Biomedical subjects

C Gridelli

Publications and source records attributed to C Gridelli.

At least 19 recordsLinked to original sources

PubMed2006

New antiangiogenetic agents and non-small cell lung cancer.

New blood vessel formation, known as angiogenesis is a fundamental event in the process of tumor growth and metastatic dissemination. Due to its central role in tumor angiogenesis, the vascular endothelial growth factor (VEGF) and its receptor have been a major focus of basic research and drug development in the field of oncology, including the treatment of non-small cell lung cancer (NSCLC). Approaches targeting VEGF include monoclonal antibodies and vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). Bevacizumab (Avastin) is an anti-VEGF recombinant humanized monoclonal antibody. A very recent randomized phase III trial demonstrated a statistically significant advantage in median survival favouring the combination of bevacizumab plus chemotherapy versus chemotherapy alone in the treatment of advanced non-squamous NSCLC. This study represents the first evidence of superior efficacy of targeted therapy combined with chemotherapy over chemotherapy alone in the treatment of NSCLC. ZD6474 is an orally bioavailable inhibitor of VEGFR-2 tyrosine kinase. First evidences of antitumor activity and its excellent toxicity profile make it a promising targeted agent for the treatment of NSCLC. A recent phase I/II study examined the combination of Epidermal Growth Factor Receptor (EGFR)-TKI erlotinib and bevacizumab in patients with non-squamous stage IIIB/IV NSCLC. Data on antitumor activity of this combination have to be considered very promising. Clinical trials of multiple targeted therapy may represent the second generation studies in the treatment of NSCLC.

Angiogenesis Inhibitors↗

PubMed2006

Phase II study of gefitinib in combination with docetaxel as first-line therapy in metastatic breast cancer.

We have evaluated the activity and safety of gefitinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with docetaxel as first-line treatment of women with metastatic breast cancer (MBC). In total, 41 patients with MBC were enrolled in a first-line combination therapy study with oral gefitinib (250 mg day(-1)) and intravenous docetaxel (75 mg m(-2), the first 14 patients; or 100 mg m(-2), the following 27 patients, on day 1 of a 3-week cycle). Out of 41 patients, 38 received at least one cycle of therapy. There were no differences in activity or tolerability between the two docetaxel doses. G3/4 toxicities were neutropenia (49%), diarrhoea (10%), acne-like rash (5%), and anaemia (2%). Complete plus partial responses (CR+PR) were observed in 22 out of 41 patients with a 54% response rate (95% confidence interval (CI) 45-75%). The 22 patients that achieved a response following six cycles of docetaxel plus gefitinib continued gefitinib monotherapy (median duration, 24 weeks; range, 2-108+ weeks). Two patients with PR following combination therapy achieved a CR during gefitinib monotherapy. Complete plus partial responses correlated with oestrogen receptor (ER) status, since they occurred in 19 out of 27 (70%) patients with ER-positive tumours as compared to three out of 14 (21%) patients with ER-negative tumours (P=0.01).

Adult↗

PubMed2006

Treatment of advanced non-small cell lung cancer.

In the last decade the treatment of advanced-metastatic non-small cell lung cancer has substantially improved. If in the early 90s there was still concern about the real efficacy of chemotherapy over best suppotive care alone in the advanced setting, constant developments in clinical research have demonstrated the survival advantage of active anti-cancer drugs not only in the first-line setting, but, lately, even in patients with recurrent disease after failure of two previous chemotherapy lines. With the premises of high throughput technologies, translational research is aiming to characterize patients and tumors on a molecular basis. With pharmacogenomics it would then be possible to accurately predict patient outcome and tailor the treatment strategy according to the geno-phenotype of single patients.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Chemotherapy of advanced non-small cell lung cancer in elderly patients.

Non-small cell lung cancer (NSCLC) may be considered typical of advanced age. More than 50% of NSCLC patients are diagnosed over the age of 65 and approximately one-third of all patients are over the age of 70. Elderly patients tolerate chemotherapy poorly compared to their younger counterpart because of the progressive reduction of organ function and comorbidities related to age. For this reason, these patients are often not considered eligible for aggressive platinum-based chemotherapy, the standard medical treatment for advanced NSCLC. With the current evidence, in clinical practice, single-agent chemotherapy with a third-generation drug (vinorelbine, gemcitabine, taxanes) should be the recommended option for non-selected elderly patients with advanced NSCLC. Subset analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with an acceptable increase in toxicity for elderly patients. However, feasibility of platinum-based chemotherapy remains an open issue and has to be proven in prospective randomised trials. High priority should be also given to the evaluation of the role of new targeted therapies. Moreover, a comprehensive geriatric assessment for individualized treatment choice in NSCLC elderly patients is mandatory.

Age Factors↗

PubMed2006

First line chemotherapy in advanced or metastatic NSCLC.

The lung cancer global incidence has regularly increased during the last decades. Non Small Cell Lung Cancer (NSCLC) accounts for approximately 80% of all lung tumors. Different schedules including cisplatin plus gemcitabine or vinorelbine or paclitaxel or docetaxel or irinotecan showed advantages in terms of response rate, toxicity and quality of life, but little improvement in terms of survival. Some advantage was documented in favour of the combination including cisplatin plus a new drug versus monochemotherapy with new drugs. The large phase III studies performed with doublets containing new drugs and platinum are not free of criticism but in summary the research involving more than 3000 patients failed to indicate a standard regimen. With the aim of strengthen the phase III studies results, a meta-analysis tested the survival outcomes of published randomized trials, analysing the effects of the combination of gemcitabine and platinum compounds versus any platinum-based regimens. Gemcitabine-platinum combinations appear to offer a statistically significant superior efficacy in terms of overall survival and progression free survival as compared to other platinum-based regimens. Considering the palliative role of chemotherapy in advanced NSCLC and in order to reduce toxicity, not cisplatin-containing regimens were investigated. The results support the suggestion from the last ASCO guidelines: first-line chemotherapy of advanced NSCLC should be a two-drug combination regimen and not platin-based chemotherapy may be used as alternative to platinum-based regimens. The new frontier is represented by pharmacogenomic. The potential benefits of the pharmacogenomic approach lay in the possibility of predicting the patient chemotherapy response developing customized chemotherapeutic combinations and limiting severe side effects.

Carcinoma, Non-Small-Cell Lung↗

PubMed2006

Chemotherapy of advanced NSCLC in special patient population.

The elderly and patients with Performance Status (PS) of 2, constitute the so-called special patient population. The tolerability of chemotherapy in this population is globally worse, and treatment approaches should be different. Platinum-based combination chemotherapy is currently recommended as the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), but its role in special patient population is controversial. The best treatment for elderly patients with advanced NSCLC is still debated. In the first randomized study dedicated to elderly NSCLC patients, single-agent vinorelbine showed superiority over supportive care alone, both in terms of survival and quality of life. In a large randomized trial, gemcitabine plus vinorelbine failed to show any advantage over either agent alone. Subset analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with an acceptable increase in toxicity for elderly patients. However, the role of platin-based chemotherapy needs to be defined in prospective randomised trials. With the current evidence, single-agent chemotherapy with a third-generation drug (vinorelbine, gemcitabine, taxanes) should be the recommended option for non-selected elderly patients with advanced NSCLC. Also for PS2 patients there is no consensus on standard treatment. On the basis of current evidence, chemotherapy treatment appears justified for patients with advanced NSCLC and PS2. Single-agent chemotherapy (gemcitabine, vinorelbine, taxanes) could be the preferred option, although carboplatin-based or low-dose cisplatin-based doublets may represent alternative options. Stronger evidence is expected from new clinical research specifically focused on PS2 patients. High priority should be given to the evaluation of tolerability and efficacy of platinum-based combinations and role of new targeted therapies.

Aged↗

PubMed2005

Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes.

PURPOSE: Gemcitabine-platinum combination activity has been clearly established in a number of phase II studies. It has also been compared against other combinations in many phase III trials. It is generally believed that all such regimens have an equivalent impact on survival. This meta-analysis aims to quantify the treatment effect of gemcitabine plus a platinum agent in the treatment of advanced NSCLC and compare the combination to other regimens used globally. DESIGN: Data from a total of 4556 patients from 13 randomized trials investigating gemcitabine in combination with a platinum agent versus any other platinum-containing regimen were included in a meta-analysis of time-to-event outcomes. RESULTS: A significant reduction in overall mortality in favor of gemcitabine-platinum regimens was observed, hazard ratio (HR) 0.90 (95% CI: 0.84-0.96) with an absolute benefit at 1 year of 3.9%. Median survival was 9.0 months for the gemcitabine-platinum regimens and 8.2 months for the comparator regimens. Sub-group analysis of the first- and second-generation platinum-based comparator regimens also indicated a significant benefit for gemcitabine-platinum regimens, HR 0.84 (CI: 0.71-0.9985). Analysis of third-generation agent plus platinum regimens showed a non-significant trend favoring gemcitabine-platinum regimens, HR 0.93 (CI: 0.86-1.01). There was a significant decrease in the risk of disease progression in favor of gemcitabine-platinum regimens, HR 0.88 (CI: 0.82-0.93). An absolute benefit of 4.2% at 1 year was estimated. Median progression-free survival was 5.1 months for gemcitabine-platinum regimens compared with 4.4 months for the comparator regimens. Sub-group analysis indicated a statistically significant progression-free survival benefit for patients assigned to gemcitabine-platinum treatment compared to first- and second-generation platinum regimens, HR 0.85 (CI: 0.77-0.94), and third-generation agent plus platinum regimens, HR 0.89 (CI: 0.82-0.96).

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2005

Italian clinical research in non-small-cell lung cancer.

Lung cancer is the most common cause of cancer deaths in both men and women worldwide and has a poor prognosis. Non-small-cell lung cancer (NSCLC) represents approximately 80% of all lung cancers. Surgery is the only curative treatment of NSCLC but only 15-20% of tumours can be radically resected with a survival of about 40% at 5 years. Considering these disappointing results NSCLC is one of the most frequent subjects of clinical research worldwide. Italy is playing an important role in the clinical research of NSCLC performing phase I, II and III trials, prevalently by cooperative groups, and achieving important results that contributed to define the standard treatment for NSCLC patients. In particular, Italy is leader in the clinical research of the treatment of advanced NSCLC elderly patients. Today, large controlled clinical trials are ongoing. In this paper we analyse and discuss the main trials performed by Italian groups in the fields of NSCLC.

Aged↗

PubMed2005

Treatment of locally advanced non-small cell lung cancer in the elderly.

PURPOSE OF REVIEW: Non-small cell lung cancer (NSCLC) may be considered typical of advanced age. Most cases of NSCLC are diagnosed in the advanced or locally advanced stage. It has been shown that combined chemo-radiotherapy is more efficient than either chemotherapy alone or radiation alone, for the therapeutic management of localized unresectable NSCLC. However, chemo-radiotherapy, even if given with sequential approach, in clinical practice can be contraindicated in elderly patients. In fact, this patient population often present at diagnosis with cardiovascular and/or pulmonary comorbidities that increase the risk of severe side effects from chemo-radiotherapy. The present review aims at focusing the currently available evidences on the treatment of elderly patients affected by locally advanced NSCLC and at giving future perspectives on this topic. RECENT FINDINGS: Very few specific prospective data are available on the treatment of locally advanced NSCLC in the elderly. Some phase II studies suggest that low-dose chemotherapy given concurrently with radiotherapy could be safely administered to this patient population. Retrospective analyses on full-dose sequential and concurrent chemo-radiation are to be considered globally ambiguous and at risk of selection bias. SUMMARY: Only specifically designed prospective studies will elucidate the real role and feasibility of combined chemo-radiotherapy in the treatment of locally advanced NSCLC in the elderly. Future perspectives on this topic include the evaluation of alternative schedules of chemo-radiotherapy, innovative radiation techniques more suitable to elderly patients, and the introduction of new, well-tolerated, molecularly targeted agents combined with standard treatments.

Aged↗

PubMed2005

Chemotherapy of breast cancer in the elderly.

Breast cancer arises in about 48% of patients older than 65 years and more than 30% occurs in those over 70 years being the leading cause of cancer-related death in women older than 65. Elderly patients tolerate chemotherapy poorly compared to their younger counterpart because of progressive reduction of organ function and comorbidities related to age. For this reason, the elderly have been excluded from or underrepresented in most cancer studies and, in clinical practice, they often receive inadequate and untested treatments. For adjuvant chemotherapy, a low percentage of patients over 70 years of age were included in few trials and always in a proportion much lower than the prevalence of cancer in that age group. Adjuvant chemotherapy, preferably including an anthracycline especially in patients with HER-2/neu-positive tumours, seems to be beneficial in older women who have substantial risk of dying of breast cancer. To date even if there is no specifically randomised study, single-agent chemotherapy probably might be considered a reasonable treatment for advanced breast cancer in the elderly. One of the actual main field of clinical research in the treatment of breast cancer is the role of targeted therapies. Chronologic age is a risk factor for toxicities such as myelosuppression and mucositis, and older patients may require more supportive care. In order to plan medical treatment in breast cancer elderly patients is mandatory to practice a comprehensive geriatric assessment that includes evaluation of comorbidities, functional dependence, socio-economic, emotional and cognitive conditions, an estimate of life expectancy and recognition of frailty. The authors review the literature regarding age-specific chemotherapeutic issues in the management of breast cancer elderly patients.

Aged↗

PubMed2004

A randomised clinical trial of two docetaxel regimens (weekly vs 3 week) in the second-line treatment of non-small-cell lung cancer. The DISTAL 01 study.

Docetaxel (75 mg m(-2) 3-weekly) is standard second-line treatment in advanced non-small-cell lung cancer (NSCLC) with significant toxicity. To verify whether a weekly schedule (33.3 mg m(-2) for 6 weeks) improved quality of life (QoL), a phase III study was performed with 220 advanced NSCLC patients, < or =75 years, ECOG PS < or =2. QoL was assessed by EORTC questionnaires and the Daily Diary Card (DDC). No difference was found in global QoL scores at 3 weeks. Pain, cough and hair loss significantly favoured the weekly schedule, while diarrhoea was worse. DDC analysis showed that loss of appetite and overall condition were significantly worse in the 3-week arm in the first week, while nausea and loss of appetite were more severe in the weekly arm in the third week. Response rate and survival were similar, hazard ratio of death in the weekly arm being 1.04 (95% CI 0.77-1.39). A 3-weekly docetaxel was more toxic for leukopenia, neutropenia, febrile neutropenia and hair loss; any grade 3-4 haematologic toxicity was significantly more frequent in the standard arm (25 vs 6%). The weekly schedule could be preferred for patients candidate to receive docetaxel as second-line treatment for advanced NSCLC, because of some QoL advantages, lower toxicity and no evidence of strikingly different effect on survival.

Adult↗

PubMed2004

Prevalence and management of pain in Italian patients with advanced non-small-cell lung cancer.

Pain is a highly distressing symptom for patients with advanced cancer. WHO analgesic ladder is widely accepted as a guideline for its treatment. Our aim was to describe pain prevalence among patients diagnosed with advanced non-small-cell lung cancer (NSCLC), impact of pain on quality of life (QoL) and adequacy of pain management. Data of 1021 Italian patients enrolled in three randomised trials of chemotherapy for NSCLC were pooled. QoL was assessed by EORTC QLQ-C30 and LC-13. Analgesic consumption during the 3 weeks following QoL assessment was recorded. Adequacy of pain management was evaluated by the Pain Management Index (PMI). Some pain was reported by 74% of patients (42% mild, 24% moderate and 7% severe); 50% stated pain was affecting daily activities (30% a little, 16% quite a bit, 3% very much). Bone metastases strongly affected presence of pain. Mean global QoL linearly decreased from 64.9 to 36.4 from patients without pain to those with severe pain (P<0.001). According to PMI, 616 out of 752 patients reporting pain (82%) received inadequate analgesic treatment. Bone metastases were associated with improved adequacy and worst pain with reduced adequacy at multivariate analysis. In conclusion, pain is common in patients with advanced NSCLC, significantly affects QoL, and is frequently undertreated. We recommend that: (i). pain self-assessment should be part of oncological clinical practice; (ii). pain control should be a primary goal in clinical practice and in clinical trials; (iii). physicians should receive more training in pain management; (iv). analgesic treatment deserves greater attention in protocols of anticancer treatment.

Adult↗

PubMed2004

The role of new targeted therapies in small-cell lung cancer.

Lung cancer is the leading world-wide cause of cancer death. Small-cell lung cancer (SCLC) accounts for 20-25% of lung carcinomas. Chemotherapy is the cornerstone of treatment of SCLC. In limited disease, median survival is about 12-16 months with 4-5% of long-term survivors, in extensive disease median survival is 7-11 months. Improving the survival rate of patients with SCLC requires a better understanding of tumour biology and the subsequent development of novel therapeutic strategies. Several targeted agents have been introduced into clinical trials in SCLC and some phase III studies have already produced definitive results. Currently, the minority of these new agents offers a promise of improved outcomes, and negative results are more commonly reported than positive ones. To date, no targeted therapy has been approved for use in the treatment of patients with SCLC. This review will focus on the main novel biologic agents investigated in the treatment of SCLC.

Antineoplastic Agents↗

PubMed2004

Oral vinorelbine given as monotherapy to advanced, elderly NSCLC patients: a multicentre phase II trial.

Vinorelbine intravenously (i.v.) demonstrated its efficacy and tolerability in advanced non-small cell lung cancer (NSCLC) patients, including elderly subjects. Since vinorelbine is now available as an oral formulation this phase II open study was designed to evaluate its activity and tolerability in advanced, elderly NSCLC patients. A total of 56 chemonaive patients were recruited from April 2001 through to March 2002. The dosage schedule, already tested in younger NSCLC patients, was 60 mg/m(2)once a week for three weeks (first cycle), followed by 80 mg/m(2) once a week until disease progression or development of unacceptable toxicity. A limited sampling scheme was used for performing pharmacokinetic analysis on 52 of 56 patients enrolled in the study. Treatment was well tolerated with grade 3/4 neutropenia in 11/17 patients (20/30%) and febrile neutropenia in 1 (2%). Six partial responses (11%) and 25 stable disease responses were recorded, with a disease control rate of 55%. Median overall survival was 8.2 months (95% Confidence Interval (CI) [6.2-11.3]). The clinical benefit response rate was 31% on 32 evaluable patients. Pharmacokinetic profiles appeared quite similar to the historical profiles recorded following i.v. administration. Oral vinorelbine appears to be a reasonable alternative to i.v. vinorelbine, both in terms of activity and tolerability, in advanced, elderly NSCLC patients.

Administration, Oral↗

PubMed2004

Treatment of advanced non-small-cell lung cancer patients with ECOG performance status 2: results of an European Experts Panel.

BACKGROUND: Platinum-based combination chemotherapy is currently recommended as the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), but its benefit seems limited to fit patients with a performance status (PS) of 0 or 1. For PS2 patients, there is no consensus on standard treatment. With the aims of reviewing the evidence supporting each of these therapeutic options, possibly reaching a consensus for treatment of PS2 patients affected by advanced NSCLC in clinical practice, and suggesting the priorities for clinical research in this field, an European Experts Panel took place in Avellino, Italy in April 2003. RESULTS: and conclusions On the basis of current evidence, chemotherapy treatment appears justified for patients with advanced NSCLC and PS2. Single-agent chemotherapy (gemcitabine, vinorelbine, taxanes) could be the preferred option, although carboplatin-based or low-dose cisplatin-based doublets may represent alternative options. Stronger evidence is expected from new clinical research specifically focused on PS2 patients. Single-agent chemotherapy should be the standard arm against which experimental treatments are tested in randomised trials dedicated to PS2 patients. High priority should be given to the evaluation of tolerability and efficacy of platinum-based combinations, and to the testing of new biological agents. Another research priority is the improvement of supportive care. Patients strongly need symptomatic improvement: end points such as symptom relief, clinical benefit and quality of life should have a central position in trials dedicated to PS2 NSCLC patients.

Antineoplastic Agents↗

PubMed2003

Gefitinib in elderly and unfit patients affected by advanced non-small-cell lung cancer.

Elderly and poor performance status advanced non-small-cell lung cancer (NSCLC) patients often tolerate chemotherapy poorly. Special approaches are needed for these patient populations. Gefitinib (Iressa) was used in 59 elderly and/or unfit NSCLC pretreated patients participating in a compassionate use programme showing some activity and good tolerability.

Adult↗

PubMed2003

Supportive care in patients with advanced non-small-cell lung cancer.

The present study describes supportive care (SC) in patients with advanced non-small-cell lung cancer (NSCLC), evaluating whether it is affected by concomitant chemotherapy, patient's performance status (PS) and age. Data of patients enrolled in three randomised trials of first-line chemotherapy, conducted between 1996 and 2001, were pooled. The analysis was limited to the first three cycles of treatment. Supportive care data were available for 1185 out of 1312 (90%) enrolled patients. Gastrointestinal drugs (45.7%), corticosteroids (33.4%) and analgesics (23.8%) were the most frequently observed categories. The mean number of drugs per patient was 2.43; 538 patients (45.4%) assumed three or more supportive drugs. Vinorelbine does not produce substantial variations in the SC pattern, while cisplatin-based treatment requires an overall higher number of supportive drugs, with higher use of antiemetics (41 vs 27%) and antianaemics (10 vs 4%). Patients with worse PS are more exposed to corticosteroids (42 vs 30%). Elderly patients require drugs against concomitant diseases significantly more than adults (20 vs 7%) and are less frequently exposed to antiemetics (12 vs 27%). In conclusion, polypharmacotherapy is a relevant issue in patients with advanced NSCLC. Chemotherapy does not remarkably affect the pattern of SC, except for some drugs against side effects. Elderly patients assume more drugs for concomitant diseases and receive less antiemetics than adults.

Adult↗

PubMed2003

Targeted therapies: focus on a new strategy for gastrointestinal tumors.

In the last few years the knowledge of molecular oncology has led to the development of many new biological agents whose targets are extracellular or intracellular molecules involved in the main signalling pathways that play major roles in cancer development. These agents represent a new approach to gastrointestinal malignancies, as for many other types of tumors; preliminary data show that targeted therapy may enhance activity of chemotherapeutic agents (i.e. cetuximab in metastatic colorectal cancer (CRC)) or be active as monotherapy (i.e. imatinib in gastro-intestinal stromal tumors). Despite the encouraging preclinical results, the majority of these compounds have not yet produced convincing clinical results. However, these new agents raise a new challenge in the treatment of gastrointestinal cancers, especially for CRC.

Alkyl and Aryl Transferases↗