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Presents a viewpoint on the use of edrecolomab (Monoclonal Antibody 17-1A) for the treatment of metastatic tumors. Categories of immunotherapy; Rationale for using monoclonal antibodies.

BACKGROUND: Systemic adjuvant chemotherapy can improve overall survival and reduce the incidence of distant metastases for patients with advanced colon cancer. This study aimed to investigate whether regional chemotherapy (given by intraperitoneal or intraportal methods) combined with systemic chemotherapy was more effective than was systemic chemotherapy alone in terms of survival and recurrence for patients with stage II-III colorectal cancer. The study also compared systemic chemotherapy with fluorouracil and folinic acid with that of fluorouracil and levamisole. METHODS: During surgery, 753 patients with stage II-III colorectal cancer were randomly assigned to systemic chemotherapy alone (379 with fluorouracil and folinic acid, and 374 with fluorouracil and levamisole), and 748 to postoperative regional chemotherapy with fluorouracil followed by systemic chemotherapy with fluorouracil and folinic acid (n=368) or with fluorouracil and levamisole (n=380). Regional chemotherapy was given intraperitoneally (n=415) or intraportally (n=235) according to institution. The primary endpoint was 5-year overall survival. Secondary endpoints were 5-year disease-free survival and toxic effects. Analyses were by intention to treat. FINDINGS: Median follow-up was 6.8 years (range 0.0-10.1). 5-year overall survival was 72.3% (95% CI 69.0-75.6) for patients assigned regional and systemic chemotherapy, compared with 72.0% (68.7-75.3) for those assigned systemic chemotherapy alone (hazard ratio [HR] 0.97 [0.81-1.15], p=0.69). 5-year overall survival for all patients assigned fluorouracil and levamisole was 72.0% (68.7-75.2) compared with 72.3% (69.0-75.6) for all those assigned fluorouracil and folinic acid (HR 0.98 [0.82-1.17], p=0.81). The hazard ratios for 5-year disease-free survival were 0.94 (0.80-1.10) for regional versus non-regional treatment, and 0.92 (0.79-1.08) for all fluorouracil and levamisole versus fluorouracil and folinic acid. Grade 3-4 toxic effects were low in all groups. INTERPRETATION: Fluorouracil-based regional chemotherapy adds no further benefit to that obtained with systemic chemotherapy alone in patients with advanced colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan.Methods: We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment.Results: The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone.Conclusions: Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer. [ABSTRACT FROM AUTHOR]

A single-agent dose-escalating phase I study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile and recommended dose for phase II studies. Plasma pharmacokinetics were determined as well as the SCH 66336-induced inhibition of farnesyl protein transferase in vivo. SCH 66336 was given orally once daily (OD) without interruption to patients with histologically-confirmed solid tumours. Routine antiemetics were not prescribed. 12 patients were enrolled into the study. Dose levels studied were 300 mg (6 patients) and 400 mg (6 patients) OD. Pharmacokinetic sampling was performed on days 1 and 15. Although at 400 mg OD only 1 patient had a grade 3 diarrhoea, 3 out of 6 patients interrupted treatment early due to a combination of various grade 1-3 toxicities (diarrhoea, uremiacreatinine, asthenia, vomiting, weight loss) indicating that this dose was not tolerable for a prolonged period of time. At 300 mg OD, the same pattern of toxicities was observed, but all were grade 1-2. Therefore, this dose can be recommended for phase II studies. Pharmacokinetic analysis showed that peak plasma concentrations as well as the AUCs were dose-related, with increased parameters at day 15 compared with day 1, indicating some accumulation upon multiple dosing. Plasma half-life ranged from 5 to 9 h and appeared to increase with increasing dose. Steady state plasma concentrations were attained by day 14. A large volume of distribution at steady state suggested extensive distribution outside the plasma compartment. There is evidence of inhibition of protein prenylation in some patients after OD oral administration of SCH 66336. SCH 66336 can be safely administered using a continuous oral OD dosing regimen. The recommended dose for phase II studies using this regimen is 300 mg OD. [Copyright &y& Elsevier]

Traditionally, the efficacy of cancer treatment in patients with advance or metastatic disease in clinical studies has been studied using overall survival and more recently tumor-based end points such as progression-free survival, measurements of response to treatment. However, these seem not to be the relevant clinical end points in current situation if such end points were no validated as surrogate of overall survival to demonstrate the clinical efficacy. Appropriate, meaningful, primary patient-oriented and patient-reported end points that adequately measure the effects of new therapeutic interventions are then crucial for the advancement of clinical research in metastatic colorectal cancer to complement the results of tumor-based end points. Health-related quality of life (HRQoL) is effectively an evaluation of quality of life and its relationship with health over time. HRQoL includes the patient report at least of the way a disease or its treatment affects its physical, emotional and social well-being. Over the past few years, several phase III trials in a variety of solid cancers have assessed the incremental value of HRQoL in addition to the traditional end points of tumor response and survival results. HRQoL could provide not only complementary clinical data to the primary outcomes, but also more precise predictive and prognostic value. This end point is useful for both clinicians and patients in order to achieve the dogma of precision medicine. The present article examines the use of HRQoL in phase III metastatic colorectal cancer clinical trials, outlines the importance of HRQoL assessment methods, analysis, and results presentation. Moreover, it discusses the relevance of including HRQoL as a primary/co-primary end point to support the progression-free survival results and to assess efficacy of treatment in the advanced disease setting., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: In respect of the principle of autonomy and the right of self-determination, obtaining an informed consent of potential participants before their inclusion in a study is a fundamental ethical obligation. The variations in national laws, regulations, and cultures contribute to complex informed consent documents for patients participating in clinical trials. Currently, only few ethics committees seem willing to address the complexity and the length of these documents and to request investigators and sponsors to revise them in a way to make them understandable for potential participants. The purpose of this work is to focus on the written information in the informed consent documentation for drug development clinical trials and suggests (i) to distinguish between necessary and not essential information, (ii) to define the optimal format allowing the best legibility of those documents., Methods: The Aide et Recherche en Cancérologie Digestive (ARCAD) Group, an international scientific committee involving oncologists from all over the world, addressed these issues and developed and uniformly accepted a simplified informed consent documentation for future clinical research., Results: A simplified form of informed consent with the leading part of 1200-1800 words containing all of the key information necessary to meet ethical and regulatory requirements and 'relevant supportive information appendix' of 2000-3000 words is provided., Conclusions: This position paper, on the basis of the ARCAD Group experts discussions, proposes our informed consent model and the rationale for its content., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Objective: To examine changes in colorectal cancer mortality in 34 European countries between 1970 and 2011., Design: Retrospective trend analysis., Data Source: World Health Organization mortality database., Population: Deaths from colorectal cancer between 1970 and 2011. Profound changes in screening and treatment efficiency took place after 1988; therefore, particular attention was paid to the evolution of colorectal cancer mortality in the subsequent period., Main Outcomes Measures: Time trends in rates of colorectal cancer mortality, using joinpoint regression analysis. Rates were age adjusted using the standard European population., Results: From 1989 to 2011, colorectal cancer mortality increased by a median of 6.0% for men and decreased by a median of 14.7% for women in the 34 European countries. Reductions in colorectal cancer mortality of more than 25% in men and 30% in women occurred in Austria, Switzerland, Germany, the United Kingdom, Belgium, the Czech Republic, Luxembourg, and Ireland. By contrast, mortality rates fell by less than 17% in the Netherlands and Sweden for both sexes. Over the same period, smaller or no declines occurred in most central European countries. Substantial mortality increases occurred in Croatia, the former Yugoslav republic of Macedonia, and Romania for both sexes and in most eastern European countries for men. In countries with decreasing mortality, reductions were more important for women of all ages and men younger than 65 years. In the 27 European Union member states, colorectal cancer mortality fell by 13.0% in men and 27.0% in women, compared with corresponding reductions of 39.8% and 38.8% in the United States., Conclusion: Over the past 40 years, there has been considerable disparity in the level of colorectal cancer mortality between European countries, as well as between men and women and age categories. Countries with the largest reductions in colorectal cancer mortality are characterised by better accessibility to screening services, especially endoscopic screening, and specialised care., (© Ait Ouakrim et al 2015.)

The traditional endpoint for assessing efficacy of chemotherapies for advanced/recurrent gastric cancer is overall survival (OS), but OS requires prolonged follow-up. We investigated whether progression-free survival (PFS) is a valid surrogate for OS. Using individual patient data from the GASTRIC meta-analysis, surrogacy of PFS was assessed through the correlation between the endpoints and through the correlation between the treatment effects on the endpoints. External validation of the prediction based on PFS was also evaluated. Individual data from 4069 patients in 20 randomized trials were analyzed. The rank correlation coefficient between PFS and OS was 0.853 (95% confidence interval [CI] = 0.852 to 0.854). The R (2) between treatment effects on PFS and on OS was 0.61 (95% CI = 0.04 to 1.00). Treatment effects on PFS and on OS were only moderately correlated, and we could not confirm the validity of PFS as a surrogate endpoint for OS in advanced/recurrent gastric cancer.

Background: In investigations of the effectiveness of surgery and adjuvant chemotherapy for gastric cancers, overall survival (OS) is considered the gold standard endpoint. However, the disadvantage of using OS as the endpoint is that it requires an extended follow-up period. We sought to investigate whether disease-free survival (DFS) is a valid surrogate for OS in trials of adjuvant chemotherapy for gastric cancer., Methods: The GASTRIC group initiated a meta-analysis of individual patient data collected in randomized clinical trials comparing adjuvant chemotherapy vs surgery alone for patients with curatively resected gastric cancer. Surrogacy of DFS was assessed through the correlation between the endpoints as well as through the correlation between the treatment effects on the endpoints. External validation of the prediction based on DFS was also evaluated., Results: Individual patient data from 14 randomized clinical trials that included a total of 3288 patients were analyzed. The rank correlation coefficient between DFS and OS was 0.974 (95% confidence interval [CI] = 0.971 to 0.976). The coefficient of determination between the treatment effects on DFS and on OS was as high as 0.964 (95% CI = 0.926 to 1.000), and the surrogate threshold effect based on adjusted regression analysis was 0.92. In external validation, the six hazard ratios for OS predicted according to DFS were in very good agreement with those actually observed for OS., Conclusions: DFS is an acceptable surrogate for OS in trials of cytotoxic agents for gastric cancer in the adjuvant setting.

We conducted an individual-patient-data meta-analysis of the efficacy of chemotherapy on overall survival (OS) and progression-free survival (PFS) in advanced/recurrent gastric cancer (AGC). Our primary research question was whether the experimental arms of the trials included in the meta-analysis showed a benefit as compared with their corresponding control arms. MEDLINE (up to 2010), Cochrane Central Register of Controlled Trials, National Institutes of Health (NIH) trial registry and proceedings of major oncologic and gastrointestinal cancer meetings were searched. Randomised controlled trials for AGC closed to patient accrual before the end of 2006 were eligible. As of December 2010, individual patient data were available from 22 trials (4245 patients, representing 47% of the targeted data) of 55 eligible trials. The overall comparison of experimental arms with the corresponding control arms showed statistically significant differences in terms of both OS and PFS. Hazard ratio was 0.88 (95% confidence interval 0.82-0.94, P<0.0001) for OS and 0.81 (0.76-0.88, P<0.0001) for PFS. The results of the sub-analysis of adding a given chemotherapeutic agent to any chemotherapy confirm the results of the overall analysis, with a hazard reduction of 11% for OS (P<0.01) and 26% for PFS (P<0.0001). This meta-analysis of individual patient data shows that the additions of experimental chemotherapeutic agents to pre-existing control or standard regimens have produced a modest improvement in OS and PFS. Median survival remained below 1 year for all investigated chemotherapy regimens and none emerged as a clear standard., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: To assess the value of ovarian Histo-Scanning(™) , a novel computerized technique for interpreting ultrasound data, in combination with the risk of malignancy index (RMI) in improving triage for women with adnexal masses., Methods: RMI indices were assessed in 199 women enrolled in a prospective study to investigate the use of HistoScanning. Ultrasound scores were obtained by blinded analysis of archived images. The following sequential test was developed: HistoScanning was modeled as a second-line test for RMI between a lower cut-off and an upper cut-off. The optimal combination of these cut-offs that together maximized the Youden index (Sensitivity + Specificity - 1) was determined., Results: Using RMI at the standard cut-off value of 250 resulted in a sensitivity of 74% and a specificity of 86%. When RMI was combined with HistoScanning, the highest accuracy was achieved by using HistoScanning as a sequential second-line test for patients with RMI values between 105 and 2100. At these cut-off values, sequential use of RMI and HistoScanning resulted in mean sensitivity and specificity estimates of 88% and 95%, respectively., Conclusions: Our data suggest that HistoScanning may have the potential to improve the diagnostic accuracy of RMI, which could result in better triage for women with adnexal masses. Further prospective validation is warranted., (Copyright © 2011 ISUOG. Published by John Wiley & Sons, Ltd.)

Purpose: Accurate preoperative clinical assessment of adnexal masses can optimize outcomes by ensuring appropriate and timely surgery. This article addresses whether a new technology, ovarian HistoScanning, has an additional diagnostic value in mathematical models developed for the differential diagnosis of adnexal masses., Patients and Methods: Transvaginal sonography-based morphological variables were obtained through blinded analysis of archived images in 199 women enrolled in a prospective study to assess the performance of ovarian HistoScanning. Logistic regression (LR) and neural network (NN) models including these variables and clinical and patient data along with the HistoScanning score (HSS) (range, 0-125; based on mathematical algorithms) were developed in a learning set (60% patients). The remaining 40% patients (evaluation set) were used to assess model performance., Results: Of all morphological and clinical variables tested, serum CA-125, presence of a solid component, and HSS were most significant and used to develop the LR model. The NN model included all variables. The novel variable, HSS, offered significant improvement in the LR and NN models' performance. The LR and NN models in an independent evaluation set were found to have area under the receiver operating characteristic curve = 0.97 (95% confidence interval [CI], 94-99) and 0.93 (95% CI, 88-98), sensitivities = 83% (95% CI, 71%-91%) and 80% (95% CI, 67%-89%), and specificities = 98% (95% CI, 89%-99%) and 86% (95% CI, 72%-95%), respectively. In addition, these models showed an improved performance when compared with 3 other existing models (all P < 0.05)., Conclusions: This initial report shows a clear benefit of including ovarian HistoScanning into mathematical models used for discriminating benign from malignant ovarian masses. These models may be specifically helpful to the less experienced examiner. Future research should assess performance of these models in prospective clinical trials in different populations.

Objective: To determine the extent to which computer-aided ultrasonography of the prostate (HistoScanning, Advanced Medical Diagnostics, Waterloo, Belgium) can identify tumour foci that correspond to a volume of >or=0.50 mL., Patients and Methods: Between September 2004 and February 2006, 29 men were HistoScanned before scheduled radical prostatectomy. The three-dimensional raw (grey-scaled) data required for HistoScanning analysis were acquired by transrectal ultrasonography, and analysed using organ-specific tissue-characterization algorithms which form the core of the HistoScanning technology. The HistoScanning analysis results were compared with the histology of the whole-mounted prostate, step-sectioned sagittally at 5-mm intervals, and each slide analysed by 5 x 5 mm grid analysis., Results: Of 29 patients, 13 had histology unknown to those evaluating the HistoScanning data. With 0.50 mL as the lower threshold for delineating and visualizing cancer volume, HistoScanning correctly predicted the presence of all 12 lesions that were subsequently confirmed to occupy >or=0.50 mL. In addition three lesions were predicted as being present and of >or=0.50 mL. These three lesions were subsequently confirmed to be present but were or=0.50 mL; these encouraging results will need to be verified in a larger group of patients.

Background: The study aimed to demonstrate the noninferiority of capecitabine to 5-fluorouracil (5-FU)/folinic acid (FA), in relation to progression-free survival (PFS) after first-line treatment of metastatic colorectal cancer and the benefit of adding celecoxib (C) to irinotecan/fluoropyrimidine regimens compared with placebo (P)., Patients and Methods: Patients were randomly assigned to receive FOLFIRI: irinotecan (180 mg/m(2) i.v. on days 1, 15 and 22); FA (200 mg/m(2) i.v. on days 1, 2, 15, 16, 29 and 30); 5-FU (400 mg/m(2) i.v. bolus, then 22-h, 600 mg/m(2) infusion) or CAPIRI: irinotecan (250 mg/m(2) i.v. infusion on days 1 and 22); capecitabine p.o. (1000 mg/m(2) b.i.d. on days 1-15 and 22-36). Patients were additionally randomly assigned to receive either placebo or celecoxib (800 mg: 2 x 200 mg b.i.d.)., Results: The trial was closed following eight deaths unrelated to disease progression in the 85 enrolled (629 planned) patients. Response rates were 22% for CAPIRI + C, 48% for CAPIRI + P, 32% for FOLFIRI + C and 46% for FOLFIRI + P. Median PFS and overall survival (OS) times were shorter for CAPIRI versus FOLFIRI (PFS 5.9 versus 9.6 months and OS 14.8 versus 19.9 months) and celecoxib versus placebo (PFS 6.9 versus 7.8 months and OS 18.3 versus 19.9 months)., Conclusion: Due to the small sample size following early termination, no definitive conclusions can be drawn in relation to the noninferiority of CAPIRI compared with FOLFIRI.

Objective: To assess the extent to which prostate HistoScanning (PHS), a new ultrasound-based technology that uses computer-aided analysis to quantify tissue disorganization induced by malignant processes, can identify and characterize foci of prostate cancer compared with step-sectioned radical prostatectomy (RP) specimens., Patients and Methods: Between September 2004 and February 2006, 29 men had PHS before their scheduled RP. A three-dimensional ultrasound raw-data file was acquired, and PHS analysed regions of interest (ROI) corresponding to tissue volumes of approximately 0.04 mL. In 13 men the histology was examined on sections of the whole-mount prostate onto which a grid of 5 x 5 mm squares was applied. On a test set of 14 of the 29 patients, PHS analysis was used before knowing the histology results (blinded data), to predict the maximum tumour diameter, focality, laterality and extraprostatic extension (EPE)., Results: Identification and characterization by PHS of the index tumour in the 14 patients in the test set correlated closely (r = 0.95, P < 0.001) with the reference test. The concordance in the attribution of multifocality (present/absent), unilateral/bilateral disease between PHS and histology was 100%. EPE as determined by PHS was attributed to all three pT3a pathological specimens in the blinded paired data. In the same set of data, EPE was attributed to one prostate cancer that on pathological inspection was deemed to be organ-confined (pT2b)., Conclusions: PHS has the potential to identify and characterize prostate cancer foci noninvasively. The precision appears to be sufficient to suggest that PHS might be useful as a triage test for men deemed to be at risk of prostate cancer and who wish to avoid prostate biopsy.

Objectives: To evaluate long-term survival of patients resected for primarily unresectable colorectal liver metastases downstaged by systemic chemotherapy., Methods: Among a group of 82 patients with advanced colorectal cancer, 39 had unresectable liver metastases. After treatment with systemic 3-weekly 5FU/folinic acid/oxaliplatin chemotherapy, the outcome of 11 patients made resectable thanks to chemotherapy was compared to that of 28 patients who were not. Criteria for non-resectability consisted of diffuse bilobar invasion with inability to achieve complete resection, unilobar or bilobar invasion plus vascular extension (invasion of inferior vena cava or 2 supra-hepatic veins plus continuity with the 3rd) or involvment of hepatic pedicle. Before and after surgery, CT scan evaluation was performed every 2 months. Progression free survival was defined as the time between starting chemotherapy and recurrence of the disease. We used Kaplan-Meier survival curves and log-rank test for comparisons, P values were two-sided and considered significant if<0.05., Results: Progression free survival times were 14 and 6 months, median overall survival were 60 and 18.5 months, respectively, in favour of secondary resected subjects., Conclusion: Considering the magnitude of the survival benefit, one may question the need and feasibility for trials to assess more formally the impact of surgery in that setting.

Purpose: Oxaliplatin, fluorouracil, and leucovorin are commonly used to treat advanced and resected colorectal cancer. This analysis compares the safety and efficacy of oxaliplatin plus fluorouracil/leucovorin administered bimonthly (FOLFOX4) in patients age younger than and at least 70 years., Patients and Methods: This retrospective analysis included 3,742 colorectal cancer patients (614 age > or = 70) from four clinical trials testing FOLFOX4 in the adjuvant, first-, and second-line settings. End points included grade > or = 3 adverse events, response rate (in advanced disease), progression or relapse-free survival, dose-intensity, and overall survival in the studies with mature survival data., Results: Grade > or = 3 hematologic toxicity (neutropenia [43% v 49%; P = .04] and thrombocytopenia [2% v 5%; P = .04]) were significantly higher in older patients. Older age was not associated with increased rates of severe neurologic adverse events, diarrhea, nausea/vomiting, infection, overall incidence of grade > or = 3 toxicity (63% v 67%; P = .15), or 60-day mortality (1.1% v 2.3%; P = .20). The relative benefit of FOLFOX4 versus control did not differ by age for response rate, progression or recurrence free-survival (hazard ratio, 0.70 for FOLFOX4 v control for age < 70, 0.65 for age > or = 70; P = .42), or overall survival (hazard ratio, 0.77 age < 70, 0.82 age > or = 70; P = .79). Dose-intensity did not differ by age at cycles 1, 3, 6, or 12., Conclusion: FOLFOX4 maintains its efficacy and safety ratio in selected elderly patients with colorectal cancer. Its judicious use should be considered without regard to patient age, although scant data are available among patients older than 80 years.

Background: Advanced distal neoplasia found at sigmoidoscopy could be the marker for more proximal lesions., Patients and Methods: In the setting of a screening clinic, subjects underwent flexible sigmoidoscopy. If no significant lesion was found, sigmoidoscopy was planned after 5 years. If an advanced neoplasia was found, colonoscopy was performed just after the first sigmoidoscopy and at 1, 3 and 5 years. If a non-advanced neoplasia was found, sigmoidoscopy was performed at 1, 3 and 5 years and followed by colonoscopy if advanced lesion was found., Results: At first screening 1704/1912 (88%) subjects had a negative sigmoidoscopy, 104 (5.4%) had an advanced neoplasia, 96 (6%) had a non-advanced neoplasia and eight (0.4%) had invasive colorectal cancer (CRC). At follow-up examinations at 1, 3 and 5 years, among 170 subjects with advanced and non-advanced neoplasia, one developed invasive CRC and 47 (31.6%), advanced neoplasia. At 5 years, among 718 first negative sigmoidoscopies, 572 (80%) were confirmed negative and 97 (14%) had advanced neoplasia. Colorectal cancer status at 5 years could be checked for interval cancers in 97% of subjects and no CRC was diagnosed in subjects who did not attend sigmoidoscopy at 5 years. Comparison of the incidence of invasive CRC to the data of registries of the Netherlands and Luxembourg suggested that the incidence of CRC was decreased by 36%-46%. Seven of the nine CRCs were Duke's A and the two others were Duke's B and C., Conclusions: Screening with sigmoidoscopy followed by colonoscopy in case of positive sigmoidoscopy leads to substantial decreases in the incidence of CRC. Most CRCs found are at an early, curable stage of their development.

This year, for the first time, the American Society of Clinical Oncology (ASCO) is publishing Clinical Cancer Advances 2005: Major Research Advances in Cancer Treatment, Prevention, and Screening, an annual review of the most significant clinical research presented or published over the past year across all cancer types. ASCO embarked on this project to provide the public, patients, policymakers, and physicians with an accessible summary of the year's most important research advances. While not intended to serve as a comprehensive review, this report provides a year-end snapshot of research that will have the greatest impact on patient care. As you will read, there is much good news from the front lines of cancer research. These pages report on new chemotherapy regimens that sharply reduce the risk of recurrence for very common cancers; the "coming of age" of targeted cancer therapies; promising studies of drugs to prevent cancer; and improvements in quality of life for people living with the disease, among many other advances. Survival rates for cancer are on the rise, increasing from 50% to 64% over the last 30 years. Cancer still exacts an enormous toll, however. Nearly 1.4 million Americans will be diagnosed this year, and some 570,000 will die of the disease. Clearly, more research is needed to find effective therapies for the most stubborn cancer types and stages. We need to know more about the long-term effects of newer, more targeted cancer therapies, some of which need to be taken over long periods of time. And we need to devote far greater attention to tracking and improving the care of the nearly 10 million cancer survivors in the United States today. Despite these and other challenges, the message of this report is one of hope. Through the dedicated, persistent pursuit of clinical research and participation in clinical trials by people with cancer, we steadily uncover new and better ways of treating, diagnosing, and preventing a disease that touches the lives of so many. I want to thank the Editorial Board members, the Specialty Editors, and the ASCO Cancer Communications Committee for their dedicated work to develop this report, and I hope you find it useful.

Despite staining positive for the epidermal growth factor receptor (EGFR), a significant number of EGFR-expressing colorectal cancers are resistant to cetuximab, a chimeric monoclonal antibody directed against EGFR. Activation of EGFR through the autophosphorylation of its tyrosine residues stimulates different signaling downstream pathways and may reflect the level of receptor utilization by the tumor. This study investigated activated/phosphorylated EGFR (pEGFR) in 23 patients with EGFR-positive metastatic colorectal cancer refractory to irinotecan and treated with cetuximab, alone or in combination with irinotecan. Seven patients received cetuximab, and 16 patients received cetuximab plus irinotecan. Among the 23 patients, six (26%) had a partial response, 10 (44%) had stable disease, and seven (30%) had progressive disease. Median duration of disease control (partial response + stable disease) was 6 months. Nineteen out of 20 EGFR-positive tumors (95%) stained positive for pEGFR and had a median pEGFR immunohistochemical score of 5. Disease control rates differed between patients with a pEGFR immunohistochemical score >or= 7 (7/7, 100%) and less than 7 (7/13, 53.8%), showing a trend toward higher disease control in patients with high levels of pEGFR (>or= 7) who were treated with cetuximab with or without irinotecan (P = .05).

Purpose of Review: Colon cancer is the second leading cause of cancer death in Western countries. Although most colon cancer patients will undergo curative surgery, survival, depending on the pathologic stage, varies from 30-60% for Dukes C to 60-80% for Dukes B. Until very recently, the absolute benefit for survival obtained with adjuvant therapy compared with control was about 6%. The present review analyzes the results of the new combination of 5-fluorouracil/leucovorin/oxaliplatin (MOSAIC study), the oral fluoropyrimidines, and the studies of genetic and molecular markers, attempting to identify the patients at risk of recurrence., Recent Findings: Both 5-fluorouracil/leucovorin/oxaliplatin and the oral fluoropyrimidines show a statistically significant benefit of experiments treatment compared with 5-fluorouracil/leucovorin and no treatment, respectively. A reduction of 23% in the risk of relapse (disease-free survival rates of 78.2% in the 5-fluorouracil/leucovorin/oxaliplatine arm compared with 72.9% for 5-fluorouracil/leucovorin; P = 0.002) for the former and an overall hazard ratio of 0.89 for survival (95% CI, 0.80-0.99; P = 0.04) and 0.85 for disease-free survival (95% CI, 0.77-0.93; P < 0.001) in favor of oral therapy compared with control. A review of the literature on translational research indicates that patients at risk of recurrence can be identified by a 23-gene signature as well as by the combination of p27, p53, and vascular endothelial growth factor molecular alterations., Summary: The present review shows that adjuvant therapy of colon cancer is still improving and that the use of genetic/molecular markers together with the new targeted therapies has the potential to improve survival further.

Since its first use 40 years ago, 5-fluorouracil (5-FU) has become an unquestionable component of colorectal cancer treatment. It is also now well established that infusional 5-FU administration, in combination with leucovorin, is associated with better tolerance and at least equal efficacy than bolus administration. However, requiring catheter and infusion pumps, infusional 5-FU administration is costly, rather inconvenient for patients and potentially associated with morbidity, initiating subsequent oral chemotherapy development. To address intravenous 5-FU related issues, oral fluoropyrimidines have been developed such as capecitabine, preferentially converted to 5-FU into tumour cells, and UFT, able of bypassing intestinal dihydropyrimidine dehydrogenase. We discuss in this article current oral fluoropyrimidines achievements in colorectal cancer management.

This article reviews the current developments and significant trends in the treatment of hepatocarcinoma (HCC). Prevention programs should be based on large vaccination campaigns and the use of immunologic or biologic molecules to delay the onset of HCC in already cirrhotic patients. Surgery remains the therapy of choice in patients with a small and limited number of tumor nodules. To date, no preoperative treatment has been proven useful. Adjuvant treatments involving systemic chemotherapy, intra-arterial infusion, or chemoembolization failed to improve survival, whereas immune therapy, retinoids, radiolabeled isotopes, and antiangiogenic agents seem promising. Such local treatments as percutaneous ethanol injection, cryotherapy, and radiofrequency are proposed for patients with limited hepatic function and should be combined with other treatment modalities to optimize their efficacy and limit their toxicity. Regional therapy should take a selective, subsegmental approach at intervals depending on tumor response and possibly combined with other treatment modalities. Systemic therapy with cytotoxic agents remains disappointing. Hormonal therapy with tamoxifen or antiandrogens has shown no efficacy and might even be detrimental. Further progress may be expected from targeted therapy.

Background: The adequacy of overall survival (OS) as study end point in phase III trials for advanced solid tumors is questionable. The present review highlights the limits of OS as study end point to evaluate the efficacy of new drugs., Methods: Four phase III clinical trials comparing a fluorouracil-based regimen with the same regimen plus either CPT-11 or oxaliplatin in advanced colorectal cancer patients were reviewed. The primary aim of the critical assessment was to explain the lack of OS advantage observed in two of the four trials, despite the presence of increased response rate (RR) and time to progression (TTP). Four possible reasons for the lack of OS benefit (i.e. statistical power, cross-over, magnitude of the effect on RR and TTP, non-tumor-related deaths) were systematically reviewed in the trials, and the detectable 1-year OS difference, assuming a statistical power of 80%, was calculated for each., Results: None of these reasons for the lack of OS advantage in presence of RR and TTP benefits convincingly explained the results of the evaluated trials. Three of the four trials had roughly the same statistical power to detect 1-year OS differences, while the fourth trial was underpowered to detect realistic OS differences. The lack of OS advantage observed in the two oxaliplatin trials is therefore likely fortuitous, and due to lack of statistical power., Conclusions: Although increase in OS remains the ultimate goal of many clinical trials, the choice of OS benefit as a mandatory requirement to register new compounds can lead to a serious underestimation of a drug's real efficacy.

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.

Accurate assessment of health-related quality of life (HRQoL) in patients with advanced colorectal cancer is essential to improve our understanding of how cancer and chemotherapy influence patients' life and to adapt treatment strategies. Specific questionnaires have descriptive and predictive value and can be used to evaluate new therapies. Results from HRQoL assessments in randomised trials help patients and physicians to choose between treatment options. More than half of the patients treated with palliative chemotherapy have an improvement or at least a preservation of their HRQoL. However, several trials have found small differences in HRQoL between treatment groups. This may be due to the insufficient sensitivity of tools, low numbers of patients or missing data. An international consensus on the methods of measurement of HRQoL in oncology is warranted to enhance compliance, to better interpret results and to optimise the publication of precise HRQoL data.

In the three trials that tested screening with biennial fecal occult blood test (FOBT), follow-up of control patients for colorectal cancer (CRC) differed: in the Minnesota (United States) trial, the follow-up was equivalent to patients in the intervention groups, while in the Nottingham (United Kingdom) and Funen (Denmark) trials, control patients just received usual care. In the two latter trials, mortality from colorectal cancer was lower in subjects with interval colorectal cancer than in control subjects, while in the Minnesota trial, survival was equivalent in patients with interval CRC and in control patients. We examined whether better disease awareness of subjects allocated to the intervention group contributed to changes in colorectal cancer mortality observed in the FOBT trials. In the Nottingham and Funen trials, we evaluated the amount of colorectal cancer mortality reduction attributable to better survival of subjects in whom an interval colorectal cancer developed. In the Minnesota trial, we examined whether earlier detection of colorectal cancer in control subjects could explain the small (6%) reduction in colorectal cancer mortality observed with biennial FOBT. In the Nottingham and Funen trials, about one-quarter of the reduction in colorectal cancer mortality could be attributed to better awareness of patients with interval colorectal cancer. After correction for the effects of disease awareness, the absolute reduction in colorectal cancer mortality due to FOBT itself was 12% instead of 16%, and was no longer statistically significant (P>0.05). The results from biennial FOBT in the Minnesota trial published in 1993 would probably have been similar to those obtained in the Nottingham and Funen trials if disease awareness had not influenced the stage at diagnosis of colorectal cancers found in the control group. Better awareness of colorectal cancer contributes to the reduction of colorectal cancer mortality and should be encouraged. Because of a study design effect, the decrease in colorectal cancer mortality attributable to the FOBT itself is about 25% lower than that reported in the Nottingham and Funen trials. Therefore, recommending general population screening with biennial FOBT is still an open question.

S 16020, a new 9-OH olivacine derivative, is a novel topoisomerase II inhibitor with activity in cell lines presenting the classical multidrug resistance phenotype. This report summarizes, in addition to pharmacokinetic data, the whole phase I clinical experience of S 16020 using three different infusion schedules. Asthenia and skin toxicity were the main side effects. In an attempt to understand the skin toxicity mechanism, experiments in animals were performed, the results of which are reported. S 16020 showed rapid tumor necrotizing activity in some patients, with soft tissue metastases of epidermoïd tumors and pain at the tumor site. To document the side effects of S 16020 and tumor site reactions (pain, edema, inflammatory signs), inflammatory parameters and some cytokines were measured. In our patients there was no hemolysis and no detection of anti-S 16020 antibodies, confirming the absence of immunogenicity of the compound. Based on the overall data of the three infusion schedules of S 16020, the dose of 100 mg/m(2) over 3 h every 3 weeks was selected for phase II studies.

The goal of the present paper is to review how treatment of advanced colorectal cancer has evolved during the last 10 years and to make some suggestions on how that disease could be managed today. 5-Fluorouracil (5-FU) combined with folinic acid (FA) remains the basis for advanced colorectal cancer treatment. In Europe, infusional 5-FU is considered to be more active and better tolerated than bolus 5-FU. New agents including oral 5-FU prodrugs UFT/FA, and capecitabine, tomudex, irinotecan and oxaliplatin have been shown active in advanced colorectal cancer. At presentation the combination of infusional 5-FU/FA with irinotecan or oxaliplatin is considered to be superior to any of these agents used alone, yielding a median survival of up to 16-19 months. Second-line therapy could further prolong survival in selected patient populations. Eventually chemotherapy could allow curative resection of previously unresectable hepatic and pulmonary metastases.

Purpose: Based on preclinical in vitro synergy data, this study evaluated the activity and toxicity of a gemcitabine/oxaliplatin combination in patients with metastatic and locally advanced pancreatic adenocarcinoma., Patients and Methods: Previously untreated metastatic and locally advanced unresectable pancreatic adenocarcinoma patients were enrolled onto this multicenter phase II study. Patients received gemcitabine 1,000 mg/m(2) as a 10-mg/m(2)/min infusion on day 1 and oxaliplatin 100 mg/m(2) as a 2-hour infusion on day 2 every 2 weeks. Patients with metastatic disease were treated until evidence of progressive disease, whereas patients with locally advanced disease received six cycles in the absence of progression, followed when appropriate by concomitant radiochemotherapy., Results: Among 64 eligible patients included in eight centers, 30 had locally advanced and 34 had metastatic disease. Response rate for the 62 patients with measurable disease was 30.6% (95% confidence interval, 19.7% to 42.3%), 31.0% for locally advanced and 30.3% for metastatic patients. Among 58 assessable patients, 40% had clinical benefit. Median progression-free survival and median overall survival (OS) were 5.3 and 9.2 months, respectively, with 36% of patients alive at 1 year. Median OS for patients with metastatic disease and locally advanced disease were 8.7 and 11.5 months, respectively. With 574 treatment cycles (median per patient, nine; range, zero to 27), grade 3/4 toxicity per patient was 11% for neutropenia and thrombocytopenia, 14% for nausea or vomiting, 6.2% for diarrhea, and 11% for peripheral neuropathy, with no toxic deaths., Conclusion: Palliative effects, response rate, and survival observed with this well-tolerated gemcitabine/oxaliplatin combination deserve additional evaluation. A comparative study of combination therapy versus gemcitabine alone is ongoing.

Loco-regional chemotherapy, an alternative to systemic chemotherapy in the management of colorectal cancer, has been evaluated in both adjuvant and palliative settings. The rationale for loco-regional delivery is to achieve higher dose concentrations of drugs at the tumour site or at the most common sites of tumour recurrence, while limiting systemic exposure and associated toxicity. Adjuvant intraportal chemotherapy and palliative hepa-tic arterial chemotherapy have been most extensively investigated. Intraperitoneal chemotherapy has also been studied as an adjuvant treatment after complete resection of colorectal cancer or cytoreductive surgery in patients with established peritoneal carcinomatosis. The results obtained have been disappointing, and none of these procedures can be considered as a standard therapeutic option today. However, methodological difficulties were encountered in most published studies, and the investigated schedules and doses may not have been optimal. New combinations of cytotoxic drugs and new indications are currently under consideration. Promising results have recently been published for adjuvant intraperitoneal chemotherapy and hepatic arterial chemotherapy following surgical resection of hepatic metastases, but additional well-designed multicentre phase III trials are needed to determine the true benefits of these treatment modalities and to address the issues of cost and quality of life.

In patients with non-colon digestive carcinomas, various schedules and doses of 5-fluorouracil (5-FU) and leucovorin combined with cisplatin (CDDP) have been used extensively. The present study explored the toxicity and activity of a weekly 24-h infusion of high dose 5-FU modulated by high dose leucovorin with bi-weekly CDDP. 59 patients with measurable disease were treated with a weekly infusion of high dose 5-FU (2 or 2.6 g/m2)+leucovorin 500 mg/m2 for 6 weeks and a bi-weekly dose of CDDP (50 mg/m2). All patients had metastatic or locoregionally advanced disease and had a performance status < or =3. All patients were evaluable for toxicity and 58 for response. Toxicity was different according to the schedule of 5-FU. Serious adverse events occurred most frequently when 5-FU was given at a dose of 2.6 g/m2 with a high incidence of grade 3/4 neutropenia (16%) and febrile neutropenia (13%), and led to dose reductions in both CDDP and 5-FU in 13 patients (34%). For patients who started 5-FU at a dose of 2 g/m2, no reduction in 5-FU was required, and only 4 patients required a dose reduction of CDDP (19%). Grade 3/4 neutropenia was seen in 10% of patients of this group and only 1 patient required hospitalisation for febrile neutropenia. Other grade 3/4 toxicities were rare in both groups. Renal toxicity was infrequent and mild and did not require dose adjustments. The overall response rate was 33%; 19 patients achieved a partial responses (PR). No patient had a complete response (CR). The median duration of response was 5.7 months (range 2-24 months) and the median survival was 7.9 months ( range: 1-30, 95% confidence interval (CI): 7-9). The combination of weekly 24-h infusion of high dose 5-FU with leucovorin and bi-weekly cisplatin seems a well-tolerated and active treatment in non-colon digestive carcinomas. A dose of 2 g/m2 of 5-FU seems to be recommended.

A statistical analysis was performed on the patient data collected from two compassionate-use programmes using oxaliplatin (Eloxatin(R)) + 5-fluorouracil (5-FU) +/- folinic acid (FA), to identify predictive factors for oxaliplatin-based salvage treatment in patients with 5-FU-resistant advanced colorectal cancer (ACRC). 481 5-FU-resistant ACRC patients, most with performance status < or = 2, > or = 3 involved sites, and > or = 2 prior lines of chemotherapy, received oxaliplatin + 5-FU +/- FA. Prognostic factors associated with overall response rate (ORR), time to progression (TTP) and overall survival (OS) were identified using univariate and multivariate logistic and/or Cox proportional hazards analyses. The ORR was 16% (95% CI: 13-20), the median TTP was 4.2 months (95% CI: 3.4-4.6), and the median OS was 9.6 months (95% CI: 8.6-10.6). The multivariate analysis indicated poor (> or = 2 WHO) performance status (PS), a large number of prior chemotherapy regimens (> or = 3), a low baseline haemoglobin level (< 10 g/dl), and a triweekly (vs biweekly) treatment administration schedule as significantly associated (P< 0.05) with a lower ORR. Sex (male), number of organs involved (> or =3) and alkaline phosphatase (AP) level (> or = 2 x the upper limit of normal) were associated (P< 0.05) with shorter TTP. Poor PS, a large number of organs involved, and elevated AP were independently and significantly correlated with shorter OS. Our analysis identified a relationship between efficacy results of oxaliplatin + 5-FU +/- FA treatment in 5-FU-resistant ACRC patients and baseline prognostic factors related to PS, extent of disease and number of prior regimens., (Copyright 2001 Cancer Research Campaign.)

Emesis is one of the most unpleasant and debilitating side effects of anticancer chemotherapy. In acute emesis (vomiting occurring 0-24 hours after chemotherapy administration), the 5-HT3 receptor antagonists and corticosteroids are highly effective, with few significant side effects, and can safely be combined. Delayed emesis (vomiting occurring >24 hours after chemotherapy administration), however, is both not well understood and less well controlled. Studies have yielded conflicting results concerning the use of 5-HT3 receptor antagonists alone in delayed emesis. The data of NK-1 receptor antagonists in the control of acute emesis, although promising, need confirmation in a properly designed study.