Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy

Purpose

Gefitinib and erlotinib are potent EGFR TKIs, with antitumor activity. In this randomized, single-center, non-comparative phase II trial, the efficacy and safety of gefitinib and erlotinib was evaluated as the second-line therapy for advanced non-small cell lung cancer (NSCLC).

Patients and methods

Patients with locally advanced, metastatic stage IIIB/IV NSCLC who failed first-line chemotherapy and had either EGFR mutation or at least two out of three clinical factors associated with higher incidence of EGFR mutations (female, adenocarcinoma histology, and never-smoker) were eligible.

Results

A total of 96 (48 per arm) patients were randomly assigned to gefitinib- or erlotinib-arm, respectively. Baseline characteristics were well-balanced between the two arms. The response rates (RR) were 47.9% in the gefitinib arm and 39.6% in the erlotinib arm. Median PFS was 4.9 months (95% CI, 1.3-8.5) in the gefitinib arm and 3.1 months (95% CI, 0.0-6.4) in the erlotinib arm. The most common grade 3/4 toxicity was skin rash. Exploratory analyses showed that there was no significant difference in RR and PFS in the gefitinib arm compared to the erlotinib arm (RR (%) 47.9 vs. 39.6, p = 0.269; median survival (months) 4.9 vs. 3.1, p = 0.336). There was no significant difference in QOL between the two arms.

Conclusion

Both gefitinib and erlotinib showed effective activity and tolerable toxicity profiles as second-line treatment for the selected population of NSCLC. We may consider conducting a phase III trial to directly compare the efficacy and toxicity between gefitinib and erlotinib in an enriched patient population.     

Comparison of gefitinib and erlotinib in advanced NSCLC and the effect of EGFR mutations

Introduction

Erlotinib and gefitinib are tyrosine kinase (TK) inhibitors of epidermal growth factor receptor (EGFR) that are effective in treating non-small cell lung cancer (NSCLC). This study aimed to compare their clinical uses and the influence of EGFR mutation.

Methods

The usages of erlotinib and gefitinib in advanced NSCLC were analyzed. Clinical data and EGFR mutational status of tumors were collected.

Results

Seven hundred and sixteen (716) patients received gefitinib (n = 440) or erlotinib (n = 276) for stage IIIb or IV NSCLC. Erlotinib was prescribed more frequently than gefitinib in males (58.2% vs. 41.8%, p < 0.001), smokers (60.5% vs. 39.5%, p < 0.001), and non-adenocarcinoma (70.6% vs. 29.4%, p < 0.001). Of the 716 study patients, 327 underwent testing for EGFR mutations (170 with mutant EGFR and 157 with wild-type EGFR). Adenocarcinoma in patients with mutant EGFR and non-smoker status in patients with wild-type EGFR were associated with better overall survival after TK inhibitor treatment. In both patient groups with mutant EGFR or wild-type EGFR, the effectiveness of gefitinib and erlotinib, including drug response or overall survival, were not different.

Conclusions

Our study revealed the obvious disparity in drug selection between erlotinib and gefitinib in clinical practice. Type of TK inhibitors did not influence treatment outcomes in patients with EGFR mutation or wild-type EGFR.     

The characteristics and failure pattern of gefitinib responders with postoperative recurrence of pulmonary adenocarcinoma

Aims

Gefitinib shows prominent anti-tumor activity against advanced or recurrent non-small cell lung cancer (NSCLC). However, most gefitinib-responsive patients ultimately relapse. We reviewed postoperatively recurrent NSCLC patients who received gefitinib treatment, and analyzed both the clinical features and manifestations of treatment failure in patients who initially responded to gefitinib.

Methods

From 2002 to 2006, gefitinib was administered to in 34 postoperative recurrent lung adenocarcinoma patients. There were 13 men and 21 women with a mean age of 65 years. Twenty patients had never smoked while 14 were former smokers. Epidermal growth factor receptor (EGFR) gene mutation was measured using surgical specimens of the primary tumor.

Results

The study group showed 1 complete response, 16 partial responses, 7 stable diseases and 8 progressive diseases. Mutations of EGFR gene were detected in 20 of 34 patients. Only the presence of EGFR gene mutations was significantly associated with the clinical response of gefitinib in our limited study (p = 0.036). In 9 of 12 responders, gefitinib treatment failed due to the appearance of new lesions.

Conclusions

Gefitinib was significantly effective for patients with mutations of the EGFR gene and most responders failed due to the appearance of new lesions without progression of the pre-existent target lesions.     

Gefitinib plus cisplatin and radiotherapy in previously untreated head and neck squamous cell carcinoma: A phase II, randomized, double-blind, placebo-controlled study

Background and purpose

To assess the efficacy and safety of gefitinib given concomitantly and/or as maintenance therapy to standard cisplatin/radiotherapy for previously untreated, unresected, stage III/IV non-metastatic SCCHN.

Materials and methods

In this phase II, double-blind, study, 226 patients were randomized to gefitinib 250 mg/day, 500 mg/day or placebo in two phases: a concomitant phase (gefitinib or placebo with chemoradiotherapy), followed by a maintenance phase (gefitinib or placebo alone). Primary endpoint was local disease control rate (LDCR) at 2 years; secondary endpoints were LDCR at 1 year, objective response rate, progression-free survival, overall survival, and safety and tolerability.

Results

Gefitinib (250 and 500 mg/day) did not improve 2-year LDCR compared with placebo either when given concomitantly with chemoradiotherapy (32.7% vs. 33.6%, respectively; OR 0.921, 95% CI 0.508, 1.670 [1-sided p = 0.607]) or as maintenance therapy (28.8% vs. 37.4%, respectively; OR 0.684, 95% CI 0.377, 1.241 [1-sided p = 0.894]). Secondary efficacy outcomes were broadly consistent with the 2-year LDCR results. In both doses, gefitinib was well-tolerated and did not adversely affect the safety and tolerability of concomitant chemoradiotherapy.

Conclusion

Gefitinib was well-tolerated, but did not improve efficacy compared with placebo when given concomitantly with chemoradiotherapy, or as maintenance therapy alone.     

Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma

Background

Brain metastases (BM) are a common in patients with lung cancer. Although whole-brain radiation therapy (WBRT) is the standard therapy, it may have a risk of decline in cognitive function of patients. In this study, we evaluated the efficacy of gefitinib alone without radiation therapy for the treatment of patients with BM from lung adenocarcinoma.

Materials and methods

Eligible patients had BM from lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Gefitinib was given at 250 mg orally once a day until tumor progression or unacceptable toxicity.

Results

Forty-one patients were enrolled. The response rate was 87.8%. No patient experienced grade ≥4 toxicity. The median progression-free survival time was 14.5 months (95% CI, 10.2–18.3 months), and the median overall survival time was 21.9 months (95% CI, 18.5–30.3 months). In compared with L858R, exon 19 deletion was associated with better outcome of patients after treatment with gefitinib in both progression-free (p = 0.003) and overall survival (p = 0.025).

Conclusion

Favorable response of BM to gefitinib even without irradiation was demonstrated. Exon 19 deletion was both a predictive and prognostic marker of patients with BM treated by gefitinib.     

Expression of estrogen receptor beta predicts a clinical response and longer progression-free survival after treatment with EGFR-TKI for adenocarcinoma of the lung

Purpose

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (EGFR-TKI) demonstrates a dramatic clinical response for the lung adenocarcinoma patients harboring a somatic mutation of EGFR. Such EGFR mutations are frequently found in adenocarcinoma with a strong expression of estrogen receptor (ER) beta, which has been shown to correlate with a favorable prognosis for the patients with EGFR mutations. The aim of this study is to elucidate the correlation between expression of ER beta and the therapeutic effect of EGFR-TKI in adenocarcinoma of the lung.

Patients and methods

Forty-three patients who were treated with EGFR-TKI for adenocarcinoma of the lung were evaluated. The expression of ER beta and the EGFR mutation were evaluated by immunohistochemistry and the polymerase chain reaction, respectively. Patients divided into two groups by the nuclear expression of ER beta. The clinical response and survival data were compared between the two groups.

Result

Strong (S) and weak (W) expression of ER beta was observed in 21 and 22 patients, respectively. EGFR mutations were detected in 30 (69.8%) cases. The S group had more frequent EGFR mutations than the W group (85.7%, 54.5%, p = 0.045). The S group had better response rate (p = 0.006) and longer progression-free survival (PFS; p = 0.001) than the W group. Even in a limited analysis in the patients with EGFR mutations, the S group had tended to have a better response rate (77.8%, 41.7%, p = 0.063), and significant longer PFS (p = 0.012) than the W group.

Conclusion

A strong expression of ER beta predicts a good clinical outcome for patients with adenocarcinoma of the lung after treatment with EGFR-TKI. This suggests that the expression status of ER beta can be a candidate surrogate marker for EGFR-TKI treatment of patients with adenocarcinoma of the lung. Further investigation will be necessary to identify biomarkers using a larger cohort of patients in a prospective study.     

Duration of prior gefitinib treatment predicts survival potential in patients with lung adenocarcinoma receiving subsequent erlotinib

Purpose

We investigated survival potential in patients receiving erlotinib after failure of gefitinib, focusing on response and time to progression (TTP) with gefitinib.

Methods

We retrospectively reviewed lung adenocarcinoma patients who received erlotinib after experiencing progression with gefitinib. Our primary objective was to evaluate the prognostic significance of erlotinib therapy.

Results

A total 42 lung adenocarcinoma patients were included in this study. Overall disease control rate was 59.5% (partial response [PR], 2.4%; stable disease [SD], 57.1%). Median overall survival was 7.1 months, and median progression-free survival was 3.4 months. The number of patients who achieved PR and non-PR (SD+ progressive disease [PD]) with gefitinib were 22 (52%) and 20 (48%), respectively. Patients with PR for gefitinib showed significantly longer survival times than those with non-PR (9.2 vs. 4.7 months; p = 0.014). In particular, among PR patients, those with TTP <12 months on gefitinib showed significantly longer survival times than those with TTP ≥12 months (10.3 vs. 6.4 months; p = 0.04).

Conclusions

Erlotinib may exert survival benefit for lung adenocarcinoma patients with less than 12 months of TTP of prior gefitinib who achieved PR for gefitinib.     

Association between plasma hepatocyte growth factor and gefitinib resistance in patients with advanced non-small cell lung cancer

Purpose

It has been suggested that hepatocyte growth factor (HGF) and insulin-like growth factor binding protein (IGFBP)-3 are associated with gefitinib resistance in non-small cell lung cancer (NSCLC). We investigated the predictive and prognostic roles of these proteins in NSCLC patients treated with gefitinib.

Patients and methods

Of 106 patients enrolled in a randomized phase II study of gefitinib, 97 had plasma samples available for ELISA testing. Of these samples, seven and eight, respectively, had HGF and IGFBP-3 values that could not be measured. Therefore, the correlations between clinical outcomes and plasma levels of HGF and IGFBP-3 were evaluated in 90 and 89 patients, respectively.

Results

Plasma HGF levels were significantly higher in older patients, male patients, patients with squamous cell carcinoma, current smokers, and patients with epidermal growth factor receptor (EGFR) wild-type tumors. Low HGF levels were significantly associated with higher response rate, and longer progression-free survival (PFS) and overall survival (OS) irrespective of EGFR mutation status. In a multivariate analysis, the presence of EGFR mutations (P = 0.002) and low HGF levels (P = 0.031) were independently predictive of longer PFS, and an ECOG PS of 0 (P = 0.001) and low HGF levels (P = 0.002) were independently predictive of longer OS. No statistically significant differences were found for IGFBP-3.

Conclusion

High HGF levels are significantly associated with resistance to gefitinib and can be used as a predictive marker for the differential outcome of gefitinib treatment in NSCLC irrespective of EGFR mutation status.     

Phosphorylation of EGFR measured with in situ proximity ligation assay: Relationship to EGFR protein level and gene dosage in cervical cancer

Purpose

We have applied the sensitive and specific in situ proximity ligation assay (PLA) to characterize Tyr1068 phosphorylation of the epidermal growth factor receptor (EGFR) in cervical cancer in relation to the protein level and gene dosage.

Materials and methods

Pretreatment tumor biopsies from 178 patients were analyzed. EGFR protein level was determined by immunohistochemistry, and Tyr1068 phosphorylation was detected with PLA in 97 EGFR positive tumors. EGFR gene dosage was derived from array comparative genomic hybridization of 86 cases.

Results

EGFR was expressed in most tumors, whereas phosphorylation was seen in about half of the EGFR positive ones. A correlation was found between the expression of EGFR and phosphorylated EGFR (p = 0.016, membrane; p = 0.012, cytoplasm). However, tumor regions with high protein level without phosphorylation were occasionally seen and the percentage of EGFR positive cells was higher than the phosphorylated percentage (p < 0.001). Moreover, an increase in the phosphorylation in both the membrane (p = 0.014) and cytoplasm (p = 0.002) was seen in 11 tumors with gain of EGFR. The protein level was not correlated with gene dosage.

Conclusion

In contrast to gain of the EGFR chromosomal region, high EGFR protein level may not necessarily indicate Tyr1068 phosphorylation and thereby receptor activation in cervical cancer.     

Tubulin, BRCA1, ERCC1, Abraxas, RAP80 mRNA expression, p53/p21 immunohistochemistry and clinical outcome in patients with advanced non small-cell lung cancer receiving first-line platinum-gemcitabine chemotherapy

Background

The aim of this study was to assess the predictive value of tumor expression of nine genes on clinical outcome in patients with advanced NSCLC receiving platinum-gemcitabine chemotherapy.

Methods

Quantitative PCR or immunohistochemistry were used to analyze the expression of β-tubuline IIA (TUBB2A), β-tubuline III (TUBB3), BRCA1, ERCC1, Abraxas (ABRX) and RAP80 in mRNA isolated from paraffin-embedded tumor biopsies of 45 NSCLC patients treated as part of a larger observational trial. All patients received first-line platinum-gemcitabine chemotherapy for stage IIIB or IV NSCLC.

Results

Median progression-free survival (PFS) was 7 months, overall survival (OS) 12 months. A partial treatment response was found in 14 patients (33%). Patients with low ERCC1 or ABRX expression had a significantly better response to chemotherapy (R = −0.45, p < 0.01 for ERCC1; R = −0.40, p = 0.016 for ABRX). A significant correlation was found between the individual time for PFS and the expression of both ERCC1 (R = −0.36, p = 0.015) and ABRX (R = −0.46, p = 0.001). Patients with low ERCC1 expression had a longer OS as compared to patients with high ERCC1 expression (HR = 0.26, log-rank p = 0.02).

Conclusions

The study confirms tumor expression of ERCC1 as a predictor for clinical outcome in patients with advanced NSCLC receiving platinum-based chemotherapy, and found ABRX expression to be similarly predictive of clinical outcome. Prospective validation is warranted and - if confirmed - non platinum-containing chemotherapy should be explored as the preferred treatment in patients with high ERCC1 or ABRX expression and no activating mutations of EGFR.     

CYP1A1*2A polymorphism as a predictor of clinical outcome in advanced lung cancer patients treated with EGFR-TKI and its combined effects with EGFR intron 1 (CA)n polymorphism

Background

Mutations in the epidermal growth factor receptor (EGFR) have been confirmed as predictors of efficacy for EGFR-tyrosine kinase inhibitors (TKIs). We investigated whether polymorphisms of the EGFR and cytochrome P450, family 1, member A1 (CYP1A1) genes were associated with clinical outcome in NSCLC patients treated with EGFR-TKI.

Methods

Genotypes for the intron 1 (CA)n repeat and R497K polymorphisms in the EGFR gene and the *2A (3801 T → C) and *2C (2455 A → G) polymorphisms in CYP1A1 gene were evaluated in 115 NSCLC patients by PCR-RFLP and DNA sequencing. Genetic polymorphisms were correlated with clinical outcomes of EGFR-TKIs. From a subgroup of patients whose tumour tissues were available, associations between somatic EGFR mutations, EGFR expression, and genomic polymorphisms were also analysed.

Results

EGFR intron 1 (CA)n and CYP1A1*2A polymorphisms were independent predictive factors (p = 0.046, p = 0.011, respectively) and the latter was also a prognostic factor (p = 0.001) for patients treated with EGFR-TKIs. We also observed a strong synergistic effect from two genotypes. Specifically, patients with both the T/T allele of the CYP1A1 gene and shorter intron 1 CA repeats (?16 CA) of the EGFR gene showed an improved response (p = 0.002) compared with patients with the T/C or C/C allele and longer intron 1 CA repeats (both alleles >16 CA). In contrast, for R497K and CYP1A1*2C, no relationship was observed with clinical outcome for patients treated with EGFR-TKIs (p = 0.573; p = 0.629, respectively). Both SNPs in the CYP1A1 gene showed a correlation with EGFR somatic mutations.

Conclusions

The findings of this study suggest that the CYP1A1*2A polymorphism is a predictor for clinical outcome in NSCLC patients treated with EGFR-TKI therapy, and combining analysis of both CYP1A1*2A and EGFR intron 1 (CA)n polymorphisms may be useful for predicting treatment outcome in NSCLC patients treated with EGFR-TKIs.     

Phase I study of icotinib hydrochloride (BPI-2009H), an oral EGFR tyrosine kinase inhibitor, in patients with advanced NSCLC and other solid tumors

Purpose

The goal of this study was to assess the safety and tolerability of icotinib hydrochloride (BPI-2009H), a new selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), and to explore its pharmacokinetics (PK) and clinical activity in patients with advanced solid tumors, mainly those with non-small-cell lung cancer (NSCLC) after the failure of the prior platinum-based chemotherapy.

Experimental design

Different doses of oral icotinib were administered once every 8 h (Q8H) for a 28-continuous-day cycle until disease progression and or undue toxicity was observed. PK studies of subjects’ blood were performed during cycle one (day 1 through 28). Patients aged ≥18 and ≤70 years with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and adequate organ functions eligible for the study. Tumor responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST). K-ras and EGFR mutations in the extracted DNA of fourteen specimens were examined using PCR-based direct sequencing assay.

Results

Thirty-six patients were enrolled in the study. PK analysis demonstrated that the mean elimination half-life of icotinib was 6 h, and the T_max was around 2 h. The steady-state concentration of icotinib administered at a dose of 125 mg once every 8 h (Q8H) was significantly higher than that achieved by a dose of 100 mg Q8H. The most frequent treatment-related adverse events (TRAEs) were an acne-like (folliculitis) rash (16/36, 44.4%), diarrhea (8/36, 22.2%) and a decrease in white blood cells (4/36, 11.1%). The maximum-tolerated dose (MTD) was not reached. Among 33 patients with NSCLC, 7 patients exhibited a partial response, 7 showed stable disease at the 24 weeks. Among 14 patients undergoing DNA sequence for K-ras and EGFR mutations, 3 with K-ras mutation presented 2 stable disease (SD) and 1 partial response (PR), 5 with EGFR exon 19 or 21 mutation 2 PR and 3 SD within 4 weeks.

Conclusions

Oral icotinib was generally well tolerated, with manageable and reversible adverse events (AEs) and showed positive clinical anti-tumor activities in patients with advanced NSCLC. The recommended dose for phase II/III studies with icotinib is 125 mg or 150 mg Q8H.     

Risk of interstitial lung disease with gefitinib and erlotinib in advanced non-small cell lung cancer: A systematic review and meta-analysis of clinical trials

Objectives

Gefitinib and erlotinib are oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) widely used in advanced non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) events have been described with these agents, although the overall risk remains unclear. We performed a systematic review and meta-analysis to determine the incidence and the relative risk (RR) associated with the use of gefitinib and erlotinib.

Materials and methods

PubMed databases were searched for articles published from January 2000 to October 2012, and abstracts presented at the American Society of Clinical Oncology and the European Society of Medical Oncology meetings held between 2000 and 2012 were searched for relevant studies. Eligible studies included randomized controlled trials with gefitinib and erlotinib in advanced NSCLC patients. Summary incidence rates, relative risks, and 95% CIs were calculated using fixed-effects or random-effects models, depending on the heterogeneity of the included studies.

Results

15,618 patients from 29 randomized controlled trials were selected for this meta-analysis. The overall incidence for all-grade ILD events was 1.2% (95% CI, 0.9–1.6%) among patients receiving gefitinib and erlotinib, with a mortality of 22.8% (95% CI, 14.6–31.0%). Compared with controls, the RR of all-grade ILD events associated with gefitinib and erlotinib was 1.53 (95% CI, 1.13–2.08; P = 0.006) using a fixed-effects model. The RR of fatal ILD events associated with EGFR TKIs treatment was 1.96 (95% CI, 1.03–3.72, P = 0.041) compared with control patients. The analysis was also stratified for drug type, study location, treatment arm, and treatment line, but no significant differences in RRs were observed.

Conclusion

Treatment with EGFR TKIs gefitinib and erlotinib is associated with a significant increase in the risk of developing both all-grade and fatal ILD events in advanced NSCLC.     

Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients

Background

Our previous individual patient data (IPD) meta-analysis showed that chemotherapy improved survival in patients curatively treated for non-metastatic head and neck squamous cell carcinoma (HNSCC), with a higher benefit with concomitant chemotherapy. However the heterogeneity of the results limited the conclusions and prompted us to confirm the results on a more complete database by adding the randomised trials conducted between 1994 and 2000.

Methods

The updated IPD meta-analysis included trials comparing loco-regional treatment to loco-regional treatment + chemotherapy in HNSCC patients and conducted between 1965 and 2000. The log-rank-test, stratified by trial, was used to compare treatments. The hazard ratios of death were calculated.

Results

Twenty-four new trials, most of them of concomitant chemotherapy, were included with a total of 87 trials and 16,485 patients. The hazard ratio of death was 0.88 (p < 0.0001) with an absolute benefit for chemotherapy of 4.5% at 5 years, and a significant interaction (p < 0.0001) between chemotherapy timing (adjuvant, induction or concomitant) and treatment. Both direct (6 trials) and indirect comparisons showed a more pronounced benefit of the concomitant chemotherapy as compared to induction chemotherapy. For the 50 concomitant trials, the hazard ratio was 0.81 (p < 0.0001) and the absolute benefit 6.5% at 5 years. There was a decreasing effect of chemotherapy with age (p = 0.003, test for trend).

Conclusion

The benefit of concomitant chemotherapy was confirmed and was greater than the benefit of induction chemotherapy.     

The prognostic relevance of tumor hypoxia markers in resected carcinoma of the gallbladder

Background

Intratumoral hypoxia has been suggested to drive more aggressive tumor behavior. Our aim was to define whether markers of tumor hypoxia are predictors of outcome in patients with gallbladder carcinoma.

Patients and methods

From 1996 to 2006, 34 patients underwent resection for gallbladder carcinoma. The median follow-up was 12.6 months. Immunohistochemical stains for VEGF, HIF1α, GLUT1, GLUT3, CA9 and EGFR were performed on archival tissue. Immunohistochemical results were correlated with clinical and histopathological parameters. Cumulative overall survival (OS) rates were estimated using the Kaplan-Meier method. Multivariable Cox regression models were used to identify predictors of OS.

Results

The median OS was 11.9 (IQR: 3.4-22.0) months. Ubiquitous VEGF staining was observed in all gallbladder carcinomas. High (>50% of tumor cells) EGFR expression was associated with worse OS (p 0.03). CA9 expression was less prevalent in poorly differentiated tumors (p 0.02). GLUT3, GLUT1 and HIF1α expression were not associated with survival, but did correlate with the presence of lymph node metastasis (p 0.02), tumor differentiation (p 0.04) and tumor stage (p 0.03) respectively. High EGFR expression, TNM stage and preoperative serum CA19.9 were retained as independent predictors of OS in multivariable analysis.

Conclusion

In gallbladder cancer high expression of EGFR is an independent predictor of survival.     

Determinants of variability in waiting times for radiotherapy in the treatment of breast cancer

Purpose

To examine psycho-social and geographic determinants of delay in starting radiotherapy in early invasive breast cancer patients.

Material and methods

Waiting time was defined as the time elapsed until the beginning of radiotherapy, starting from the date of surgery (in absence of chemotherapy) or from the end of chemotherapy.

Results

Eight hundred and ninety six women aged 24-89 took part in the study. Mean waiting times were 52 days (sd = 19) between surgery and radiotherapy and 31 days (sd = 14) between chemotherapy and radiotherapy. Differences between radiotherapy centres (p < 0.0001) accounted for 30% and 12%, respectively, of total variance in waiting times. Using a multivariate mixed analysis that took into account intra-centre correlation, the time between surgery and radiotherapy was shorter for young patients (p = 0.020), those who had sought information about their illness (p = 0.024) and those who had undergone surgery and radiotherapy in the same centre (p = 0.021). On the other hand, no patient characteristic was associated with the time between chemotherapy and radiotherapy.

Conclusion

Centre is the major factor that explained longer waiting times in radiotherapy, emphasising the structural hypothesis. It is important to pursue initiatives to improve the organization within radiotherapy centres and then to verify that these initiatives have succeeded in shortening waiting times.     

Chemoreirradiation for recurrent salivary gland malignancies

Background and purpose

To report our experience in treating recurrent salivary gland malignancies using concurrent chemotherapy and reirradiation.

Materials and methods

Between 1986 and 2007, 14 patients with locoregionally recurrent salivary gland cancer underwent maximal surgical resection followed by adjuvant 5-fluorouracil and hydroxyurea-based chemotherapy concurrently with 1.5 Gy twice daily or 2 Gy daily reirradiation. Each cycle consisted of chemoreirradiation for 5 consecutive days followed by a 9-day break. The median reirradiation dose was 66 Gy (R 30-72 Gy) after a mean radiation treatment interval of 48 months.

Results

The median follow-up for all patients was 18 months (R 2-125 months) and 41 months for survivors. The parotid gland (n = 6) and minor salivary glands (n = 6) were involved more commonly than the submandibular gland (n = 2). Locoregional control at 1 and 3 years was 72.2% and 51.6%, respectively. Actuarial overall survival at 3 and 5 years was 35.7% and 26.8%, respectively. Tracheostomies and feeding tubes were placed in 2 and 8 patients, respectively. Six patients had feeding tubes at last follow-up or death.

Conclusions

Concurrent chemotherapy and reirradiation for recurrent salivary malignancies result in promising locoregional control for patients with recurrent salivary gland malignancies.     

Pharmacokinetic and pharmacodynamic study of Gefitinib in a mouse model of non-small-cell lung carcinoma with brain metastasis

Introduction

Some studies showed that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib could improve the outcome of non-small-cell lung cancer (NSCLC) patients with brain metastasis (BM), while the concentration of gefitinib in cerebrospinal fluid (CSF) was low. Therefore, we designed the present study to investigate whether gefitinib could actively penetrate blood brain barrier (BBB) in a mouse model of lung cancer brain metastasis (BM).

Materials and methods

In vitro MDCK-MDR1 assay was used to determine permeability and efflux ratio (R_E) of gefitinib. In vivo pharmacokinetic and pharmacodynamic evaluation was performed in both normal nude mice and a BM model established by intra-carotid artery (ICA) injection of PC-9 cells.

Results

The result showed that R_E of gefitinib at the concentrations of 1 μM and 10 μM was 4.12 and 4.05, respectively, but significantly decreased to 1 and 1.35 after adding a P-glycoprotein (P-gp) inhibitor, cyclosporine A. In both normal mice and BM model, dose dependent increase of gefitinib was detected in the blood, brain and CSF at the doses of 50, 100 and 200 mg/kg. In BM model, AUC_totalbrain/AUC_totalblood in 50 mg/kg and 200 mg/kg groups were 0.4 and 0.7, respectively, while AUC_CSF/AUC_freeblood were 0.21 and 0.18, respectively. Positive correlation between concentration of gefitinib in CSF and pEGFR modulation in the brain tumor was identified.

Conclusion

Gefitinib is a P-gp substrate and has limited active BBB penetration. Increased doses of gefitinib potentially accelerated passive permeability.     

Prophylactic irradiation of intervention sites in malignant pleural mesothelioma

Background and purpose

To assess the effectiveness of prophylactic irradiation of intervention track (PIT) to prevent tumor seeding in patients with malignant pleural mesothelioma.

Materials and methods

A retrospective review was conducted of 171 patients with a histological diagnosis of pleural mesothelioma with some undergoing prophylactic irradiation of intervention sites.

Results

Forty-eight patients (28%) received PIT. A majority of patients were followed until death. Thoracoscopy (88%) was the procedure most often performed. Thirty-three percent of patients received chemotherapy. The median dose of PIT was 21 Gy in 3 fractions with electrons or 6 MV photons. The local progression free survival (LPFS) at the intervention site was significantly higher in the PIT group and was not influenced by chemotherapy. At 6 months, LPFS for the intervention sites was 91% with PIT and 74% without PIT (p = 0.002). During the follow-up, 6 patients (13%) in the PIT group had tumor invasion of the subcutaneous tissue compared to 40 patients (33%) in the group without PIT (p = 0.008).

Conclusions

This study suggests that PIT in mesothelioma reduces the incidence of procedure tract metastasis. Finally, chemotherapy does not seem to have an influence on the incidence of tract metastasis.     

Mutational spectrum and therapy response of metastasized GIST in Central Switzerland - a population-based study

Background

Until now, no population-based studies investigated the mutational status of primary GIST (PT) and corresponding metastases and correlated these data with response to Imatinib or Sunitinib therapy.

Patients and methods

In a retrospective observation study, all metastatic GISTs of the last 15 years of our institution were investigated for mutations in c-kit and in PDGFRα gene in each PT and corresponding metastasis. Correlation with clinical outcome and response to Imatinib or Sunitinib therapy was performed.

Results

In 13 PT c-kit mutations in exon 9 (3), exon 11 (7) and exon 13 (1), 2 wild type genotypes, and no PDGFRα mutation were detected. In three metastases a switch from heterozygosity to homozygosity and one additional exon 13 mutation was observed. All 10 persons with available follow-up received Imatinib as first-line chemotherapy. Five of them (3 exon 9 mutations, 1 wild type, 1 additional exon 13 mutation) stopped Imatinib due to tumour progression. In three cases, Sunitinib as second-line chemotherapy was ended due to the same reasons.

Conclusions

Our data support previous observations, that PDGFRα mutations play no important role in metastasized GISTs. The influence of Imatinib and Sunitinib therapy in metastasized GISTs with wild type genotype and c-kit exon 9 mutations needs further investigation.