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Cesare Gridelli

Publications and source records attributed to Cesare Gridelli.

At least 37 records · Page 2Linked to original sources
PubMed2004

Potential role of molecularly targeted therapy in the management of advanced nonsmall cell lung carcinoma in the elderly.

BACKGROUND: More than 50% of all lung carcinoma cases are diagnosed in patients age > 65 years, and approximately 30% are diagnosed in patients age > 70 years. Elderly patients do not tolerate chemotherapy as well as their younger counterparts do, primarily because of the increased prevalence of comorbid conditions and organ failure. Thus, at present, the majority of elderly patients with malignant disease do not receive aggressive chemotherapy. For such elderly patients, alternatives to conventional chemotherapy, such as novel molecularly targeted therapy regimens, are of interest. METHODS: The current review summarizes contemporary approaches to and recent advances in the treatment of elderly patients with nonsmall cell lung carcinoma (NSCLC) and offers perspectives on the future of molecularly targeted therapy in this population. Inhibitors of epidermal growth factor receptor, vascular endothelial growth factor, and cyclooxygenase-2 are discussed in the current report, with such inhibitors being, in our opinion, among the best candidates for clinical development in the setting of interest. RESULTS: Novel biologic agents with putative activity against advanced NSCLC are at various stages of clinical development. Some of these agents have yielded benefits in terms of disease-related symptom reduction, quality of life, and survival. For elderly patients, the potential advantages of such agents include improved tolerability compared with conventional chemotherapy. This feature also makes these novel agents attractive alternatives for younger patients who cannot tolerate or are reluctant to receive conventional chemotherapy. CONCLUSIONS: Current studies are investigating the safety and efficacy of these novel biologic agents administered alone, in combination with other noncytotoxic agents, and in combination with conventional chemotherapy. These studies will help elucidate the role of targeted therapy in the management of elderly patients with advanced NSCLC.

Angiogenesis Inhibitors↗
PubMed2004

Factors influencing the choice of 5-HT3-receptor antagonist antiemetics: focus on elderly cancer patients.

With old age comes declining organ function, cognitive impairment, increased likelihood of comorbid conditions and multiple prescription and nonprescription pharmacotherapy. These issues are particularly relevant in elderly cancer patients, who commonly receive combination chemotherapy and supportive care agents along with radiation therapy and surgery. This situation can complicate medical care, particularly since over half of all cancers occur in those aged over 65 years. The 5-HT(3)-receptor antagonists as a class are highly effective antiemetics and are currently considered the gold standard for treatment of chemotherapy- and radiotherapy-induced nausea and vomiting. However, these agents do possess different pharmacologic properties, such as varying terminal half lives, routes of metabolism and selectivity for 5-HT(3) receptors. These differences may have an impact on efficacy (e.g., duration of action of the drug) safety (e.g., the risk of drug interactions and potential adverse effects), and simplicity of the dosing regimen. The focus of this review is on some of the pertinent issues of 5-HT(3) antagonists relating to elderly cancer patients.

Aged↗
PubMed2004

The role of targeted therapy in non-small cell lung cancer.

The therapy of non-small cell lung cancer (NSCLC) has reached a plateau in improving patient survival, with overall disappointing results. Thus, clinical research for new treatment strategies is warranted. Advances in the singling out molecular targets for NSCLC treatment has granted the development of several new biological agents. In the present paper we describe the main clinical data currently available on targeted agents in the treatment of NSCLC, focusing on epidermal growth factor receptor family inhibitors, angiogenesis inhibitors, signal transduction inhibitors, eicosanoid pathway inhibitors, vaccines and gene therapy. Several targeted agents have been introduced into clinical trials in NSCLC, mainly in advanced disease, with the first phase III study results being recently made available. To date, few of these new agents can offer hope of a substantial impact on the natural history of NSCLC, and negative results are more commonly reported than positive ones. Nevertheless, clinically-meaningful advances have already been achieved in chemotherapy refractory advanced NSCLC patients, with gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, representing a further chance of tumor control and symptom palliation. Moreover, important lessons can be learned from this first generation of clinical trials.

Animals↗
PubMed2004

Same old story? Do we need to modify our supportive care treatment of elderly cancer patients? Focus on antiemetics.

The incidence of cancer is highest among individuals > or =65 years of age. Physiological changes associated with aging, such as cognitive decline, renal and hepatic dysfunction, can often complicate treatment options, and the elderly represent a particular challenge to the oncologist because of the high incidence of comorbidity and polypharmacy. Effective supportive care is of particular importance in elderly cancer patients as they may recover less satisfactorily if adverse events are poorly controlled. Nevertheless, evidence suggests that supportive care agents, for example, antiemetics, are underutilised in this patient population. Chemotherapy and radiotherapy regimens are frequently associated with nausea and vomiting--symptoms that can have deleterious effects on vulnerable patients if not adequately managed. The serotonin 5-HT3-receptor antagonists represent a class of antiemetics that are currently regarded as the gold standard treatment for chemotherapy- and radiotherapy-induced nausea and vomiting. They are recommended as first-line treatment for patients at moderate-to-high risk of emesis. However, antiemetic guidelines do not differentiate between these agents and, more importantly, do not contain specific recommendations for the elderly. Pharmacological differences exist between the commonly available 5-HT3-receptor antagonists (dolasetron, granisetron, ondansetron, tropisetron and palonosetron), namely receptor sensitivity, duration of action, metabolism and tolerability profile. Of particular concern with prescriptions to elderly cancer patients is the convenience of once-daily administration, the low potential for drug-drug interactions and cardiovascular adverse effect profile. Moreover, the addition of the newly approved neurokinin NK1-receptor antagonist aprepitant to the choice of antiemetic regimen may complicate therapy and exacerbate the drug-drug interaction risk in elderly patients. Therefore, the use of antiemetics that are well tolerated and with the lowest risk of drug-drug interactions is imperative in this patient population and will enable even those patients with several comorbidities and a high level of polypharmacy to receive effective antiemetic therapy.

Aged↗
PubMed2004

Non-small-cell lung cancer in elderly patients: influence of age on vinorelbine oral pharmacokinetics.

The majority of cancer-related deaths are attributed to lung carcinoma. Age increases this incidence, which is also likely associated with physiologic modifications that affect drug pharmacokinetics and metabolism. Therefore, knowledge of pharmacokinetics in elderly patients is one of the major factors in deciding whether or not to reduce the dose to prevent toxicity. This phase II study was aimed at evaluating the influence of age on oral vinorelbine pharmacokinetics in elderly patients with non-small-cell lung cancer (NSCLC). Inclusion criteria were > 70 years of age; histologically or cytologically proven NSCLC; inoperable stage IIIB, IV, or delayed relapse of any stage becoming unresectable; Karnofsky performance status > 80%; and normal hematology and biochemistry. Blood-limited sampling at intervals of 1.5, 3, and 24 hours after dosing was performed during the first administration of oral vinorelbine at 60 mg/m2. Bayesian pharmacokinetic parameters were calculated through previously published nonlinear mixed-effect modeling (NONMEM), and compared with a reference population of 52 patients (age, 56 years 12) selected from vinorelbine pharmacokinetic database. There were 48 patients evaluable for pharmacokinetics out of the 52 elderly patients enrolled (age, 74 years 3). There was no difference between pharmacokinetic parameters, including the bioavailability factor evaluated by NONMEM, even without intravenous administration, and a similar interindividual variability (32%-33%) was observed between the 2 groups. Furthermore, no correlation between age (range, 31-82 years) and oral vinorelbine total clearance was observed in 100 patients pooled together. Therefore, no requirement for oral vinorelbine dose reduction was suggested from a pharmacokinetic standpoint.

Administration, Oral↗
PubMed2003

Gemcitabine, paclitaxel, and cisplatin as induction chemotherapy for patients with biopsy-proven Stage IIIA(N2) nonsmall cell lung carcinoma: a Phase II multicenter study.

BACKGROUND: The objective of the current study was to define the activity and tolerability, as well as the influence on resectability, of the combination of gemcitabine, paclitaxel, and cisplatin (GTP) as induction chemotherapy for patients with Stage IIIA(N2) nonsmall cell lung carcinoma (NSCLC). METHODS: Forty-nine chemotherapy-naïve patients (median age, 61 years; World Health Organization performance status, 0-1) with biopsy-proven Stage IIIA(N2) disease received 1000 mg/m(2) gemcitabine, 125 mg/m(2) paclitaxel, and 50 mg/m(2) cisplatin on Days 1 and 8 of every 3 weeks until reevaluation for surgery or definitive radiotherapy. RESULTS: Grade 3-4 neutropenia was the most common hematologic toxicity, occurring in 32.7% of patients; however, only 1 case of febrile neutropenia was reported. Grade 3-4 thrombocytopenia occurred in 12.2% of patients but was not associated with bleeding. Severe nonhematologic toxicities were uncommon; the only Grade 4 nonhematologic toxicity was diarrhea, which occurred in 4% of patients. One patient died after the first course of therapy, but this event was found to be unrelated to treatment. Thirty-six patients (73.5%) achieved an objective response, and an additional 4 patients had stable disease with clearance of mediastinal lymph nodes. Overall, 29 patients underwent thoracotomy and 27 (55%) underwent complete resection. Mediastinal nodes were free of tumor in 35% of all cases, and 8 pathologic complete responses (16%) were reported. Median survival was 23 months, with a 1-year survival rate of 85%. CONCLUSIONS: GTP is highly active as an induction chemotherapy regimen for Stage IIIA(N2) NSCLC and yields good toxicity results. The use of GTP in combination with radiotherapy and new biologic drugs should be explored.

Adult↗
PubMed2003

Treatment of non-small-cell lung cancer: state of the art and development of new biologic agents.

Conventional treatment of non-small-cell lung cancer (NSCLC) has apparently reached a plateau of effectiveness in improving the survival of NSCLC patients. Although neoadjuvant and adjuvant therapies in early stages are under investigation and some progress has been achieved in the management of locally advanced and advanced disease, treatment outcomes for NSCLC are still to be considered dismal. The majority of patients affected from NSCLC experience metastatic disease and optimization of chemotherapy is unlikely to produce further substantial survival improvement, with symptom relief and quality of life still being the primary goal of treatment. Based on this background, clinical investigation of novel treatment strategies is mandatory. As our understanding of tumor cell biology has increased and several molecular targets for NSCLC have been identified, a number of new biologic agents have been developed. Targeted therapy describes treatment strategies that focus on cell signaling and other biologic pathways involved in tumorigenesis. Several targeted agents have been introduced in clinical trials in NSCLC, the majority in advanced disease, and some phase III studies have already produced definitive results. Currently, the minority of these new agents offer promise of improved outcomes and negative results are more common to be reported than positive ones. However, important lessons can be learned from this first generation of clinical trials that should be considered the first step of clinical research in this field.

Antibodies, Monoclonal↗
PubMed2003

Prolonged gemcitabine infusion in advanced non-small cell lung carcinoma: a randomized phase II study of two different schedules in combination with cisplatin.

BACKGROUND: Preclinical and clinical evidence suggests that a fixed infusion rate of 10 mg/m2 per minute may be more effective than the standard 30-minute infusion of gemcitabine. To investigate the activity and toxicity of the cisplatin plus gemcitabine combination with gemcitabine at a fixed infusion rate in patients with advanced non-small cell lung carcinoma (NSCLC), the authors conducted a randomized Phase II trial of cisplatin plus gemcitabine at the 30-minute standard infusion (calibration arm) or cisplatin plus gemcitabine at a fixed infusion rate (experimental arm). METHODS: A total of 112 chemonaive patients with advanced NSCLC entered the study: 57 patients in Arm A and 55 patients in Arm B. The patients were randomly assigned to receive gemcitabine at a dose of 1000 mg/m2 on Days 1, 8, and 15 over 30 minutes (Arm A) or at a rate of 10 mg/m2 per minute (Arm B). In both treatment arms, cisplatin at a dose of 80 mg/m2 was administered on Day 15 every 28 days. RESULTS: The overall response rates in Arms A and B were 26% (95% confidence interval [95% CI], 10-42%) and 34% (95% CI, 17-52%) (intent-to-treat-analysis), respectively. The median time to disease progression was 6 months (range, 1-26 months) and 8 months (range, 2-21 months), respectively, for Arms A and B and the median overall survival was 13 months (range, 2-26 months) for each arm. It is interesting to note that a high response rate (67%) of brain metastases was noted in the experimental arm. Toxicity was tolerable and comparable in the two arms. CONCLUSIONS: The results of this randomized Phase II trial demonstrated that cisplatin plus gemcitabine with gemcitabine at fixed infusion rate (10 mg/m2 per minute) is active and well tolerated in patients with advanced NSCLC.

Adult↗
PubMed2003

Gemcitabine plus vinorelbine compared with cisplatin plus vinorelbine or cisplatin plus gemcitabine for advanced non-small-cell lung cancer: a phase III trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: Platinum-containing chemotherapy regimens are the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), although toxicity is common and may significantly affect the patient's quality of life (QoL). This trial aimed to assess whether a combination of gemcitabine and vinorelbine had benefits in terms of QoL, without influencing negatively on survival, compared with cisplatin-containing regimens. PATIENTS AND METHODS: Patients with stage IIIB (effusion and supraclavicular nodes) or IV documented NSCLC who were younger than 70 years of age were randomly assigned gemcitabine plus vinorelbine (GemVin) or either gemcitabine plus cisplatin or vinorelbine plus cisplatin (cisplatin-based). European Organization for Research and Treatment of Cancer scales were used for QoL analysis. RESULTS: Five hundred one patients were randomly assigned to treatment. The median age was 62 years. There were no significant differences in global QoL scores between the two arms after 2 months of treatment. However, worsening scores for appetite, vomiting, and alopecia were significantly more common in the cisplatin-based arm. Median survival was 38 v 32 weeks and median progression-free survival was 23 v 17 weeks in the cisplatin-based versus GemVin arms, respectively. For the GemVin arm the hazard ratio for death was 1.15 (90% confidence interval [CI], 0.96 to 1.37) and the hazard ratio for progression was 1.29 (90% CI, 1.10 to 1.52). Grade 3 or 4 myelosuppression, vomiting, alopecia, and ototoxicity were significantly more frequent with cisplatin-based treatment. CONCLUSION: Global QoL is not improved with GemVin, although advantages in some components of QoL were apparent. GemVin is less toxic than standard cisplatin-based chemotherapy. There is a nonsignificant slight survival advantage with cisplatin-based chemotherapy. GemVin could be offered to advanced NSCLC patients who express concern about toxicity.

Adult↗
PubMed2003

Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial.

BACKGROUND: Vinorelbine prolongs survival and improves quality of life in elderly patients with advanced non-small-cell lung cancer (NSCLC). Some studies have also suggested that gemcitabine is well tolerated and effective in such patients. We compared the effectiveness and toxicity of the combination of vinorelbine plus gemcitabine with those of each drug given alone in an open-label, randomized phase III trial in elderly patients with advanced NSCLC. METHODS: Patients aged 70 years and older, enrolled between December 1997 and November 2000, were randomly assigned to receive intravenous vinorelbine (30 mg/m(2) of body surface area), gemcitabine (1200 mg/m(2)), or vinorelbine (25 mg/m(2)) plus gemcitabine (1000 mg/m(2)). All treatments were delivered on days 1 and 8 every 3 weeks for a maximum of six cycles. The primary endpoint was survival. Survival curves were drawn using the Kaplan-Meier method and analyzed by the Mantel-Haenszel test. Secondary endpoints were quality of life and toxicity. RESULTS: Of 698 patients available for intention-to-treat analysis, 233 were assigned to receive vinorelbine, 233 to gemcitabine, and 232 to vinorelbine plus gemcitabine. Compared with each single drug, the combination treatment did not improve survival. The hazard ratio of death for patients receiving the combination treatment was 1.17 (95% confidence interval [CI] = 0.95 to 1.44) that of patients receiving vinorelbine and 1.06 (95% CI = 0.86 to 1.29) that of patients receiving gemcitabine. Although quality of life was similar across the three treatment arms, the combination treatment was more toxic than the two drugs given singly. CONCLUSION: The combination of vinorelbine plus gemcitabine is not more effective than single-agent vinorelbine or gemcitabine in the treatment of elderly patients with advanced NSCLC.

Aged↗
PubMed2003

Epidermal growth factor receptor targeted therapy by ZD 1839 (Iressa) in patients with brain metastases from non-small cell lung cancer (NSCLC).

PURPOSE: We report four cases of Brain Metastases (BM) from non-small cell lung cancer (NSCLC) responding to ZD 1839 therapy after standard therapy failure. PATIENTS AND METHODS: Four patients with BM from NSCLC, pretreated with two or more lines of chemotherapy, received ZD 1839 (Iressa), on a compassionate use basis, at the daily dose of 250 mg until disease progression. Three patients received Iressa after whole brain radiotherapy (WBRT) failure. RESULTS: After 3 months of ZD 1839 therapy, one patient had complete response on the brain with stabilization of extracranial disease, while the other three patients had partial response both on the brain and on extracranial sites. At the time of this analysis, two patients discontinued the treatment after 5 and 7 months for disease progression, while two patients are still on treatment with no evidence of treatment failure after 3+ and 12+ months. ZD 1839 was generally well tolerated, with skin toxicity recorded in two patients. CONCLUSION: ZD 1839 may be effective in NSCLC patients with pretreated BM. Large and prospective trials need to clarify the role of ZD 1839 in the treatment of BM from NSCLC.

Aged↗
PubMed2002

Carboplatin plus vinorelbine plus G-CSF in elderly patients with extensive-stage small-cell lung cancer: a poorly tolerated regimen. Results of a multicentre phase II study.

PURPOSE AND METHODS: A multicentre phase II trial (single-stage design) was undertaken to test the activity and toxicity of carboplatin (AUC 5 according to Calvert, day 1) plus vinorelbine (25 mg/m(2) days 1 and 8) with lenograstim support, every 3 weeks in the first line treatment of elderly patients, aged 65 or more, affected by extensive small-cell lung cancer (SCLC). The primary end-point of the trial was the objective response rate. Twenty-three responses among 37 patients were considered necessary to proceed to a phase III trial. RESULTS: Twenty-eight patients were enrolled (median age 70 years). Treatment was remarkably toxic. Three patients died while on treatment. Eleven patients (39.3%, 95% exact confidence interval (CI): 21.5-59.4) had an objective response, that was complete in 2 cases. Median time to progression was 5.1 months (95% CI: 3.3-6.7). Median survival was 7.9 months (95% CI: 4.8-14.4). CONCLUSION: Carboplatin plus vinorelbine is poorly tolerated and not sufficiently active to warrant phase III comparison with standard chemotherapy regimens in elderly patients with extensive SCLC.

Aged↗
PubMed2002

Vinorelbine plus cisplatin versus cisplatin plus vindesine and mitomycin C in stage IIIB-IV non-small cell lung carcinoma: a prospective randomized study.

PURPOSE: To compare a regimen of vinorelbine and cisplatin (VC) to the combination of mitomycin, vindesine, and cisplatin (MVP) in patients with stage IIIB or stage IV non-small cell lung cancer (NSCLC). The main endpoits were analysis of objective response rates, toxicity, time to progression, and overall survival. PATIENTS AND METHODS: 247 eligible patients were randomized to receive (a) vinorelbine 25 mg/m(2) intravenous bolus on days 1 and 8 plus cisplatin 100 mg/m(2) on day 1 every 4 weeks, or (b) mitomycin c 8 mg/m(2) i.v. on day 1, vindesine 3 mg/m(2) i.v. on days 1, 8, 15 and 22, plus cisplatin 100 mg/m(2) on day 1 every 4 weeks. In subsequent cycles vindesine was given every other week. For both treatments a maximum of six cycles was planned. Patients with performance status 0-2 according to the ECOG scale were enrolled. Response and toxicity were evaluated according to the WHO criteria. Analysis of clinical efficacy was performed according to an intent-to-treat analysis. RESULTS: No statistically significant differences in clinical efficacy were observed between the two chemotherapy regimens. The overall objective response rates were 39% (95% CL, 31-49%) in the VC arm and 42% (95% CL, 33-51%) in the MVP arm (P=0.13). Median time to progression was 4.2 and 4.5 months for the MVP arm and the VC arm, respectively. Median overall survival was 7 months in the VC arm and 8 months in the MVP one (log-rank test, P=0.898). These differences were not statistically significant. However, leukopenia and thrombocytopenia were significantly higher in the MVP arm than in the VC (P=0.0001; P=0.0002). Grade 3 alopecia was more frequent in the MVP arm than in the VC one (P<0.001), which was associated with higher rate of phlebitis (P=0.037). CONCLUSION: Data achieved in this study suggest that the vinorelbine-cisplatin doublet is similar to the three-drug MVP regimen in term of overall response rate, time to progressive disease, and overall survival. However, hematological toxicity and alopecia are more frequent and severe in the MVP regimen which therefore appears to be less tolerable than the VC regimen. The combination of vinorelbine and cisplatin may be considered as a reference treatment for future studies on the treatment of advanced NSCLC.

Adult↗