Vassilis Golfinopoulos

Survival and disease-progression benefits with treatment regimens for advanced colorectal cancer: a meta-analysis

BACKGROUNDnMany randomised trials have compared different systemic treatment regimens in patients with advanced colorectal cancer. While survival advances have apparently been achieved, the magnitude of these incremental benefits across diverse regimens is less clear. The aim of our study was to estimate the magnitude of survival and disease progression benefits with the use of different regimens in patients with advanced colorectal cancer.nnnMETHODSnWe systematically reviewed randomised trials comparing systemic treatment regimens in advanced colorectal cancer. Treatment was categorised by use of or no use of fluorouracil-based regimens, irinotecan, oxaliplatin, bevacizumab, and cetuximab. We used multiple-treatment meta-analysis methodology to combine information from direct comparisons (ie, treatments compared within a randomised trial) and indirect comparisons (ie, treatments compared between trials by combining results on how effective they are against a common comparator treatment) of different chemotherapy regimens. The primary endpoint was death and the secondary endpoint was disease progression. Monte Carlo simulations were used to establish which regimen offered the most benefit for these endpoints. We did analyses of all trials and analysed separately trials that studied first-line treatments and non-first-line treatments.nnnFINDINGSn242 trials published in 1967-2007 (N=56 677 patients) involved 137 different chemotherapy regimens. 37 of these trials were eligible for the multiple-treatment meta-analysis, according to our categorisation, including 47 comparisons of data on death (N=13 875 patients) and 48 comparisons of data on disease progression (N=15 158 patients). Compared with fluorouracil plus leucovorin alone, the risk of death was most decreased with the addition of irinotecan plus bevacizumab (hazard ratio [HR] 0.60, 95% credibility intervals (CrI) 0.44-0.84) and considerable benefits were also noted with addition of irinotecan plus oxaliplatin (HR 0.72 [95% CrI 0.54-0.97]); oxaliplatin plus bevacizumab (HR 0.72 [0.57-0.90]); bevacizumab alone (HR 0.78 [0.60-1.03]); and oxaliplatin alone (HR 0.87 [0.78-0.98]). The disease progression benefits were even more prominent for the addition of irinotecan plus bevacizumab (HR 0.41 [0.28-0.60]); irinotecan plus oxaliplatin (0.53 [0.38-0.73]); oxaliplatin plus bevacizumab (0.46 [0.34-0.61]); bevacizumab alone (0.56 [0.41-0.76]); oxaliplatin alone (0.64 [0.56-0.73]); irinotecan plus cetuximab (HR 0.62 [0.42-0.92]); and irinotecan alone (HR 0.73 [0.65-0.82]). Findings were similar for first-line and non-first-line treatment analyses although data were sparse for non-first-line treatment analyses. Compared with a patient with an anticipated 1-year survival who is treated with fluorouracil and leucovorin, the absolute survival benefit is estimated at 8 months prolongation with addition of irinotecan plus bevacizumab, 4.7 months prolongation with addition of oxaliplatin plus bevacizumab or irinotecan plus oxaliplatin, and 1-1.8 months prolongation with addition of irinotecan alone or oxaliplatin alone.nnnINTERPRETATIONnDistinct incremental benefits are noted for diverse chemotherapy regimens in patients with advanced colorectal cancer, with more prominent effects on disease progression than on death. More data are needed at least for the newest drugs to estimate more accurately the magnitude of the benefit derived from their use.

Comparative survival with diverse chemotherapy regimens for cancer of unknown primary site: Multiple-treatments meta-analysis

OBJECTIVESnTo synthesize the evidence from randomized controlled trials concerning systemic treatment regimens for patients with cancer of unknown primary site (CUP).nnnDATA SOURCESnPubMed and the Cochrane Library Central Registry of Controlled Trials.nnnREVIEW METHODSnWe retrieved all randomized controlled trials comparing at least two arms of different systemic treatment regimens or a systemic regimen to no treatment in patients with CUP, excluding data on favorable subset CUP, whenever these could be separated. Treatments were categorized according to whether they involved platinum, taxane, both, or neither; non-platinum/non-taxane regimens were also categorized in monotherapy and combination regimens. We extracted or estimated the logarithm of the hazard ratio and its variance for death for each randomized comparison. Multiple-treatments meta-analysis with a hierarchical Bayesian model obtained summary hazard ratios with 95% credibility intervals.nnnRESULTSnTen articles were eligible for the meta-analysis. No trials compared systemic treatment to best supportive care and all arms referred to chemotherapy regimens. Overall 683 subjects were randomly assigned and eight randomized comparisons were used for the multiple-treatments meta-analysis of survival (543 patients). Multiple-treatments meta-analysis showed no significant benefit for any treatment group over others, with wide credibility intervals. Point estimates of hazard ratios favored platinum, taxane, or both (hazard ratios 0.69, 0.66, and 0.81, respectively, as compared with monotherapy with an agent other than platinum or taxane).nnnCONCLUSIONnNo type of chemotherapy has been solidly proven to prolong survival in patients with CUP. Regimens using either platinum or taxanes or both need further testing.

Evaluating novel agent effects in multiple treatments meta-regression

Multiple-treatments meta-analyses are increasingly used to evaluate the relative effectiveness of several competing regimens. In some fields which evolve with the continuous introduction of new agents over time, it is possible that in trials comparing older with newer regimens the effectiveness of the latter is exaggerated. Optimism bias, conflicts of interest and other forces may be responsible for this exaggeration, but its magnitude and impact, if any, needs to be formally assessed in each case. Whereas such novelty bias is not identifiable in a pair-wise meta-analysis, it is possible to explore it in a network of trials involving several treatments. To evaluate the hypothesis of novel agent effects and adjust for them, we developed a multiple-treatments meta-regression model fitted within a Bayesian framework. When there are several multiple-treatments meta-analyses for diverse conditions within the same field/specialty with similar agents involved, one may consider either different novel agent effects in each meta-analysis or may consider the effects to be exchangeable across the different conditions and outcomes. As an application, we evaluate the impact of modelling and adjusting for novel agent effects for chemotherapy and other non-hormonal systemic treatments for three malignancies. We present the results and the impact of different model assumptions to the relative ranking of the various regimens in each network. We established that multiple-treatments meta-regression is a good method for examining whether novel agent effects are present and estimation of their magnitude in the three worked examples suggests an exaggeration of the hazard ratio by 6 per cent (2-11 per cent).

Colorectal cancer screening coverage in Greece. PACMeR 02.01 study collaboration

Background and aimsColorectal cancer is a major cause of cancer death in European countries and differences in screening implementation may in part explain USA vs European survival differences. Despite the evidence, no study has evaluated the population colorectal cancer screening (CCS) coverage in any European country. We aimed to index the current CCS practices among a large sample of Greek healthy adults.Materials and methodsThe study was designed as a cross-sectional survey. Screening practice habits of 5,259 healthy adults, aged 50–80, were surveyed. Both overall and screening practices of stool occult blood test (SOBT), digital rectal examination (DRE), and colonoscopy or sigmoidoscopy (COL/SIG) were analyzed.ResultsOf the population analyzed, 90.1% declared that they were interested in cancer prevention activities. Overall SOBT practice rate within the last 2xa0years was 4.77%. When only screening procedures were analyzed, this percentage shrank to 1.73%. Overall and screening COL/SIG rates within the last 10xa0years were 8.76 and 1.74%, respectively. The respective proportions of individuals who underwent DRE were 14.54 and 5.2%. Evidence-based screening practices were influenced by age, family history of colorectal cancer, profession, and educational level; however, SOBT and colonoscopy/sigmoidoscopy did not overcome 4.1 and 4.6% in any subpopulation analyzed.ConclusionThe level of CCS coverage among the examined sample of Greek adults was discouraging. Surveys among other European countries are encouraged.

Colorectal cancer screening awareness among physicians in Greece

BackgroundData comparison between SEER and EUROCARE database provided evidence that colorectal cancer survival in USA is higher than in European countries. Since adjustment for stage at diagnosis markedly reduces the survival differences, a screening bias was hypothesized. Considering the important role of primary care in screening activities, the purpose of the study was to investigate the colorectal cancer screening awareness among Hellenic physicians.Methods211 primary care physicians were surveyed by mean of a self-reported prescription-habits questionnaire. Both physicians colorectal cancer screening behaviors and colorectal cancer screening recommendations during usual check-up visits were analyzed.ResultsOnly 50% of physicians were found to recommend screening for colorectal cancer during usual check-up visits, and only 25% prescribed cost-effective procedures. The percentage of physicians recommending stool occult blood test and sigmoidoscopy was 24% and 4% respectively. Only 48% and 23% of physicians recognized a cancer screening value for stool occult blood test and sigmoidoscopy. Colorectal screening recommendations were statistically lower among physicians aged 30 or less (p = 0.012). No differences were found when gender, level and type of specialization were analyzed, even though specialists in general practice showed a trend for better prescription (p = 0.054).ConclusionContemporary recommendations for colorectal cancer screening are not followed by implementation in primary care setting. Education on presymptomatic control and screening practice monitoring are required if primary care is to make a major impact on colorectal cancer mortality.

Targeting c-KIT, PDGFR in cancer of unknown primary: a screening study for molecular markers of benefit

AimsIn view of available targeted therapies, we investigated the presence of c-kit, PDGFR gene mutations and protein expression in cancer of unknown primary (CUP) in order to study their contribution in pathogenesis, their prognostic value and potential as therapeutic targets.MethodsMutations in hot spots c-kit exon 11 and PDGFR exons 12 and 18 were studied in paraffin-embedded tumour samples from 50 patients with CUP by means of PCR-based single-strand conformational polymorphism and protein expression by means of streptavidin-biotin immunoperoxidase assays. Molecular markers were screened for possible correlations with patient outcome.ResultsNo shifted band was detected in any of the polyacrylamide gel electrophoreses, indicating absence of c-kit exon 11 and PDGFR exon 12, 18 mutations. Immunohistochemical analysis in 37 tumours revealed positive membranous CD117 expression in 30 samples (81%) of which five exhibited strong (+3), four moderate (+2) and 21 weak (+1) staining. PDGFRa protein staining was seen in 15 out of 30 (50%) cases, mostly weak (13) and rarely moderate (1) or strong (1). The expression of KIT or PDGFRa protein did not correlate with the clinical outcome of the patients in our cohort.ConclusionsIn a moderate-sized CUP patient cohort, KIT or PDGFRa protein overexpression is rare, does not have gross prognostic significance for survival and is not associated with presence of activating mutations.

Weekday on-weekend off oral capecitabine: a phase I study of a continuous schedule better simulating protracted fluoropyrimidine therapy

BackgroundAlthough protracted intravenous 5-fluorouracil is superior to bolus regimens in terms of tumour exposure to the drug during DNA synthesis as well as activity and safety, the oral fluoropyrimidine capecitabine is administered intermittently. In this phase I study, we investigated an alternative, dose-intense continuous regimen.Materials and methodsOral capecitabine was administered twice daily continuously with weekend breaks, in patients with advanced solid tumours refractory to standard therapy. Dose escalation proceeded from 1,331 to 2,510xa0mg/m2 daily. Dose limiting toxicity (DLT) consisted of any grade-3 or 4 adverse event except for alopecia and skin toxicity resolving within 7xa0days.ResultsTwenty-five heavily pretreated patients participated in the study. No DLT occurred in the first four cohorts. Two out of four patients developed grade III diarrhoea in the fourth week of capecitabine at 2,510xa0mg/m2 (DLT). The most common toxic episodes during all cycles of treatment were grade 1–2 fatigue, skin erythema, abdominal cramps, nausea, constipation and neutropenia. Disease regression was seen in three and stabilisation with clinical benefit in ten patients (clinical benefit response 54%). Pharmacokinetic studies of capecitabine and metabolites in four patients at 2,250xa0mg/m2 daily showed rapid absorption, short plasma half-lives with the exception of FBAL and absence of accumulation or conversion saturation during the course of therapy. At this dose, administered dose intensity in eight patients was 99.3% of the planned one.ConclusionsWeekday on-weekend off capecitabine maximizes cytotoxic impact on tumour cells during S-phase by safely simulating protracted fluoropyrimidine therapy at a recommended dose (2,250xa0mg/m2) close to that of the intermittent schedule and clearly higher than the continuous one of 1,331xa0mg/m2.

Screening chest radiography: results from a Greek cross-sectional survey

BackgroundPublic health authorities worldwide discourage the use of chest radiography as a screening modality, as the diagnostic performance of chest radiography does not justify its application for screening and may even be harmful, since people with false positive results may experience anxiety and concern. Despite the accumulated evidence, various reports suggest that primary care physicians throughout the world still prescribe chest radiography for screening. We therefore set out to index the use of chest radiography for screening purposes among the healthy adult population and to analyze its relationship with possible trigger factors.MethodsThe study was designed as a cross-sectional survey. Five thousand four hundred and ninety-nine healthy adults, coming from 26 Greek provinces were surveyed for screening practice habits in the nationwide anticancer study. Data were obtained for the use of screening chest radiography. Impact of age, gender, tobacco exposure, family history positive for malignancies and professional-risk for lung diseases was further analyzed.Resultswe found that 20% (n = 1099) of the surveyed individuals underwent chest radiography for screening purposes for at least one time during the previous three years. Among those, 24% do so with a frequency equal or higher than once yearly, and 48% with a frequency equal or higher than every three years. Screening for chest radiography was more commonly adopted among males (OR 1.130, 95% CI 0.988–1.292), pensioners (OR 1.319, CI 1.093–1.593) and individuals with a positive family history for lung cancer (OR 1.251, CI 0.988–1.583). Multivariate analysis confirmed these results.ConclusionDespite formal recommendations, chest radiography for screening purposes was a common practice among the analyzed sample of Greek adults. This practice is of questionable value since the positive predictive value of chest radiography is low. The implementation of even a relatively inexpensive imaging study on a national scale would greatly burden health economics and the workload of radiology departments.

Phase I trial of weekly irinotecan and paclitaxel combined with carboplatin in patients with advanced cancer: a Hellenic Cooperative Oncology Group Study.

This trial aimed to define a recommended safe dose (RSD) of weekly paclitaxel and irinotecan combined with carboplatin in patients with advanced cancer. Patients with advanced cancer were eligible for this trial. Dose-limiting toxicity (DLT) was considered to be any grade greater than or equal to 3 (G≥3) nonhematological toxicity except nausea/vomiting, G4 hematological toxicity of more than 4 days without recombinant human granulocyte colony-stimulating factor support, concurrent diarrhea G≥2 and neutropenia G≥3, and a treatment delay for more than 14 days because of toxicity. Patients were given carboplatin area under the curve (AUC) 5u2009mg*min/ml on day 1 combined with irinotecan and paclitaxel on days 1 and 8, every 3 weeks. The starting dose of both irinotecan and paclitaxel was 50u2009mg/m2 and a toxicity-guided escalation/de-escalation was planned by 10u2009mg/m2 steps. Sixteen patients were enrolled. DLTs occurred in three of the four patients treated at the starting dose level, which defined that dose as the maximum tolerated dose. Accrual continued with irinotecan and paclitaxel doses, which were de-escalated by one step. At this dose level, two of the 12 patients developed DLT, which defined that dose as the RSD. We concluded that the maximum tolerated dose of weekly irinotecan and paclitaxel when given in combination with carboplatin AUC 5u2009mg*min/ml was 50u2009mg/m2 and the RSD 40u2009mg/m2. DLTs were febrile neutropenia, concurrent neutropenia (G3) and diarrhea (G3), and prolonged treatment delay because of toxicity. The most common non-DLT G3/G4 toxicity was leukopenia and neutropenia (18%), and thrombocytopenia and diarrhea (6%). A patient with metastatic endometrial carcinoma treated at the RSD had a compete response of retroperitoneal lymph node metastases, lasting for more than 3 years. Two other patients had their minimal tumor shrinkage documented. Paclitaxel (40u2009mg/m2) and irinotecan (40u2009mg/m2) can safely be administered on days 1 and 8 in combination with carboplatin AUC 5u2009mg*min/ml given on day 1. At the recommended doses this is a well-tolerated regimen with noticeable antitumor activity and warrants further investigation in phase II studies.