Clinical predictors versus epidermal growth factor receptor mutation in gefitinib-treated non-small-cell lung cancer patients

BACKGROUND: Clinical predictors including Asian, female, adenocarcinoma and never-smoker and epidermal growth factor mutation are associated with gefitinib responsiveness in non-small-cell lung cancer. Direct comparison between clinical predictors and EGFR mutation for their predictive power has not been reported. PATIENTS AND METHODS: For 120 Korean NSCLC patients treated with gefitinib, we have analyzed EGFR mutational status in exons 18, 19 and 21. Patients were grouped according to the number of clinical predictors (female, adenocarcinoma and never-smoker). Response rate (RR), time-to-progression (TTP) and overall survival (OS) were analyzed. Multivariate analysis was performed to investigate which approach yielded better prediction. RESULTS: RRs according to number of clinical predictors were 0: 3.4%, 1: 17.1%, 2: 29.4% and 3: 33.3% (p=0.002). Patients with gefitinib-sensitive EGFR mutation showed 61.9% RR compared with 12.1% in the remaining patients (p<0.001). RRs were higher in patients with the EGFR mutations regardless of the number of clinical predictors. In multivariate analysis, gefitinib-sensitive EGFR mutation showed higher odds ratio of response (9.6, 95% confidence interval [CI] 3.2-28.7) compared with number of clinical predictors (1.7, 95% CI 1.1-2.7). Hazard ratio (HR) of TTP was also better in gefitinib-sensitive EGFR mutation (0.24, 95% CI 0.12-0.47) than number of clinical predictors (0.83, 95% CI 0.69-0.99). Only gefitinib-sensitive EGFR mutation was associated with improved OS (HR 0.25, 95% CI 0.12-0.52). CONCLUSION: EGFR mutation should be analyzed whenever possible for effective prediction of objective benefit from gefitinib in NSCLC patients with one or more clinical predictors.     

Randomized study of chemotherapy and surgery versus radiotherapy for stage IIIA non-small-cell lung cancer: a National Cancer Institute of Canada Clinical Trials Group Study.

Thirty-one patients with stage IIIA (N2) non-small-cell lung cancer were randomized to receive radiotherapy alone or chemotherapy with cisplatin and vinblastine followed by surgery. Response rates to induction chemotherapy and radiotherapy were 50% and 53.3% respectively. Complete surgical resection was possible for 62.5% of patients. Median survival times were 16.2 and 18.7 months for radiotherapy alone and chemotherapy-surgery respectively (P = Ns), with no long-term improvement in survival seen with combined-modality treatment.     

Phase I study of paclitaxel (TaxolTM) and ifosfamide in previously untreated patients with advanced non-small-cell lung cancer: A study of the National Cancer Institute of Canada Clinical Trials Group

BACKGROUND:: Paclitaxel (Taxol^TM) and ifosfamide are among the most activesingle agents for the treatment of non-small-cell lung cancer.We undertook this phase I dose escalation study to determinethe maximum tolerated doses of these drugs which could be administeredwithout growth factors to untreated patients with tumours ofthis type. PATIENTS AND METHODS:: Forty patients with advanced non-small-cell lung cancer weretreated with a 3-hour infusion of paclitaxel and a 1-hour infusionof ifosfamide every 3 weeks. Groups of 3 patients were enteredat escalating dose levels in traditional phase I design. Startingdoses were paclitaxel, 100 mg/m², and ifosfamide 3 g/m², andall patients received premedication with dexamethasone, diphenhydramineand a 5-HT3 blocker. Dose escalation occurred only after fulltoxicity assessment for 2 cycles for all patients in the doselevel. RESULTS:: Dose escalation of paclitaxel continued to 225 mg/m² withoutdose-limiting toxicity, but further escalation was not attemptedbecause of the known likelihood of neurotoxicity above thislevel. Instead, ifosfamide was increased to 4 g/m² for the finallevel. At these doses, dose-limiting myelosuppression was notseen, and there was only 1 episode of febrile neutropenia in164 treatment cycles. Drug-related toxicities of ifosfamideincluded gross hematuria and confusion in 1 patient each, andpaclitaxel-related symptoms included flu-like syndrome in mostpatients, mild to moderate arthralgia and/or myalgia in 8 and25 patients, respectively, parasthesiae in 15 patients and mildto moderate hypersensitivity reactions in 15 patients each.Partial response was seen in 20.5% of patients (CI 9.3%–36.5%). CONCLUSIONS:: The frequency of tumour cell detection in peripheral blood frompatients with advanced disease was lower than previously reported.It may be only small numbers of circulating tumour cells arepresent at any one time in the peripheral blood of patientswith malignant melanoma. If this is the case increased samplingwill improve detection fre quency. Alternatively, disseminationof melanoma through peripheral blood may be a rare event. Inour experience, RT PCR for tyrosinase mRNA as a staging testfor melanoma patients must be interpreted cautiously. Out-patient paclitaxel given over 3 hours and single-dose ifosfamideover 1 hour may be combined safely without the need for hematopoieticgrowth factors for the treatment of patients with non-small-celllung cancer. The recommended doses for phase II study are paclitaxel,225 mg/m² and ifosfamide, 4 g/m² every 3 weeks. chemotherapy, ifosfamide, non-small-cell lung cancer, paclitaxel     

NSCLC非经典EGFR突变患者临床特点及治疗预后分析

目的 了解表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor-tyrosine kinase inhibitor,EGFR-TKI)对非经典突变非小细胞肺癌(non-small-cell lung cancer,NSCLC)的治疗疗效,为非经典突变患者选择最合适的靶向药物...     

表皮生长因子受体、血管内皮生长因子受体和BAD在非小细胞肺癌中的表达

背景与目的：表皮生长因子受体（epidermal growth factor receptor，EGFR）和血管内皮生长因子受体（vascular endothelial growth factor receptor，VEGFR）均属酪氨酸激酶受体（receptor tyrosine kinase，RTK），可调控细胞的增殖、分化与生存。BAD是Bcl-2家族中的促凋亡信号成分，在调控细胞凋亡特别是肿瘤细胞凋亡过程中发挥重要作用。但目前人们对上述这些重要蛋白在非小细胞肺癌（non—small—cell lung cancer，NSCLC）中的表达与肿瘤病理学的关系所知甚少。本研究探讨ECFR、VEGFR、BAD和磷酸化BAD在NSCLC中的表达情况以及与肿瘤病理的关系。方法：使用组织微阵列（tissue microarray，TMA）切片的免疫组织化学法，NSCLC患者51例（26例腺癌，16例鳞癌，8例大细胞癌，1例大细胞神经内分泌癌）。结果：51例患者中EGFR和VEGFR分别在10例（加％）和14例（27％）中出现过度表达。大细胞癌中未见VEGFR表达（0／8例），而鳞癌和腺癌患者中VEGFR表达分别为44％（7／16）和27％（7／26）。EGFR和VEGFR的表达与性别，肿瘤细胞分化及肿瘤浸润程度（包括胸膜浸润，血管浸润，淋巴结转移，肺内播散，脑转移情况）无关。51例患者中22例（43％）出现BAD蛋白表达缺失，且NSCLC的不同病理类型间差异有显著性。BAD蛋白表达缺失在16例鳞癌患者中10例（63％），8例大细胞癌患者中5例（63％），26例鳞癌患者中有7例（27％）（P=0．04）。51例患者中25例（49％）出现磷酸化BAD蛋白过度表达[其中26例腺癌患者中有13例（50％），16例鳞癌患者中有8例（50％），8例大细胞癌患者中有4例（50％）]。BAD蛋白的表达缺失与磷酸化BAD蛋白的过度表达经统计检验与上述肿瘤浸润程度无相关性。结论：肺鳞癌出现VEGFR表达增高的可能较大，而大细胞癌出现VEGFR表达增高的可能最小。在鳞癌和大细胞癌中可见BAD蛋白表达的显著缺失。NSCLC患者EGFR，VEGFR，磷酸化BAD蛋白的过度表达以及BAD蛋白表达的缺失与病理浸润程度无关。但这些受体酪氨酸激酶表达以及与NSCLC凋亡直接相关的媒介因子可能成为未来多靶向治疗中的候选靶标。     

表皮生长因子受体抑制剂在非小细胞肺癌治疗中的应用

特异性阻断肿瘤生长的表皮生长因子受体（EGFR）抑制剂在非小细胞肺癌（NSCLC）的治疗中具有极大潜力。目前，有两种通过修正细胞内外酪氨酸激酶信号传导过程来达到阻断此信号传导通路的治疗方法已被应用于NSCLC的治疗中。现以吉非替尼、西妥昔单抗等药物为例，综述EGFR抑制剂在NSCLC治疗中单独及与化疗或其他靶向治疗药物联合应用的临床研究进展。     

表皮生长因子受体抑制剂在非小细胞肺癌治疗中的应用

特异性阻断肿瘤生长的表皮生长因子受体(EGFR)抑制剂在非小细胞肺癌(NSCLC)的治疗中具有极大潜力。目前,有两种通过修正细胞内外酪氨酸激酶信号传导过程来达到阻断此信号传导通路的治疗方法已被应用于NSCLC的治疗中。现以吉非替尼、西妥昔单抗等药物为例,综述EGFR抑制剂在NSCLC治疗中单独及与化疗或其他靶向治疗药物联合应用的临床研究进展。     

Phase II study of oral menogaril as first line chemotherapy for advanced breast cancer: a National Cancer Institute of Canada Clinical Trials Group study.

The National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a phase II study of weekly oral menogaril as first-line therapy in 51 patients with incurable, metastatic or locally advanced breast cancer. While no prior chemotherapy for metastatic disease was permitted, prior adjuvant chemotherapy was allowed provided that no anthracycline or anthracene had been given. Forty-eight patients were evaluable for response. Two patients (4%) achieved complete remissions, 9 patients (19%) achieved partial remissions, 26 patients (54%) were stable and 11 patients (23%) failed. At the initial menogaril dose of 275 mg/m2 per week, 13 of 14 patients required a dose reduction and/or a treatment delay of one or more weeks. Therefore, the menogaril dose was reduced to 225 mg/m2 per week for the last 37 patients. At that those, 20 of 37 patients developed grade 3 or 4 granulocytopenia and 22 required dosage delays. At the initial starting dose, the average dose intensity actually delivered was 169 mg/m2 per week. At 225 mg/m2 the average dose intensity actually delivered was 197 mg/m2 per week. Toxic effects included mild to moderate nausea and vomiting, diarrhea, hair loss and occasional hyperpigmentation. In summary, menogaril is an anthracycline derivative that has modest activity when administered orally to minimally pretreated patients with breast cancer.     

Epirubicin in extensive small-cell lung cancer: a phase II study in previously untreated patients: a National Cancer Institute of Canada Clinical Trials Group Study

The Clinical Trials Group of the National Cancer Institute of Canada (NCIC) studied single-agent epirubicin in 40 previously untreated patients with extensive small-cell lung cancer (SCLC). The starting dose of epirubicin was 100 (eight patients) or 120 (32 patients) mg/m2 administered intravenously every 3 weeks. Twenty patients (50%) achieved an objective response (95% confidence limits, 33% to 66%) and three of the 20 had complete responses (CRs). The median survival of all 40 patients was 8.3 months (35.4 weeks). Myelosuppression, mild or moderate nausea and vomiting, and hair loss were commonly seen. There was one chemotherapy-related death. This drug is active and well tolerated in SCLC and the use of it as first-line therapy did not appear to compromise survival in this group of patients.     

Biologically targeted treatment of non-small-cell lung cancer: focus on epidermal growth factor receptor

The epidermal growth factor receptor (EGFR) has emerged in recent years as a key target of molecular therapy for solid tumors. The postembryonic role of EGFR is normally limited. In cancer, however, abnormal EGFR-tyrosine kinase (TK) activity plays a central role in many of the processes involved in tumor progression, such as proliferation, angiogenesis, invasiveness, decreased apoptosis, and loss of differentiation. Several different approaches have been taken to inhibit EGFR-mediated activity in tumor cells, including monoclonal antibodies directed at the ligand-binding portion of the EGFR and small-molecule agents that directly inhibit the intracellular TK domain of EGFR. Two of these TK inhibitors, gefitinib and erlotinib (OSI-774, Tarceva ), have shown antitumor activity and good tolerability across several tumor types in early dose-finding clinical trials, particularly for non-small-cell lung cancer (NSCLC). In heavily pretreated patients with advanced NSCLC, gefitinib showed clinically significant tumor responses and symptom relief with good tolerability. Based on these results, gefitinib has now been approved for the third-line treatment of advanced NSCLC. The use of gefitinib in standard treatment programs or combined with other molecular targeted agents may substantially improve the outlook for patients with NSCLC or other types of solid tumors     

Apoptosis and bcl-2 expression as predictors of survival in radiation-treated non-small-cell lung cancer

OBJECTIVES: We assessed the role of apoptosis and the expression of bcl-2, p53, and c-myc oncoproteins in pretreatment histologic specimens as a predictor of response to radiation therapy and survival in non-small-cell lung cancer (NSCLC) patients. METHODS: Pretreatment biopsy specimens of 68 patients with NSCLC (62 squamous cell carcinoma, 6 adenocarcinoma) were stained with hematoxylin and eosin. From 5 high-powered fields, the apoptotic index (AI) was calculated as the ratio of apoptotic tumor cells to the total number of tumor cells. Bcl-2, p53, and c-myc oncoprotein expression was detected by immunohistochemical staining. RESULTS: Twenty-nine cases showed partial or complete remission, whereas 39 showed no response. AI ranged from 0.2 to 12.0% (mean +/- SD; 4.3 +/- 2.6%, median 4.0%). There was no difference in AI between responders (4.0 +/- 2.3) and nonresponders (4.5 +/- 2.8, p > 0.05). However, in the responders, AI was correlated with the degree of change in tumor volume (r = 0.41, p < 0.05). In an analysis of 53 subjects who survived more than 1 month after the completion of radiation therapy, the patients with a higher AI (n = 27, MST = 22.8 m) survived longer than those with a lower AI (n = 26, MST = 9.2, log-rank, p = 0.03). Patients expressing bcl-2 had poorer survival (n = 22, MST = 6.0 m) than patients without bcl-2 (n = 31, 22.8 m, p < 0.003). According to multivariate analysis, three variables, bcl-2 expression, AI, and response to radiation, were independent prognostic factors for survival. CONCLUSION: A low level of spontaneous apoptosis and expression of apoptosis blocking bcl-2 protein in pretreatment histology predict a poor prognosis for radiation-treated NSCLC patients.     

VP-16 and carboplatin in previously untreated patients with extensive small cell lung cancer: a study of the National Cancer Institute of Canada Clinical Trials Group

Thirty-four previously untreated patients with extensive small cell lung cancer were treated with a combination of carboplatin 300 mg m-2 i.v. on day 1 and etoposide 100 mg m-2 i.v. on days 1, 2 and 3 every 28 days. Thirty-two patients were assessable for response. Eighteen patients (56%) achieved an objective response (95% confidence limits 38%-73%). Five (16%) had a complete response and 13 (41.0%) had a partial response. The median time to response was 7.8 weeks and the median duration of response was 23.1 weeks (range 6.2 to 54 weeks). The median survival of all 34 extensive disease patients was 34.7 weeks (range 1.3-59.3 weeks). Myelosuppression (leukopenia) was the main toxicity. There was one early death that may have been treatment-related. Biochemical renal dysfunction was noted in two patients. Paresthesiae and tinnitus/hearing loss were described by three and two patients respectively. Serious gastrointestinal toxicity was infrequent. This and other studies have shown this combination to be active and well tolerated in small cell lung cancer; however, it is not yet clear if it is as efficacious as the more commonly used VP-16-cisplatin regimen.     

Interstitial lung disease in patients with non-small-cell lung cancer treated with epidermal growth factor receptor inhibitors

Interstitial lung disease (ILD) refers to a diverse range of pulmonary fibrotic disorders and may be hard to accurately diagnose, as distinguishing it from other pulmonary diseases can be difficult. Estimations of the incidence in populations are confounded by the complexity of the different forms of the disorder. In addition, ILD is a comorbid disease of lung cancer and is seen after most forms of chemotherapy and radiotherapy for advanced lung cancer. Incidences of >or=10% have been reported; however, whatever the true incidence, both chemotherapy and radiotherapy enhance the risk of developing ILD. ILD has also been reported with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, including erlotinib (Tarceva, OSI-774) and gefitinib (IRESSA). In a large number of gefitinib-treated patients (n > 185,000) an incidence of approx 1% has been observed (approx 2% in Japan; 0.3% in the rest of the world). Nevertheless, as with other treatments for advanced non-small-cell lung cancer, the clinical benefit outweighs the risk of ILD. In this article, we review the data on ILD with EGFR inhibitors and other common lung cancer treatments.     

The National Cancer Institute of Canada Clinical Trials Group MAP.3 trial: an international breast cancer prevention trial

Several large phase III trials have demonstrated that tamoxifen-and more recently, raloxifene-can effectively reduce the incidence of invasive breast cancer by 50%. However, these selective estrogen receptor modulators can also be associated with several rare, but serious, adverse events. Recently, the third-generation aromatase inhibitors (AIS) have demonstrated excellent efficacy in adjuvant breast cancer trials, and they show particular promise in the breast cancer prevention setting. The National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) has developed a randomized phase III study to determine the efficacy of an ai (exemestane) to reduce the incidence of invasive breast cancer in postmenopausal women at an increased risk for developing breast cancer. The NCIC CTG map.3 (ExCel) trial is a double-blind placebo-controlled multicentre, multinational trial. Based on the known preclinical and clinical profile of the ais, a greater reduction in breast cancer incidence with fewer side effects is hypothesized with this class of agents than with tamoxifen or raloxifene.     

Phase II trial of erlotinib in patients with advanced non-small-cell lung cancer harboring epidermal growth factor receptor mutations: additive analysis of pharmacokinetics

Background

We conducted a phase II trial of erlotinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and evaluated the relationship between plasma concentration and efficacy of erlotinib.

Methods

Patients who were previously treated but naive to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), with advanced NSCLC harboring EGFR mutations, were enrolled. Erlotinib was given at 150 mg once daily until disease progression. The primary end point was objective response rate (ORR). Plasma trough levels of erlotinib were measured on Days 2 (D2) and 8 (D8) by high-performance liquid chromatography.

Results

In total, 29 patients were enrolled from September 2008 to January 2011. ORR was 61.5 % (95 % confidence interval [CI] 40.57–79.8) of 26 assessable patients. The median progression-free survival (PFS) and overall survival (OS) were 6.3 months and 16.9 months, respectively. Skin rash was observed in 24 patients, mostly at grade 1 or 2. Grade 2 pneumonitis was observed in one patient. We collected blood samples from 16 patients. The median PFS of the high and low D8/D2 ratio group was 11.2 months and 5.7 months, respectively (p = 0.044, hazard ratio = 0.301, 95 % CI 0.094–0.968).

Conclusion

Erlotinib showed an ORR comparable to that seen in previous studies for patients with NSCLC harboring EGFR mutations, although response, the primary end point, did not reach the predetermined threshold level. The D8/D2 ratio of erlotinib plasma trough levels might be a predictive factor for PFS.     

Effective inhibition of the epidermal growth factor/epidermal growth factor receptor binding by anti-epidermal growth factor antibodies is related to better survival in advanced non-small-cell lung cancer patients treated with the epidermal growth factor cancer vaccine.

PURPOSE: Epidermal growth factor (EGF) might be a suitable immunotherapeutic target in non-small-cell lung cancer (NSCLC). Our approach consists of active immunotherapy with EGF. The aim of the study is to characterize the humoral response and its effects on signal transduction in relation with the clinical outcome. EXPERIMENTAL DESIGN: Eighty NSCLC patients treated with first-line chemotherapy were randomized to receive the EGF vaccine or supportive care. EGF concentration in sera, anti-EGF antibodies and their capacity to inhibit the binding between EGF/EGF receptor (EGFR), and the EGFR phosphorylation were measured. RESULTS: Seventy-three percent of vaccinated patients developed a good antibody response, whereas none of the controls did. In good antibody-responder patients, self EGF in sera was significantly reduced. In 58% of vaccinated patients, the post-immune sera inhibited EGF/EGFR binding; in the control group, no inhibition occurred. Post-immune sera inhibited the EGFR phosphorylation whereas sera from control patients did not have this capacity. Good antibody-responder patients younger than 60 years had a significantly better survival. A high correlation between anti-EGF antibody titers, EGFR phosphorylation inhibition, and EGF/EGFR binding inhibition was found. There was a significantly better survival for vaccinated patients that showed the higher capacity to inhibit EGF/EGFR binding and for those who showed an immunodominance by the central region of EGF molecule. CONCLUSIONS: Immunization with the EGF vaccine induced neutralizing anti-EGF antibodies capable of inhibiting EGFR phosphorylation. There was a significant positive correlation between antibody titers, EGF/EGFR binding inhibition, immunodominance of anti-EGF antibodies, and survival in advanced NSCLC patients.