and using Bayesian parameter estimation with a priori estimates based on our previous phase I trial, proved to be much more precise than the linear method and was unbiased when applied retrospectively to the same observations, with a mean error (within 24 h of a change in infusion rate) of 0.02 (SE 0.06) mM and a mean absolute error of 0.22 (SE 0.03) mM. Toxicity was reversible in all cases. Neurotoxicity, consisting of hallucinations, agitation, somnolence, or confusion, was seen in 2 patients. Four patients complained of insomnia or anxiety. Mild asymptomatic acidosis was seen in 3 patients. Other toxicity included grade 1-2 nausea and vomiting (10 patients), grade 2 diarrhea (2 patients), grade 3 thrombocytopenia (3 patients), grade 1-3 leukopenia (3 patients), and oral herpes simplex infection (4 patients). Mild reversible renal insufficiency (measured by creatinine clearance) was seen in 8 patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetamides↗
PubMed1989

Carboplatin (CBDCA) and radiotherapy for stage IV carcinoma of the head and neck: a phase I-II study.

The prognosis of patients with squamous cell carcinoma (SQC) of the head and neck (H&N) depends on the primary site and anatomical extent of the disease. Recurrence rates after conventional surgery (S) and/or radiotherapy (RT) remain low for localized tumors, whereas in advanced loco-regional disease they occur in over 60% of all cases. Several combinations of treatment modalities have been attempted in order to improve local control in Stages III and IV. Unfortunately, the recurrence rate remains high with added morbidity when conventional surgery is combined with pre or post-operative radiotherapy. Induction chemotherapy (CT) with Cisplatinum and Bleomycin has resulted in severe toxicities when combined with radiotherapy. To evaluate the toxicity of Carboplatin (CBDCA), a second generation platinum analog, when given simultaneously with conventional doses of radiotherapy, 26 patients with Stage IV SQC of the head and neck were treated at the University of Maryland Medical Systems. There were 23 males and 3 females; median age was 59 years and median Karnofski performance status was 60. Twenty patients had received no prior therapy; six had surgical exploration and excision with measurable residual disease. Anatomically, six patients had tumors of the oral cavity, twelve in the pharynx, one in the nasopharynx, four in the larynx, one in the hypopharynx, one in the maxillary antrum, and one was an unknown primary. These patients were treated as out-patients with weekly injections of Carboplatin. The dose was escalated: two patients received 60 mg/M2, seven received 75 mg/M2, thirteen were treated with 100 mg/M2, and four with 400 mg/M2. The radiotherapy was given daily with conventional fractions of 180 cGy and total tumor doses of 60-75 Gy. Toxicities were mainly hematological with median nadirs decreasing with increasing doses of Carboplatin. Mucositis was seen in over 80% of the patients, but interestingly enough, it has never been more severe than that observed with radiotherapy alone. So far, there has not been any kidney, ear, or neurotoxicities. Of 25 evaluable patients, 19 (76%) responded with 13 (52%) showing complete response. The overall median survival time is 266+ days (324+ for responders and 179+ for non-responders). The follow-up is still short, 10-14 months, but 9 of 13 patients with complete response have not yet progressed.

Antineoplastic Agents↗
PubMed1989

A comparison of carboplatin plus methotrexate versus methotrexate alone in patients with recurrent and metastatic head and neck cancer.

Patients with recurrent and metastatic squamous cell carcinoma of the head and neck (SCCHN) were stratified by performance status, extent of disease, and prior radiotherapy and subsequently randomized to receive carboplatin (CBDCA; Bristol-Myers, Wallingford, CT) administered intravenously (IV) monthly, initially at doses of 400 mg/m2 in combination with methotrexate (MTX) given IV weekly at doses of 40 mg/m2 or MTX alone at the same dose/schedule. Significant dose-limiting myelosuppression required CBDCA dose reductions to 300 mg/m2 and, subsequently, 200 mg/m2. Nonhematological toxicities were not significant. Our study objective was to determine whether CBDCA plus MTX produce a substantial improvement in response rate over single-agent MTX. A response rate of 50% (complete [CR] plus partial response [PR]) for CBDCA plus MTX compared with 25% for MTX was specified as the difference to be detected. We employed a two-stage study design for randomized trials that allowed for early termination of studies involving relatively ineffective treatment regimens. With this design, the study could be closed after the first stage (20 patients entered onto each treatment arm) if the number of responders to CBDCA plus MTX were not superior to MTX. Five of 20 patients responded to treatment in each arm, and we were able to conclude that the addition of CBDCA to MTX is unlikely to result in a twofold increase in response rate compared with MTX alone in this group of patients. This two-stage design represents a simple and efficient method of testing the relative efficacy of new combinations containing at least one active agent against a suitable control arm in this disease. It addresses scientific and ethical issues of continuing testing with relatively ineffective treatments, and at the same time provides a reliable method for identifying very active regimens likely to represent significant therapeutic advances.

Adult↗
PubMed1987

Phase I study and pharmacokinetics of menogaril (NSC 269148) in patients with hepatic dysfunction.

We performed a phase I study of menogaril to determine if dosage reduction was required in patients with hepatic dysfunction and if the relationship between pharmacokinetics and leukopenia, previously defined in patients with normal hepatic and renal function, was altered. Eighteen patients received 27 courses of menogaril, of which 26 were evaluable for toxicity. Patient characteristics were median age, 63 years (range, 28-80 years), 14 male/4 female, and median Karnofsky performance status 80% (range, 60-100%). Prior therapy included none, five; chemotherapy only, seven; radiotherapy only, two; and chemotherapy and radiotherapy, four. Menogaril was administered as a 2-h.i.v. infusion every 28 days at 62.5 (one patient), 125 (eight patients), 187.5 (seven patients), and 250 mg/m2 (six patients), based on pretreatment serum bilirubin, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Patients also had indocyanine green and antipyrine clearances measured before menogaril treatment. Menogaril and metabolites were assayed by high performance liquid chromatography. Dose-limiting toxicity was leukopenia. WBC nadirs occurred between days 8 and 20 (median, 15). Three patients developed platelet nadirs below 100,000/microliters. Other toxicities included grade I nausea and vomiting in three patients and phlebitis at the site of drug infusion in six patients. Correlations were defined between pretreatment indocyanine green clearance and serum concentrations of alkaline phosphatase and total bilirubin. There were no correlations between pretreatment serum concentrations of bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, indocyanine green clearance or antipyrine and menogaril clearances. Menogaril pharmacokinetics in patients with elevated liver function tests was indistinguishable from that described in patients with normal liver function tests. There were excellent correlations between plasma area under the curve of menogaril and the percentage decreases in WBC and neutrophils. These were well described by two models previously used to study the same relationships in patients with normal hepatic and renal function. When compared to previous studies, patients with hepatic and renal dysfunction had a greater percentage decrease in WBC for any given area under the curve than did patients with normal hepatic and renal function. On the other hand, there was no difference in the relationship between percentage decrease in neutrophils and menogaril area under the curve in these two groups of patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1975

[Experimental contribution to the study of the anticellular effect of diphenyl mercury (author's transl)].

The effect of diphenyl mercury on the chick embryo erythroblastic cell population and rat's bone marrow cells has been studied. The predominant cytologically observed effect of this compound was the c-mitotic action. Besides the well known capacity of spindle inactivation, the diphenyl mercury was able to induce chromosome fragmentation; a radiomimetic action of the compound is suggested.

Animals↗
PubMedDate not supplied

Suramin.

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Clinical Trials as Topic↗