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Biomedical subjects

A M Storniolo

Publications and source records attributed to A M Storniolo.

At least 19 recordsLinked to original sources
PubMed1999

A review of hemolytic uremic syndrome in patients treated with gemcitabine therapy.

BACKGROUND: Hemolytic uremic syndrome (HUS) is a rare condition that occasionally is reported in cancer patients. Recently it has been observed that gemcitabine rarely may be associated with this condition. METHODS: The manufacturer's safety database and literature were reviewed for any report regarding gemcitabine associated with renal and hematologic abnormalities. Descriptive analysis was used to examine each case for an association between gemcitabine therapy and HUS and to identify its incidence and risk factors. RESULTS: Through December 31, 1997, 12 cases were identified that fit either the clinical (uremia, microangiopathic hemolytic anemia, and thrombocytopenia) or pathologic (renal biopsy) criteria for HUS. There were 7 males (58%) and 5 females (42%) with a median age of 55.5 years (range, 37-73 years). The median duration of gemcitabine therapy was 5.8 months (range, 3.8-13.1 months). Six patients died, five improved, and one patient's outcome was unknown. Among the six deaths, three patients died of cancer progression, one patient died of an unrelated myocardial infarction, and two patients died of HUS or HUS-related complications. For the five patients who improved, treatment was comprised of dialysis, plasmapheresis, splenectomy, or a combination. Attempts to correlate patient demographics, primary malignancy, and cumulative gemcitabine dose failed to identify consistent risk factors in predisposing patients to HUS. Confounding factors were common, including mitomycin-C and/or 5-fluorouracil exposure, advanced stage tumors, or preexisting renal dysfunction. CONCLUSIONS: Based on a patient exposure of 78,800, a crude overall incidence rate of 0.015% (range, 0.008-0.078%) was determined, showing that HUS associated with gemcitabine treatment appears to be rare. Nonetheless, as with other cancer treatments, clinicians should weigh the appropriate risk/benefit ratio in using gemcitabine to treat their patients.

Adult↗
PubMed1999

An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma.

BACKGROUND: An Investigational New Drug (IND) treatment program allows patients access to a drug that has shown activity against a serious or life-threatening disease prior to full Food and Drug Administration (FDA) review and approval. This treatment IND program, in which patients with locally advanced or metastatic pancreatic carcinoma were treated with gemcitabine, began in 1995. METHODS: Eligibility criteria were < or =1 prior chemotherapy regimen; a Karnofsky performance status (KPS) of > or =50; and adequate bone marrow, liver, and renal function. Gemcitabine was given at a dose of 1000 mg/m2 weekly x 7 followed by a week of rest, then weekly x 3 every 4 weeks thereafter. In this program, disease-related symptom improvement (DRSI) was defined retrospectively as 1) improvement in pain (on a 7-point scale) and/or analgesic class (e.g., morphine improving to codeine) and/or KPS (> or =20 points), or 2) stability of these three parameters with a 7% increase in weight from baseline. RESULTS: A total of 3023 patients enrolled. At baseline, 80% of them had Stage IV disease, and 84% had a baseline KPS > or = 70. The median age was 65 years, and 56% of the patients were male. The cumulative DRSI response rate after the fourth cycle was 18.4%. Of 982 patients with tumor response data, there were 14 with complete response and 104 with partial response, for an overall response rate of 12.0% (95% confidence interval [CI], 10.0-14.0%). For 2380 patients with survival data, the median survival was 4.8 months (95% CI, 4.5-5.1 months) and the 12-month survival was 15%. Gemcitabine was well tolerated; only 4.6% of discontinuations were due to adverse events. CONCLUSIONS: Notable disease-related symptom improvement and survival were seen with gemcitabine in this large, compassionate-use setting, and these findings were in agreement with those of earlier registration trials.

Aged↗
PubMed1997

Assessing clinical benefit in the treatment of pancreas cancer: gemcitabine compared to 5-fluorouracil.

An early study with gemcitabine in pancreas cancer indicated greater relief of disease-related symptoms than expected from the objective tumour response rate. A novel design was created to assess changes in symptomatology prospectively in two studies. The design focuses on typical features seen in patients with advanced pancreas cancer (pain, impaired function, weight loss) and the endpoint is 'clinical benefit response'. Traditional endpoints of objective tumour response and survival were also included. In a randomised study, the clinical benefit response rate for gemcitabine was 24% compared with 5% for 5-fluorouracil (5-FU) (P = 0.0022). The median survival was 5.65 months for gemcitabine compared with 4.41 months for 5-FU (P = 0.0025). The corresponding objective response rates were 5.4% and 0%. Disease stabilised in 39% and 19% of gemcitabine and 5-FU patients, respectively. In a second study of 5-FU-refractory patients, 27.0% of patients were clinical benefit responders. The median survival in this second study was 3.8 months; the objective response rate was 11%, and 30% of patients had stable disease. These trials show that gemcitabine improves disease-related symptoms and survival in patients with pancreas cancer.

Antimetabolites, Antineoplastic↗
PubMed1997

Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.

PURPOSE: Most patients with advanced pancreas cancer experience pain and must limit their daily activities because of tumor-related symptoms. To date, no treatment has had a significant impact on the disease. In early studies with gemcitabine, patients with pancreas cancer experienced an improvement in disease-related symptoms. Based on those findings, a definitive trial was performed to assess the effectiveness of gemcitabine in patients with newly diagnosed advanced pancreas cancer. PATIENTS AND METHODS: One hundred twenty-six patients with advanced symptomatic pancreas cancer completed a lead-in period to characterize and stabilize pain and were randomized to receive either gemcitabine 1,000 mg/m2 weekly x 7 followed by 1 week of rest, then weekly x 3 every 4 weeks thereafter (63 patients), or to fluorouracil (5-FU) 600 mg/m2 once weekly (63 patients). The primary efficacy measure was clinical benefit response, which was a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight. Clinical benefit required a sustained (> or = 4 weeks) improvement in at least one parameter without worsening in any others. Other measures of efficacy included response rate, time to progressive disease, and survival. RESULTS: Clinical benefit response was experienced by 23.8% of gemcitabine-treated patients compared with 4.8% of 5-FU-treated patients (P = .0022). The median survival durations were 5.65 and 4.41 months for gemcitabine-treated and 5-FU-treated patients, respectively (P = .0025). The survival rate at 12 months was 18% for gemcitabine patients and 2% for 5-FU patients. Treatment was well tolerated. CONCLUSION: This study demonstrates that gemcitabine is more effective than 5-FU in alleviation of some disease-related symptoms in patients with advanced, symptomatic pancreas cancer. Gemcitabine also confers a modest survival advantage over treatment with 5-FU.

Adult↗
PubMed1997

Preclinical, pharmacologic, and phase I studies of gemcitabine.

Gemcitabine (2',2'-difluorodeoxycytidine) is a novel nucleoside analogue that exerts its antitumor activity via multiple mechanisms of action. These include (1) incorporation of gemcitabine into replicating DNA, which inhibits DNA replication and cell growth, (2) masked DNA chain termination, and (3) several self-potentiation mechanisms that serve to increase intracellular levels of the active compound. Preclinical experiments in various cell lines and animal models demonstrate a broad range of cytotoxic activity. Pharmacokinetic studies of gemcitabine delivered by its usual schedule (30-minute weekly infusion) reveal a short plasma half-life and a high clearance into central and peripheral compartments (two-compartment model). The drug is excreted almost completely in the urine as the parent compound and primary metabolite (difluorodeoxyuridine). Phase I trials demonstrate that pharmacokinetics are schedule dependent and that, in general, gemcitabine is well tolerated. Dose-limiting toxicities are primarily myelosuppression, with other toxicities being rash, flu-like symptoms, and transient elevations in liver function tests.

Animals↗
PubMed1997

A pilot clinical/pharmacological study of the protein kinase C-specific inhibitor safingol alone and in combination with doxorubicin.

We performed a pilot clinical trial with safingol (L-threo-dihydrosphingosine), a protein kinase C-specific inhibitor that potentiates the effect of doxorubicin (DOX) in tumor-bearing animals. Safingol was initially administered as a 1-h infusion at escalating doses. Fourteen days later, patients received the same dose of safingol in combination with a fixed dose of DOX. The combination was repeated at 3-week intervals. Safingol dose levels ranged from 15 to 120 mg/m2. The plasma levels achieved at the final dose level were comparable to those associated with potentiation of DOX in animals. The mean Cmax and area under the curve for safingol at the 120 mg/m2 dose level were 1040 +/- 196 ng/ml and 1251 +/- 317 mg x h/ml, respectively. The mean plasma half-life for safingol was 3.97 +/- 2.51 h, the mean estimated clearance was 3140 +/- 765 ml/min, and the mean volume of distribution was of 995 +/- 421 liters. Coadministration of a fixed dose of DOX did not significantly change the pharmacokinetics of safingol, nor did increasing doses of safingol significantly affect the pharmacokinetics of DOX. Minor responses were observed in three patients with pancreatic cancer and one patient with angiosarcoma of the scalp. This pilot Phase I study indicates that the protein kinase C inhibitor safingol can be given safely with 45 mg/m2 of DOX at a dose that is potentially pharmacologically active without dose-limiting toxicity.

Adult↗
PubMed1996

A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer.

PURPOSE: To assess the effect of gemcitabine in patients with metastatic pancreas cancer that had progressed despite prior treatment with 5-FU. PATIENTS AND METHODS: Seventy-four patients were enrolled in this multicenter trial. Alleviation of cancer-related symptoms was the primary endpoint. Sixty-three patients completed a pain stabilization period and were treated with gemcitabine. Clinical Benefit Response was defined as a > or = 50% reduction in pain intensity, > or = 50% reduction in daily analgesic consumption, or > or = 20 point improvement in KPS that was sustained for > or = 4 consecutive weeks. RESULTS: Seventeen of 63 pts (27.0%) attained a Clinical Benefit Response (95% CI: 16.0%-38.0%). The median duration of Clinical Benefit Response was 14 weeks (range: 4-69 weeks). Median survival for patients treated with gemcitabine was 3.85 months (range: 0.3-18.0+ months). Therapy was generally well-tolerated with a low incidence of grade 3 or 4 toxicities. CONCLUSION: Systematic assessment of subjective outcomes can be used to evaluate the clinical impact of new therapies for pancreas cancer, a highly symptomatic disease. Our findings suggest that gemcitabine is a useful palliative agent in patients with 5-FU-refractory pancreas cancer.

Adenocarcinoma↗
PubMed1996

"Decadose" effects of cisplatin on squamous cell carcinoma of the upper aerodigestive tract. II. Clinical studies.

There is evidence that solid tumors rapidly acquire cellular resistance to cisplatin. This resistance is usually mild to moderate and could be circumvented with higher concentrations of drug exposure if ancillary methods were available to avoid systemic cytotoxicity. The purpose of this study was to determine whether a tenfold increase in dose (decadose) would overcome cisplatin resistance. In a clinical trial, response effects of cisplatin at dose intensities ranging from 32.5 to 200 mg/m2 per week, which were delivered by highly selective intra-arterial infusions with a simultaneously administered intravenous neutralizing agent, were measured in 31 patients with squamous cell carcinoma (SCC) of the upper aerodigestive tract (UADT). The overall response rate (complete response [CR] and partial response [PR] to cisplatin therapy at dose intensity intervals of 0 to 74, 75 to 149, and 150 to 200 mg/m2 per week were 45.5%, 72.7%, and 100%, respectively. The average received dose intensities for nonresponders and responders (CR and PR) were 57.8 and 120.7 mg/m2 per week, respectively (P = .031). The results indicate that resistance to standard doses of cisplatin by SCC of the UADT, both previously untreated and recurrent, can be substantially overcome with "decadose" cisplatin therapy. Progress toward improving survival of patients with head and neck cancer, and possibly other site-specific malignancies, may be achieved by incorporating decadose cisplatin therapy into a multimodality treatment plan.

Adult↗
PubMed1994

Sponge-gel-supported histoculture drug-response assay for head and neck cancer. Correlations with clinical response to cisplatin.

OBJECTIVE: Sponge-gel-supported histoculture drug-response assay (SSHDRA) represents a promising method to determine chemosensitivity of solid tumors. To determine whether the assay correlates clinically, we compared the in vivo and in vitro effects of cisplatin in 23 of 26 patients with head and neck cancers. DESIGN: The criterion for in vitro sensitivity to cisplatin was an 84% or greater inhibition by cisplatin of the number of tritiated thymidine-incorporating cells of the histocultured tumors compared with untreated control culture preparations, as measured by means of histologic autoradiography. Comparisons were made with clinical responses, ie, complete response, partial response, or no response. PATIENTS: The study was carried out in patients with head and neck cancers and comprised 21 patients with squamous-cell carcinoma, three patients with other carcinomas, and two patients with sarcoma. RESULTS: Ten of 12 patients with in vitro-sensitive tumors had either complete or partial response clinically. The overall accuracy of the SSHDRA was 74% in this correlative clinical trial; the predictive-positive value was 83%, the sensitivity was 71%, and the specificity was 78%. Seven of 11 patients with in vitro-resistant tumors demonstrated no response for a predictive-negative value of 64%. CONCLUSIONS: We conclude that the SSHDRA shows a high correlation for tumors that demonstrate both in vivo drug resistance and sensitivity. The in vitro-like maintenance of three-dimensional tissue architecture of the tumors in histoculture probably contributes to high clinical predictivity of drug response of the SSHDRA. The data support further comparisons to determine the clinical usefulness of the SSHDRA for identifying complete and partial responders to chemotherapy.

Adenocarcinoma↗
PubMed1994

Phase I study of highly selective supradose cisplatin infusions for advanced head and neck cancer.

PURPOSE: To determine the maximum dose-intensity of cisplatin (DDP) that could be administered by selective intraarterial (IA) infusion in combination with systemic sodium thiosulfate neutralization to patients with head and neck carcinoma. PATIENTS AND METHODS: Forty-two patients (23 untreated stage III/IV, 19 recurrent) received highly selective IA DDP, rapidly delivered through microcatheters placed angiographically, to a maximum dose-intensity of 200 mg/m2/wk. Concurrently, the systemic effects of DDP were neutralized by intravenous (IV) bolus sodium thiosulfate. RESULTS: Problems related to the infusion technique occurred in eight of 140 courses, all of which were inconsequential. The rates of reversible grade I/II and grade III/IV toxicity were 14.8% and 1.1%, respectively. Dose-limiting toxicity, which consisted of severe electrolyte loss, occurred at a dose of 200 mg/m2/wk. The maximum-tolerated dose of DDP was 150 mg/m2 administered weekly for four doses. The overall and complete response rates in 38 assessable patients were 19 of 22 (86%) and nine of 22 (41%) for stage III/IV untreated tumors and 10 of 16 (62%) and four of 16 (25%) for patients with recurrent disease, respectively. CONCLUSION: This pharmacologic strategy permits the selective and rapid delivery of extremely high doses of DDP to head and neck carcinomas with minimal procedural complications, low systemic toxicity, and high tumor response rates.

Adult↗
PubMed1993

High-dose carboplatin chemotherapy with GM-CSF and peripheral blood progenitor cell support: a model for delivering repeated cycles of dose-intensive therapy.

High-dose chemotherapy regimens can cure a number of otherwise incurable diseases, such as Hodgkin's disease, non-Hodgkin's lymphoma, neuroblastoma, acute leukemia (in remission), and breast cancer. Trials of high-dose chemotherapy have generally used autologous bone marrow transplant or peripheral blood stem cell support to ensure hematologic recovery after intensive chemotherapy and/or radiation. This report describes an approach in which high-dose carboplatin chemotherapy was followed initially by granulocyte-macrophage colony-stimulating factor (GM-CSF; Escherichia coli. Sandoz-Schering, East Hanover and Kenilworth, NJ) and in subsequent patients, by both GM-CSF and repeated cycles of peripheral blood progenitor cell (PBPC) collection and administration. The addition of PBPC to this regimen led to significant reductions in the duration of neutropenia and thrombocytopenia, the requirement for erythrocyte and platelet transfusions, the length of hospital stay, and the use of intravenous antibiotics in this group relative to those patients who received GM-CSF alone. In addition, laboratory studies are presented that show a direct correlation between the number of progenitor cells reinfused and the duration of neutropenia and thrombocytopenia. The report also reviews data indicating that circulating progenitor cells are depleted by this approach. This suggests that the number of progenitor cells available for mobilization is finite. Finally, the magnitude of these effects, and their implications for future trials with repetitive cycles of dose-intensive therapy, are discussed.

Adult↗
PubMed1992

Sequential cycles of high-dose carboplatin administered with recombinant human granulocyte-macrophage colony-stimulating factor and repeated infusions of autologous peripheral-blood progenitor cells: a novel and effective method for delivering multiple courses of dose-intensive therapy.

PURPOSE: The trial was undertaken to study the effect of administering granulocyte-macrophage colony-stimulating factor (GM-CSF) with and without peripheral-blood progenitor cells (PBPC) on the hematologic and nonhematologic toxicity observed with multiple cycles of high-dose carboplatin chemotherapy. PATIENTS AND METHODS: Eighteen patients with a variety of solid tumors received a total of 40 cycles of carboplatin, 1,200 mg/m2 per cycle, administered by continuous infusion over 96 hours. All 40 courses were administered with a daily 4-hour intravenous (IV) infusion of either 5 or 10 micrograms/kg/d of recombinant human Escherichia coli-derived GM-CSF. The first 20 courses were administered without PBPC support (treatment A). Because of severe neutropenia and thrombocytopenia, the next 20 courses of therapy were administered with GM-CSF, PBPC, and oral antibiotic prophylaxis (treatment B). RESULTS: The addition of PBPC support led to a significant reduction in the duration of neutropenia (10.5 v 7.5 days; P = .027) and thrombocytopenia (12.4 v 5.2 days; P = .001), number of RBC transfusions (six v three; P = .01) and platelet transfusions (10.3 v 3.7; P = .013), number of hospital days (12.6 v 2.9; P = .01), and days of IV antibiotics (11.8 v 2.4; P = .007) per cycle. Significant increases in the weekly dose intensity (206 v 285 mg/m2/wk; P = .014) and total dose (2,287 v 3,600 mg/m2; P = .018) of carboplatin delivered were also observed with treatment B. The overall response rate in this study was 70%, with 11 of 16 assessable patients achieving either a complete (three patients) or partial (eight patients) remission. CONCLUSION: This combination of GM-CSF and PBPC infusion represents an effective method for delivering multiple cycles of high-dose carboplatin chemotherapy and may serve as a model for the administration of high-dose chemotherapy in future trials.

Adult↗
PubMed1992

A dose-escalation study of carboplatin/cyclophosphamide/etoposide along with autologous bone marrow or peripheral blood stem cell rescue.

Twenty patients have received 21 courses of high-dose cyclophosphamide (6 g/m2 over 4 days), etoposide (1,800 mg/m2 over 3 days), and carboplatin (800 to 1,600 mg/m2 by continuous infusion over 96 hours) and autologous bone marrow or peripheral blood stem cell rescue. The maximum tolerated dose of this regimen included these doses of cyclophosphamide and etoposide with a total of 1,600 mg/m2 carboplatin. Acute renal failure was the dose-limiting toxicity and, at the maximum tolerated dose, was observed in two patients of 14 evaluable courses. Nonhematologic toxicity was otherwise modest, and the overall response rate was 70% in patients with a wide variety of solid hematologic neoplasms.

Acute Kidney Injury↗
PubMed1991

Drug response of head and neck tumors in native-state histoculture.

We describe a chemosensitivity testing of head and neck tumors, in which a native-state histoculture, ie, a three-dimensional culture system that maintains important in vivo properties, including tissue architecture, was used. Fifteen specimens of head and neck tumors were evaluated for sensitivity to the following drugs: cisplatin (DDP) at concentrations of 1.5, 15, and 37.5 micrograms/mL; fluorouracil at concentrations of 4.0, 40, and 100 micrograms/mL; and combinations of cisplatin and fluorouracil in corresponding doses. Growth and measurement of drug responses were successfully completed in 10 specimens (five others were contaminated, four of them prior to instituting rigorous antibiotic washes). The results indicated cisplatin sensitivity in five of 10 patients; fluorouracil sensitivity in four of 10 patients; and fluorouracil-cisplatin sensitivity in seven of eight patients. Our preliminary results indicate that the native-state histoculture technique is feasible to test chemosensitivity of head and neck tumors.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Chronic myelomonocytic leukemia.

Thirty adult patients with CMML were evaluated to determine prognostic factors that might have an impact on conversion to acute leukemia and survival. Neither leukocyte count nor monocyte count correlated with survival. The median survival for all 30 cases was 41 months. Patients with less than 5% marrow blasts had a median survival of 60 months but those with 5-20% blasts had only a 9-month median survival.

Aged↗
PubMed1987

Spontaneous hemoperitoneum in two patients with myeloproliferative disorders.

Spontaneous hemoperitoneum developed in two patients with hitherto undiagnosed myeloproliferative disorders. No other known etiology could be attributed to the two patients described. The report of these two patients suggests that the diagnosis of a myeloproliferative disorder should be considered in the evaluation of patients with spontaneous hemoperitoneum.

Aged↗
PubMedDate not supplied

Rapid superselective high-dose cisplatin infusion for advanced head and neck malignancies.

Advances in vascular radiology techniques for superselective arterial infusions and methods to overcome systemic toxicity from high-dose cisplatin chemotherapy encouraged us to reevaluate the effects of rapid regional cisplatin infusion for patients with head and neck malignancies. Twenty patients (17 carcinomas, three sarcomas) received high-dose cisplatin (100-200 mg/m2) by this method. Fifteen of the 17 patients with upper aerodigestive tract carcinoma are part of an ongoing phase I dose escalation of cisplatin with sodium thiosulfate neutralization. Three additional patients with sarcomas were treated with intra-arterial (IA) cisplatin and systemic Adriamycin. Fifty-three IA infusions were performed without any complications. Only minimal toxicity related to the chemotherapy was observed. The overall response rate for previously untreated patients was nine of 10 (90%) [complete response (CR) 67%; partial response (PR) 33%]. The response rate for patients with recurrent disease was five of eight (63%) (CR 20%, PR 80%). The average length of follow-up is 9.5 months and the actuarial survival rate is 56%. Superselective rapid infusion of high-dose cisplatin for patients with advanced head and neck malignancies is feasible, relatively nontoxic, and may have important applications in multimodality therapy, particularly for patients with bulky primary disease.

Antidotes↗