Search

Contains fulltext : 111010pub.pdf (Publisher’s version ) (Closed access) Colorectal cancer (CRC) is the most common tumour type in both sexes combined in Western countries. Although screening programmes including the implementation of faecal occult blood test and colonoscopy might be able to reduce mortality by removing precursor lesions and by making diagnosis at an earlier stage, the burden of disease and mortality is still high. Improvement of diagnostic and treatment options increased staging accuracy, functional outcome for early stages as well as survival. Although high quality surgery is still the mainstay of curative treatment, the management of CRC must be a multi-modal approach performed by an experienced multi-disciplinary expert team. Optimal choice of the individual treatment modality according to disease localization and extent, tumour biology and patient factors is able to maintain quality of life, enables long-term survival and even cure in selected patients by a combination of chemotherapy and surgery. Treatment decisions must be based on the available evidence, which has been the basis for this consensus conference-based guideline delivering a clear proposal for diagnostic and treatment measures in each stage of rectal and colon cancer and the individual clinical situations. This ESMO guideline is recommended to be used as the basis for treatment and management decisions.

Pemetrexed-carboplatin and gemcitabine‑vinorelbine combination therapies were efficacious in phase II and phase III studies as first-line breast cancer treatment. Thus, Arm A and Arm B combinations were investigated in patients pretreated with anthracycline and taxanes. Women with advanced breast cancer, with ≥1 measurable lesion per RECIST, were stratified by line of treatment (1st, 2nd), visceral disease (yes/no), ECOG PS (0-1 vs. 2) and randomized 1:1 to Arm A (pemetrexed 600 mg/m², D1 i.v. q21; carboplatin, AUC 5, D1 i.v. q21) or Arm B (gemcitabine 1,200 mg/m² D1, D8 i.v. q21; vinorelbine 30 mg/m² D1, D8 i.v. q21). Treatment continued until progression. The primary endpoint was objective response rate (RR). Secondary endpoints were duration of response (DoR), time-to-response (TTR), time-to-progressive disease (TTPD), time-to-treatment failure (TTTF) and safety. A two-stage design was employed independently for each arm. Of 135 randomized patients, 125 (Arm A, n=64; Arm B, n=61) qualified for tumor-response analysis. The mean (standard deviation) number of cycles administered was 6.3 (4.13) in Arm A and 6.2 (4.39) in Arm B. Efficacy in Arm A and Arm B were: RR (95% CI), 26.6 (16.3-39.1) and 29.5 (18.5-42.6); time-to-events (months), DoR 7.7 and 7.5; TTPD, 5.1 and 5.6; TTR, 1.8 and 1.8; TTTF, 4.8 and 5.1; respectively. Most common grade 3/4 adverse events possibly related to study-drug were neutropenia, thrombocytopenia, anemia and leucopenia in Arm A and neutropenia, leucopenia and fatigue in Arm B. In this study, both combinations showed moderate activity as predefined RR was not reached and were well tolerated.

Background Sorafenib has proven efficacy in metastatic renal cell carcinoma (mRCC). Interferon (IFN) has antiangiogenic activity that is thought to be both dose- and administration-schedule dependent. Objective To compare two different schedules of IFN combined with sorafenib. Design, setting, and participants Single-stage, prospective, noncomparative, randomized, open-label, multicenter, phase 2 study on previously untreated patients with mRCC and Eastern Cooperative Oncology Group performance status 0–2. Intervention Sorafenib 400mg twice daily plus subcutaneous IFN, 9 million units (MU) three times a week (Arm A) or 3 MU five times a week (Arm B). Outcome measurements and statistical analysis Primary end points were progression-free survival (PFS) for each arm and safety. Data were evaluated according to an intent-to-treat analysis. Results and limitations A total of 101 patients were evaluated. Median PFS was 7.9 mo in Arm A and 8.6 mo in Arm B ( p =0.049) and the median duration of response was 8.5 and 19.2 mo, respectively ( p =0.0013). Nine partial responses were observed in Arm A, and three complete and 14 partial responses were observed in Arm B (17.6% vs 34.0%; p =0.058); 24 and 21 patients (47% and 42%), respectively, achieved stable disease. The most common grade 3–4 toxicities were fatigue plus asthenia (28% vs 16%; p =0.32) and hand-foot skin reactions (20% vs 18%). Conclusions Sorafenib plus frequent low-dose IFN showed good efficacy and tolerability. Further investigations should be warranted to identify a possible positioning of this intriguing regimen (6% complete response rate) in the treatment scenario of mRCC.

The purpose of the present study was to evaluate the activity and the tolerability of the FOLFIRI regimen, administered as second-line chemotherapy in patients with locally advanced or metastatic pancreatic cancer after the failure of a gemcitabine-based regimen.Patients with locally advanced/metastatic disease who received a first-line chemotherapy (one line only) with gemcitabine±platinoid (cisplatin, oxaliplatin) and who had measurable disease conform with the RECIST criteria were eligible for the study. FOLFIRI consists of irinotecan 180mg/m(2) iv on day 1, leucovorin (l-form) 200mg/m(2) iv on day 1 and 2, 5-FU 400mg/m(2) iv bolus on days 1 and 2, and 5-FU 600mg/m(2) iv by ci for 22h on days 1 and 2, repeated every 2weeks. The primary end point was the response rate.Among the 50 enrolled patients, 4 partial responses (PR) (8%) and 14 stable diseases were observed, for a disease control rate of 18/50 (36%). Forty-one patients (82%) have been pretreated with cisplatin/oxaliplatin+gemcitabine as first-line chemotherapy. The median progression-free and overall survivals were 3.2 and 5months, respectively. The 6-month survival rate was 32%. Grade 3-4 neutropenia and diarrhea occurred in 10 (20%) and 6 (12%) patients, respectively.The FOLFIRI regimen showed a modest clinical activity in this quite heavily pretreated patients' population with locally advanced or metastatic pancreatic cancer with a manageable toxicity profile.

Chronic pain is a major healthcare issue in Europe and globally, and inadequate or undertreated pain significantly reduces the ability of many patients to participate in ordinary daily activities, adversely affects their employment status and contributes to a substantial rate of depression and anxiety in patients with chronic pain. There is a broad distinction of chronic pain into chronic non-cancer pain and chronic cancer pain, and important subgroups of these include patients with rheumatic and/or orthopaedic diseases, pain syndromes caused by cancer itself and caused by cancer treatment. Despite comprising the majority of non-cancer pain in Europe, chronic non-cancer pain associated with rheumatic diseases and/or orthopaedic conditions is often inadequately managed. Although paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) play a continuing role in the treatment of chronic rheumatic diseases, accumulating evidence of potential toxicity with both traditional non-selective NSAIDs and selective cyclooxygenase 2 inhibitors has prompted a reassessment of their use. This has particular resonance for the elderly, who are more likely to have significant pain issues than younger patients and are at high risk of NSAID-related adverse events. The use of mild opioids, such as codeine and tramadol, and strong opioids, such as morphine, hydromorphone and oxycodone, may be appropriate where paracetamol and other non-opioid analgesics are ineffective in chronic non-cancer pain. Cancer pain, either related to the underlying disease or caused by cancer treatment, is also a common cause of chronic pain in the elderly. An understanding of individual needs is essential in providing adequate pain relief, which is a central goal of care in all patients with chronic pain.

Purpose To compare efficacy of pemetrexed versus pemetrexed plus carboplatin in pretreated patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with advanced NSCLC, in progression during or after first-line platinum-based chemotherapy, were randomly assigned to receive pemetrexed (arm A) or pemetrexed plus carboplatin (arm B). Primary end point was progression-free survival (PFS). A preplanned pooled analysis of the results of this study with those of the NVALT7 study was carried out to assess the impact of carboplatin added to pemetrexed in terms of overall survival (OS). Results From July 2007 to October 2009, 239 patients (arm A, n = 120; arm B, n = 119) were enrolled. Median PFS was 3.6 months for arm A versus 3.5 months for arm B (hazard ratio [HR], 1.05; 95% CI, 0.81 to 1.36; P = .706). No statistically significant differences in response rate, OS, or toxicity were observed. A total of 479 patients were included in the pooled analysis. OS was not improved by the addition of carboplatin to pemetrexed (HR, 90; 95% CI, 0.74 to 1.10; P = .316; P heterogeneity = .495). In the subgroup analyses, the addition of carboplatin to pemetrexed in patients with squamous tumors led to a statistically significant improvement in OS from 5.4 to 9 months (adjusted HR, 0.58; 95% CI, 0.37 to 0.91; P interaction test = .039). Conclusion Second-line treatment of advanced NSCLC with pemetrexed plus carboplatin does not improve survival outcomes as compared with single-agent pemetrexed. The benefit observed with carboplatin addition in squamous tumors may warrant further investigation.

Chronic pain is a debilitating condition that is associated with many common diseases; this places a major burden on the healthcare system. There are currently numerous analgesic agents available for the treatment of chronic pain. In general, the oral non-opioid analgesic, paracetamol, is recommended for the initial treatment of mild to moderate pain. Therapeutic doses of paracetamol do not appear to result in hepatotoxicity, although overdose may lead to acute liver failure. Current data suggest that paracetamol has acceptable gastrointestinal tolerability. Another class of non-opioid analgesic with confirmed efficacy for the treatment of chronic mild to moderate pain are non-steroidal anti-inflammatory drugs (NSAIDs), although this efficacy is offset by the potential of adverse gastrointestinal events. In particular, non-selective NSAIDs, also known as cyclooxygenase (COX) inhibitors, carry an increased risk of serious upper gastrointestinal complications, including ulcers, perforation and bleeding. The introduction of COX-2 inhibitors provided a NSAID-based option with improved gastrointestinal safety, but increased risk of cardiovascular effects. Opioids are powerful analgesic agents used to treat moderate to severe chronic pain. However, treatment with opioids is associated with a number of common adverse effects, including constipation, nausea or vomiting, pruritus, somnolence or cognitive impairment, dry mouth, tolerance or dependence and urinary retention. Although there are multiple strategies in place to manage adverse events that arise from both non-opioid and opioid analgesic therapy, a better understanding of the mechanisms involved in the development of specific drug-related adverse effects is required along with proper prescribing practices and adequate physician/patient education. Balanced against the adverse effects of pain management medications, there is a need to be mindful of the widespread, often serious, adverse consequences of poorly managed pain itself.

The prognostic potential of individual clinical and molecular parameters in stage II/III colon cancer has been investigated, but a thorough multivariable assessment of their relative impact is missing.Tumors from patients (N = 1404) in the PETACC3 adjuvant chemotherapy trial were examined for BRAF and KRAS mutations, microsatellite instability (MSI), chromosome 18q loss of heterozygosity (18qLOH), and SMAD4 expression. Their importance in predicting relapse-free survival (RFS) and overall survival (OS) was assessed by Kaplan-Meier analyses, Cox regression models, and recursive partitioning trees. All statistical tests were two-sided.MSI-high status and SMAD4 focal loss of expression were identified as independent prognostic factors with better RFS (hazard ratio [HR] of recurrence = 0.54, 95% CI = 0.37 to 0.81, P = .003) and OS (HR of death = 0.43, 95% CI = 0.27 to 0.70, P = .001) for MSI-high status and worse RFS (HR = 1.47, 95% CI = 1.19 to 1.81, P.001) and OS (HR = 1.58, 95% CI = 1.23 to 2.01, P.001) for SMAD4 loss. 18qLOH did not have any prognostic value in RFS or OS. Recursive partitioning identified refinements of TNM into new clinically interesting prognostic subgroups. Notably, T3N1 tumors with MSI-high status and retained SMAD4 expression had outcomes similar to stage II disease.Concomitant assessment of molecular and clinical markers in multivariable analysis is essential to confirm or refute their independent prognostic value. Including molecular markers with independent prognostic value might allow more accurate prediction of prognosis than TNM staging alone.

TO THEEDITOR:WereadwithinterestthearticlebyMullinsetal 1 reportingrecommendationsforclinicaltrialsofoff-labeldrugsusedto treat advanced-stage cancer. The 14 statements summarizing their recommendations are absolutely shareable and actually represent an excellentchecklistforimprovingqualityofclinicaltrials,nomatterthe field to which they are applied. However, we doubt that they can significantlyaffecttheoff-labelphenomenon,drivenbytheawareness ofsafety(atleastinthesettinginwhichthetreatmentisapproved)and the existence of true unmet medical needs. In 2006, we conducted a survey in 15 Italian centers, 2 collecting data on treatment of 644 patients corresponding to 1,053 prescriptions.Overall,199prescriptions(18.9%)wereofflabelbecauseofone of four reasons: drug used in a cancer different than that authorized (n 92; 46.2%), drug used within an inappropriate combination (n 41; 20.6%), drug used in a line of treatment different than the registeredone(n39;19.6%),anddrugusedinararetumor(n27; 13.6%). All the prescriptions of the first group had supporting scientific evidence (assessed by physicians different from those who wrote the prescription) from one or more randomized trials or several positivephaseIIstudiespublishedinmajoroncologyjournals.Therefore, clinical trials in this case had been performed but had not produced registration. In the second group, the only drug used in combination but approved as a single agent (at that time) was capecitabine (20 prescriptions; 10%). The remaining were drugs approved for use in combination that were instead used as single agents, possibly because of toxicity and consideration of patients’ conditions. From the perspectiveofMullinsetal, 1 thelattershouldprobablybetestedinclinical trials dedicated to unfit patients. The third group mostly (28 v 11 patient cases) included drugs that were used for lines of treatment subsequent to those for which they were registered, in common cancers such as breast and colorectal. It is hard to believe that proper randomized trials can be planned involving patients receiving their fourth or fifth line of treatment, primarily because of the difficulty of identifying a control arm that should probably be placebo or best supportive care. Finally, the fourth group included rare neoplasms, which represent a well-knownfield of debate because of the impossibility of applying common rules of clinical trial methodology. 3

Despite the availability of effective pain treatments, there are numerous barriers to effective management resulting in a large proportion of patients not achieving optimal pain control. Chronic pain is inadequately treated because of a combination of cultural, societal, educational, political and religious constraints. The consequences of inadequately treated pain are physiological and psychological effects on the patient, as well as socioeconomic implications. Unreasonable failure to treat pain is viewed as unethical and an infringement of basic human rights. The numerous barriers to the clinical management of pain vary depending on whether they are viewed from the standpoint of the patient, the physician, or the institution. Identification and acknowledgement of the barriers involved are the first steps to overcoming them. Successful initiatives to overcome patient, physician and institutional barriers need to be multifaceted in their approach. Multidisciplinary initiatives to improve pain management include dissemination of community-based information, education and awareness programmes to attempt to change attitudes towards pain treatment. A better awareness and insight into the problems caused by unrelieved pain and greater knowledge about the efficacy and tolerability of available pain management options should enable physicians to seek out and adhere to treatment guidelines, and participate in interventional and educational programmes designed to improve pain management, and for institutions to implement the initiatives required. Although much work is underway to identify and resolve the issues in pain management, many patients still receive inadequate treatment. Continued effort is required to overcome the known barriers to effective pain management.

Approximately 15% of colorectal cancers develop because of defective function of the DNA mismatch repair (MMR) system. We determined the association of MMR status with colon cancer recurrence and examined the impact of 5-fluorouracil (FU)-based adjuvant therapy on recurrence variables.We included stage II and III colon carcinoma patients (n = 2141) who were treated in randomized trials of 5-FU-based adjuvant therapy. Tumors were analyzed for microsatellite instability by polymerase chain reaction and/or for MMR protein expression by immunohistochemistry to determine deficient MMR (dMMR) or proficient MMR (pMMR) status. Associations of MMR status and/or 5-FU-based treatment with clinicopathologic and recurrence covariates were determined using χ(2) or Fisher Exact or Wilcoxon rank-sum tests. Time to recurrence (TTR), disease-free survival (DFS), and overall survival (OS) were analyzed using univariate and multivariable Cox models, with the latter adjusted for covariates. Tumors showing dMMR were categorized by presumed germline vs sporadic origin and were assessed for their prognostic and predictive impact. All statistical tests were two-sided.In this study population, dMMR was detected in 344 of 2141 (16.1%) tumors. Compared with pMMR tumors, dMMR was associated with reduced 5-year recurrence rates (33% vs 22%; P.001), delayed TTR (P.001), and fewer distant recurrences (22% vs 12%; P.001). In multivariable models, dMMR was independently associated with delayed TTR (hazard ratio = 0.72, 95% confidence interval = 0.56 to 0.91, P = .005) and improved DFS (P = .035) and OS (P = .031). In stage III cancers, 5-FU-based treatment vs surgery alone or no 5-FU was associated with reduced distant recurrence for dMMR tumors (11% vs 29%; P = .011) and reduced recurrence to all sites for pMMR tumors (P.001). The dMMR tumors with suspected germline mutations were associated with improved DFS after 5-FU-based treatment compared with sporadic tumors where no benefit was observed (P = .006).Patients with dMMR colon cancers have reduced rates of tumor recurrence, delayed TTR, and improved survival rates, compared with pMMR colon cancers. Distant recurrences were reduced by 5-FU-based adjuvant treatment in dMMR stage III tumors, and a subset analysis suggested that any treatment benefit was restricted to suspected germline vs sporadic tumors.

Colon cancer is the third most common cause of cancer diagnosed in the United States, and the second leading cause of cancer death. Although rates of the disease have been going down in recent years, results can be further improved. About 90% of people whose colon cancer is caught before it has spread to nearby lymph nodes or organs survive more than 5 years after diagnosis. However, only 10% of patients whose cancer has spread to distant parts of the body survive 5 years. Diagnosis at an early stage aims to reduce the incidence of tumors in an advanced stage and hence mortality.We analyzed the literature to understand what new tests to use and new directions to take.There is evidence to support the screening of average-risk individuals over the age of 50 years to detect and prevent colon cancer. Screening of these people can only reduce mortality rates, not incidence, identifying cancer at an early stage and through the removal of clinically significant adenomas. Patient preferences and availability of resources play an important role in the selection of screening tests, because each test presents specific risks and specific benefits.The American Cancer Society has added two new screening methods, CT colonography, also known as virtual colonoscopy, and stool DNA tests to the list of options. A small revolution in screening for colon cancer is in the making. The availability of these less invasive tests should increase the number of people who undergo regular screening.

OBJECTIVE: To investigate the influence of socioeconomic status (SES) on Breslow thickness, disease-free survival, and overall survival in patients with stage I-II primary cutaneous melanoma (PCM). PATIENTS AND METHODS: The study consists of all consecutive patients who were diagnosed as having PCM and were treated and followed up at our hospital between November 1, 1998, and July 31, 2009. Pathologic and sociodemographic characteristics of the patients were obtained. We categorized SES into 3 levels: low (manual employees and skilled/unskilled workers, including farmers, with primary education level), middle (nonmanual employees and clerks with middle education level), and high (professionals, executives, administrators, and entrepreneurs with tertiary education). RESULTS: A total of 1443 consecutive patients were evaluated. In a multivariate logistic regression analysis, sex (female vs male: odds ratio [OR], 1.37; 95% confidence interval [CI], 1.08-1.75), SES (high vs middle: OR, 1.27; 95% CI, 0.96-1.69; high vs low: OR, 1.73; 95% CI, 1.26-2.38), age (

Background. Using a wide range of interferon (IFN) doses and schedules, a number of authors have found them to be active against neuroendocrine tumors. Methods. To verify the clinical activity of IFN, 49 evaluable patients with advanced stage low- and intermediate-grade neuroendocrine tumors were treated with recombinant IFN-alpha-2a at a daily dose of 6 × 106 IU intramuscularly for 8 weeks, and 3 times weekly thereafter. The predominant histotype was carcinoid, although a few cases had malignant islet cell tumors, medullary thyroid carcinoma, Merkel cell carcinoma, or other neuroendocrine tumors. All of the patients had measurable lesions and most had multiple sites. Carcinoid syndrome was present in 14 cases. Results. After a median treatment duration of 6 months, complete regression was achieved in 1 of the 7 cases of medullary thyroid carcinoma, and partial response was observed in 4 of 34 carcinoids. Response duration ranged from 1–11 months. Control of the syndrome was obtained in nine patients and a greater than or equal to 50% reduction of 5-hydroxyindoleacetic acid in eight patients. The treatment was well-tolerated. The most frequently observed side effects were fever, flu-like syndrome, and leukopenia. After 12 months of recombinant IFN-alpha-2a, 15 cases in progression and 4 with stable disease or partial response received another treatment (either radiometabolic therapy with I131 metaiodobenzylguanidine or polychemotherapy with streptozotocin plus epirubicin). Conclusions. The use of recombinant IFN-alpha-2a at these doses is well-tolerated and effective in controlling carcinoid syndrome (complete remission plus partial remission, 64%), although it has limited activity on tumor growth inhibition. No definitive data can be given for the other protocol treatments.

To clarify the role of epidermal growth factor receptor (EGFR) promoter methylation in primary colorectal cancers and corresponding metastases and its relationship to EGFR expression.Formalin-fixed tumor samples (primary site and metastasis)from colorectal cancer patients were analyzed for EGFR promoter methylation and EGFR immunohistochemistry expression.Among the 63 assessable patients, 25 cases (39.7%) showed EGFR promoter methylation. Forty-two primary colorectal tumors and corresponding metastases were available for paired analysis of EGFR methylation status. EGFR methylation status of the primary tumor was in accordance with that of metastasis in 29 patients (69%). In contrast, 7 patients (50%) with EGFR promoter methylation in the primary tumor showed unmethylated EGFR in metastasis, and 6 metastases (46%) showed EGFR promoter hypermethylation derived from unmethylated EGFR primary tumors. Lack of EGFR protein expression was observed in 8 EGFR promoter methylated primary tumors (44%) and in 7 EGFR promoter methylated metastatic sites (44%).EGFR promoter hypermethylation does not seem to represent a rare event in colorectal cancer and may be present differently in different tumor sites. These findings may be relevant to further studies investigating the role of EGFR in colorectal cancer patients.

We present the rationale and study design of the Tarceva Italian Lung Optimization trial phase III, multicenter, open-label, randomized trial on efficacy of second-line therapies in different subgroups of non-small-cell lung cancer (NSCLC) patients identified using molecular and clinical evaluations. To date, we can assume that advanced NSCLC epidermal growth factor receptor (EGFR)-mutated patients benefit from EGFR tyrosine kinase inhibitors, such as gefitinib and erlotinib, whereas their role in the treatment of patients who do not have EGFR mutations is controversial. The aim of this study is to assess whether it is possible to optimize second-line treatment in NSCLC patients with absence of EGFR mutations. Moreover, the predictive value of the K-ras mutation, EGFR protein expression, and EGFR gene copy number, as well as a smoking habit and histotype for determining a different effect of erlotinib compared with chemotherapy will be assessed in patients who do not have EGFR mutations. The primary endpoint is overall survival; the secondary endpoints are progression-free survival, response rate, quality of life, and toxicity. We have planned to collect blood samples to identify different prognosis-related polymorphisms and to assess their sensitivity and specificity in the detection of EGFR and K-ras mutations with respect to histologic samples.

The incidence of Cholangiocellular carcinoma (CCA) is increasing, due to a sharp increase of the intrahepatic form. Evidence-ascertained risk factors for CCA are primary sclerosing cholangitis, Opistorchis viverrini infection, Caroli disease, congenital choledocal cist, Vater ampulla adenoma, bile duct adenoma and intra-hepatic lithiasis. Obesity, diabetes, smoking, abnormal biliary-pancreatic junction, bilio-enteric surgery, and viral cirrhosis are emerging risk factors, but their role still needs to be validated. Patients with primary sclerosing cholangitis should undergo surveillance, even though a survival benefit has not been clearly demonstrated. CCA is most often diagnosed in an advanced stage, when therapeutic options are limited to palliation. Diagnosis of the tumor is often difficult and multiple imaging techniques should be used, particularly for staging. Surgery is the standard of care for resectable CCA, whilst liver transplantation should be considered only in experimental settings. Metal stenting is the standard of care in inoperable patients with an expected survival >4 months. Gemcitabine or platinum analogues are recommended in advanced CCA whilst there are no validated neo-adjuvant treatments or second-line chemotherapies. Even though promising results have been obtained in CCA with radiotherapy, further randomized controlled trials are needed.

Clinical data suggested that a regimen incorporating doxorubicin to 5-fluorouracil (5-FU) and cisplatin may be more effective but probably quite toxic for advanced gastric cancer patients. With the aim to maintain efficacy while reducing toxicity, we compared the activity and safety of a combination of 5-FU, cisplatin and pegylated liposomal doxorubicin with a combination of 5-FU, cisplatin and mitomycin-C.Seventy-eight patients were randomised to receive 5-FU (400 mg/m(2) bolus, 600 mg/m(2) 22 h continuous infusion day 1 and 2) and cisplatin (50 mg/m(2) day 1) every 2 weeks, combined either with pegylated liposomal doxorubicin (20 mg/m(2) day 1 every two weeks) (arm A) or mitomycin-C (7 mg/m(2) every 6 weeks) (arm B).The overall response rate was 64.1% in arm A and 38.5% in arm B (P = 0.041). The median time to tumour progression and overall survival were 7.93 and 5.14 months (P = 0.04) and 12.1 and 8.3 months (P = 0.02) in arm A and B, respectively. Fourteen patients in arm A and 18 patients in arm B experienced a grade 3/4 toxic effect.A combination of pegylated liposomal doxorubicin, cisplatin and 5-FU can be safely administered in gastric cancer patients with a promising efficacy profile.

Purpose Mutations within the KRAS proto-oncogene have predictive value but are of uncertain prognostic value in the treatment of advanced colorectal cancer. We took advantage of PETACC-3, an adjuvant trial with 3,278 patients with stage II to III colon cancer, to evaluate the prognostic value of KRAS and BRAF tumor mutation status in this setting. Patients and Methods Formalin-fixed paraffin-embedded tissue blocks (n = 1,564) were prospectively collected and DNA was extracted from tissue sections from 1,404 cases. Planned analysis of KRAS exon 2 and BRAF exon 15 mutations was performed by allele-specific real-time polymerase chain reaction. Survival analyses were based on univariate and multivariate proportional hazard regression models. Results KRAS and BRAF tumor mutation rates were 37.0% and 7.9%, respectively, and were not significantly different according to tumor stage. In a multivariate analysis containing stage, tumor site, nodal status, sex, age, grade, and microsatellite instability (MSI) status, KRAS mutation was associated with grade (P = .0016), while BRAF mutation was significantly associated with female sex (P = .017), and highly significantly associated with right-sided tumors, older age, high grade, and MSI-high tumors (all P < 10−4). In univariate and multivariate analysis, KRAS mutations did not have a major prognostic value regarding relapse-free survival (RFS) or overall survival (OS). BRAF mutation was not prognostic for RFS, but was for OS, particularly in patients with MSI-low (MSI-L) and stable (MSI-S) tumors (hazard ratio, 2.2; 95% CI, 1.4 to 3.4; P = .0003). Conclusion In stage II-III colon cancer, the KRAS mutation status does not have major prognostic value. BRAF is prognostic for OS in MS-L/S tumors.

Background K-RAS wild type colorectal tumors show an improved response rate to anti-EGFR monoclonal antibodies. Nevertheless 70% to 40% of these patients still does not seem to benefit from this therapeutic approach. FISH EGFR GCN has been previously demonstrated to correlate with clinical outcome of colorectal cancer treated with anti-EGFR monoclonal antibodies. CISH also seemed able to provide accurate EGFR GCN information with the advantage of a simpler and reproducible technique involving immunohistochemistry and light microscopy. Based on these findings we investigated the correlation between both FISH and CISH EGFR GCN and clinical outcome in K-RAS wild-type colorectal cancer treated with irinotecan-cetuximab. Methods Patients with advanced K-RAS wild-type, colorectal cancer receiving irinotecan-cetuximab after failure of irinotecan-based chemotherapy were eligible. A cut-off value for EGFR GCN of 2.6 and 2.12 for FISH and CISH respectively was derived from ROC curve analysis. Results Forty-four patients were available for analysis. We observed a partial remission in 9 (60%) and 2 (9%) cases with a FISH EGFR GCN ≥ 2.6 and < 2.6 respectively (p = 0.002) and in 10 (36%) and 1 (6%) cases with a CISH EGFR GCN ≥ 2.12 and < 2.12 respectively (p = 0.03). Median TTP was 7.7 and 6.4 months in patients showing increased FISH and CISH EGFR GCN whereas it was 2.9 and 3.1 months in those with low FISH and CISH EGFR GCN (p = 0.04 and 0.02 respectively). Conclusion FISH and CISH EGFR GCN may both represent effective tools for a further patients selection in K-RAS wild-type colorectal cancer treated with cetuximab.

This is the first phase III randomised trial to evaluate maintenance immunotherapy in metastatic renal cell cancer (mRCC). Patients were randomised to receive treatment with a 4-week cycle of subcutaneous low doses IL-2 + IFN in months 1, 3 and 5, and then every 3 months until the first documented disease progression (arm A, suspension), or the same regimen, with chronic maintenance of immunotherapy, regardless of tumour response, until death or intolerable toxicity (arm B, maintenance). The primary endpoint was overall survival (OS); secondary endpoints were time from first progression to death (TFPTD) and tolerability. One hundred and eighty-three patients were enrolled between January 1998 and November 2003. After a median follow-up of 53.9 months, response rate, median OS and median TFPTD were 14.7% (6.3% CR) versus 11.3% (5.5% CR), 14 versus 14 months, 6 versus 5 months, in arms A and B, respectively with no significant differences between the groups. Cox regression analysis showed that the use of chemotherapy after first progression (HR 0.54; 95% CI 0.35-0.86; p = 0.008), PS = 0 (HR 0.53; 95% CI 0.35-0.81; p = 0.001) and female gender (HR 0.63; 95% CI 0.41-0.98; p = 0.038) were significantly associated with a longer TFPTD; treatment arm was not significant (HR 0.88; 95% CI 0.60-1.31; p = 0.54). Toxicity was mainly limited to WHO grades 1 or 2. Chronic maintenance immunotherapy after disease progression is feasible, but does not significantly increase OS or the TFPTD.

Purpose Limited data are available on the time course of treatment failures (recurrence and/or death), the nature and duration of adjuvant treatment benefit, and long-term recurrence rates in patients with resected stage II and III colon cancer. Methods The data set assembled by the Adjuvant Colon Cancer Endpoints Group, a collection of individual patient data from 18 trials and more than 20,800 patients testing fluorouracil-based adjuvant therapy in patients with stage II or III colon cancer, was analyzed. Results A significant overall survival (OS) benefit of adjuvant therapy was consistent over the 8-year follow-up period. The risk of recurrence in patients treated with adjuvant chemotherapy never exceeds that of control patients, signifying that adjuvant therapy cures some patients, as opposed to delaying recurrence. After 5 years, recurrence rates were less than 1.5% per year, and after 8 years, they were less than 0.5% per year. Significant disease-free survival (DFS) benefit from adjuvant chemotherapy was observed in the first 2 years. After 2 years, DFS rates in treated and control patients were not significantly different, and after 4 years, no trend toward benefit was demonstrated. This benefit was primarily driven by patients with stage III disease. Conclusion Adjuvant chemotherapy provides significant DFS benefit, primarily by reducing the recurrence rate, within the first 2 years of adjuvant therapy with some benefit in years 3 to 4, translating into long-term OS benefit. This reflects the curative role of chemotherapy in the adjuvant setting. After 5 years, recurrence rates in patients treated on clinical trials are low, and after 8 years, they are minimal; thus, long-term follow-up for recurrence is of little value.

Purpose No structured modality for providing information and support to patients in oncology wards has been validated in clinical trials. Methods This is a pragmatic, two-arm, cluster randomized trial, with the oncology ward as random assignment unit. Centers were allocated to implement a Point of Information and Support (PIS) or to a control group. The PIS included a library for cancer patients and a specifically trained oncology nurse. End points, measured at patient level, were psychological distress and satisfaction with received information. Both intent-to-treat and per-protocol analyses considering clustering were performed. Results Thirty-eight Italian cancer centers were randomly assigned, and 6 months after PIS creation, 3,286 unselected, consecutive cancer patients were surveyed (1,654 in the experimental group and 1,632 in the control group). Three thousand one hundred ninety-seven (97%) questionnaires were collected and deemed valid. Fifty-two percent of centers (11 of 21 centers) in the experimental arm did not implement the PIS in accordance with the protocol. Overall, 34% of patients showed moderate to severe psychological distress, and only 9% declared dissatisfaction. Intent-to-treat analysis did not yield significant differences. Although the per-protocol analysis did show a reduction in psychological distress (28.9% for functioning PIS v 33.3% for no PIS) and dissatisfaction (6.4% for functioning PIS v 9.3% for no PIS), differences did not reach significance. Conclusion This is the first cluster randomized trial aiming to demonstrate that a structured modality of providing information reduces psychological distress. We did not find this, but we believe results should be interpreted cautiously, particularly because of the low compliance with PIS implementation. Context analysis preceding such interventions is essential.

Purpose The primary objective of this randomized, multicenter, phase III trial was to investigate whether the addition of irinotecan to the de Gramont infusional fluorouracil (FU)/leucovorin (LV) adjuvant regimen (LV5FU2) would improve disease-free survival (DFS) in patients with stage III colon cancer. Patients and Methods After curatively intentioned surgery, patients with stage II and III colon cancer were randomly allocated surgery to receive LV5FU2 (LV 200 mg/m2 as a 2-hour infusion, followed by FU; as a 400 mg/m2 bolus and then a 600 mg/m2 continuous infusion over 22 hours, days 1 and 2, every 2 weeks for 12 cycles: de Gramont regimen) with or without irinotecan (180 mg/m2 as a 30- to 90-minute infusion, day 1, every 2 weeks). In total, 260 (7.9%) of 3,278 patients received an alternative high-dose infusional FU/LV regimen (Arbeitsgemeinschaft Internische Onkologie regimen) with or without irinotecan. Results The principal efficacy analysis was based on 2,094 treated patients with stage III disease, randomly allocated in the LV5FU2 strata. After a median follow-up of 66.3 months, the 5-year DFS rate was 56.7% with irinotecan/LV5FU2 and 54.3% with LV5FU2 alone (primary end point: log-rank P = .106). Combining irinotecan with LV5FU2 did not significantly improve overall survival in this patient group compared with LV5FU2 alone (5-year rate 73.6% v 71.3%, respectively; log-rank P = .094). The addition of irinotecan to LV5FU2 was associated with an increased incidence of grade 3 to 4 GI events and neutropenia. Conclusion Irinotecan added to LV5FU2 as adjuvant therapy did not confer a statistically significant improvement in DFS or overall survival in patients with stage III colon cancer compared with LV5FU2 alone.

Aim of the study To investigate the incidence and clinical implications of venous thromboembolism (VTE) in advanced colorectal cancer (ACC) patients treated and followed-up through a prospective randomised trial, comparing FOLFIRI chemotherapy given as an intermittent or as a continuous schedule. Patients, materials and methods A total of 266 patients were randomised by 15 experimental centres: 168 (63.2%) were males, median age: 64.6 years, age range: 37–76 years. Almost all (95.5%) patients had metastatic disease, while the remainder were classified with locally advanced irresectable disease. For 138 (51.9%) of the patients, the chemotherapy treatment was intermittent FOLFIRI and the remaining patients received continuous treatment. All toxicities, including VTE, were prospectively collected. Results During the study protocol, the central data management gathered two cases of VTE. Our analysis retrieved 27 (10.2%) patients who developed a VTE, almost all (89%) during the course of chemotherapy treatment: 20 out of 27 during FOLFIRI, the remaining 7 during following lines or follow-up. VTE was the most frequent grade 3/4 toxicity. The incidence of VTE was significantly increased in the patients receiving continuous rather than intermittent treatment (HR 2.67, 95% CI 1.17–6.10; p Conclusion VTE is a common complication among advanced colorectal cancer patients and yet this type of toxicity is widely underestimated. In this randomised trial, VTE was the most frequent grade 3/4 toxicity. Use of an intermittent schedule is associated with a reduced risk of developing VTE.

Summary Purpose: This multicenter phase II study was designed to assess the efficacy of the alternating schedule of tomudex with methotrexate (MTX)/5-fluorouracil (5-FU)/leucovorin (LV) in first-line chemotherapy for metastatic colorectal cancer. Patients and methods: Patients with histologically proven metastatic colorectal cancer and at least one bidimensionally measurable lesion, aged 18-70, with performance status =S 2, normal baseline biological values, and no prior chemotherapy, were selected. Treatment was tomudex 3 mg/m 2 and, after two weeks, MTX, 200 mg/m 2 by 30' infusion after hydration with 1500 ml saline solution, followed on day 2 by 5-FU, 600 mg/m 2 and leucovorin, orally, 15 mg for six times every 6 hours, beginning 24 hours after MTX. Cycles were repeated every four weeks. Tumor response assessment was performed after three cycles. Results: Thirty-four patients were enrolled in this study, of whom twenty-four had liver metastases, nine local relapse, five lymph node involvement, four lung metastases, and three peritoneal carcinomatosis. Four patients achieved objective responses (one complete and three partial), for an overall response rate of 12% (95% CI: 0%-22%). Twelve patients had stable disease and 18 progressed on therapy. Median survival for all patients was 13 months. Two patients experienced grade 3 WHO neutropenia while hepatotoxicity was reported in 13 patients (6 grade 1, 3 grade 2, 3 grade 3, 1 grade 4), suggesting that this combination could increase hepatic toxicity in comparison to tomudex or MTX/5-FU alone. Conclusions: Our results suggest that this regimen does not warrant further investigation in advanced colorectal cancer patients, at least not with this schedule and doses.

In the recent X-ACT (Xeloda in Adjuvant Colon cancer Therapy) trial, oral capecitabine (Xeloda) demonstrated superior efficacy and an improved safety profile compared with infused fluorouracil + leucovorin (folinic acid) [FU+LV] in patients with Dukes' C colorectal cancer. We used the X-ACT results to determine the cost effectiveness of capecitabine compared with FU+LV from the perspective of the Italian National Health Service (NHS).Medical resource use data were collected throughout the treatment period. Unit costs for drug administration, hospitalization, emergency room visits and concomitant medications were obtained using Italian published sources. A health-state transition model was used to estimate the incremental cost-effectiveness ratio per quality-adjusted life-month (QALM) gains in the intent-to-treat population (1004 and 983 patients in the capecitabine and FU+LV arms, respectively). Costs and effectiveness were discounted at 3.5%. Costs were calculated in euros (2005 values).Administration of capecitabine required fewer clinic visits per patient than FU+LV (7.35 vs 28.0, respectively). Mean acquisition costs per patient for capecitabine were higher than for FU+LV (euro 2533 vs euro 231, respectively), but this difference was offset by the difference in mean chemotherapy administration costs per patient for FU+LV (euro 4338, compared with euro 152 for capecitabine). Mean total hospital days and medication costs for treatment-related adverse events were higher for FU+LV than for capecitabine (euro 352 vs euro 78, respectively). The cost of emergency room visits for the treatment of adverse events did not differ between the treatment groups. With respect to the lifetime horizon, compared with FU+LV, capecitabine is projected to increase QALMs by a mean 6.5 months, with overall cost savings of euro 2234 over the treatment period. These findings show that capecitabine is an economically dominant treatment in this setting.Adjuvant capecitabine for patients with Dukes' C colon cancer has the same activity in terms of outcome when compared with FU+LV but is a lower cost option from the economic perspective of the Italian NHS.

Introduction: Pemetrexed has established efficacy, and is the backbone for chemotherapy in patients with malignant pleural mesothelioma (MPM). An International Expanded Access Program provided >3000 mesothelioma patients with access to single-agent pemetrexed or pemetrexed plus platinum analogs (cisplatin or carboplatin) in 13 countries. In this article, we report the safety and efficacy data of MPM patients who were treated with single-agent pemetrexed (n = 812). Methods: Patients with histologically confirmed MPM, not amenable to curative surgery, received pemetrexed (500 mg/m(2)) once (day 1) every 21 days with standard premedication and vitamin supplementation. Investigator-determined response and survival data were recorded at the end of study participation. Myelosuppression data were also collected. Results: All 812 MPM patients (319 chemonaive; 493 pretreated) received single-agent pemetrexed (>= 1 dose) and were evaluated for safety. A total of 643 patients (247 chemonaive, 396 pretreated) were evaluated for efficacy. Of the chemonaive patients evaluated for efficacy (n = 247), the overall response rate was 10.5%, median time to progressive disease (TTPD) was 6.0 months, and median survival was 14.1 month. Of the pretreated patients evaluated for efficacy (n = 396), the overall response rate was 12.1%, median TTPD was 4.9 months, and the median survival was not estimable due to high censoring. Common terminology criteria grade 3/4 hematologic toxicity was mild in both groups, with neutropenia (= 54.7%, and mild hematologic toxicity.

Background: Erlotinib demonstrated significantly prolonged survival versus placebo in patients with advanced NSCLC who had progressed after standard chemotherapy. TRUST is a phase IV trial initiated to provide erlotinib access to patients with advanced NSCLC. We report the interim analysis for patients enrolled in the TRUST trial in Italy. Patients and methods: Eligible patients had stage IIIB/IV NSCLC and had failed or were unsuitable for chemotherapy. Erlotinib (150 mg/day orally) was given until disease progression or unacceptable toxicity. Patients were monitored monthly. Results: At time of this analysis, data from 651 patients were available. Patient characteristics were: median age 66 years (range 30-87), male 69%, former or current smoker 71%, ECOG PS 0-1 81%, adenocarcinoma histology 52% and stage IV 82%. Erlotinib was administered as first-, second-, third- or other-line in 12, 45,43 and

Background Single-agent gemcitabine (GEM) is a standard treatment for advanced and metastatic pancreatic cancer. This study examines the question whether GEM-based combination chemotherapy can further improve treatment efficacy. Methods A meta-analysis was performed to evaluate randomized trials comparing GEM versus GEM+X (X = cytotoxic agent). Fifteen trials including 4465 patients were eligible for an analysis of overall survival, the primary end-point of this investigation. Results The meta-analysis revealed a significant survival benefit for GEM+X with a pooled hazard ratio (HR) of 0.91 (95% CI: 0.85 – 0.97, p = 0.004). The overall test for heterogeneity resulted in p = 0.82 (I2 = 0%). The analysis of platinum-based combinations indicated a HR of 0.85 (95% CI: 0.76 – 0.96, p = 0.010), while for fluoropyrimidine-based combinations the HR was 0.90 (95% CI: 0.81 – 0.99, p = 0.030). No risk reduction was observed in the group of trials combining GEM with irinotecan, exatecan or pemetrexed (HR = 0.99). A meta-analysis of the trials with adequate information on baseline performance status (PS) was performed in five trials with 1682 patients. This analysis indicated that patients with a good PS had a marked survival benefit when receiving combination chemotherapy (HR = 0.76; 95% CI: 0.67 – 0.87; p < 0.0001). By contrast, application of combination chemotherapy to patients with an initially poor PS appeared to be ineffective (HR = 1.08; 95% CI: 0.90 – 1.29, p = 0.40). Conclusion The meta-analysis of randomized trials indicated a significant survival benefit when GEM was either combined with platinum analogs or fluoropyrimidines. Based on a preliminary subgroup analysis (representing 38% of all patients included in this meta-analysis), pancreatic cancer patients with a good PS appear to benefit from GEM-based cytotoxic combinations, whereas patients with a poor PS seem to have no survival benefit from combination chemotherapy.

Purpose Adjuvant systemic chemotherapy administered after surgical resection of colorectal cancer metastases may reduce the risk of recurrence and improve survival, but its benefit has never been demonstrated. Two phase III trials (Fédération Francophone de Cancérologie Digestive [FFCD] Trial 9002 and the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada Clinical Trials Group/Gruppo Italiano di Valutazione Interventi in Oncologia [ENG] trial) used a similar design and showed a trend favoring adjuvant chemotherapy, but both had to close prematurely because of slow accrual, thus lacking the statistical power to demonstrate the predefined difference in survival. We report here a pooled analysis based on individual data from these two trials. Patients and Methods After complete resection of colorectal liver or lung metastases, patients were randomly assigned to chemotherapy (CT arm; fluorouracil [FU] 400 mg/m2 administered intravenously [IV] once daily plus dl-leucovorin 200 mg/m2 [FFCD] × 5 days or FU 370 mg/m2 plus l-leucovorin 100 mg/m2 IV × 5 days [ENG] for six cycles at 28-day intervals) or to surgery alone (S arm). Results A total of 278 patients (CT, n = 138; S, n = 140) were included in the pooled analysis. Median progression-free survival was 27.9 months in the CT arm as compared with 18.8 months in the S arm (hazard ratio = 1.32; 95% CI, 1.00 to 1.76; P = .058). Median overall survival was 62.2 months in the CT arm compared with 47.3 months in the S arm (hazard ratio = 1.32; 95% CI, 0.95 to 1.82; P = .095). Adjuvant chemotherapy was independently associated with both progression-free survival and overall survival in multivariable analysis. Conclusion This pooled analysis shows a marginal statistical significance in favor of adjuvant chemotherapy with an FU bolus–based regimen after complete resection of colorectal cancer metastases.

International audience; Knowledge of the biology and management of rectal cancer continues to improve. A multidisciplinary approach to a patient with rectal cancer by an experienced expert team is mandatory, to assure optimal diagnosis and staging, surgery, selection of the appropriate neo-adjuvant and adjuvant strategy and chemotherapeutic management. Moreover, optimal symptom management also requires a dedicated team of health care professionals. The introduction of total mesorectal excision has been associated with a decrease in the rate of local failure after surgery. High quality surgery and the achievement of pathological measures of quality are a prerequisite to adequate locoregional control. There are now randomized data in favour of chemoradiotherapy or short course radiotherapy in the preoperative setting. Preoperative chemoradiotherapy is more beneficial and has less toxicity for patients with resectable rectal cancer than postoperative chemoradiotherapy. Furthermore chemoradiotherapy leads also to downsizing of locally advanced rectal cancer. New strategies that decrease the likelihood of distant metastases after initial treatment need be developed with high priority. Those involved in the care for patients with rectal cancer should be encouraged to participate in well-designed clinical trials, to increase the evidence-based knowledge and to make further progress. Health care workers involved in the care of rectal cancer patients should be encouraged to adopt quality control processes leading to increased expertise.

632 Background: FOLFOX/FOLFIRI are effective as first-line treatment but FOLFOX might be more effective in second line. The optimal first-line in RAS wild type mCRC is still unclear even after 2 trials comparing chemotherapy with bevacizumab or cetuximab. While bevacizumab seems to loose efficacy across treatment lines, cetuximab has a similar activity across all treatment lines. It might be a better choice for the third-line in the view of an optimal sequence strategy. We designed a phase III randomised trial to compare two different treatment sequences of cetuximab and FOLFOX in mCRC patients refractory to FOLFIRI/bevacizumab first-line. Methods: Pts were randomized to receive Irinotecan/Cetuximab as 2nd line followed by FOLFOX-4 as 3rdline (Arm A) or the inverse sequence. Primary endpoint was progression free survival (PFS); secondary endpoints were overall survival and toxicity. 101 events were required in order to detect an hazard ratio of 0.57, translating in an increase of median PFS from 4 to 7 months (two-sided type I error 5%, power 80%). Results: 110 mCC pts were enrolled in this trial: 64 pts were males and 46 females with a mean age of 61 years. Efficacy results are reported in the table. Treatment was well tolerated with a low number of serious adverse reactions (2 in each treatment arm). Conclusions: Cetuximab is less effective immediately after bevacizumab. This is in accordance with data suggesting that EGFR inhibition is not active after VEGF blockade. The sequence of biological agents seems to be more relevant than the first-line choice. In RAS wild type patients progressing after a first line bevacizumab based therapy cetuximab should be given as first line or third line. Clinical trial information: NCT01030042. [Table: see text]

AIM: To improve the results of New therapeutic strategies in hepatocellular carcinoma (HCC). We have conducted a phase II study with pegylated liposomal doxorubicin (PLD), 5-fluorouracil (5FU) and folinic acid (FA). METHODS: Thirty-one patients with hystologically-confirmed, inoperable HCC, received combination chemotherapy with PLD 25 mg/mq on d 1, 5FU 1200 mg/mq in 48 h continuous infusion, and oral FA 30 mg on d 1 and 2 every 3 wk until disease progression or intolerable toxicity. RESULTS: The median age was 65 years (range 41-82) and 28 patients were hepatitis C virus seropositive (90%). The majority of patients were Child-Pugh Class B (55%). Two patients showed a partial response (PR), and 16 had stable disease (SD). With a median follow-up of 14 mo, the median time to progression of all evaluable patients was 4 mo (95% CI 1.7-7). Median overall survival was 9 mo (95% CI 3-24 mo). After 1 year, 9 of 18 PR/SD patients were alive. Chemotherapy was well tolerated. CONCLUSION: PLD/FU/FA combination seems capable of achieving durable stabilization of HCC. The manageable toxicity supports a role for combination with other anticancer agents.

Purpose The traditional end point for colon adjuvant clinical trials is overall survival (OS). We previously validated disease-free survival (DFS) after 3-year follow-up as an excellent predictor of 5-year OS results. Here we explore shorter term DFS and OS end points, as well as stage dependency. Methods Individual patient data from 18 phase III trials including 43 arms and 20,898 patients were pooled. Association measures included correlation of event rates within arms, correlation of hazard ratios (HRs) between arms, trial level significance comparisons (via log-rank testing), and a formal surrogacy model. Results DFS at earlier times was less accurate in predicting OS than 3-year DFS, but 2-year DFS remained a strong predictor. DFS with 1-year minimum follow-up demonstrated perfect negative predicted value; all trials negative at 1 year for DFS were negative for 5-year OS. OS with 3-year minimum follow-up was also an excellent predictor for 5-year OS; OS at earlier time points provided inaccurate prediction. The association between 3-year DFS and 5-year OS was greater for stage III patients; correlation of HR within trials was 0.92 (95% CI, 0.85 to 0.95) for stage III patients and 0.70 (95% CI, 0.44 to 0.80) for stage II patients. Conclusion DFS outcomes after 2- or 3-year median follow-up are excellent predictors of 5-year OS. DFS outcomes are appropriate for trials in which the majority of patients are stage III. DFS after 2- or 3-year median follow-up should be considered as the primary end point in future colon adjuvant trials.

Aims and background Cancer is an age-related disease, and the increase in life expectancy will lead to a progressive increase of cancer cases in the elderly (≥70 years of age). We have created a group called GONG (Gruppo Oncologico Geriatrico) to apply cancer geriatric assessment in elderly cancer patients, in order to select which of them are eligible for oncological treatment or supportive care only. Patients and methods We applied this model to evaluate 153 patients from March 2004 to August 2005. Our model included three categories of patients: frail (at least one of the following items: Activities of Daily Living scale Results Applying the aforementioned criteria, we found 30 borderline, 14 frail and 109 non-frail patients. Statistical analysis showed a significant difference in mortality between frail and non-frail patients (P Conclusions Our model was thus able to identify patients at higher risk of death. These results confirm the importance of cancer geriatric assessment also for the clinical evaluation of oncological patients. Additional randomized studies with a larger number of patients, also in an adjuvant setting, should be performed to confirm the effectiveness of this approach.

Colorectal cancer is the second most common type of cancer in industrialized countries. Despite improved resection procedures and optimized adjuvant chemotherapy, local or distant recurrences occur in 22-25% of patients with stage II/III colon cancer. Approximately 30% of patients have advanced disease at presentation. The liver is the most common site of colorectal metastases and, interestingly, 20-30% of patients with colorectal cancer have liver-only metastases. The combined modality of chemotherapy and surgery increases overall survival and the chance of cure for metastatic patients, even if there is no agreement in terms of the best schedule and how long the treatment must last. In this paper, we review the role and the rationale of neoadjuvant chemotherapy within a multimodal approach, and discuss remaining questions and future directions.

4544 Background: Cetuximab, an EGFR antibody inhibitor, has been shown to increase the activity of gemcitabine (GEM) in APC. Based on data from randomised trials and meta-analyses suggesting that the combination of a GEM with a platinum analog significantly improves survival as compared to GEM alone, we assessed the activity and feasibility of a combination of GEM/cisplatin (CDDP) plus cetuximab. Methods: Multicenter, randomised two-arm phase II trial: GEM 1,000 mg/m2 day 1,8 and CDDP 35 mg/m2 day 1,8 every 21 days alone or in combination with cetuximab 250 mg/m2 weekly after a loading dose of 400 mg/m2. Treatment was limited to a maximum of 9 cycles. With 37 patients in each arm the power was 90% to select the truly better arm if the true between arm difference in response rate (RECIST) is at least 15%. The study was open for accrual until June 2005. Results: We present here the results of 74 patients including in the study. In all the patients, the first response rate are available (investigators’ assessment after 3 cycles) as well as toxicity data. Conclusions: Cetuximab does not seem to positively interact with GEM/CDDP combination in terms of activity especially concerning time to progression. Although toxicity was not increased by cetuximab, this combination should not be assessed in a phase III trial.The trial was supported in part by by Merck KGaA. [Table: see text] No significant financial relationships to disclose.

3582 Background: Improvements in survival have been reported in mCC with the addition of bevacizumab or cetuximab to chemotherapy. However, their efficacy in different therapy lines and the optimal...

6580 Background: Clinical trials are the gold standard for evaluating novel therapeutics. Accrual of patients (pts) at substantial risk of significant treatment toxicity or early mortality compromi...

5-fluorouracil, an antimetabolite inhibiting timidilate synthetase, is one of the most used drugs in the treatment of many solid tumor types. In particular it is still central in the treatment of colorectal cancer. Nevertheless 5-FU efficency is limited, this is due to the rapidity of its metabolism (T1/2 10 min). Many attempts have been done to increase its efficency: 1) combinations with other antitumor drugs have been tested, but no one showed improved response rates with respect to 5-FU alone; 2) use of biological modifiers such as folinic acid and methotrexate. They interact with the biological actions of 5-FU improving its therapeutic effects. These combinations appear to be more effective than 5-FU alone; 3) continuous infusion increases the percentage of susceptible tumor cells, it makes possible the use of a high intensity dose which is active in patients resistant to 5-FU administered as bolus-injection. There are many schedules and methods of administration of 5-FU in the treatment of CRC, each of them showing different types of toxicities. This explains why there is the need to obtain a profile of 5-FU in clinical practice. The project called MISURA is thought to give us this kind of information. It will be a collection of data regarding patients affected by colorectal cancer and treated with 5-FU. The collected information will be about diagnosis; ways of use, schedules, doses and tolerability of the drug; obtained responses. The aims of the study are: 1) to evaluate the use of 5-FU in clinical practice; 2) to collect data about the use of supportive therapy; 3) to know the effective incidence and prevalence of CRC in Italy. The study is retrospective, the sample consists of all patients from the oncological departments chosen to represent the national territory. The analysis of the data will be descriptive.

Background Management of pain related to advanced or metastatic cancer, although the availability of several pharmacological and non-pharmacological interventions and the existence of well-known guidelines and protocols, is often difficult and inadequate. Evidence of the relative effectiveness of current options for treating cancer pain from comparative randomized studies is scanty. Methods In the context of a wider project, a multicenter, open label, prospective Outcome Research study will be launched in Italy in 2006 to investigate the epidemiology of cancer pain and of its treatments, the quality of analgesic-drug therapy and the effectiveness of alternative analgesic strategies in a large, prospective, unselected cohort of cancer patients using the state-of-the art of patient-reported-outcomes. About 100 Italian centers will recruit 2500 patients with advanced/progressive/metastatic cancer with pain (related to the cancer disease) requiring analgesic treatments. Each center is expected to recruit 25 consecutive and eligible patients during the study inception period. Approximately two months will be allowed for subject recruitment and enrollment. Subject evaluation and follow-up will be for 3 months. The effect on outcomes of various therapeutic analgesic options administered by physicians, given the observational approach where patients are not assigned at random to different treatments, will be compared using the propensity score approach, allowing the adjustment for treatment selection bias. Later, after the launch of the observational study and on the basis of results, in specific subsamples of patients and in select centers of the network, a Randomized Controlled Trial will be carried out to formally compare the efficacy of alternative analgesic strategies, with particular emphasis on oral morphine (as comparator) and buprenorphine patch (as experimental arm). Results from the outcome (cohort) and experimental (Randomized Controlled Trial) studies will ensure both the external and internal validity.