Three- versus six-month adjuvant FOLFOX or CAPOX for high-risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project.

BACKGROUND: The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) aimed to investigate whether a 3 months (3M) of oxaliplatin/fluoropyrimidine-based adjuvant chemotherapy (CT) is non-inferior to the 6-month (6M) administration in 3-year disease-free survival (3yDFS) in high-risk (HR) stage II or stage III colon cancer (CC). METHODS: Hellenic Oncology Research Group (HORG)-IDEA randomized patients between 3M and 6M of CT with FOLFOX4 or CAPOX. RESULTS: In total 1115 patients, 413 with HR stage II and 702 with stage III CC, were randomized. The median follow-up was 67.0 (38.3-126.0) months. Overall, 394 DFS events (202 in 3M arm and 192 in 6M arm) where recorded. The 3yDFS rate was 77.2% [95% confidence interval (CI) 72.1% to 82.3%] for 3M and 77.9% (72.6% to 82.5%) for 6M of treatment [hazard ratio (HR) 1.05 (95% CI 0.61-1.55); P = 0.647]. Eighty DFS events (3M N = 41; 6M N = 39) were observed in HR stage II patients for a 3yDFS rate of 82.7% and 83.4%, respectively (HR 1.05; 95% CI 0.68-1.63, P = 0.829). For stage III patients, 314 DFS events (3M N = 161 and 6M N = 153) were observed, for a 3yDFS rate of 72.9% for 3M versus 74.1% for 6M (HR 1.06; 95% CI 0.81-1.42, P = 0.622). For HR stage II patients receiving FOLFOX4, 3yDFS rate was 76.7% for 3M and 79.3% for 6M (HR 1.21; 95% CI 0.54-2.70). For HR stage II patients receiving CAPOX the 3yDFS rate was 85.4% for 3M and 83.8% for 6M (HR 0.99; 95% CI 0.59-1.67). For stage III patients receiving FOLFOX4, the 3yDFS rate was 71.5% for 3M and 77.3% for 6M (HR 1.18; 95% CI 0.74-1.86). For stage III patients receiving CAPOX, the 3yDFS rate was 74.5% for 3M and 74.7% for 6M (HR 0.99; 95% CI 0.70-1.44). CONCLUSIONS: The results of the HORG-IDEA study are in line with those of the global IDEA project, indicating that the 3yDFS is dependent on the administered adjuvant regimen and the choice and duration of regimen should be personalized. CLINICALTRIALS.GOV REGISTRATION NUMBER: NCT01308086.

Association of BRCA1, ERCC1, RAP80, PKM2, RRM1, RRM2, TS, TSP1, and TXR1 mRNA expression levels between primary tumors and infiltrated regional lymph nodes in patients with resectable non-small cell lung cancer.

Differences in gene expression levels between the primary tumors (PTs) and matched regional lymph nodal metastases (LNs) in patients with totally excised non-small cell lung cancer (NSCLC) were explored. Microdissected formalin-fixed paraffin-embedded (FFPE) samples from (PT) and their matched infiltrated LNs, from 239 patients [183 (with matched PT and LNs samples)-case and 56 PT only samples-control cohorts] were analyzed for BRCA1, ERCC1, RAP80, PKM2, RRM1, RRM2, TS, TSP1, and TXR1 mRNA expression by quantitative real-time polymerase-chain reaction (PCR). Moderately positive correlation between the expression of each gene in the PT and the matched LNs was observed. Concordance rates between the PT and the LNs were: BRCA1 (67.7%), ERCC1 (68.4%), PKM2 (63.4%), RAP80 (68.8%), RRM1 (70.9%), RRM2 (69%), TS (72.9%), TSP1 (69.8%), TXR1 (63.7%). Expression levels and their differences were correlated with Relapse-Free Survival (RFS) and Overall Survival (OS). High BRCA1 PT in patients with squamous histology was associated with increased OS (p = 0.036). High TSP1 PT levels were shown to be the only independent prognostic factor for OS and RFS (p = 0.023 and p = 0.007). PKM2 low levels in both PT and matched LNs were associated with better OS irrespective of the underlying histology (p = 0.031). RRM1 discordant levels between PT and matched LNs were associated with worse OS in squamous tumors (p = 0.019) compared to patients with both low expression in PT and LN.TXR1 high levels in both PT and matched LNs were associated with better OS in patients with squamous tumors (p = 0.007).These findings indicate that there is different gene expression between PT and matched LNs which may affect the outcome in early NSCLC and therefore PT's molecular biology should not be the sole determinant for prognostication.

Predictive value of ATP7b, BRCA1, BRCA2, PARP1, UIMC1 (RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) genes in patients with epithelial ovarian cancer who received platinum-taxane first-line therapy.

To evaluate the predictive value of genes involved in resistance to platinum-taxane chemotherapy in patients with epithelial ovarian cancer (EOC). Microdissected formalin-fixed tumoral samples from 187 EOC patients' primary tumors (90 and 97 samples from matched patients in the experimental and validation sets, respectively) were analyzed. All specimens were analyzed for ATP7b, BRCA1, BRCA2, PARP1, UIMC1(RAP80), HOXA9, DAXX, TXN (TRX1), THBS1 (TSP1) and PRR13 (TXR1) mRNA expression by quantitative real-time PCR. Most of the patients (172 out of 187) received front-line carboplatin-paclitaxel regimen. Expression levels were correlated with overall (OS) and progression-free (PFS) survival by multivariate analysis. Patients with high TXN and THBS1 expression presented longer PFS (P=0.001 and P<0.001, respectively) and OS (P=0.024 and P<0.001, respectively). High TXR1 expression was associated with decreased PFS (P<0.001) and OS (P<0.001). Multivariate analysis demonstrated that high PRR13/low THBS1 expression was an independent factor for decreased PFS (hazards ratio: 1.94; 95% confidence interval (CI): 1.48-2.92; P=0.008) and OS (hazard ratio: 3.89; 95% CI: 2.16-6.87; P<0.001), whereas low TXN expression was correlated with decreased PFS (hazard ratio: 1.44; 95% CI: 1.05-2.84; P=0.043) and OS (hazard ratio: 2.38; 95% CI: 1.78-2.77; P=0.009). These findings indicate that PRR13/THBS1 and TXN expression could be used for the prediction of resistance to treatment of EOC patients and, therefore, merit to be further evaluated.

PKM2 as a biomarker for chemosensitivity to front-line platinum-based chemotherapy in patients with metastatic non-small-cell lung cancer.

BACKGROUND: Tumour cells exclusively express the embryonic M2 isoform of pyruvate kinase (PKM2). PKM2 expression levels have been correlated with the effect of platinum compounds in cancer cell lines and xenograft models. The potential predictive role of PKM2 in patients with metastatic/advanced non-small-cell lung cancer (NSCLC) receiving platinum-based chemotherapy as first-line was investigated. METHODS: Quantitative real-time PCR was used to assess the expression of PKM2 in tumour samples from 148 and 157 NSCLC patients in the training and the validation set, respectively. All patients received front-line platinum-based chemotherapy. PKM2 mRNA expression was also analysed in a control group of 85 NSCLC patients treated with non-platinum containing regimens. RESULTS: In the training set, high PKM2 mRNA levels were associated with decreased progression-free survival (PFS; 4.9 months vs 6.4, P=0.006), overall survival (OS; 10.1 vs 17.0 months, P=0.01) and disease control rate (DCR; 57.7% vs 74.3%; P=0.021) compared to patients with low PKM2 levels. In the validation set, high PKM2 mRNA levels were also associated with deceased PFS (3.7 vs 5.9 months, P=0.006), OS (8.3 vs 16.8 months, P=0.003) and DCR (57.7% vs 70.9%; P=0.049) compared to those with low PKM2 mRNA levels. There was no correlation between the PKM2 mRNA levels and the PFS (5.6 vs 5.9, P=0.43) or the OS (9.8 vs 10.1, P=0.51) in the control group. Multivariate analysis revealed high PKM2 mRNA expression as an independent predictive factor for the poor patients' outcome. CONCLUSIONS: PKM2 expression may be a predictive biomarker of platinum sensitivity in advanced NSCLC patients treated with platinum-based chemotherapy.

Frontline treatment with gemcitabine, oxaliplatin and erlotinib for the treatment of advanced or metastatic pancreatic cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG).

PURPOSE: Intravenous gemcitabine is the standard of care for patients with metastatic cancer of the pancreas. Gemcitabine-based chemotherapy combinations, either doublets or triplets, have been tested in the past but have offered a small advantage (Brodoefel et al. in Eur J Radiol 73:594-600, 2010). In the present study, we present the results of the triplet gemcitabine-oxaliplatin-erlotinib combination as firstline treatment in this setting. PATIENTS AND METHODS: Seventy-one eligible patients were included in this study. All patients received chemotherapy with gemcitabine (1,100 mg/m(2) on days 1 and 8) plus oxaliplatin (130 mg/m(2) on day 8) and erlotinib (100 mg p.o./day for 21 days). The treatment cycle was 21 days. RESULTS: Partial response was achieved in 15 patients (21%; 95% CI 11.63-30.62) and stable disease in 15 patients (21%). Forty-one patients (57.8%) experienced disease progression. Median progression-free survival was 5.2 months (range 0.6-34.7; 95% CI 3.71-6.76). The median overall survival was 10.5 months (95% CI 7.39-13.61) and the 1-year survival estimate 47.3%. The main adverse events were grade 3/4 anemia occurring in three (4.2%) patients and grade 3 and 4 thrombocytopenia occurring in eight (11.3%) and three (4.2%) patients, respectively. Grade 4 neutropenia was rare (1.4%), and one patient presented febrile neutropenia. CONCLUSION: This study demonstrated that the combination of gemcitabine, oxaliplatin and erlotinib is active, well tolerated and safe for patients with metastatic adenocarcinoma of the pancreas. However, the results do not seem to be better than those reported with chemotherapy alone.

A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial.

BACKGROUND: We conducted an open-label, pilot phase II trial to evaluate the efficacy and safety of FOLFOXIRI plus cetuximab as first-line treatment of patients with metastatic colorectal cancer (mCRC). METHODS: Thirty patients with KRAS wild-type mCRC, <70 years and with performance status 0-1 were included in the trial. RESULTS: Complete and partial responses were observed in 4 (13.3%) and 17 (56.7%) patients, respectively (overall response rate (ORR)=70%; 95% confidence interval (CI): 53.6%-86.4%); 8 patients (26.7%) had stable disease and 1 had progressive disease. The median time to tumour progression was 10.2 months (95% CI: 7.1-13.4) and the overall median survival time was 30.3 months (95% CI: 18.8-41.9). Secondary R0 resection was performed in 11 (37%) patients. Grade 3 or 4 diarrhoea and neutropenia were observed in 16 (53%) and 7 (23.3%) patients, respectively, and febrile neutropenia observed in 2 (6.6%) patients. Neurotoxicity grade 2 or 3 was reported in 7 (23.3%) and in 2 (6.7%) patients, respectively, and grade 3 rush was reported in 1 patient. CONCLUSION: The FOLFOXIRI/cetuximab combination presented increased activity in terms of response rate and R0 secondary liver metastases resection, and merits further investigation, especially in patients with initially unresectable disease confined to the liver.

Randomised phase-II trial of CAPIRI (capecitabine, irinotecan) plus bevacizumab vs FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) plus bevacizumab as first-line treatment of patients with unresectable/metastatic colorectal cancer (mCRC).

BACKGROUND: To compare the efficacy and safety of CAPIRI+bevacizumab (Bev) in comparison with FOLFIRI+Bev as first-line treatment for patients with metastatic colorectal cancer (mCRC). METHODS: Patients were randomised to receive either FOLFIRI plus Bev 5 mg kg(-1) every 2 weeks (Arm-A) or CAPIRI plus Bev 7.5 mg kg(-1) every 3 weeks (Arm-B). RESULTS: Three hundred thirty-three patients (Arm-A=167; Arm-B=166) were enrolled into the study. No difference was observed in median progression-free survival (PFS) (10.0 and 8.9 months; P=0.64), overall survival (25.7 and 27.5 months; P=0.55) or response rates (45.5 and 39.8.7%; P=0.32) for FOLFIRI-Bev and CAPIRI-Bev, respectively. Patients treated with CAPIRI-Bev presented significantly higher incidence of diarrhoea (P=0.005), febrile neutropenia (P=0.003) and hand-foot skin reactions (P=0.02) compared with patients treated with FOLFIRI-Bev. Treatment delays (P=0.05), dose reduction (P<0.001) and treatment discontinuation owing to toxicity (P=0.01) occurred more frequently in the CAPIRI-Bev arm. CONCLUSION: The PFS of FOLFIRI-BEV is not superior to that observed with the CAPIRI-Bev regimen. CAPIRI-Bev has a less favourable toxicity profile, requiring dose reductions, in order to be considered as an option in first-line treatment of patients with mCRC.

Correlation of BRCA1, TXR1 and TSP1 mRNA expression with treatment outcome to docetaxel-based first-line chemotherapy in patients with advanced/metastatic non-small-cell lung cancer.

BACKGROUND: We explored the predictive significance of BRCA1, TXR1 and TSP1 expression in non-small-cell lung cancer (NSCLC) patients treated with docetaxel in association with cisplatin or gemcitabine. METHODS: To analyse BRCA1, TXR1 and TSP1 mRNA expression from microdissected primary tumours of 131 patients with stage IIIB (wet) and IV NSCLC, RT-qPCR was used. RESULTS: The mRNA levels of TXR1/TSP1 were inversely correlated (Spearman's test: -0.37; P=0.001). Low TXR1 mRNA levels were associated with higher response rate (RR; P=0.018), longer median progression-free survival (PFS; P=0.029) and median overall survival (mOS P=0.003), whereas high TSP1 expression was correlated with higher RR (P=0.035), longer PFS (P<0.001) and mOS (P<0.001). Higher BRCA1 mRNA expression was associated with higher RR (P=0.028) and increased PFS (P=0.021), but not mOS (P=0.4). Multivariate analysis demonstrated that low TXR1/high TSP1 expression was an independent factor for increased PFS (HR 0.49; 95% CI 0.32-0.76; P<0.001) and mOS (HR 0.37; 95% CI 0.2-0.58; P<0.001), whereas high BRCA1 expression was correlated with increased PFS (HR 0.53; 95% CI 0.37-0.78; P=0.001). CONCLUSIONS: These data indicate that TXR1/TSP1 and BRCA1 expression could be used for the prediction of taxanes' resistance in the treatment of NSCLC.

BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients' outcome.

BACKGROUND: The significance of BRAF mutations, microsatelite instability (MSI) status and cyclin D1 expression in patients with metastatic colorectal cancer (mCRC) was evaluated. METHODS: Primary tumours from 144 patients treated for mCRC were assessed for BRAF (V600E) mutation, MSI status and cyclin D1. The data were correlated with progression-free survival (PFS) and overall survival (OS). RESULTS: BRAF mutations were detected in 10 (out of 22, 45%) patients with MSI-H tumours compared with 2 (out of 122, 1.6%) in those with microsatellite stable tumours (P<0.001). The presence of BRAF mutations was correlated with cyclin D1 overexpression (7 out of 26 patients, 58% vs 5 out of 118 patients, 14%; P=0.001). Patients with BRAF-mutated primary tumours had a significantly decreased PFS (2.7 vs 9.8 months; P<0.001) and median OS (14 vs 30 months; P<0.001) than patients with wild-type (wt) tumours. Patients with MSI-H and BRAF-mutated tumours experienced significantly lower PFS (3.1 vs 11.4 months; P=0.008) and OS (14.5 vs 35.5 months; P=0.004) than patients with MSI-H and BRAF wt tumours. Similarly, BRAF mutations and cyclin D1 overexpression were correlated with decreased PFS (3.1 vs 8.6 months; P=0.03) and OS (17.8 vs 39.2 months; P=0.01). CONCLUSION: BRAF V600E mutations are associated with MSI-H status and cyclin D1 overexpression and characterize a subgroup of patients with poor prognosis.

Clinical outcome of elderly patients with metastatic colorectal cancer treated with FOLFOXIRI versus FOLFIRI: Subgroup analysis of a randomized phase III trial from the Hellenic Oncology Research Group (HORG).

BACKGROUND: A subgroup analysis of oxaliplatin (LOHP)+irinotecan (CPT-11)+5-fluorouracil (5FU) and leucovorin (LV) (FOLFOXIRI regimen) versus irinotecan+5FU/LV (FOLFIRI regimen) as first-line treatment of patients >65 years old with metastatic colorectal cancer is presented. PATIENTS AND METHODS: Eighty-two (56%) and 75 (55%) patients with metastatic colorectal cancer aged >65 years were enrolled in the FOLFOXIRI and FOLFIRI regimen, respectively. RESULTS: There was no statistically statistical difference in terms of overall survival or time-to-tumor progression between young and aged patients between the two chemotherapy arms. The objective response rate was significantly lower in older patients treated with FOLFOXIRI (32% vs. 52%; OR: 1.45, 95% CI: 1.06-2.09; p=0.03). Elderly patients experienced a significantly higher incidence of grade 3/4 diarrhea compared to younger patients, irrespectively of the chemotherapy regimen (p=0.005 for FOLFIRI; p=0.017 for FOLFOXIRI). Dose reductions and treatment delays were more frequent in the FOLFOXIRI arm. CONCLUSION: FOLFOXIRI does not seem to offer substantial benefit compared to FOLFIRI regimen in elderly patients with metastatic colorectal cancer.

Prognostic and predictive value of common mutations for treatment response and survival in patients with metastatic colorectal cancer.

BACKGROUND: We address the prognostic and predictive value of KRAS, PIK3CA and BRAF mutations for clinical outcomes in response to active agents in the treatment of metastatic colorectal cancer (mCRC). METHODS: We determined KRAS, BRAF and PIK3CA mutations in tumours from 168 patients treated for mCRC at two institutions. All patients received 5-FU-based first-line chemotherapy and treatment outcome was analysed retrospectively. RESULTS: KRAS, BRAF and PIK3CA mutations were present in 62 (37%), 13 (8%) and 26 (15%) cases, respectively. Multivariate analysis uncovered BRAF mutation as an independent prognostic factor for decreased survival (hazard ratio (HR) 4.0, 95% confidence interval (CI) 2.1-7.6). In addition, patients with BRAF-mutant tumours had significantly lower progression-free survival (PFS: HR 4.0, 95% CI 2.2-7.4) than those whose tumors that carried wild-type BRAF. Among 92 patients treated using chemotherapy and cetuximab as salvage therapy, KRAS mutation was associated with lack of response (P=0.002) and shorter PFS (P=0.09). BRAF (P=0.0005) and PIK3CA (P=0.01) mutations also predicted reduced PFS in response to cetuximab salvage therapy. CONCLUSIONS: These results underscore the potential of mutational profiling to identify CRCs with different natural histories or treatment responses. The adverse significance of BRAF mutation should inform patient selection and stratification in clinical trials.

Docetaxel plus gemcitabine as front-line chemotherapy in elderly patients with lung adenocarcinomas: a multicenter phase II study.

BACKGROUND: The docetaxel/gemcitabine (DG) combination is an active and well-tolerated regimen against non-small cell lung cancer (NSCLC). A phase II study was conducted in order to evaluate its efficacy in elderly patients with lung adenocarcinomas. METHODS: Chemotherapy-naive patients, aged > or =70 years, with locally advanced or metastatic lung adenocarcinomas and performance status (PS) < or =2 (ECOG) received gemcitabine 1100 mg/m(2) (days 1+8) and docetaxel 100 mg/m(2) (day 8) with rhG-CSF support. RESULTS: Seventy-seven patients were enrolled. One (1.3%) complete and 23 (29.9%) partial responses were achieved (intention to treat analysis: ORR 31.2%; 95% CI 20.82-41.51%) whereas tumor growth control was achieved in 53.3% of patients. The median TTP was 4.1 months, the median overall survival 9.4 months and the 1- and 2-year survival rate 37.9% and 10.7%, respectively. Grade 3-4 neutropenia occurred in 18.2% and febrile neutropenia in 3 (3.9%) patients. Non-haematological toxicity was mild with grade 2-3 asthenia occurring in 22.1% patients. CONCLUSIONS: The DG regimen is an active and well-tolerated front-line chemotherapy for elderly patients with lung adenocarcinomas and merits further evaluation in prospective randomized trials.

Modified CAPOX (capecitabine plus oxaliplatin) regimen every two weeks as second-line treatment in patients with advanced colorectal cancer previously treated with irinotecan-based frontline therapy: a multicenter phase II study.

BACKGROUND: To evaluate the efficacy and tolerance of capecitabine (CAP) given every other week and biweekly oxaliplatin (OX; modified CAPOX regimen) in patients with advanced colorectal cancer previously treated with irinote- can-based frontline chemotherapy. METHODS: Sixty-seven patients were enrolled; the median age was 62 years and 62 (92.5%) had a performance status (ECOG) of 0-1. OX and CAP were administered at the dose of 100 mg/m(2) on day 1 and 2,000 mg/m(2) on days 1-7, respectively, every 2 weeks. RESULTS: A total of 429 treatment cycles were administered. Grade 3/4 neutropenia and thrombocytopenia were observed in 4 (6%) and 2 (3%) patients, respectively. Febrile neutropenia complicated 1 treatment cycle. The main nonhematologic toxicities were grade 2/3 peripheral sensory neurotoxicity (10% of patients) and grade 3/4 diarrhea (7%). In an intention-to-treat analysis, 3 (4.5%) complete and 13 (19.4%) partial responses (overall response rate 24%) were observed. Seventeen (24.5%) patients had stable and 27 (40.3%) progressive disease. The median time to tumor progression and overall survival were 5 months and 11.3 months, respectively. CONCLUSIONS: The results indicate that the modified CAPOX regimen is safe and effective as salvage treatment in patients with advanced colorectal cancer who were previously treated with irinotecan-based frontline therapy.

Ribonucleotide reductase subunits M1 and M2 mRNA expression levels and clinical outcome of lung adenocarcinoma patients treated with docetaxel/gemcitabine.

Ribonucleotide reductase subunits M1 (RRM1) and M2 (RRM2) are involved in the metabolism of gemcitabine (2',2'-difluorodeoxycytidine), which is used for the treatment of nonsmall cell lung cancer. The mRNA expression of RRM1 and RRM2 in tumours from lung adenocarcinoma patients treated with docetaxel/gemcitabine was assessed and the results correlated with clinical outcome. RMM1 and RMM2 mRNA levels were determined by quantitative real-time PCR in primary tumours of previously untreated patients with advanced lung adenocarcinoma who were subsequently treated with docetaxel/gemcitabine. Amplification was successful in 42 (79%) of 53 enrolled patients. Low levels of RRM2 mRNA were associated with response to treatment (P< 0.001). Patients with the lowest expression levels of RRM1 had a significantly longer time to progression (P=0.044) and overall survival (P=0.02) than patients with the highest levels. Patients with low levels of both RRM1 and RRM2 had a significantly higher response rate (60 vs 14.2%; P=0.049), time to progression (9.9 vs 2.3 months; P=0.003) and overall survival (15.4 vs 3.6; P=0.031) than patients with high levels of both RRM1 and RRM2. Ribonucleotide reductase subunit M1 and RRM2 mRNA expression in lung adenocarcinoma tumours is associated with clinical outcome to docetaxel/gemcitabine. Prospective studies are warranted to evaluate the role of these markers in tailoring chemotherapy.

Comparison of EGFR and K-RAS gene status between primary tumours and corresponding metastases in NSCLC.

In non-small-cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) and K-RAS mutations of the primary tumour are associated with responsiveness and resistance to tyrosine kinase inhibitors (TKIs), respectively. However, the EGFR and K-RAS mutation status in metastases is not well studied. We compared the mutation status of these genes between the primary tumours and the corresponding metastases of 25 patients. Epidermal growth factor receptor and K-RAS mutation status was different between primary tumours and corresponding metastases in 7 (28%) and 6 (24%) of the 25 patients, respectively. Among the 25 primary tumours, three 'hotspot' and two non-classical EGFR mutations were found; none of the corresponding metastases had the same mutation pattern. Among the five (20%) K-RAS mutations detected in the primary tumours, two were maintained in the corresponding metastasis. Epidermal growth factor receptor and K-RAS mutations were detected in the metastatic tumours of three (12%) and five (20%) patients, respectively. The expressions of EGFR and phosphorylated EGFR showed I 0 and 50% discordance, in that order. We conclude that there is substantial discordance in EGFR and K-RAS mutational status between the primary tumours and corresponding metastases in patients with NSCLC and this might have therapeutic implications when treatment with TKIs is considered.

'Classical' but not 'other' mutations of EGFR kinase domain are associated with clinical outcome in gefitinib-treated patients with non-small cell lung cancer.

'Classical' mutations in the EGFR tyrosine kinase domain (exons 18, 19 and 21) have been associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with NSCLC. The aim of the current study was to evaluate whether other than the classical G719X, DEL19 and L858R mutations of EGFR confer sensitivity to TKIs. Genomic DNA was extracted from microdissected formalin-fixed paraffin-embedded tumour tissue from 86 patients treated with gefitinib. Exons 18, 19 and 21 were amplified and subjected to direct sequencing. Eleven (13%) patients harboured the classical exon's 18, 19 and 21 mutations, while 14 (16%) had 'other' variants. There was a significantly higher percentage of 'never-smoker' patients with 'classical' EGFR mutations (P=0.002). Among patients with 'classical' mutations 3 patients achieved PR and 7 SD, while in the 'other' mutations group 10 patients had SD as best response. In the wild-type group, there were 3 patients with PR and 25 with SD. Median TTP was 16, 64 (P=0.002) and 21 weeks and median survival was 36, 78 and 67 weeks for patients with wild-type, 'classical' and 'other' EGFR mutations, respectively. The clinical relevance of 'other' EGFR mutation variants remains uncertain and requires further assessment in a prospective study.

Dose escalating clinical study of high dose infusional 5-fluorouracil and leukovorin (AIO regimen) plus alternate weekly administration of oxaliplatin and irinotecan in patients with advanced tumors of the gastrointestinal tract.

PURPOSE: To determine the dose-limiting toxicities (DLTs) and the maximum tolerated doses (MTDs) of weekly high dose 5-fluorouracil (5FU) continuous infusion and leukovorin (LV) alternatively combined with oxaliplatin and irinotecan in patients with advanced tumors of the gastrointestinal (GI) tract. PATIENTS AND METHODS: Patients received a fixed dose of LV (500 mg/m(2)) over 2 h infusion on weeks 1 to 4 and escalated doses of: oxaliplatin (starting dose 65 mg/m(2): 120 min i.v. infusion on weeks 1 and 3); irinotecan (starting dose 80 mg/m(2); 90 min i.v. infusion on weeks 2 and 4) and 5FU (starting dose 1500 mg/m(2); 22 h continuous i.v. infusion, on weeks 1 to 4), in cycles of 5 weeks. DLTs were evaluated during the fi rst cycle. RESULTS: Twenty-eight patients were treated on 8 dose levels and all but two patients received the regimen at least as second-line treatment. The DLT level was reached at the oxaliplatin dose of 90 mg/m(2), irinotecan dose of 110 mg/m(2), LV dose of 500 mg/m(2) and 5FU dose of 1750 mg/m(2); the recommended MTDs were 85 mg/m(2) for oxaliplatin, 110 mg/m(2) for irinotecan, 1750 mg/m(2) for 5FU and 500 mg/m(2) for LV. Grade 3 or 4 diarrhea and grade 3 nausea/vomiting were the dose-limiting events. Diarrhea was the most common toxicity of the regimen, occurring in 12 (42.8%) patients. Hematological toxicity was mild and there were no treatment- related deaths. CONCLUSION: This weekly regimen showed a favorable toxicity profile and merits further investigation in patients with advanced/metastatic tumors of the GI tract.

Irinotecan plus weekly 5-fluorouracil and leucovorin as salvage treatment for patients with metastatic colorectal cancer: a phase II trial.

BACKGROUND: A phase II study was conducted to evaluate the toxicity and efficacy of irinotecan/5-fluorouracil/leucovorin (CPT-11/5-FU/LV (AIO schedule)) as salvage treatment in patients with metastatic colorectal cancer. PATIENTS AND METHODS: 33 patients relapsing after oxaliplatin (L-OHP)-based first-line chemotherapy were enrolled. Their median age was 69 years, 20 (61%) patients were male, and performance status (WHO) was 0, 1, and 2 in 15, 16 and 2 patients respectively; prior surgery 20 (61%) patients; adjuvant chemotherapy 11 (33%) patients, and adjuvant radiotherapy 6 (18%) patients. The number of metastatic sites was 1, 2, and > or =3 in 11, 11, and 11 patients, respectively. CPT-11 was administered on day 1 at the dose of 80 mg/m(2) in 30-90 min infusion and LV (500 mg/m(2)) on the same day as a 2-hour infusion followed by 5-FU (2,600 mg/m(2)/day) as a 22-hour infusion on day 1 for 6 subsequent weeks. The regimen was repeated every 7 weeks. RESULTS: All patients were evaluable for toxicity and for response. Complete response was achieved in 2 patients (6%) and partial response in 4 patients (12%) (RR 18%, CI 5.95-35.43%); 13 patients (40%) had stable disease, and 14 (42%) progressive disease. After a median follow-up period of 9 months, the median duration of response was 5 months, the median time to progression 7.5 months, and OS 14 months. Grade 3-4 neutropenia occurred in 13 patients (39%), febrile neutropenia in 3 (9%), grade 2 anemia in 11 (33%), grade 4 thrombocytopenia in 1 (3%). Grade 3-4 diarrhea occurred in 12 patients (36%), grade 3-4 neurotoxicity in 3 (9%), and grade 3 asthenia in 4 (12%). No treatment-related deaths occurred. The median dose intensity was 85% for CPT-11, and 88% for 5-FU and LV. CONCLUSIONS: The combination of weekly CPT-11 and infusional 5-FU/LV is an active and relatively well-tolerated regimen as salvage treatment in MCC.

Sequential administration of docetaxel followed by maintenance gefitinib, as salvage treatment in patients with advanced NSCLC: a multicenter phase II trial.

PURPOSE: To evaluate the activity and toxicity of the sequential administration of docetaxel followed by gefitinib in patients with advanced non-small cell lung cancer (NSCLC). PATIENTS AND TREATMENT: Forty-one patients pre-treated with at least one prior chemotherapy regimen (platinum- or taxane-based) for advanced/metastatic NSCLC received three cycles of docetaxel 30 mg/m2, administered as a 1-h IV infusion, on days 1, 8 and 15 of each 4-week cycle followed by gefitinib 250 mg daily po. Gefitinib treatment was continued until disease progression, development of unacceptable toxicity, or withdrawal of patients consent. RESULTS: Two (4.9%) patients achieved a partial response and 10 (24.4%) stable disease, for a disease control rate of 29.3% (95% CI: 15.3%-43.2%) while on weekly docetaxel treatment. Additionally, progressive disease (PD) was observed in 29 (70.7%). No objective responses were observed during the gefitinib maintenance therapy; however, 17 (41.5%) patients presented stable disease maintained for more than 2 months. Median time to progression was 3.0 months (range: 1-38.3 months; 95% CI: 2.4-3.6); median overall survival 6.9 months (range: 1.2-40.2 months; 95% CI: 5.34-8.52) while the 1-year survival was 28.8%. Therapy was generally well tolerated with diarrhea and rash being the most frequent toxicities. CONCLUSIONS: The sequential administration of docetaxel and gefitinib was well tolerated and moderately active against advanced pre-treated NSCLC.

Phase II trial of capecitabine and oxaliplatin (CAPOX) plus cetuximab in patients with metastatic colorectal cancer who progressed after oxaliplatin-based chemotherapy.

BACKGROUND: Cetuximab is an IgG1 monoclonal antibody targeting the epidermal growth factor receptor and is able to reverse the resistance to irinotecan in patients with metastatic colorectal cancer (mCRC). This phase II trial evaluates the safety and efficacy of cetuximab combined with capecitabine and oxaliplatin (CAPOX) in the treatment of patients with mCRC progressing under oxaliplatin-based chemotherapy. PATIENTS AND TREATMENT: Forty patients with mCRC were treated with cetuximab (loading dose 400 mg/m(2) and then 250 mg/m(2) i.v. weekly) in combination with CAPOX (d(1): L-OHP 85 mg/m(2) and d(1-7) capecitabine 2000 mg/m(2) every 2 weeks). Thirty-one (77.5%) and nine (22.5%) patients had oxaliplatin-refractory and -resistant disease, respectively; in addition, 32 (80%) patients had also progressed on prior irinotecan-based chemotherapy. RESULTS: One hundred and thirty-four cycles were administered (median of four cycles per patient). Main toxic effects included grade 3-4 neutropenia (12.5%), grade 3/4 diarrhea (7.5%), grade 3 fatigue (2.5%), and grade 2-3 neurotoxicity (22.5%). One (2.5%) complete and seven (17.5%) partial responses were achieved [overall objective response rate (ORR): 20%; 95% confidence interval (CI): 9% to 32%)], whereas 11 (27.5%) patients had stable disease [disease control rate (DCR): 47.5%; 95% CI: 30.2% to 64.5%]. The ORR and DCR were 18.7% and 46.8%, respectively, in patients with oxaliplatin-refractory disease. The median time to tumor progression was 3 months, the median survival 10.7 months and the probability of 1-year survival rate 53.4%. CONCLUSIONS: The combination of cetuximab plus CAPOX is safe and has a promising activity in patients with mCRC refractory or resistant to oxaliplatin.