Upfront primary tumour resection and survival in synchronous metastatic colorectal cancer according to primary tumour location and RAS status: Pooled analysis of the Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD).

INTRODUCTION: Retrospective studies and meta-analyses suggest that upfront primary tumour resection (UPTR) confers a survival benefit in patients with asymptomatic unresectable metastatic colorectal cancer (mCRC) undergoing chemotherapy, however a consensus of its role in routine clinical practice in the current era of targeted therapies is lacking. This retrospective study aimed to analyse the survival benefit of UPTR in terms of tumour location and mutational status, in patients with synchronous mCRC receiving chemotherapy and targeted therapy. PATIENTS AND METHODS: Survival was analysed in a pooled cohort of synchronous mCRC patients treated with a first-line anti-VEGF or anti-EGFR inhibitor in seven trials of the Spanish TTD group, according to UPTR, tumour-sidedness and mutational profiling. RESULTS: Of 1334 eligible patients, 642 (48%) had undergone UPTR. UPTR was associated with significantly longer overall survival (OS; 25.0 vs 20.3 months; HR 1.30, 95%CI 1.15-1.48; p < 0.0001). UPTR was associated with significant OS benefit in both left-sided (HR 1.38, 95%CI 1.13-1.69; p = 0.002) and right-sided (HR 1.39, 95%CI 1.00-1.94; p = 0.049) tumours, RASwt (HR 1.29, 95%CI 1.05-1.60; p = 0.016) and BRAFwt (HR 1.49, 95%CI 1.21-1.84; p = 0.0002) tumours, and treatment with anti-EGFRs (HR 1.47, 95%CI 1.13-1.92; p = 0.004) and anti-VEGFs (HR 1.25, 95%CI 1.08-1.44; p = 0.003). Multivariate analysis identified number of metastatic sites, RAS status, primary tumour location and UPTR as independent prognostic factors for OS. CONCLUSION: Considering the selection bias inherent to this study, our results support UPTR before first-line anti-EGFR or anti-VEGF targeted therapy in right and left-sided asymptomatic unresectable synchronous mCRC patients. RAS/BRAF mutational status may also influence UPTR function.

First-Line Biological Agents Plus Chemotherapy in Older Patients with Metastatic Colorectal Cancer: A Retrospective Pooled Analysis.

BACKGROUND: Biologicals, in combination with chemotherapy, are recommended as first-line treatment of metastatic colorectal cancer (mCRC); however, evidence guiding the appropriate management of older patients with mCRC is limited. OBJECTIVE: This study was undertaken to compare the efficacy and safety outcomes in older versus younger patients with mCRC who received first-line biological therapy. METHODS: This retrospective analysis used pooled data from five trials undertaken by the Spanish Cooperative Group for the Treatment of Digestive Tumours. All were studies of adults with advanced CRC who received first-line treatment with chemotherapy plus bevacizumab, cetuximab or panitumumab, stratified by age (≥ 65 vs. < 65 years). Endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and safety. RESULTS: In total, 999 patients from five studies were included in the analysis: 480 (48%) were aged ≥ 65 years, and 519 (52%) were aged < 65 years. Median PFS did not differ significantly between patients aged ≥ 65 and < 65 years (9.9 vs. 9.4 months; hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.88-1.17). Median OS was significantly shorter in older than in younger patients (21.3 vs. 25.0 months; HR 1.21; 95% CI 1.04-1.41). There was no significant difference between older and younger patients in ORR (59 vs. 62%). Patients aged ≥ 65 years experienced significantly more treatment-related grade 3 or higher adverse events (61.67%) than did patients aged < 65 years (45.86%). CONCLUSIONS: Biologicals plus chemotherapy is an effective first-line treatment option for selected patients aged ≥ 65 years with mCRC and has a manageable safety profile and efficacy comparable to that observed in younger patients.

New insights of tricuspid regurgitation: a large-scale prospective cohort study.

AIMS: To evaluate the burden of tricuspid regurgitation (TR) in a large cohort, determine the right ventricle involvement of patients with TR and determine the characteristics of isolated TR. METHODS AND RESULTS: Prospective study where consecutive patients undergoing an echocardiographic study in 10 centres were included. All studies with significant TR (at least moderate) were selected. We considered that patients with one of pulmonary systolic hypertension >50 mmHg, left ventricular ejection fraction <35%, New York Heart Association III-IV, or older than 85 years, had a high surgical risk. A total of 35 088 echocardiograms were performed. Significant TR was detected in 6% of studies. Moderate TR was found in 69.6%, severe in 25.5%, massive in 3.9%, and torrential in 1.0% of patients. Right ventricle was dilated in 81.7% of patients with massive/torrential TR, in 55.9% with severe TR, and in 29.3% with moderate TR (P < 0.001). Primary TR was present in 7.4% of patients whereas secondary TR was present in 92.6%. Mitral or aortic valve disease was the most common aetiology (54.6%), following by isolated TR (16%). Up to 51.9% of patients with severe, massive, or torrential primary TR and 57% of patients with severe, massive, or torrential secondary TR had a high surgical risk. CONCLUSION: Significant TR is a prevalent condition and a high proportion of these patients have an indication for valve intervention. More than a half of patients with severe, massive, or torrential TR had a high surgical risk. Massive/torrential TR may have implications regarding selection and monitoring patients for percutaneous treatment.

FOLFOXIRI plus bevacizumab versus FOLFOX plus bevacizumab for patients with metastatic colorectal cancer and ≥3 circulating tumour cells: the randomised phase III VISNÚ-1 trial.

PURPOSE: 5-Fluorouracil/leucovorin, oxaliplatin, irinotecan (FOLFOXIRI) plus bevacizumab is more effective than doublets plus bevacizumab as first-line therapy for metastatic colorectal cancer, but is not widely used because of concerns about toxicity and lack of predictive biomarkers. This study was designed to explore the role of circulating tumour cell (CTC) count as a biomarker to select patients for therapy with FOLFOXIRI-bevacizumab. PATIENTS AND METHODS: VISNÚ-1 was a multicentre, open-label, randomised, phase III study in patients with previously untreated, unresectable, metastatic colorectal carcinoma and ≥3 CTC/7.5 mL blood. Patients received bevacizumab 5 mg/kg plus FOLFOXIRI (irinotecan 165 mg/m2, oxaliplatin 85 mg/m2, leucovorin 400 mg/m2 and 5-fluorouracil 3200 mg/m2) or FOLFOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil 400 mg/m2 then 2400 mg/m2) by intravenous administration every 2 weeks. The primary outcome was progression-free survival (PFS). RESULTS: The intention-to-treat population comprised 349 patients (FOLFOXIRI-bevacizumab, n=172; FOLFOX-bevacizumab, n=177). Median PFS was 12.4 months (95% CI 11.2 to 14.0) with FOLFOXIRI bevacizumab and 9.3 months (95% CI 8.5 to 10.7) with FOLFOX-bevacizumab (stratified HR, 0.64; 95% CI 0.49 to 0.82; p=0.0006). Grade≥3 adverse events were more common with FOLFOXIRI-bevacizumab 85.3% vs 75.1% with FOLFOX-bevacizumab (p=0.0178). Treatment-related deaths occurred in 8 (4.7%) and 6 (3.4%) patients, respectively. CONCLUSIONS: First-line FOLFOXIRI-bevacizumab significantly improved PFS compared with FOLFOX-bevacizumab in patients with metastatic colorectal cancer and ≥3 CTCs at baseline, which indicate a poor prognosis. CTC count may be a useful non-invasive biomarker to assist with the selection of patients for intensive first-line therapy.

Phase I/II trial of sequential treatment of nab-paclitaxel in combination with gemcitabine followed by modified FOLFOX chemotherapy in patients with untreated metastatic exocrine pancreatic cancer: Phase I results.

BACKGROUND: Although occasioned through different mechanisms, the potential neurotoxicity and also haematological toxicity of nab-paclitaxel and oxaliplatin-based chemotherapy regimen were studied in this trial, which aimed to determine the maximum-tolerated dose (MTD) and to evaluate safety and efficacy of the combination in a sequential regimen of nab-paclitaxel, gemcitabine (GEM) and modified FOLFOX (mFOLFOX) in untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: Treatment consisted of nab-paclitaxel (125/100 mg/m2) plus GEM (1000/800 mg/m2) on days 1, 8 and 15, followed by mFOLFOX (oxaliplatin [85/75/65 mg/m2], 5-FU bolus [400/300/200 mg/m2], 5-FU infusion [2400/2000/1600 mg/m2]) on day 28, of a 42-day cycle. Patients were enrolled at the highest dose level with a subsequent 3 + 3 dose de-escalation plan. RESULTS: Eleven patients (median age = 61, 64% with performance status [PS] = 1) were eligible. All patients received the highest dose level. No de-escalation was needed. A dose-limiting toxicity was reported, an upper gastrointestinal haemorrhage. The MTD was nab-paclitaxel 125 mg/m2, GEM 1000 mg/m2, oxaliplatin 85 mg/m2, 5-FU bolus 400 mg/m2 and 5-FU infusion 2400 mg/m2. Common all-grade toxicities were neutropenia (73%), anaemia (55%), thrombocytopenia (55%) and asthenia (55%). Other relevant toxicities were paraesthesia (46%), nausea (36%), dysesthesia (27%) and pyrexia (27%). Objective response rate was 50% and disease control rate was 80%. CONCLUSIONS: The regimen of nab-paclitaxel plus GEM followed by mFOLFOX showed favourable safety and tolerability profiles with significant anti-tumor activity. More data are being achieved in a randomised phase II trial, to confirm efficacy rates and dismiss long-term neurotoxicity concerns regarding the sequencing of nab-paclitaxel and oxaliplatin.

Correlation of RECIST, Computed Tomography Morphological Response, and Pathological Regression in Hepatic Metastasis Secondary to Colorectal Cancer: The AVAMET Study.

Background: The prospective phase IV AVAMET study was undertaken to correlate response evaluation criteria in solid tumors (RECIST)-defined response rates with computed tomography-based morphological criteria (CTMC) and pathological response after liver resection of colorectal cancer metastases. Methods: Eligible patients were aged ≥18 years, with Eastern Cooperative Oncology Group (ECOG) performance status 0/1 and histologically-confirmed colon or rectal adenocarcinoma with measurable liver metastases. Preoperative treatment was bevacizumab (7.5 mg on day 1) + XELOX (oxaliplatin 130 mg/m2, capecitabine 1000 mg/m2 bid on days 1-14 q3w). After three cycles, response was evaluated by a multidisciplinary team. Patients who were progression-free and metastasectomy candidates received one cycle of XELOX before undergoing surgery 3-5 weeks later, followed by four cycles of bevacizumab + XELOX. Results: A total of 83 patients entered the study; 68 were eligible for RECIST, 67 for CTMC, and 51 for pathological response evaluation. Of these patients, 49% had a complete or partial RECIST response, 91% had an optimal or incomplete CTMC response, and 81% had a complete or major pathological response. CTMC response predicted 37 of 41 pathological responses versus 23 of 41 responses predicted using RECIST (p = 0.008). Kappa coefficients indicated a lack of correlation between the results of RECIST and morphological responses and between morphological and pathological response rates. Conclusion: CTMC may represent a better marker of pathological response to bevacizumab + XELOX than RECIST in patients with potentially-resectable CRC liver metastases.

Association Between Baseline Circulating Tumor Cells, Molecular Tumor Profiling, and Clinical Characteristics in a Large Cohort of Chemo-naïve Metastatic Colorectal Cancer Patients Prospectively Collected.

BACKGROUND: Clinicopathologic characteristics and prognostic and predictive factors offer valuable guidance when selecting optimal first-line treatment in patients with metastatic colorectal cancer (CRC). The association between baseline circulating tumor cell (bCTC) count, molecular tumor profile, and clinicopathologic features was analyzed in a chemo-naïve metastatic CRC population. PATIENTS AND METHODS: A total of 1202 patients from the Spanish VISNÚ-1 (FOLFIRINOX/bevacizumab vs. FOLFOX/bevacizumab) and VISNÚ-2 (FOLFIRI/bevacizumab vs. FOLFIRI/cetuximab; RAS-wildtype) studies were analyzed for mutational status and bCTC count. The association between clinicopathologic characteristics and bCTC count, mutational status, and microsatellite instability (MSI) was analyzed in 589 eligible patients. RESULTS: Interestingly, 41% of the population studied presented ≥3 bCTC count. bCTC count ≥3 was associated with worse performance status (according Eastern Cooperative Oncology Group scale), stage IV at diagnosis, at least 3 metastatic sites, and elevated carcinoembryonic antigen (CEA) levels; but not with RAS or BRAF mutations or high MSI. BRAFmut (BRAF mutated) tumors were associated with right-sided primary tumors, peritoneum, distant lymph node metastasis, and less frequent liver involvement. RASmut (RAS mutated) was associated with worse performance status; stage IV at diagnosis; right-sided primary tumors; liver, lung, and bone metastases; at least 3 metastatic sites; and elevated CEA, whereas PIK3CAmut (PIK3CA mutated) tumors were associated with right-sided primary tumors, high CEA serum levels, and older age. High MSI was associated with right-sided primary tumors, distant lymph nodes metastasis, and lower CEA levels. CONCLUSIONS: In our study, elevated bCTCs and RASmut were associated with clinicopathologic features known to be associated with poor prognosis; whereas the poor prognosis of BRAFmut tumors in chemo-naïve metastatic CRC is not explained by associations with poor clinicopathologic prognostic factors, except right-sided primary tumors. TRIAL REGISTRATION NUMBER: VISNU 1 ClinicalTrials.gov ID: NCT01640405/ VISNU 2 ClinicalTrials.gov ID: NCT01640444.

Mid-term outcome of severe tricuspid regurgitation: are there any differences according to mechanism and severity?

AIMS: Patients with significant tricuspid regurgitation (TR) addressed according the new classification in torrential TR may have different prognosis compared with just severe TR patients. We sought to determine distribution and mechanism of consecutive severe TR patients, in accordance with aetiology and severity by applying the new proposed classification scheme and their long-term outcomes. METHODS AND RESULTS: Between January and December 2013, 249 patients with significant TR referred to the cardiac imaging unit (mean age 79.9 ± 10.2 years; 29.8% female) were included. Patients were divided according to aetiology in six groups, and TR severity was reclassified into severe, massive, and torrential TR. The follow-up period was of 313 ± 103 days. When considering cardiovascular mortality, patients in the massive/torrential group showed the highest number of events (P < 0.007). Patients with TR due to pulmonary diseases had the worst prognosis according to different aetiology. Noteworthy, the best predictors for the combined endpoint [cardiovascular mortality and readmission admission for heart failure (HF)] were TR severity according to the new classification [hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.25-4.93] and clinical scores such as New York Heart Association classification and congestive status (HR 1.78, 95% CI 1.28-2.49; HR 2.08, 95% CI 1.06-4.06, respectively). CONCLUSION: Patients with massive/torrential TR and patients with comorbidities, especially pulmonary disease, were identified as populations at higher risk of death and readmission for HF. New classification scheme and clinical assessment may establish who may benefit the most of intensive therapeutic treatments and intervention on the tricuspid valve.

Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry.

BACKGROUND: The choice of chemotherapy in HER2-negative gastric cancer is based on centre's preferences and adverse effects profile. No schedule is currently accepted as standard, nor are there any factors to predict response, other than HER2 status. We seek to evaluate whether Lauren type influences the efficacy of various chemotherapies and on patient overall survival (OS). METHODS: We have conducted a multicenter study in 31 hospitals. The eligibility criteria include diagnosis of stomach or gastroesophageal junction adenocarcinoma, HER2 negativity, and chemotherapy containing 2-3 drugs. Cox proportional hazards regression adjusted for confounding factors, with tests of 'treatment-by-histology' interaction, was used to estimate treatment effect. RESULTS: Our registry contains 1303 tumours analysable for OS end points and 730 evaluable for overall response rate (ORR). A decrease in ORR was detected in the presence of a diffuse component: odds ratio 0.719 (95% confidence interval (CI), 0.525-0.987), P=0.039. Anthracycline- or docetaxel-containing schedules increased ORR only in the intestinal type. The diffuse type displayed increased mortality with hazard ratio (HR) of 1.201 (95% CI, 1.054-1.368), P=0.0056. Patients receiving chemotherapy with docetaxel exhibited increased OS limited to the intestinal type: HR 0.65 (95% CI, 0.49-0.87), P=0.024, with no increment in OS for the subset having a diffuse component. With respect to progression-free survival (PFS), a significant interaction was seen in the effect of docetaxel-containing schedules, with better PFS limited to the intestinal type subgroup, in the comparison against any other schedule: HR 0.65 (95% CI, 0.50-0.85), P=0.015, and against anthracycline-based regimens: HR 0.64 (95% CI, 0.46-0.88), P=0.046. CONCLUSIONS: As a conclusion, in this registry, Lauren classification tumour subtypes predicted survival and responded differently to chemotherapy. Future clinical trials should stratify effect estimations based on histology.

Recommendations for SIR-Spheres Y-90 resin microspheres in chemotherapy-refractory/intolerant colorectal liver metastases.

A Spanish expert panel reviewed current evidence for the use of SIR-Spheres Y-90 resin microspheres in patients with chemotherapy refractory/intolerant unresectable colorectal liver metastases. Substantial evidence for its efficacy and safety is available from a randomized controlled study, retrospective comparative studies and several single arm studies. Clinical evidence data obtained from more than 1500 patients have led to the inclusion of selective internal radiation therapy in the 2016 ESMO Clinical Guidelines as third-line treatment. This publication results from an expert panel meeting, where published evidence and author's experiences were shared to position SIR-Spheres Y-90 resin microspheres in Spain for the treatment of chemotherapy refractory/intolerant unresectable colorectal liver metastases, and second, to define the patient subgroup that will benefit the most with this treatment.

Optimization of RAS/BRAF Mutational Analysis Confirms Improvement in Patient Selection for Clinical Benefit to Anti-EGFR Treatment in Metastatic Colorectal Cancer.

In metastatic colorectal cancer (mCRC), recent studies have shown the importance to accurately quantify low-abundance mutations of the RAS pathway because anti-EGFR therapy may depend on certain mutation thresholds. We aimed to evaluate the added predictive value of an extended RAS panel testing using two commercial assays and a highly sensitive and quantitative digital PCR (dPCR). Tumor samples from 583 mCRC patients treated with anti-EGFR- (n = 255) or bevacizumab- (n = 328) based therapies from several clinical trials and retrospective series from the TTD/RTICC Spanish network were analyzed by cobas, therascreen, and dPCR. We evaluated concordance between techniques using the Cohen kappa index. Response rate, progression-free survival (PFS), and overall survival (OS) were correlated to the mutational status and the mutant allele fraction (MAF). Concordance between techniques was high when analyzing RAS and BRAF (Cohen kappa index around 0.75). We observed an inverse correlation between MAF and response in the anti-EGFR cohort (P < 0.001). Likelihood ratio analysis showed that a fraction of 1% or higher of any mutated alleles offered the best predictive value. PFS and OS were significantly longer in RAS/BRAF wild-type patients, independently of the technique. However, the predictability of both PFS and OS were higher when we considered a threshold of 1% in the RAS scenario (HR = 1.53; CI 95%, 1.12-2.09 for PFS, and HR = 1.9; CI 95%, 1.33-2.72 for OS). Although the rate of mutations observed among techniques is different, RAS and BRAF mutational analysis improved prediction of response to anti-EGFR therapy. Additionally, dPCR with a threshold of 1% outperformed the other platforms. Mol Cancer Ther; 16(9); 1999-2007. ©2017 AACR.

Bevacizumab and temozolomide versus temozolomide alone as neoadjuvant treatment in unresected glioblastoma: the GENOM 009 randomized phase II trial.

We sought to determine the impact of bevacizumab on reduction of tumor size prior to chemoradiotherapy in unresected glioblastoma patients. Patients were randomized 1:1 to receive temozolomide (TMZ arm) or temozolomide plus bevacizumab (TMZ + BEV arm). In both arms, neoadjuvant treatment was temozolomide (85 mg/m(2), days 1-21, two 28-day cycles), concurrent radiation plus temozolomide, and six cycles of adjuvant temozolomide. In the TMZ + BEV arm, bevacizumab (10 mg/kg) was added on days 1 and 15 of each neoadjuvant cycle and on days 1, 15 and 30 of concurrent treatment. The primary endpoint was investigator-assessed response to neoadjuvant treatment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and the impact on outcome of MGMT methylation in tumor and serum. One hundred and two patients were included; 43 in the TMZ arm and 44 in the TMZ + BEV arm were evaluable for response. Results favored the TMZ + BEV arm in terms of objective response (3 [6.7 %] vs. 11 [22.9 %]; odds ratio 4.2; P = 0.04). PFS and OS were longer in the TMZ + BEV arm, though the difference did not reach statistical significance. MGMT methylation in tumor, but not in serum, was associated with outcome. More patients experienced toxicities in the TMZ + BEV than in the TMZ arm (P = 0.06). The combination of bevacizumab plus temozolomide is more active than temozolomide alone and may well confer benefit in terms of tumor shrinkage in unresected patients albeit at the expense of greater toxicity.

Challenges in first line chemotherapy and targeted therapy in advanced gastric cancer.

Chemotherapy prolongs survival in advanced gastric cancer (AGC). The challenges involved in this procedure are providing a framework to aid in determining the best single or combined chemotherapy protocols for targeted agents in front-line therapy for patients in a clinical setting. A review of Phase II-III studies published or referenced in major oncology congress publications from 1970 to 2013 was performed. Cisplatin and fluoropyrimidine remain the reference regimen. Fluoropyrimidine combined with oxaliplatin or irinotecan may also be employed in special situations. There are no comparative studies of the same regimens with or without anthacyclines; thus, the effectiveness of anthacyclines remains under debate. The introduction of trastuzumab in the front-line therapy of HER2-positive patients and ramucirumab in refractory patients ushered in an age of targeted therapy for this disease.

Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial.

BACKGROUND: Bevacizumab plus fluoropyrimidine-based chemotherapy is standard treatment for first-line and bevacizumab-naive second-line metastatic colorectal cancer. We assessed continued use of bevacizumab plus standard second-line chemotherapy in patients with metastatic colorectal cancer progressing after standard first-line bevacizumab-based treatment. METHODS: In an open-label, phase 3 study in 220 centres in Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, the Netherlands, Norway, Portugal, Saudi Arabia, Spain, Sweden, and Switzerland, patients (aged ≥18 years) with unresectable, histologically confirmed metastatic colorectal cancer progressing up to 3 months after discontinuing first-line bevacizumab plus chemotherapy were randomly assigned in a 1:1 ratio to second-line chemotherapy with or without bevacizumab 2·5 mg/kg per week equivalent (either 5 mg/kg every 2 weeks or 7·5 mg/kg every 3 weeks, intravenously). The choice between oxaliplatin-based or irinotecan-based second-line chemotherapy depended on the first-line regimen (switch of chemotherapy). A combination of a permuted block design and the Pocock and Simon minimisation algorithm was used for the randomisation. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00700102. FINDINGS: Between Feb 1, 2006, and June 9, 2010, 409 (50%) patients were assigned to bevacizumab plus chemotherapy and 411 (50%) to chemotherapy alone. Median follow-up was 11·1 months (IQR 6·4-15·6) in the bevacizumab plus chemotherapy group and 9·6 months (5·4-13·9) in the chemotherapy alone group. Median overall survival was 11·2 months (95% CI 10·4-12·2) for bevacizumab plus chemotherapy and 9·8 months (8·9-10·7) for chemotherapy alone (hazard ratio 0·81, 95% CI 0·69-0·94; unstratified log-rank test p=0·0062). Grade 3-5 bleeding or haemorrhage (eight [2%] vs one [<1%]), gastrointestinal perforation (seven [2%] vs three [<1%]), and venous thromboembolisms (19 [5%] vs 12 [3%]) were more common in the bevacizumab plus chemotherapy group than in the chemotherapy alone group. The most frequently reported grade 3-5 adverse events were neutropenia (65 [16%] in the bevacizumab and chemotherapy group vs 52 [13%] in the chemotherapy alone group), diarrhoea (40 [10%] vs 34 [8%], respectively), and asthenia (23 [6%] vs 17 [4%], respectively). Treatment-related deaths were reported for four patients in the bevacizumab plus chemotherapy group and three in the chemotherapy alone group. INTERPRETATION: Maintenance of VEGF inhibition with bevacizumab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients with metastatic colorectal cancer. This approach is also being investigated in other tumour types, including metastatic breast and non-small cell lung cancers. FUNDING: F Hoffmann-La Roche.

A randomized phase II study of raltitrexed and gefitinib versus raltitrexed alone as second line chemotherapy in patients with colorectal cancer. (1839IL/0143).

PURPOSE: To determine the efficacy of the addition of gefitinib to raltitrexed in patients with colorectal cancer (CRC) that have progressed after first line chemotherapy. The study also sought to explore the safety of the combination and to investigate biomarkers predictive outcome. METHODS: A total of 76 patients were randomized to raltitrexed (3 mg/m(2) i.v.) every 21 days plus either daily gefitinib (250 mg p.o.) or placebo. The primary endpoint of the study was progression free survival (PFS). Tumor tissues were collected to determine the expression of EGFR, pEGFR, pMAPK, and pAkt. RESULTS: Both groups were well balanced with regard to prognostic factors. Treatment was well tolerated with no increased in toxicity except diarrhea and skin rash in the combination group. There were no differences in PFS between the combination arm [63 days (95% CI: 57-84)] compared to the raltitrexed alone arm [72 days (95% CI: 59-132)], or overall survival 361 days (95% CI: 283-533 days) versus 291 days (95% CI: 255-539 days) respectively. The objective response rate was 7.9% (3 patients) (CI 95%: 1,66-21,38) versus 5.3% (2 patients) (CI 0,64-17,75), respectively. The biomarker studies were not conclusive. CONCLUSION: The combination of raltitrexed and gefitinib was well tolerated although was not associated with improved progression free survival in patients with refractory CRC.

Activity of topotecan given intravenously for 5 days every three weeks in patients with advanced non-small cell lung cancer pretreated with platinum and taxanes: a phase II study.

Topotecan, a semi-synthetic camptothecin analogue with topoisomerase I interaction, has shown to be an active agent in the treatment of advanced refractory lung cancer. This paper describes the authors' experience with this drug when used as a single agent in patients (pts) with advanced non-small cell lung cancer (NSCLC) refractory to platinum- and taxane-containing chemotherapy regimens. Thirty-five patients with NSCLC refractory to previous chemotherapy and KI ≥ 60% were included in the study. Their characteristics are as follows: median age of 52 years (range 43-69) and Karnofsky PS of 70 (60-80); 27 were male and 8 were female. Twenty-one (60%) patients had adenocarcinoma; eleven (31.4%), squamous cell, and three (8.5%), undifferentiated carcinoma. There was a median of two disease sites and two prior chemotherapy regimens. Topotecan was administered at a dose of 1.25 mg/m(2) I.V. daily for 5 days, repeated every 21 days until disease progression, maximal response, or intolerable toxicity. After 73 cycles, patients received a median of 2 treatment cycles (1-9). All patients except one were considered evaluable for toxicity; eight episodes (24%) of nausea/vomiting and two episodes (6%) of grade 1-2 asthenia, respectively, were reported. Four (12%) patients developed grade 1-2 anemia and two (6%) subjects suffered grade 3 anemia. Seven (21%) patients had grade 1-2 neutropenia and one (3%) presented grade 5 neutropenia. In 33 patients evaluable for activity of the 35 subjects included in the study; one (2.8%) presented a partial response; nine (25.7%) had stable disease, and 23 (65.7%) exhibited disease progression. Median time to progression and overall survival were 54 (12-210) and 70 (12-324) days, respectively. Intravenous topotecan at that dose and administration schedule displays scant activity in terms of response rate in individuals with advanced NSCLC previously treated with platinum and taxanes. The role and usefulness of chemotherapy in this setting warrants further investigation and confirmation through comparative studies.

Impact of the incorporation of tyrosine kinase inhibitor agents on the treatment of patients with a diagnosis of advanced renal cell carcinoma: study based on experience at the Hospital Universitario Central de Asturias.

INTRODUCTION: For nearly the past two decades, cytokines (CKs) have been the only systemic treatment option available for advanced renal cell carcinoma (RCC). In recent years, tyrosine kinase inhibitors (TKIs) have demonstrated clinical activity on this tumour. Our purpose is to describe one centre's experience with the use of CKs and TKIs in the treatment of patients with advanced RCC. MATERIALS AND METHODS: This study was designed as a retrospective chart review of RCC patients who were treated with CKs and/or TKIs in our department between July 1996 and June 2008. Efficacy and toxicity were assessed using World Health Organization (WHO) criteria. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall (OS) survival. RESULTS: Ninety-four patients were classified into three groups depending on the modality of treatment administered: 46 were treated with CKs alone and/or chemotherapy (27 with immunotherapy, one with chemotherapy and 18 with both), 28 with TKIs alone (25 with sunitinib and 13 with sorafenib) and 20 with TKIs in second-line treatment following failure with CKs (17 with sunitinib, eight with sorafenib, four with bevacizumab and one with lapatinib). The median age was 60 years in the CK group and 65 and 62, respectively, in TKI in first and second-line treatment groups. Eighty-five percent of patients treated with CKs and 75% in the TKI group in first-line treatment and 80% in second-line treatment were men. Overall, 89% of patients had favourable risk, and 11% had intermediate risk. All patients were considered evaluable for toxicity. The main grade 3-4 (%) toxicity was asthenia for both groups, (ten in TKIs and 15 in CKs). Other grade 1-2 toxicities were mucositis (39), bleeding (8), hypertension (19), skin toxicity (33) and hypothyroidism (12.5) associated with TKIs; and anaemia (33), cough (29), asthenia (39) and emesis (14) associated with CKs. The objective response rate among 80 patients evaluable for activity was 10.6% with CKs and 46.5% and 35%, respectively, with TKIs in first- and second-line treatments. Disease stabilisation with CKs was recorded at 59% of patients and with TKIs 25% and 50% in first- and second-line treatment groups, respectively. The median progression-free survival (PFS) with CKs was 122 days [95% confidence interval (CI) 82-162] and with TKIs 201 days (65-337) in the first and 346 days (256-436) in second-line treatment groups. The median overall survival (OS) was 229 days (142-316) and 2,074 days (1,152-2,996) for patients treated with CKs and TKIs. CONCLUSIONS: Our results are in line with the activity and survival rates previously reported in the literature regarding the use of TKIs for patients with advanced RCC in first- and second-line treatment, which has demonstrated an acceptable toxicity level.

Combination of docetaxel, epirubicin and vinorelbine administered every 2 weeks as first-line therapy in patients with metastatic breast cancer: a dose-finding study.

AIMS: To assess efficacy and optimum combination dosage of intravenous docetaxel (T), epirubicin (E) and vinorelbine (N) administered every 2 weeks and without colony stimulating factor (CSF) support in patients with metastatic breast cancer (MBC). PATIENTS AND METHOD: Patients (n = 5 1) with MBC were consecutively assigned to four different dose levels (DL) to receive (in mg/m2): Level I = T35 + E30 + N25; Level II = T30 + E30 + N25; Level III = T30 + E25 + N25; and Level IV = T25 + E25 + N25. Consecutive cycles were delayed if absolute neutrophil and/or platelet counts fell below 1.5 x 10(9) and 100 x 10(9) l(-1), respectively. Treatment at a given dose level was suspended if 33% or more of patients included in a given cohort had unacceptable toxicity. RESULTS: The patients evaluable for toxicity (n = 48) received 448 cycles (median 9; range 1-23). There was neutropenia G 3-4 in 30 patients (63%) with fever in 3 (6%). The G 2-3 non-hematological toxicities were alopecia in 39 patients (81%), mucositis in 11 (23%), and nausea/vomiting in 8 (17%). There were no toxic deaths. Treatment delay or dose reduction after first cycle occurred in > or = 30% of patients treated in all DLs, except the fourth. Objective response was achieved in 29 of the 47 evaluable patients (58%; 95% CI: 50-66). The median duration of response, time-to-progression and overall survival were 13, 11 (range 8-14) and 20 (range 16-24) months, respectively. CONCLUSION: The combination of docetaxel, epirubicin and vinorelbine without CSF support ought not to exceed 25 mg/m2 every 2 weeks. The efficacy is no greater than other existing regimens for first-line treatment of MBC.

Phase I/II study of gemcitabine and vinorelbine plus cisplatin in non-small cell lung cancer.

PURPOSE: We determine the maximum tolerated dose (MTD) and efficacy of gemcitabine plus vinorelbine combined with cisplatin in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemo naive patients with stage IIIA to IV non-small cell lung cancer received outpatient administration of gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 intravenously on days 1 and 8 every 21 days. Doses of gemcitabine and vinorelbine were escalated by 250 mg/m2 and 5 mg/m2, respectively, at each dose level. Cisplatin was administered at a fixed dose of 50 mg/m2 on days 2 and 9. After the MTD was reached, the study was continued as a phase II trial. RESULTS: From January 1998 to March 1999, sixty-five patients were enrolled. The first 38 patients participated in the phase I evaluation. After 130 cycles, the dose-limiting toxicities were neutropenia, stomatitis, asthenia, and hepatotoxicity occurring at the third and fourth dose levels (doses of gemcitabine/vinorelbine of 1,500/25 and 1,000/30 mg/m2). For the subsequent phase II evaluation, 27 additional patients, out of a total of 53, receiving the MTD of gemcitabine and vinorelbine (1000-1250/25 mg/m2) followed (24 hours later) by cisplatin 50 mg/m2. Thirty one (58%) of 53 assessable patients responded. Objective response for patients with stages III and IV disease, respectively, were 65% and 47%. The median time to progression and the overall survival time were 9 months (95% CI: 5-12) and 11 months (95% CI: 9-13), respectively. World Health Organization toxicity > or = grade 3 neutropenia was registered in 28 (54%) of 52 assessable patients (2% with febrile neutropenia), and > or = grade 3 thrombocytopenia in 15 (29%) patients (4% with bleeding). Nausea/vomiting (> or = grade 2) and asthenia (moderate to severe) occurred in 24 (46%) and 14 (27%) patients, respectively. CONCLUSION: Gemcitabine 1,000-1,250 mg/m2 plus vinorelbine 25 mg/m2 on days 1 and 8, followed by cisplatin 50 mg/m2 24 hours later, is safe for outpatient administration and active in patients with NSCLC.

Phase I/II study of gemcitabine plus vinorelbine in non-small cell lung cancer.

BACKGROUND: Because gemcitabine and vinorelbine have demonstrated single-agent activity in non-small cell lung cancer (NSCLC), we conducted this phase I/II study to determine the maximum tolerated dose (MTD) and activity of these drugs combined. PATIENTS AND METHODS: Patients with inoperable or advanced NSCLC and no prior chemotherapy were treated with gemcitabine plus vinorelbine on days 1 and 8 every 21 days. The initial doses of gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 were escalated by 250 mg/m2 and 5 mg/m2, respectively, in separate patient cohorts until the MTD was established. RESULTS: In phase I, 32 patients received a total of 115 cycles. Dose-limiting toxicities were neutropenia and hepatotoxicity, occurring at the dose level of 1,500 mg/m2 and 30 mg/m2. Thus, the MTD used for phase II was 1,250 mg/m2 and 30 mg/m2. Of 41 patients in phase II, 16 (39%) achieved objective responses (95% confidence interval [CI] 24% to 54%), with a median time to progression of 4.2 months. Overall survival was 9 months (95% CI 5.7 to 12.7 months) and the 1-year survival rate was 31%. World Health Organization (WHO) > or = grade 3 neutropenia and reversible thrombocytosis occurred in 15% and 65% of patients, respectively. Non-hematologic toxicity was mild at all dose levels. Grades 3 and 4 hepatotoxicity were reported in one patient each. CONCLUSION: The combination of 1,250 mg/m2 gemcitabine and 30 mg/m2 vinorelbine on days 1 and 8 every 21 days is well tolerated and active in patients with NSCLC. These results should be confirmed in comparative studies.