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Nick Thatcher

Publications and source records attributed to Nick Thatcher.

17 recordsLinked to original sources
PubMed2006

Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non-small-cell lung cancer.

PURPOSE: The phase III Iressa Survival Evaluation in Lung Cancer (ISEL) trial compared gefitinib with placebo in 1,692 patients with refractory advanced non-small-cell lung cancer. We analyzed ISEL tumor biopsy samples to examine relationships between biomarkers and clinical outcome after gefitinib treatment in a placebo-controlled setting. METHODS: Biomarkers included epidermal growth factor receptor (EGFR) gene copy number by fluorescence in situ hybridization (n = 370); EGFR (n = 379) and phosphorylated Akt (p-Akt) protein expression (n = 382) by immunohistochemistry; and mutations in EGFR (n = 215), KRAS (n = 152), and BRAF (n = 118). RESULTS: High EGFR gene copy number was a predictor of a gefitinib-related effect on survival (hazard ratio [HR], 0.61 for high copy number and HR, 1.16 for low copy number; comparison of high v low copy number HR, P = .045). EGFR protein expression was also related to clinical outcome (HR for positive, 0.77; HR for negative, 1.57; comparison of high v low protein expression HR, P = .049). Patients with EGFR mutations had higher response rates than patients without EGFR mutations (37.5% v 2.6%); there were insufficient data for survival analysis. No relationship was observed between p-Akt protein expression and survival outcome, and the limited amount of data collected for KRAS and BRAF mutations prevented any meaningful evaluation of clinical outcomes in relation to these mutations. CONCLUSION: EGFR gene copy number was a predictor of clinical benefit from gefitinib in ISEL. Additional studies are warranted to assess these biomarkers fully for the identification of patients most likely to benefit from gefitinib treatment.

Adult↗
PubMed2006

Integrating new targeted agents into the treatment of non-small-cell lung cancer.

Lung cancer is the most common cause of cancer-related deaths worldwide, and the discovery and implementation of more effective therapy remains challenging. The development of agents that target the epidermal growth factor receptor/human epidermal growth factor receptor 1 (EGFR/HER1) signal transduction pathway have provided a class of novel targeted therapies that are applicable in the treatment of non-small-call lung cancer (NSCLC). Current challenges include the determination of how best these promising new agents can be integrated into current methods of treatment for patients with NSCLC, and clarification of the extent to which early lines of treatment can influence outcome in the later stages.

Animals↗
PubMed2006

Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study.

PURPOSE: Erlotinib has proven activity in pretreated patients with advanced non-small cell lung cancer (NSCLC). We evaluated erlotinib in the frontline treatment of advanced NSCLC and assessed biological predictors of outcome. EXPERIMENTAL DESIGN: In this phase II study, chemotherapy-naive patients with stage IIIB/IV NSCLC received oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity occurred. Tumor response was assessed every 6 weeks, and samples were analyzed for potential molecular markers of treatment response and survival. The primary end point was the proportion of patients without disease progression after 6 weeks of treatment. RESULTS: Fifty-three patients were eligible. The overall rate of nonprogression at 6 weeks was 52.8% (28 of 53 patients). Tumor response rate was 22.7%, with 1 complete response, 11 partial responses, and 16 cases of stable disease. Responses were seen across most patient clinical characteristics. The median duration of tumor response was 333 days; median overall survival was 391 days; and median time to disease progression was 84 days. Erlotinib was well tolerated, the main treatment-related adverse events being mild-to-moderate rash and diarrhea. Histologic material for biological studies was available in 29 cases. Four of five responders and one patient with stable disease had a classic epidermal growth factor receptor tyrosine kinase mutation. Two progressing patients exhibited epidermal growth factor receptor point mutations (one with T790M mutation), and K-ras mutations were detected in 10 nonresponders. CONCLUSIONS: Erlotinib shows significant antitumor activity in the first-line treatment of advanced NSCLC and may be a viable alternative to chemotherapy. Patient selection cannot easily be based on clinical or biological variables.

Administration, Oral↗
PubMed2006

Where next for gefitinib in patients with lung cancer?

Gefitinib belongs to the small-molecule class of epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors. It was given conditional approval by the US Food and Drug Administration (FDA) in 2003 for treatment of advanced, chemorefractory non-small-cell lung cancer (NSCLC), but was relabelled for restricted use for patients that were already receiving and benefiting from it after the negative result of the phase III Iressa Survival Evaluation in Advanced Lung Cancer (ISEL) trial. By contrast, erlotinib, another EGFR tyrosine-kinase inhibitor, showed an overall survival benefit compared with placebo and best supportive care in the National Cancer Institute of Canada's BR21 trial, and now has full FDA approval for treatment of patients with NSCLC who have progressed after treatment with chemotherapy. Although the ISEL trial result was negative overall, preplanned subgroup analyses showed a significant overall survival benefit for gefitinib treatment in never-smokers and in patients of Asian origin. Here, we review the clinical experience with gefitinib and, in light of the licensing of erlotinib, address the lessons learned, the ongoing trials, and whether scope remains for clinical development of gefitinib in selected patients.

Adult↗
PubMed2006

Novel therapies for the treatment of small-cell lung cancer: a time for cautious optimism?

Small-cell lung cancer accounts for up to one-fifth of all lung cancers diagnosed. While the response rates to chemotherapy are high, ultimately the majority of patients will relapse and die from their disease. Long-term outcomes are poor. A number of new agents and novel strategies for the treatment of small-cell lung cancer are under evaluation, and this review outlines the current most promising agents and pivotal trials. Oblimersen, an antisense oligonuclide to the oncogene bcl-2, has been safely combined with chemotherapy. The proteosome inhibitor bortezomib has not demonstrated single-agent activity in phase II trials but is now being evaluated with proapoptotic triggers. A number of anti-angiogenic strategies have been evaluated in small-cell lung cancer. The vascular endothelial growth factor (VEGF) antibody bevacizumab and a number of VEGF receptor tyrosine kinase inhibitors are in the early phases of clinical trials. Results from trials have not demonstrated any survival advantage with the addition of matrix metalloproteinase inhibitors. A phase III trial has reported improvements in median survival with the addition of thalidomide to chemotherapy, but toxicity has been problematic. Immunotherapy with p53 vaccines and BEC2 antibodies have shown some promise and require further evaluation to determine whether humoral responses can predict for response. Trials with the immunoconjugate BB-10901 and temirolimus are ongoing.

Animals↗
PubMed2006

Cost effectiveness of increasing the dose intensity of chemotherapy with granulocyte colony-stimulating factor in small-cell lung cancer: based on data from the Medical Research Council LU19 trial.

BACKGROUND: The use of granulocyte colony-stimulating factor (G-CSF) can enable dose intensification of chemotherapy in small-cell lung cancer (SCLC). However, given its acquisition cost, it is important to assess its cost effectiveness within a resource-constrained health service. OBJECTIVE: To assess the cost effectiveness, from the UK NHS perspective, of G-CSF given in addition to doxorubicin, cyclophosphamide and etoposide (ACE) versus ACE alone in the management of SCLC. METHODS: Using data from a UK Medical Research Council trial (LU19) to assess chemotherapy dose intensification in patients with previously untreated SCLC of any disease extent, a retrospective cost-effectiveness analysis was undertaken. Resource use data, including hospitalisations and non-protocol cancer treatments, were collected during the first 6-month treatment phase of the trial. Mean costs ( pound, 2003 values) of managing patients in the two arms of the trial were calculated. Mean survival duration was calculated for the two groups using patient-specific follow-up data collected in the trial. Incremental cost-effectiveness analysis was undertaken, and uncertainty in cost effectiveness was expressed using cost-effectiveness acceptability curves. RESULTS: The use of G-CSF in addition to ACE chemotherapy is more costly ( 4647 pounds) but results in longer mean survival duration (0.20 years; 0.18 years when discounted). This generates an incremental cost per additional life-year of 25,816 pounds for ACE + G-CSF therapy. The probability of the addition of G-CSF being cost effective, if decision makers are willing to pay 30,000 pounds for an additional life-year, is 0.57. Secondary analysis suggests that cost effectiveness is likely to be sensitive to assumptions about the health-related quality of life (HR-QOL) experienced by patients. CONCLUSION: Based on data collected in the LU19 trial, chemotherapy dose intensification using G-CSF in SCLC adds to health service costs but increases survival duration. Its overall cost effectiveness is likely to be finely balanced.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Sequential platinum-based chemotherapy-thoracic radiotherapy in early stage non-small cell lung cancer.

Combined chemoradiotherapy (CTRT) is intended to reduce the risk of local regional recurrence and distant relapse in patients with early stage non-small cell lung cancer (NSCLC). Sequential CTRT allows full doses of each modality while avoiding the additive toxicity that occurs with concurrent therapy. This review will encompass studies in the three main settings where sequential CTRT has been applied in early stage NSCLC: as adjuvant therapy after resection, as neoadjuvant chemotherapy and surgery followed by radiotherapy, and in unresectable stage III disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2005

Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer.

BACKGROUND: Recent dose-intensity studies of small-cell lung cancer (SCLC) have yielded conflicting results. We carried out a phase III randomized trial in patients with better-prognosis SCLC (i.e., prognostic score of 0-1) to investigate whether doubling the dose density of ifosfamide, carboplatin, and etoposide (ICE) chemotherapy with filgrastim and blood-progenitor-cell support improves survival, compared with standard ICE chemotherapy. METHODS: We studied 318 patients with pathologically proven SCLC who were randomly assigned to receive six cycles of ICE chemotherapy with a 4-week (standard arm) or 2-week (dose-dense arm) interval between cycles. Patients in the dose-dense arm received filgrastim subcutaneously daily on days 4 through 14 and had autologous blood collected before cycles 2 through 6, which was returned 24 hours after treatment. Toxicities, including hematologic toxicity and incidence of neutropenic sepsis, were monitored. Survival was calculated by the Kaplan-Meier method. All statistical tests were two-sided. RESULTS: The delivered median dose intensity was 99% (interquartile range = 96%-100%) for the standard arm and 182% (interquartile range = 163%-196%) for the dose-dense arm. After a median follow-up of 14 months, overall response to treatment was observed in 118 (80%) of the 148 evaluable patients in the standard arm and in 129 (88%) of the 147 evaluable patients in the dose-dense arm, a statistically non-significant difference. Median overall survival was 13.9 months (95% confidence interval [CI] = 12.9 to 15.8 months) in the standard arm and 14.4 months (95% CI = 12.7 to 16.0) in the dose-dense arm, and the 2-year survival was 22% (95% CI = 16% to 29%) and 19% (95% CI = 14% to 27%), respectively--neither difference being statistically significant. The median treatment free time was 286 days (95% CI = 229 to 343 days) for the standard arm and 367 days (95% CI = 321 to 413 days) for the dose-dense arm (difference = 81 days; P = .109). Statistically significantly more hematologic toxicity was reported in the dose-dense arm than in the standard arm, but the number of cycles complicated by neutropenic sepsis was statistically significantly higher in the standard arm than in the dose-dense arm (15.3% versus 11.6%, respectively; difference = 3.7%, 95% CI = -4.1% to 11.5%; P = .03). CONCLUSIONS: Dose-dense ICE chemotherapy for SCLC led to shorter treatment duration and less neutropenic sepsis than did standard ICE but did not improve overall survival.

Adult↗
PubMed2005

Lung cancer after treatment for Hodgkin's lymphoma: a systematic review.

Developments in modern chemotherapy and radiotherapy mean that most patients with Hodgkin's lymphoma can now be cured. However, the long-term effects of anticancer treatment include an increased risk of a second malignant disease. We have done a systematic review of studies reporting long-term complications of the treatment of Hodgkin's lymphoma published in English since 1985. These studies show that risk of lung cancer is significantly increased in patients treated for Hodgkin's lymphoma, with a reported mean relative risk of 2.6-7.0 and a significantly increased absolute excess risk. The absolute excess risk increases with time from treatment, for as long as 20-25 years, and is highest in patients treated at age 45 years or older. Both chemotherapy and radiotherapy contribute to the risk, and evidence suggests that the effects are additive. Cigarette smoking seems to multiply the risk associated with both chemotherapy and radiotherapy. In the high-risk group of patients, 50-150 patients per 1000 are expected to develop lung cancer by 10-20 years after treatment. The role of screening in this group of patients has not yet been assessed, but an international study combining CT with genomic and proteomic assessment is planned.

Adolescent↗
PubMed2005

Thoracic radiation therapy for limited-stage small-cell lung cancer: unanswered questions.

The role of thoracic radiation therapy (RT; TRT) is now established in the management of limited-stage small-cell lung cancer (SCLC). There is increasing evidence in the literature in favor of early concurrent chemoradiation therapy, and a gold standard of care for patients with a good performance status is twice-daily TRT (45 Gy in 3 weeks) with concurrent cisplatin/etoposide. Five-year survival rates > 20% can be expected with this combined-modality approach. Although current clinical trials are exploring the efficacy of new chemotherapeutic strategies for the disease, essential questions related to the optimization of TRT remain unanswered. In particular, the optimal RT dose, fractionation, and treatment volume have not been defined. This review highlights the need for well-designed multinational trials aimed at the optimization and standardization of RT for limited-stage SCLC. These trials should integrate translational research studies to investigate the molecular basis of RT resistance and to develop biomarker profiles of prognosis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Quality-of-life assessment in advanced lung cancer: considerations for evaluation in patients receiving chemotherapy.

There is increasing awareness of the need for accurate assessment of quality of life in patients with lung cancer who are on clinical trials and in patient management. Self-reported multidimensional, validated, quality-of-life instruments assess physical, functional, psychological, social, and spiritual dimensions associated with lung cancer and its treatment. Such validated instruments are now available and are being utilized more frequently in clinical trials assessing the value of particular anticancer therapies. Such findings may influence the treatment of choice for patients with non-small-cell lung cancer (NSCLC), particularly in the advanced-disease setting where survival benefits from current treatments are modest, and the majority of patients present with three or more symptoms. Recently, a number of studies assessing quality of life in NSCLC have been published providing more insight into the effects of the disease and its treatment on the patient's perspective. Quality-of-life instruments that include patient reported outcomes ("PROS") and quality-of-life and symptom assessment are the only way to evaluate this crucial aspect of cancer care. As an example, Fossella and colleagues reported notable findings from the largest prospective evaluation (the TAX 326 trial) of quality of life using validated instruments in patients with NSCLC who received chemotherapy. Patients who received a docetaxel plus platinum combination regimen reported modest benefits in both quality of life and in disease-related parameters, such as pain control, weight loss, and performance status, compared to patients randomly assigned to the combination of vinorelbine and cisplatin. Compliance with the PRO assessment was high, supporting the feasibility of prospective quality-of-life evaluations in NSCLC. Important goals include building on these results by including quality-of-life assessment in all major clinical trials, and demonstrating feasible ways to incorporate this evaluation into daily clinical practice.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Targeted molecular mechanisms of epoetin alfa.

Despite therapeutic improvements and ongoing efforts to develop more efficacious therapies, the majority of lung cancer patients face a poor prognosis. Therefore, the primary goal of current treatment is palliation, improvement and maintenance of quality of life (QOL), and (modest) prolongation of survival. Anemia frequently occurs in lung cancer patients and has been associated with decreased QOL, impaired treatment outcomes, and shortened survival time. Furthermore, anemia is a causative factor of tumor hypoxia, which compromises the efficacy of chemotherapy and radiotherapy. Thus, correction of even mild anemia seems to have a beneficial effect on QOL and cancer treatment outcomes. The current article describes the basis and mechanism for the use of recombinant human erythropoietin (rHuEPO, epoetin alfa), a molecular targeted therapy, for the treatment of cancer-related anemia, with a focus on lung cancer. Epoetin alfa has proven efficacy and safety in correcting anemia and improving QOL based on numerous clinical studies and over a decade of clinical practice. In addition, emerging data show that epoetin alfa may offer potential benefits beyond treating anemia, specifically in terms of treatment outcomes and cognitive function. Future research needs to be conducted to explore the potential for epoetin alfa to improve survival time in lung cancer patients.

Anemia↗
PubMed2003

Options for first- and second-line therapy in small cell lung cancer--a workshop discussion.

In a case study-based workshop, physicians were asked to discuss various aspects of patient management in small cell lung cancer (SCLC). For first-line chemotherapy, most investigators recommended treatment with etoposide/cisplatin, with possible dosing variations according to tolerability and convenience. In France (but not elsewhere), medical oncologists tend to use a four-drug regimen (etoposide/cisplatin/cyclophosphamide/epirubicin), based on the results of an extensive-stage SCLC trial. Alternative first-line regimens, such as vincristine/ifosfamide/carboplatin/etoposide (VICE) and topotecan/platinum, are currently being explored. Options for therapy in patients with recurrent disease are more varied, although there was consensus that active treatment at relapse should be considered. Regimens include topotecan (alone or in combination), cyclophosphamide/doxorubicin/vincristine (CAV) and re-induction with the earlier first-line agents. Studies are also investigating the potential benefits of other combinations, including topotecan/vinorelbine and paclitaxel/carboplatin. For patients with relapsed extensive-stage SCLC and brain metastases, whole brain radiation therapy was considered appropriate for both palliative and therapeutic reasons. The potential role of combination therapy with topotecan/temozolomide, both of which cross the blood-brain barrier, is currently being investigated.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Gefitinib plus best supportive care in previously treated patients with refractory advanced non-small-cell lung cancer: results from a randomised, placebo-controlled, multicentre study (Iressa Survival Evaluation in Lung Cancer).

BACKGROUND: This placebo-controlled phase III study investigated the effect on survival of gefitinib as second-line or third-line treatment for patients with locally advanced or metastatic non-small-cell lung cancer. METHODS: 1692 patients who were refractory to or intolerant of their latest chemotherapy regimen were randomly assigned in a ratio of two to one either gefitinib (250 mg/day) or placebo, plus best supportive care. The primary endpoint was survival in the overall population of patients and those with adenocarcinoma. The primary analysis of the population for survival was by intention to treat. This study has been submitted for registration with ClinicalTrials.gov, number 1839IL/709. FINDINGS: 1129 patients were assigned gefitinib and 563 placebo. At median follow-up of 7.2 months, median survival did not differ significantly between the groups in the overall population (5.6 months for gefitinib and 5.1 months for placebo; hazard ratio 0.89 [95% CI 0.77-1.02], p=0.087) or among the 812 patients with adenocarcinoma (6.3 months vs 5.4 months; 0.84 [0.68-1.03], p=0.089). Preplanned subgroup analyses showed significantly longer survival in the gefitinib group than the placebo group for never-smokers (n=375; 0.67 [0.49-0.92], p=0.012; median survival 8.9 vs 6.1 months) and patients of Asian origin (n=342; 0.66 [0.48-0.91], p=0.01; median survival 9.5 vs 5.5 months). Gefitinib was well tolerated, as in previous studies. INTERPRETATION: Treatment with gefitinib was not associated with significant improvement in survival in either coprimary population. There was pronounced heterogeneity in survival outcomes between groups of patients, with some evidence of benefit among never-smokers and patients of Asian origin.

Adult↗