p27 and Skp2 immunoreactivity and its clinical significance with endocrine and chemo-endocrine treatments in node-negative early breast cancer.

BACKGROUND: Low p27 and high Skp2 immunoreactivity are associated with a poor prognosis and other poor prognostic features including resistant phenotypes and antiestrogen drug resistance. We investigated these proteins in two International Breast Cancer Study Group trials studying node-negative early breast cancer. PATIENTS AND METHODS: Trial VIII compared chemotherapy followed by goserelin with either modality alone in premenopausal patients. Trial IX compared chemotherapy followed by tamoxifen with tamoxifen alone in postmenopausal patients. Central Pathology Office assessed p27 and Skp2 expression in the primary tumor by immunohistochemistry among 1631 (60%) trial patients. RESULTS: p27 and Skp2 were inversely related; 13% of tumors expressed low p27 and high Skp2. Low p27 and high Skp2 were associated with unfavorable prognostic factors including larger size and higher grade tumors, absence of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 overexpression and high Ki-67 (each P < 0.05). Low p27 and high Skp2 were not associated with disease-free survival (P = 0.42 and P = 0.48, respectively). The relative effects of chemo-endocrine versus endocrine therapy were similar regardless of p27 or Skp2. CONCLUSIONS: We confirm the association of low p27 and high Skp2 with other poor prognostic features, but found no predictive or prognostic value, and therefore do not recommend routine determination of p27 and Skp2 for node-negative breast cancer.

Development of targeted therapies in advanced gastric cancer: promising exploratory steps in a new era.

PURPOSE OF REVIEW: Many chemotherapeutic drugs, including fluoropyrimidines, platinums, CPT-11, taxanes and adriamycin have single-agent activity in advanced gastric cancer. Although combination chemotherapy has been shown to be more effective than single agents, response rates between 30 and 50% have not fulfilled their promise as progression-free survival from the best combinations ranges between 3 and 7 months and overall survival between 8 and 11 months. The development of targeted therapies in gastric cancer clearly stays behind the integration of these novel agents into new treatment concepts for patients with colorectal cancer. This review summarizes the experience and major recent advances in the development of targeted therapies in advanced gastric cancer. RECENT FINDINGS: Recent publications on targeted therapies in gastric cancer are limited to nonrandomized phase I or II trials. The majority of agents tested were angiogenesis inhibitors or agents targeting the epidermal growth factor receptors epidermal growth factor receptor 1 and HER2. SUMMARY: Adequately powered, randomized phase III trials are necessary to define the clinical role of targeted therapies in advanced gastric cancer. Biomarker studies to correlate with treatment outcomes will be critical to identify patients who benefit most from chemotherapy and targeted therapy.

Evaluation of heterogeneity of DNA ploidy in early gastric cancers.

DNA ploidy has been shown to be a predictive parameter for prognosis in various solid tumours. The prognostic value of DNA-ploidy in gastric cancers is still a matter of controversy. A possible explanation for the discrepant results reported in the literature could be sampling error in tumours with multiple stemlines differing in DNA-ploidy. In order to determine whether or not such heterogeneity exists in early gastric carcinoma, we have performed DNA cytophotometry on multiple samples of a group of 17 early gastric carcinomas, of which 8 were pure intramucosal and 9 were infiltrating into the submucosa. We found an aneuploid DNA-stemline in 8 (47%) early gastric cancers, more often in tumours invading into the submucosa (5/9) than in purely mucosal tumours (3/8). Multiple DNA-stemlines were found more frequently in submucosally infiltrating tumours (4/5). These results confirm the presence of DNA-aneuploid early gastric carcinoma which are frequently heterogeneous and suggest that heterogeneity occurs more frequently in tumours invading the submucosa. This heterogeneity is best detected by analysing multiple samples of tumours for DNA-ploidy.

Worldwide trends in gastric cancer mortality (1980-2011), with predictions to 2015, and incidence by subtype.

Gastric cancer incidence and mortality decreased substantially over the last decades in most countries worldwide, with differences in the trends and distribution of the main topographies across regions. To monitor recent mortality trends (1980-2011) and to compute short-term predictions (2015) of gastric cancer mortality in selected countries worldwide, we analysed mortality data provided by the World Health Organization. We also analysed incidence of cardia and non-cardia cancers using data from Cancer Incidence in Five Continents (2003-2007). The joinpoint regression over the most recent calendar periods gave estimated annual percent changes (EAPC) around -3% for the European Union (EU) and major European countries, as well as in Japan and Korea, and around -2% in North America and major Latin American countries. In the United States of America (USA), EU and other major countries worldwide, the EAPC, however, were lower than in previous years. The predictions for 2015 show that a levelling off of rates is expected in the USA and a few other countries. The relative contribution of cardia and non-cardia gastric cancers to the overall number of cases varies widely, with a generally higher proportion of cardia cancers in countries with lower gastric cancer incidence and mortality rates (e.g. the USA, Canada and Denmark). Despite the favourable mortality trends worldwide, in some countries the declines are becoming less marked. There still is the need to control Helicobacter pylori infection and other risk factors, as well as to improve diagnosis and management, to further reduce the burden of gastric cancer.

Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial.

BACKGROUND: To compare the incidence and timing of bone fractures in postmenopausal women treated with 5 years of adjuvant tamoxifen or letrozole for endocrine-responsive early breast cancer in the Breast International Group (BIG) 1-98 trial. METHODS: We evaluated 4895 patients allocated to 5 years of letrozole or tamoxifen in the BIG 1-98 trial who received at least some study medication (median follow-up 60.3 months). Bone fracture information (grade, cause, site) was collected every 6 months during trial treatment. RESULTS: The incidence of bone fractures was higher among patients treated with letrozole [228 of 2448 women (9.3%)] versus tamoxifen [160 of 2447 women (6.5%)]. The wrist was the most common site of fracture in both treatment groups. Statistically significant risk factors for bone fractures during treatment included age, smoking history, osteoporosis at baseline, previous bone fracture, and previous hormone replacement therapy. CONCLUSIONS: Consistent with other trials comparing aromatase inhibitors to tamoxifen, letrozole was associated with an increase in bone fractures. Benefits of superior disease control associated with letrozole and lower incidence of fracture with tamoxifen should be considered with the risk profile for individual patients.

Time-related improvement of survival in resectable gastric cancer: the role of Japanese-style gastrectomy with D2 lymphadenectomy and adjuvant chemotherapy

Background: We investigated the change of prognosis in resected gastric cancer (RGC) patients and the role of radical surgery and adjuvant chemotherapy. Methods: We retrospectively analyze the outcome of 426 consecutive patients from 1975 to 2002, divided into 2 time-periods (TP) cohort: Before 1990 (TP1, n = 207) and 1990 or after (TP2; n= 219). Partial gastrectomy and D1-lymphadenetomy was predominant in TP1 and total gastrectomy with D2-lymphadenectomy it was in TP2. Adjuvant chemotherapy consisted of mitomycin C (MMC), 10¿20 mg/m2 iv 4 courses or MMC plus Tegafur 500 mg/m2 for 6 months. Results: Positive nodes were similar in TP2/TP1 patients with 56%/59% respectively. Total gastrectomy was done in 56%/45% of TP2/TP1 respectively. Two-drug adjuvant chemotherapy was administered in 65%/18% of TP2/TP1 respectively. Survival at 5 years was 66% for TP2 versus 42%for TP1 patients (p < 0.0001). Survival by stages II, IIIA y IIIB for TP2 versus TP1 patients was 70 vs. 51% (p = 0.0132); 57 vs. 22% (p = 0.0008) y 30 vs. 15% (p = 0.2315) respectively. Multivariate analysis showed that age, stage of disease and period of treatment were independent variables. Conclusion: The global prognosis and that of some stages have improved in recent years with case RGC patients treated with surgery and adjuvant chemotherapy.

Novel Chemotherapy Combinations in Advanced Gastric Cancer: an Updated Meta-Analysis

Combination chemotherapy is widely accepted for patients with advanced gastric cancer, but uncertainty remains regarding the choice of the regimen. Objectives: To assess the effect of: Comparison 1) irinotecan versus non-irinotecancontaining regimens, comparison 2) docetaxel versus non-docetaxel-containing regimens, comparison 3) regimens including oral 5-FU prodrugs versus intravenous fluoropyrimidines, comparison 4) oxaliplatin versus cisplatin-containing regimens on overall survival. Search Strategy: We searched: Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, proceedings from ECCO, ESMO, ASCO until December 2009. Selection Criteria: Randomised controlled trials on the above mentioned chemotherapy regimens in advanced or metastatic denocarcinoma of the stomach or GE-junction. Results: The meta-analysis of overall survival for comparison 1) included 4 trials, 640 patients, and results in a HR of 0.86 (95% CI 0.73-1.02) in favour of the irinotecancontaining regimens. For comparison 2) 4 trials with a total of 924 patients have been included in the analysis of overall survival. The resulting HR is 0.93 (95% CI 0.79-1.09) in favour of the docetaxel-containing regimens, with moderate heterogeneity (I2 =7%). For comparison 3 and 4, one major relevant study (Cunningham 2008) could not be included in this meta-analysis after discussion because it included patients with squamous cell cancer of the esophagus as well. Thus, for comparison 3) one relevant study (Kang 2009; 316 patients) comparing capecitabine versus 5-FU in combination with cisplatin is eligible. The resulting HR is 0.85 (95%CI 0.65-1.11) in favour of the oral regimen. For comparison 4) two eligible trials were identified (Al Batran 2008, Popov 2008; 292 patients) with a resulting HR of 0.82 (95% CI 0.47-1.45) in favour of the oxaliplatin-based regimens. For three further trials data is incomplete at present. Conclusions: Chemotherapy combinations including irinotecan, oxaliplatin, docetaxel or oral 5-FU prodrugs are alternative treatment options to cisplatin/5-FU or cisplatin/ 5-FU/anthracycline-combinations, but do not provide significant advantages in overall survival. Supported by: KKS Halle, grant number [BMBF/FKZ 01GH01GH0105]. Disclosure: All authors have declared no conflicts of interest.

Design, conduct, and analyses of Breast International Group (BIG) 1-98: a randomized, double-blind, phase-III study comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive, early breast cancer.

BACKGROUND: Aromatase inhibitors provide superior disease control when compared with tamoxifen as adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer. PURPOSE: To present the design, history, and analytic challenges of the Breast International Group (BIG) 1-98 trial: an international, multicenter, randomized, double-blind, phase-III study comparing the aromatase inhibitor letrozole with tamoxifen in this clinical setting. METHODS: From 1998-2003, BIG 1-98 enrolled 8028 women to receive monotherapy with either tamoxifen or letrozole for 5 years, or sequential therapy of 2 years of one agent followed by 3 years of the other. Randomization to one of four treatment groups permitted two complementary analyses to be conducted several years apart. The first, reported in 2005, provided a head-to-head comparison of letrozole versus tamoxifen. Statistical power was increased by an enriched design, which included patients who were assigned sequential treatments until the time of the treatment switch. The second, reported in late 2008, used a conditional landmark approach to test the hypothesis that switching endocrine agents at approximately 2 years from randomization for patients who are disease-free is superior to continuing with the original agent. RESULTS: The 2005 analysis showed the superiority of letrozole compared with tamoxifen. The patients who were assigned tamoxifen alone were unblinded and offered the opportunity to switch to letrozole. Results from other trials increased the clinical relevance about whether or not to start treatment with letrozole or tamoxifen, and analysis plans were expanded to evaluate sequential versus single-agent strategies from randomization. LIMITATIONS: Due to the unblinding of patients assigned tamoxifen alone, analysis of updated data will require ascertainment of the influence of selective crossover from tamoxifen to letrozole. CONCLUSIONS: BIG 1-98 is an example of an enriched design, involving complementary analyses addressing different questions several years apart, and subject to evolving analytic plans influenced by new data that emerge over time.

Transanal endoscopic microsurgery versus conventional transanal excision for patients with early rectal cancer.

OBJECTIVE: To compare transanal endoscopic microsurgery (TEMS) with conventional transanal excision (TAE) in terms of the quality of resection, local recurrence, and survival rates in patients with stage I rectal cancer. BACKGROUND: Although TEMS is often considered a superior surgical technique to TAE, it is poorly suited for excising tumors in the lower third of the rectum. Such tumors may confer a worse prognosis. METHODS: We retrospectively reviewed information on all patients with stage pT1 and pT2 rectal adenocarcinoma who underwent local excision from 1997 through mid-2006. We excluded patients with node-positive, metastatic, recurrent, previously irradiated, or snare-excised tumors. RESULTS: Our study included 42 TEMS and 129 TAE patients. We found no significant differences in patient characteristics, adjuvant therapy, tumor stage, or adverse histopathologic features. In the TAE group, 52 (40%) of tumors were <5 cm from the anal verge (AV); in the TEMS group, only 1 (2%) (P = 0.0001). Surgical margins were less often positive in the TEMS group (2%) than in the TAE group (16%) (P = 0.017). For patients with tumors > or =5 cm from the AV, the estimated 5-year disease-free survival (DFS) rate was similar between the TEMS group (84.1%) and the TAE group (76.1%) (P = 0.651). But within the TAE group, the estimated 5-year DFS rate was better for patients with tumors > or =5 cm from the AV (76.1%) vs. <5 cm from the AV (60.5%) (P = 0.029). In our multivariate analysis, the tumor distance from the anal verge, the resection margin status, the T stage, and the use of adjuvant therapy--but not the surgical technique (i.e., TEMS or TAE) itself--were independent predictors of local recurrence and DFS. CONCLUSIONS: The quality of resection is better with TEMS than with TAE. However, the apparently better oncologic outcomes with TEMS can be partly explained by case selection of lower-risk tumors of the upper rectum.

Moeglichkeiten der systemischen Therapie im metastasierten Stadium [Treatment options for chemotherapy in metastatic gastric cancer]

Die Ergebnisse mehrerer, in letzter Zeit publizierter Phase-III-Studien haben die therapeutischen Möglichkeiten in der Behandlung des metastasierten Magenkarzinoms deutlich erweitert. Die Dauerinfusion von 5-Fluorouracil (5-FU) kann ohne Verlust an Wirkung durch Capecitabin ersetzt werden, ebenso wie Cisplatin durch Oxaliplatin. Nach den Ergebnissen der REAL-2-Studie zeigt die Kombination aus Epirubicin, Oxaliplatin und Capecitabin (EOX) eine Verbesserung des Gesamtüberlebens (9,9 vs. 11,2 Monate; HR 0,8) im Vergleich zu Epirubicin, Cisplatin und 5-FU (ECF). Die Frage, ob in der First-Line-Therapie eine Dreifachkombination oder eine Zweifachkombination eingesetzt werden sollte, ist allerdings weiterhin umstritten. Die Kombination aus Irinotecan und 5-FU stellt für solche Patienten, bei denen aufgrund von Komorbiditäten eine platinfreie Therapie bevorzugt wird, eine Alternative zur Kombination Cisplatin/5-FU dar. Docetaxel, 5-FU und Cisplatin (DCF) hat sich bezüglich des Überlebens in einer randomisierten Phase-III-Studie als statistisch signifikant überlegen erwiesen, allerdings besteht eine ausgeprägte hämatologische Toxizität, welche die Anwendbarkeit insbesondere bei den häufig älteren Patienten mit einem Magenkarzinom limitiert. Randomisierte Phase-III-Studien zum Vergleich von DCF mit anderen Dreierkombinationen, wie z. B. EOX, stehen aus. Recently published results from several phase III trials have significantly increased the therapeutic options in the treatment of metastatic stomach cancer: The continuous infusion of 5-FU can be replaced by capecitabine, and cisplatin can be replaced by oxaliplatin in both cases without impairing efficacy. According to the results of the REAL-2 trial, the combination of epirubicin, oxaliplatin and capecitabine (EOX) achieved superior results for overall survival compared to epirubicin, cisplatin und 5-FU (ECF) (9.9 versus 11.2 months, HR 0.8). However, the question of whether an optimal first line therapy should include a triplet regimen or the sequential use of doublets is a matter of debate. The combination of irinotecan and 5-FU may serve as an alternative to platinum-containing regimens in patients where, due to co-morbidity, a platinum-free regimen is preferred. The 3-drug combination of docetaxel, 5-FU and cisplatin (DCF) demonstrated a statistically significant survival benefit compared to the 2-drug combination of 5-FU and cisplatin in a randomized phase III trial, although results were limited by a particularly significant hematological toxicity, which prevents its application in the large group of elderly patients with gastric cancer. Direct randomized phase III comparisons of DCF with other 3-drug combinations, such as EOX are still missing.

Recent patterns in gastric cancer: a global overview.

Until the mid-1990s, gastric cancer has been the first cause of cancer death worldwide, although rates had been declining for several decades and gastric cancer has become a relatively rare cancer in North America and in most Northern and Western Europe, but not in Eastern Europe, Russia and selected areas of Central and South America or East Asia. We analyzed gastric cancer mortality in Europe and other areas of the world from 1980 to 2005 using joinpoint regression analysis, and provided updated site-specific incidence rates from 51 selected registries. Over the last decade, the annual percent change (APC) in mortality rate was around -3, -4% for the major European countries. The APC were similar for the Republic of Korea (APC = -4.3%), Australia (-3.7%), the USA (-3.6%), Japan (-3.5%), Ukraine (-3%) and the Russian Federation (-2.8%). In Latin America, the decline was less marked, but constant with APC around -1.6% in Chile and Brazil, -2.3% in Argentina and Mexico and -2.6% in Colombia. Cancers in the fundus and pylorus are more common in high incidence and mortality areas and have been declining more than cardia gastric cancer. Steady downward trends persist in gastric cancer mortality worldwide even in middle aged population, and hence further appreciable declines are likely in the near future.

An age-period-cohort analysis of gastric cancer mortality from 1950 to 2007 in Europe.

PURPOSE: To analyze the components of the favorable trends in gastric cancer in Europe. METHODS: From official certified deaths from gastric cancer and population estimates for 42 countries of the European geographical region, during the period 1950 to 2007, age-standardized death rates (World Standard Population) were computed, and an age-period-cohort analysis was performed. RESULTS: Central and Northern countries with lower rates in the 2005 to 2007 period, such as France (5.28 and 1.93/100,000, men and women respectively) and Sweden (4.49 and 2.21/100,000), had descending period and cohort effects that decreased steeply from the earliest cohorts until those born in the 1940s, to then stabilize. Former nonmarket economy countries had mortality rates greater than 20/100,000 men and 10/100,000 women, and displayed a later start in the cohort effect fall, which continued in the younger cohorts. Mortality remained high in some countries of Southern and Eastern Europe. CONCLUSIONS: The decrease in gastric cancer mortality was observed in both cohort and period effects but was larger in the cohorts, suggesting that the downward trends are likely to persist in countries with higher rates. In a few Western countries with very low rates an asymptote appears to have been reached for cohorts born after the 1940s, particularly in women.

Interpreting Breast International Group (BIG) 1-98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer.

The Breast International Group (BIG) 1-98 study is a four-arm trial comparing 5 years of monotherapy with tamoxifen or with letrozole or with sequences of 2 years of one followed by 3 years of the other for postmenopausal women with endocrine-responsive early invasive breast cancer. From 1998 to 2003, BIG -98 enrolled 8,010 women. The enhanced design f the trial enabled two complementary analyses of efficacy and safety. Collection of tumor specimens further enabled treatment comparisons based on tumor biology. Reports of BIG 1-98 should be interpreted in relation to each individual patient as she weighs the costs and benefits of available treatments. Clinicaltrials.gov ID: NCT00004205.