PubMed Health⌕ Search

Biomedical subjects

P Bonomi

Publications and source records attributed to P Bonomi.

At least 19 recordsLinked to original sources
PubMed2004

MAX2--a convenient index to estimate the average per patient risk for chemotherapy toxicity; validation in ECOG trials.

Cancer patients, especially the elderly, present with a highly variable susceptibility to toxicity from chemotherapy. To estimate correctly a patient's risk for toxicity, both the average toxicity of a chemotherapy regimen and patient-related variables need to be assessed. However, treatment toxicities are typically reported item by item, not summarised per patient. We tested an index derived from a pilot study, the MAX2, on the ECOG database. Studies including 20 or more patients aged 70 years and older per arm were selected. Four studies were identified, representing 2526 patients, 410 (16%) being elderly. The association of the MAX2 index with the per patient incidence of grade 4 haematological and/or grade 3 or 4 non-haematological toxicity was highly significant, both for the overall group and for the elderly subgroup. The MAX2 index is a convenient and reproducible way of comparing the average per patient risk for toxicity from chemotherapy across several regimens.

Adult↗
PubMed2002

ZD0473 treatment in lung cancer: an overview of the clinical trial results.

Three open-label, non-comparative, multicentre Phase II trials have examined the efficacy and tolerability of ZD0473 as first-and second-line therapy in non-small-cell lung cancer (NSCLC) patients and second-line therapy in small-cell lung cancer (SCLC) patients. Patients with second-line NSCLC or SCLC were evaluated as either platinum-sensitive or -resistant, based upon their time to relapse/progression after platinum-based therapy. First-line NSCLC patients (n = 18) received a total of 60 treatment cycles (median number per patient 2.5) whilst second-line NSCLC (n = 50) and SCLC (n = 48) patients both received a total of 127 treatment cycles (median number per patient 2.0). Grade 3/4 anaemia, neutropenia and thrombocytopenia was observed in: 38.8%, 22.2% and 27.7% of first-line NSCLC patients; 12.0%, 24.0% and 50% of second-line NSCLC patients; and 10.4%, 25.0% and 47.9% of second-line SCLC patients, respectively. The most common grade 3/4 non-haematological toxicities in all three trials were lethargy and dyspnoea. No clinically significant oto-, nephro- or neurotoxicity was observed. The first-line treatment of NSCLC produced an overall response rate (OR) of 6.3%. No OR was seen after second-line treatment of NSCLC, while ORs of 15.4% and 8.3% were seen in the platinum-resistant and -sensitive second-line SCLC patients, respectively.

Adult↗
PubMed2002

Increased cytosol Ca(2+) and type 1 programmed cell death in Bcl-2-positive U937 but not in Bcl-2-negative PC-3 and Panc-1 cells induced by the 5-lipoxygenase inhibitor MK 886.

MK 886, an arachidonic acid-related analog which inhibits the enzyme, 5-lipoxygenase by an indirect mechanism involving the 5-lipoxygenase activating protein, rapidly increased U937 cytosol Ca(2+), much of which localized around the cell nuclei. Five-lipoxygenase activity was not directly involved since the direct redox-dependent 5-LPOx inhibitor, SC-41661A did not increase Ca(2+). U937 cells subsequently undergo classic type 1 programmed cell death. At least initially the ionized calcium originates from internal stores. Coincident with the rise in U937 ionized calcium, MK 886 rapidly increased reactive oxygen species and reduced mitochondrial membrane potential, as judged by several fluorescent probes. The Ca(2+) response of myeloid leukemia-derived HL-60 cells to MK 886 was similar and both cell lines express Bcl-2 protein. Bcl-2-negative Panc-1 and PC-3 cells did not respond to MK 886 with a Ca(2+) signal but did develop oxidative stress and a decline in mitochondrial membrane potential; these events are thought to contribute to the inhibition of cell proliferation and induction of a type 2 PCD. In addition to its marked inhibition of Bcl-2 mRNA synthesis, an interesting hypothesis is that MK 886, serving as a low molecular weight ligand, either by direct or indirect inhibition of U937 Bcl-2 protein function, possibly related to an ion channel activity, alters the distribution of intracellular, possibly nuclear Ca(2+), thereby promoting the development of type 1 programmed cell death.

Apoptosis↗
PubMed2001

The mode of cell death in H-358 lung cancer cells cultured with inhibitors of 5-lipoxygenase or the free radical spin trap, NTBN.

The 5-lipoxygenase inhibitors SC41661A and MK886 with different mechanisms of action and the free radical spin trap, NTBN inhibit proliferation of the human bronchiolar lung cancer cell line NCI H-358 (5807 CRL). With continued culture, the agents induced a form of programmed cell death in which DNA laddering was not detected and ultrastructural changes were not characteristic of classic 'type 1' cellular suicide. The changes were more consistent with a type 2 cytosolic, autophagic form of PCD. MK886 induced strikingly abnormal mitochondrial morphology. Since the lipoxygenase inhibitors and NTBN induce classic type 1 PCD in U937 monoblastoid cells, these agents can activate either pathway, depending upon cell type. It is not certain whether activation of type 1 or 2 pathways depends entirely upon cell lineage and/or initiating agent, if all cells retain both pathways, and if type 1 PCD a more effective mediator of the process. These are all relevant questions for assessing the impact of PCD on malignant cell survival and considering ways in which it might be enhanced.

Amides↗
PubMed2001

Novel approaches for the treatment of non-small cell lung cancer.

Non-small cell lung cancer is a major worldwide health problem. Approximately 80% of non-small cell lung cancer patients present with advanced disease for which there is little or no chance of cure. Although survival in stage IV non-small cell lung cancer patients is prolonged by treatment with combination chemotherapy regimens, all of these patients develop disease that is refractory to currently available systemic therapy. Basic scientists have identified a number of new therapeutic targets that offer the potential for novel therapeutic interventions, which might control chemotherapy-refractory disease or potentiate the effectiveness of chemotherapy and radiation therapy. The new targets include tumor-associated angiogenesis, biochemical pathways that stimulate tumor proliferation, and programmed cell death (apoptosis). Each of these novel targets will be discussed briefly in this review.

Angiogenesis Inhibitors↗
PubMed2000

Multicenter phase II trial of docetaxel and carboplatin in patients with stage IIIB and IV non-small-cell lung cancer.

PURPOSE: To evaluate the safety and efficacy of docetaxel and carboplatin as first-line therapy for patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this multicenter, phase II trial, 33 patients with previously untreated stage IIIB (n = 8) or IV (n = 25) NSCLC received intravenous infusions of docetaxel 80 mg/m2 followed immediately by carboplatin dosed to AUC of 6 mg/ml/min (Calvert's formula) every three weeks. Patients also received dexamethasone 8 mg orally twice daily for three days beginning one day before each docetaxel treatment. Filgrastim was not allowed during the first cycle and was added only if a patient experienced febrile neutropenia or grade 4 neutropenia lasting > or = 7 days. RESULTS: There were 1 complete and 11 partial responses for an objective response rate of 43% (95% CI: 24%-63%) in 28 evaluable patients and 36% (95% CI: 20%-55%) in the intent-to-treat population. The median duration of response was 5.5 months (range 3.0-12.5 months). The median survival was 13.9 months (range 1-35+ months); one-year survival was 52%. The most common toxicity was hematologic, which included grade 4 neutropenia (79% of patients and 7% percent of cycles) and febrile neutropenia (15% of patients); there were no episodes of grade 3 or 4 infection. The most common severe nonhematologic toxicities were asthenia (24%) and myalgia (12%); there were no grade 3 or 4 neurologic effects. CONCLUSIONS: The combination of docetaxel and carboplatin has an acceptable toxicity profile and is active in the treatment of previously untreated patients with advanced NSCLC. This combination is being evaluated in a randomized phase III trial involving patients with advanced and metastatic NSCLC.

Aged↗
PubMed2000

Widespread countervailing genomic responses induced by chemotherapy or radiation as a cause of therapeutic failure.

If chemotherapy or ionizing radiation induce widespread genomic responses tending to circumvent or antagonize their ability to kill malignant cells, an additional cause for therapeutic failure would be suggested. There is evidence that some agents evoke extensive countervailing genomic activity, the nature and extent of which can be assessed with the use of 'gene chips'.

Antineoplastic Agents↗
PubMed2000

Activity of docetaxel in platinum-treated non-small-cell lung cancer: results of a phase II multicenter trial.

PURPOSE: Although several new chemotherapeutic agents are promising as primary therapy in non-small-cell lung cancer (NSCLC), few have demonstrated activity in platinum-refractory disease. Based on encouraging results reported in two single-institution studies of docetaxel in this setting, we performed a multicenter phase II trial evaluating this novel taxane in previously treated NSCLC patients prospectively categorized by platinum response status. PATIENTS AND METHODS: Eighty patients with NSCLC previously treated with platinum-based chemotherapy received docetaxel at a dose of 100 mg/m(2) intravenously over 1 hour, repeated every 21 days, accompanied by dexamethasone 8 mg orally twice daily for 5 days. Forty-seven patients (59%) were defined as platinum-refractory based on response status to prior therapy. RESULTS: The median number of cycles delivered per patient was four (range, one to 21 cycles). Partial response was observed in 13 (16%) of 80 of patients, with similar response rates in platinum-sensitive and platinum-refractory patients. The median survival time was 7 months, and the 1-year survival rate was 25%. Docetaxel was relatively well tolerated in this previously treated population. Grade IV neutropenia was common in patients (77%) but typically of brief duration. Febrile neutropenia was observed in 11 patients (14%), with no fatal infections. Severe fluid retention was rare (4% of patients). CONCLUSIONS: This multicenter phase II trial confirms antitumor activity and encouraging survival with docetaxel therapy in platinum-treated and platinum-refractory NSCLC. To validate these results, a phase III trial randomizing platinum-treated patients to docetaxel or best supportive care is underway.

Adult↗
PubMed2000

Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial.

PURPOSE: Treatment with cisplatin-based chemotherapy provides a modest survival advantage over supportive care alone in advanced non-small-cell lung cancer (NSCLC). To determine whether a new agent, paclitaxel, would further improve survival in NSCLC, the Eastern Cooperative Oncology Group conducted a randomized trial comparing paclitaxel plus cisplatin to a standard chemotherapy regimen consisting of cisplatin and etoposide. PATIENTS AND METHODS: The study was carried out by a multi-institutional cooperative group in chemotherapy-naive stage IIIB to IV NSCLC patients randomized to receive paclitaxel plus cisplatin or etoposide plus cisplatin. Paclitaxel was administered at two different dose levels (135 mg/m(2) and 250 mg/m(2)), and etoposide was given at a dose of 100 mg/m(2) daily on days 1 to 3. Each regimen was repeated every 21 days and each included cisplatin (75 mg/m(2)). RESULTS: The characteristics of the 599 patients were well-balanced across the three treatment groups. Superior survival was observed with the combined paclitaxel regimens (median survival time, 9.9 months; 1-year survival rate, 38.9%) compared with etoposide plus cisplatin (median survival time, 7.6 months; 1-year survival rate, 31.8%; P =. 048). Comparing survival for the two dose levels of paclitaxel revealed no significant difference. The median survival duration for the stage IIIB subgroup was 7.9 months for etoposide plus cisplatin patients versus 13.1 months for all paclitaxel patients (P =.152). For the stage IV subgroup, the median survival time for etoposide plus cisplatin was 7.6 months compared with 8.9 months for paclitaxel (P =.246). With the exceptions of increased granulocytopenia on the low-dose paclitaxel regimen and increased myalgias, neurotoxicity, and, possibly, increased treatment-related cardiac events with high-dose paclitaxel, toxicity was similar across all three arms. Quality of life (QOL) declined significantly over the 6 months. However, QOL scores were not significantly different among the regimens. CONCLUSION: As a result of these observations, paclitaxel (135 mg/m(2)) combined with cisplatin has replaced etoposide plus cisplatin as the reference regimen in our recently completed phase III trial.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

The role of positron emission tomography in selecting patients with metastatic cancer for adrenalectomy.

Metastases to the adrenal glands usually signal disseminated disease. However, isolated metastases do occur that may be curable with adrenalectomy. Functional imaging with positron emission tomography (PET) can differentiate benign from malignant pathology and isolated from disseminated metastases. The purpose of this study was to determine whether PET scanning can influence the outcome of adrenalectomy for metastatic disease. We conducted a retrospective review of eight patients undergoing adrenalectomy for presumed isolated metastatic disease from 1985 through 1997. The patients included six women and two men with an average age of 58 (range, 36-74). Their primary tumors were six lung carcinomas, one renal cell carcinoma, and one colon carcinoma. The adrenal masses were located on the right in six patients, on the left in one, and bilaterally in one. Before operation, all patients were evaluated by chest and abdominal CT. Four patients were also evaluated by PET scan. Six right, one left, and one bilateral adrenalectomies were performed. Associated organ resections included two right partial nephrectomies and one right total nephrectomy, one left partial nephrectomy, two distal pancreatectomies, one splenectomy, and two partial hepatic resections. All eight patients survived operation. There were no major perioperative complications, but one patient required readmission for congestive heart failure. Three of the four patients who did not have PET scanning died from 4 to 48 months after operation with disseminated disease from lung, colon, and renal carcinoma respectively. The remaining patient who did not have PET scanning is alive and well 11 years later. Two of the four patients who had PET scans showing isolated disease are alive at 28 and 43 months after operation, whereas the other two died of disseminated disease at 29 and 36 months after operation. We conclude that 1) adrenalectomy can provide survival benefit in patients with isolated metastases, and 2) PET scanning is useful in confirming isolated metastatic disease and selecting patients for adrenalectomy.

Adrenal Gland Neoplasms↗
PubMed1999

Free radical spin traps as adjuncts for the prevention and treatment of disease.

Free radical spin traps exhibit properties consistent with a role in the prevention or amelioration of diseases mediated by the formation of free radical species in excess of optimum constitutive requirements. At first view, it may be surprising that they have not found a place in clinical medicine. Some studies of diseases in which free radicals and oxidative stress are aberrantly over- or underabundant and which might be ameliorated by inhibiting or augmenting their formation have been reported. A number of pathophysiologic categories in which such agents have been or might be employed are briefly summarized.

Animals↗
PubMed1999

Docetaxel and cisplatin in patients with advanced non small-cell lung cancer (NSCLC): a multicenter phase II trial.

We examined the safety and efficacy of the docetaxel/cisplatin combination in patients with advanced, previously untreated NSCLC and evaluated changes in quality of life over time. Docetaxel was administered before cisplatin (both 75 mg/m2, 1-hour infusions) every 3 weeks to 47 patients with stage IIIB or stage IV NSCLC. Patients also received premedication of oral dexamethasone. The median age (range) of patients was 62 (45-78) years and 26 patients (55.3%) had adenocarcinoma. Of the 40 patients evaluable for response, one achieved a complete response and 14 had partial responses; the response rate was 37.5% (95% confidence intervals; 22.5, 52.5). In the intent-to-treat population the overall response rate was 31.9%. Time to response ranged from 3 to 20 weeks, and the median duration of response was 34.6 weeks. Median survival and median time to progression were 11.3 months and 18.9 weeks, respectively. One-year survival was 40%. Grade 3 or 4 neutropenia and febrile neutropenia were observed in 74.4% and 12.8% of patients, respectively. Severe asthenia was seen in 14.9% of patients. Other grade 3 or 4 toxicities included nausea (eight patients), vomiting (five), neurosensory effects (six), neuromotor effects (five), diarrhea (four), and infection (three). There was an improvement in emotional well-being; however, the overall quality of life score did not change with treatment. Docetaxel administered in combination with cisplatin is an active regimen in patients with NSCLC. This regimen of docetaxel (75 mg/m2) and cisplatin (75 mg/m2) repeated at 3-week intervals is being evaluated in an ongoing Eastern Cooperative Oncology Group (ECOG) randomized study in patients with advanced and metastatic NSCLC.

Journal Article↗
PubMed1999

Review of paclitaxel/carboplatin in advanced non-small cell lung cancer.

The management of non-small cell lung cancer (NSCLC) has advanced in the last two decades. The greatest benefit has been achieved with the development of newer chemotherapeutic agents with single-agent response rates > or =20%. Recent research has focused on adding these newer agents to established drugs for NSCLC, like cisplatin and carboplatin, yielding notable improvement in response and survival rates. In particular, experience with the combination of carboplatin plus paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has proved encouraging. This regimen is effective, tolerable, and easy to administer and has produced response rates in NSCLC as high as 62%. Phase III trials are under way to establish the specific role of this regimen in NSCLC. The success of this combination also is being expanded through studies investigating its combination in triplets with newer agents, with follow-up therapy via sequential regimens, and by the addition of biologically based treatments. The results of these trials will determine the preferred treatment approach to NSCLC for the next decade.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Paclitaxel steady-state plasma concentration as a determinant of disease outcome and toxicity in lung cancer patients treated with paclitaxel and cisplatin.

The principal purpose of this study was to evaluate relationships between paclitaxel plasma steady-state concentration (Css) and both disease outcome and toxicity in patients with non-small cell lung cancer (NSCLC) treated with paclitaxel and cisplatin in an Eastern Cooperative Oncology Group (ECOG) Phase III study E5592. Chemotherapy-naive patients with stage IIIb and IV NSCLC were randomized to treatment with either 75 mg/m2 cisplatin i.v. on day 1 and 100 mg/m2 etoposide i.v. on days 1-3 (EC arm) or 75 mg/m2 cisplatin i.v. combined with either a low dose of paclitaxel (135 mg/m2, 24-h i.v. infusion; PC arm) or a higher dose of paclitaxel (250 mg/m2 i.v., 24-h i.v. infusion) with granulocyte colony-stimulating factor (PCG arm). End-of-24-h-infusion paclitaxel concentrations, which have been demonstrated to be nearly equal to CssS on this schedule, were obtained during the first and second courses in patients on the PC and PCG arms. Relationships between the average paclitaxel Css (Css,avg) and the best response to treatment, time to treatment failure (TTF), survival, and worst grade of leukopenia and neurotoxicity were evaluated by univariate analysis. A multivariate model was used to assess the influence of paclitaxel Css in conjunction with other potentially relevant patient variables that may affect disease outcome, including the paclitaxel treatment arm, age, sex, performance status, weight loss during the previous 6 months, and disease stage. Paclitaxel Css in both courses 1 and 2 were obtained in 71 patients treated with PC and 75 patients treated with PCG. Although Css,avgS in patients treated with PC and PCG were significantly different (median, 0.32 versus 0.81 micromol/liter; P < 0.0001), response rates were not (33.8 versus 26.7%; P = 0.3719). In addition, there were no differences between the PC and PCG arms in TTF (median, 5.1 versus 5.5 months, P = 0.6201) or survival (median, 11.6 versus 11.3 months, P = 0.7173). Combined analysis of paclitaxel concentrations from both treatment arms revealed no significant difference in paclitaxel Css,avg between responders and nonresponders [median, 0.40 (range, 0.16-1.6) micromol/liter versus 0.55 (range, 0.11-3.6)], and Css,avgS were similar in patients segregated according to whether they had a complete response, partial response, stable disease, or progressive disease as their best response to treatment (P = 0.7612). In addition, the relationship between Css,avg and TTF was weak (r2 = 0.00003, P = 0.94), as was the relationship between Css,avg and survival (P = 0.1267). With regard to the principal toxicities, neither the propensity to develop neuromuscular and neurosensory toxicity nor the worst grade of these adverse effects were related to Css,avg (P = 0.5000 and 0.2033, respectively); however, the relationship between Css,avg and the worst grade of leukopenia experienced was marginally significant (P = 0.0796). In a multivariate model, neither the combined effect of relevant demographic and stratification variables nor paclitaxel Css,avg predicted for either response (P = 0.1544) or TTF (P = 0.2574), whereas the combined effect of all covariates predicted for survival (P = 0.0249). With regard to individual covariates, a lower disease stage (stage IIIb) was the only significant positive determinant of response (P = 0.0173), female sex was the only significant favorable predictor for TTF (P = 0.0195), and a lower ECOG performance status (= 0) was the only significant positive determinant of survival (P = 0.0121) in the multivariate model. In summary, paclitaxel Css,avg was not a determinant of response, TTF, or survival in patients with advanced NSCLC treated with paclitaxel as a 24-h i.v. infusion combined with cisplatin. On the basis of both the clinical and pharmacodynamic results of E5592, there is no compelling reason to treat patients with advanced NSCLC with paclitaxel on a 24-h i.v. schedule at doses of > 135 mg/m2 in combination with cisplatin, although highe

Adult↗
PubMed1998

A randomized phase II trial of echinomycin, trimetrexate, and cisplatin plus etoposide in patients with metastatic nonsmall cell lung carcinoma: an Eastern Cooperative Oncology Group Study (E1587).

BACKGROUND: Patients with metastatic nonsmall cell lung carcinoma (NSCLC) usually have a poor prognosis. A chemotherapy regimen containing cisplatin is commonly used for symptom palliation. Echinomycin is a potent bifunctional intercalator of double-strand DNA; trimetrexate is a new derivative of methotrexate and is active against methotrexate-resistant tumor cells in vitro. METHODS: The Eastern Cooperative Oncology Group conducted a randomized Phase II study. Eligible patients were assigned to receive echinomycin 1200 microg/m2 by intravenous (i.v.) infusion over 30-60 minutes once a week for 4 weeks, repeated every 6 weeks; trimetrexate 12 mg/m2 i.v. bolus on Days 1-5 every 3 weeks, or 8 mg/m2 i.v. bolus on Days 1-5 for patients who had prior radiation to greater than 30% of their bone marrow; or cisplatin 60 mg/m2 i.v. on Day 1 and etoposide 120 mg/m2 i.v. on Days 1-3 every 4 weeks. Patients were evaluated before each cycle for tumor response, toxicity, and quality-of-life measurements. RESULTS: One hundred thirty-six patients were entered on the study, and 118 were evaluable for toxicity and response. The response rates were 16%, 5%, and 5% in patients treated with cisplatin and etoposide, echinomycin, and trimetrexate, respectively. There were no complete responses. The median survival was 37.9, 24.3, and 28.0 weeks for patients who received cisplatin and etoposide, echinomycin, and trimetrexate, respectively. Although cisplatin and etoposide appeared to give better therapeutic results, the response rate or survival did not reach statistical significance. This may have been due to inadequate sample size. Neither did quality-of-life measurement show any significant differences among treatments. CONCLUSIONS: Echinomycin and trimetrexate had minimal antitumor activity in patients with metastatic NSCLC: Response rate and survival remained poor in all three treatment arms. Patients should be encouraged to participate in clinical trials so that more effective therapy can be identified.

Adult↗
PubMed1998

Inhibition of cancer cell proliferation by disruption of interdigitated/concatenated hierarchies of metabolic control/implementation processes: a proposal.

With a combination of inhibitors at less than their individual 'therapeutic' concentrations directed against dissimilar cellular hierarchical developmental controls and 'downstream' metabolic pathways, it may be possible to modulate the biologic behavior of malignantly transformed cells synergistically. Ideally the cumulative systemic toxicity of such a 'polytherapy' would be reduced.

Cell Division↗