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A prospective, pooled analysis of six randomised phase 3 trials was done to investigate disease-free survival regarding non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer; non-inferiority was not shown. Here, we report the final overall survival results. In this prospective, pooled analysis of six randomised phase 3 trials, we included patients with stage III colon cancer aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0–1 recruited between June 20, 2007, and Dec 31, 2015, across 12 countries in the CALGB/SWOG 80702, IDEA France, SCOT, ACHIEVE, TOSCA, and HORG trials, who started any treatment (modified intention-to-treat). Patients in all trials were randomly assigned to 3 months or 6 months of adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) every 2 weeks or capecitabine and oxaliplatin (CAPOX) in different doses and methods every 3 weeks, at the treating physician's discretion. The primary endpoint was disease-free survival (time to relapse, secondary colorectal primary tumour, or death due to all causes), and overall survival (time to death due to all causes) was the prespecified secondary endpoint. The non-inferiority margin for overall survival was set as a hazard ratio (HR) of 1·11. Pre-planned subgroup analyses included regimen and risk group. Non-inferiority was declared if the one-sided false discovery rate adjusted (FDRadj) p value was less than 0·025. With median follow-up of 72·3 months (IQR 72·2–72·5), 2584 deaths among 12 835 patients were observed. 5064 (39·5%) patients received CAPOX and 7771 (60·5%) received FOLFOX. 5-year overall survival was 82·4% (95% CI 81·4–83·3) with 3 months of therapy and 82·8% (81·8–83·8) with 6 months of therapy (HR 1·02 [95% CI 0·95–1·11]; non-inferiority FDRadj p=0·058). For patients treated with CAPOX, 5-year overall survival was 82·1% (80·5–83·6) versus 81·2% (79·2–82·9; HR 0·96 [0·85–1·08]); non-inferiority FDRadj p=0·033), and for patients treated with FOLFOX 5-year overall survival was 82·6% (81·3–83·8) and 83·8% (82·6–85·0; HR 1·07 [0·97–1·18]; non-inferiority FDRadj p=0·34). Updated disease-free survival results confirmed previous findings (HR 1·08 [95% CI 1·02–1·15]; non-inferiority FDRadj p=0·25). Data on adverse events were not further recorded. Non-inferiority of 3 months versus 6 months of adjuvant chemotherapy for patients with stage III colon cancer was not confirmed in terms of overall survival, but the absolute 0·4% difference in 5-year overall survival should be placed in clinical context. Overall survival results support the use of 3 months of adjuvant CAPOX for most patients with stage III colon cancer. This conclusion is strengthened by the substantial reduction of toxicities, inconveniencies, and cost associated with a shorter treatment duration. US National Cancer Institute.

This analysis involving patients with stage III colon cancer pooled the findings of six clinical trials regarding the effect of adjuvant-therapy duration on disease-free survival. The results varied according to drug regimen and disease subgroup.

Erlotinib is registered for treatment of all patients with advanced non-small-cell lung cancer (NSCLC). However, its efficacy for treatment of patients whose tumours are EGFR wild-type—which includes most patients—is still contentious. We assessed the efficacy of erlotinib compared with a standard second-line chemotherapy in such patients. We did this randomised controlled trial in 52 Italian hospitals. We enrolled patients who had metastatic NSCLC, had had platinum-based chemotherapy, and had wild-type EGFR as assessed by direct sequencing. Patients were randomly assigned centrally (1:1) to receive either erlotinib orally 150 mg/day or docetaxel intravenously 75 mg/m2 every 21 days or 35 mg/m2 on days 1, 8, and 15, every 28 days. Randomisation was stratified by centre, stage, type of first-line chemotherapy, and performance status. Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation, investigators who analysed results were. The primary endpoint was overall survival in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT00637910. We screened 702 patients, of whom we genotyped 540. 222 patients were enrolled (110 assigned to docetaxel vs 112 assigned to erlotinib). Median overall survival was 8·2 months (95% CI 5·8–10·9) with docetaxel versus 5·4 months (4·5–6·8) with erlotinib (adjusted hazard ratio [HR] 0·73, 95% CI 0·53–1·00; p=0·05). Progression-free survival was significantly better with docetaxel than with erlotinib: median progression-free survival was 2·9 months (95% CI 2·4–3·8) with docetaxel versus 2·4 months (2·1–2·6) with erlotinib (adjusted HR 0·71, 95% CI 0·53–0·95; p=0·02). The most common grade 3–4 toxic effects were: low absolute neutrophil count (21 [20%] of 104 in the docetaxel group vs none of 107 in the erlotinib group), skin toxic effects (none vs 15 [14%]), and asthenia (ten [10%] vs six [6%]). Our results show that chemotherapy is more effective than erlotinib for second-line treatment for previously treated patients with NSCLC who have wild-type EGFR tumours. Agenzia Italiana del Farmaco.

We sought to develop criteria for ERBB2 -positivity ( HER2 ) in colorectal cancer to ensure accurate identification of ERBB2 -amplified metastatic colorectal cancer patients suitable for enrolment in a phase II trial of ERBB2-targeted therapy (HERACLES trial). A two-step approach was used. In step 1, a consensus panel of pathologists adapted existing protocols for use in colorectal cancer to test ERBB2 expression and amplification. Collegial revision of an archival test cohort of colorectal cancer samples led to specific recommendations for adapting current breast and gastric cancer criteria for scoring ERBB2 in colorectal cancer. In step 2, from September 2012 to January 2015, colorectal-specific ERBB2 testing protocols and ERBB2 scoring criteria were used to centrally screen for ERBB2 -positive KRAS wild-type colorectal cancer patients to be enrolled in the HERACLES trial (clinical validation cohort). In both archival test ( N =256) and clinical validation ( N =830) cohorts, a clinically sizeable 5% fraction of KRAS wild-type colorectal cancer patients was found to be ERBB2 -positive according to the colorectal cancer-specific ERBB2 scoring criteria. ERBB2 -positive tumors showed ERBB2 immunostaining consisting of intense membranous ERBB2 protein expression, corresponding to homogenous ERBB2 amplification, in >50% of cells. None of the immunohistochemistry 0 or 1+ cases was amplified. Concordance between SISH and FISH was 100%. In conclusion, we propose specific criteria for defining ERBB2 -positivity in colorectal cancer (HERACLES Diagnostic Criteria). In a phase II trial of trastuzumab and lapatinib in a cetuximab-resistant population, HERACLES Diagnostic Criteria shaped the selection of patients and defined ERBB2 as a predictive marker for response to ERBB2-targeted therapy in metastatic colorectal cancer.

Clinical trials are needed to assess the clinical benefit of antithrombotic prophylaxis in patients with cancer who are receiving chemotherapy, since these patients are at an increased risk of developing a thromboembolism. We did a trial to assess the clinical benefit of the low-molecular-weight heparin nadroparin for the prophylaxis of thromboembolic events in ambulatory patients receiving chemotherapy for metastatic or locally advanced solid cancer. Between October, 2003, and May, 2007, ambulatory patients with lung, gastrointestinal, pancreatic, breast, ovarian, or head and neck cancer were randomly assigned in a double-blind manner to receive subcutaneous injections of nadroparin (3800 IU anti-Xa once a day, n=779) or placebo (n=387), in a 2:1 ratio. Study treatment was given for the duration of chemotherapy up to a maximum of 4 months. The primary study outcome was the composite of symptomatic venous or arterial thromboembolic events, as assessed by an independent adjudication committee. All randomised patients who received at least one dose of study treatment were included in the efficacy and safety analyses (modified intention-to-treat population). The study is registered with ClinicalTrials.gov, NCT 00951574. 1150 patients were included in the primary efficacy and safety analyses: 769 patients in the nadroparin group and 381 patients in the placebo group. 15 (2·0%) of 769 patients treated with nadroparin and 15 (3·9%) of 381 patients treated with placebo had a thromboembolic event (single-sided p=0·02). Five (0·7%) of 769 patients in the nadroparin group and no patients in the placebo group had a major bleeding event (two-sided p=0·18). The incidences of minor bleeding were 7·4% (57 of 769) with nadroparin and 7·9% (30 of 381) with placebo. There were 121 (15·7%) serious adverse events in the nadroparin goup and 67 (17·6%) serious adverse events in the placebo group. Nadroparin reduces the incidence of thromboembolic events in ambulatory patients with metastatic or locally advanced cancer who are receiving chemotherapy. Future studies should focus on patients who are at a high risk for thromboembolic events. Italfarmaco SpA, Milan, Italy.

Background Cancer patients receiving chemotherapy are at increased risk of thrombosis. Nadroparin has been demonstrated to reduce the incidence of venous and arterial thrombotic events (TEs) by about 50% in cancer outpatients receiving chemotherapy. The aims of this retrospective analysis were to evaluate the thromboembolic risk and the benefit of thromboprophylaxis according to type of chemotherapy. Methods Cancer outpatients were randomly assigned to receive subcutaneous injections of nadroparin or placebo. The incidence of symptomatic TEs was assessed according to the type of chemotherapy. Results were reported as risk ratios with associated 95% CI and two-tailed probability values. Results 769 and 381 patients have been evaluated in the nadroparin and placebo group, respectively. In the absence of thromboprophylaxis, the highest rate of TEs was found in patients receiving gemcitabine- (8.1%) or cisplatin-based chemotherapy (7.0%). The combination of gemcitabine and cisplatin or carboplatin increased the risk to 10.2%. Thromboprophylaxis reduced TE risk by 68% in patients receiving gemcitabine; with a further decrease to 78% in those receiving a combination of gemcitabine and platinum. Conclusions This retrospective analysis confirms that patients undergoing chemotherapy including gemcitabine, platinum analogues or their combination are at higher risk of TEs. Our results also suggest that outpatients receiving chemotherapy regimens including these agents might achieve an increased benefit from thromboprophylaxis with nadroparin. Clinical Trial registration number: NCT 00951574

After successful surgery for colorectal cancer, patients over 70 years of age are less likely to receive postoperative (adjuvant) chemotherapy than younger patients, even though it prolongs life. The underuse of chemotherapy relates to the belief that it is excessively toxic in the elderly. This analysis of data from seven randomized trials of adjuvant chemotherapy for resected colorectal cancer found that selected older patients not only benefit from such treatment but tolerate it almost as well as their younger counterparts. Older patients not only benefit from such treatment but tolerate it almost as well as their younger counterparts. By 2030, one in five Americans will be over 65 years of age. 1 , 2 Physicians will be seeing increasing numbers of elderly patients with colorectal cancer and other cancers whose incidence increases with age. Currently, 60 percent of malignant disease occurs in persons over 65 years of age. More than half of these patients are over 70 years old, and one fourth of them are over 80 years old. 3 – 7 In some clinical trials, the elderly have been excluded by design. More often, their outcomes have been pooled in results that have not been analyzed according to age. Consequently, only . . .

Preclinical data have suggested a synergistic effect of cetuximab combined with gemcitabine and cisplatin and clinical data have shown a substantial improvement in response and survival when gemcitabine is combined with a platinum analogue compared with gemcitabine alone. The aim of this study was to assess the activity and feasibility of a combination of cetuximab with gemcitabine and cisplatin compared with use of gemcitabine and cisplatin alone for the treatment of advanced pancreatic cancer. In a multicentre, randomised phase II trial, 84 patients with advanced pancreatic cancer were randomly assigned to either 250 mg/m 2 cetuximab weekly, after a loading dose of 400 mg/m 2, plus 1000 mg/m 2 gemcitabine and 35 mg/m 2 cisplatin on days 1 and 8 of a 21-day cycle or to the same chemotherapeutic regimen without cetuximab. The primary endpoint was objective response (defined as the proportion of patients whose best response was either partial response or complete response). Secondary endpoints included disease control (defined as the proportion of patients whose best response was either partial response, complete response, or stable disease), progression-free survival, and overall survival. All assessments of response at each site were done blindly by a local experienced radiologist who was not directly involved in the trial. Responses were measured according to an intention-to-treat analysis. This trial is registered with the Clinical Trial registry, number NCT00536614. 29 men and 13 women were randomly assigned to cetuximab plus gemcitabine and cisplatin (median age 61 years [range 38–78]) and 22 men and 20 women were randomly assigned to gemcitabine and cisplatin (median age 64 years [range 40–76]). Seven of 40 (17·5%) patients had an objective response in the cetuximab group (95% CI 7·3–32·8) and five of 41 (12·2%) patients had an objective response in the non-cetuximab group (95% CI 4·1–26·2). No significant difference was noted between the groups both for objective response (5·3% higher in the cetuximab group [95% CI −16·5 to 27·1]; χ 2 test=0·360; p=0·549) or for disease control (3·5% higher in the non-cetuximab group [−34·0% to 27·0%]; 0·446; p=0·504). Overall median follow-up was 11·8 months (range 2·5–18·5). No significant differences between the groups were noted in median progression-free survival (hazard ratio 0·96, 95% CI 0·60–1·52, p=0·847) or in median overall survival (0·91, 0·54–1·55, p=0·739): median progression-free survival was 3·4 months (95% CI 2·4–5·1) in the cetuximab group and 4·2 months (2·6–5·4) in the non-cetuximab group; median overall survival was 7·5 months (5·1–8·8) and 7·8 months (5·3–15·0), respectively. 33 patients from both groups had at least one grade 3–4 toxic effect. The addition of cetuximab to a combination of gemcitabine and cisplatin does not increase response or survival for patients with advanced pancreatic cancer. Although toxic effects were not increased by cetuximab, this combination should not be further assessed in phase III trials.

Background/Aims: Nephrotoxicity is the major limitation to cisplatin therapy for solid tumors. We aimed at evaluating whether early increases in serum/urine levels of neutrophil gelatinase-associated lipocalin (NGAL), a biomarker of tubular damage and regeneration, predict cisplatin-induced acute kidney injury (AKI). Methods: We compared changes in serum creatinine and serum/urine NGAL levels (ELISA assay) at 1 and 4 h and 1, 2, 3, 7 and 15 days after cisplatin infusion (70-80 mg/m2) versus baseline in 12 consecutive cancer patients (cases) with AKI (>25% serum creatinine increase vs. baseline) and 12 consecutive controls without AKI. Results: Baseline characteristics and posttreatment serum NGAL levels were similar in both groups. Urinary NGAL levels increased significantly more in cases than in controls at 1, 2, 3 and 15 days after cisplatin. The NGAL increase preceded AKI by 4.5 days and the NGAL increase at day 2 after cisplatin independently predicted AKI (p < 0.05). Six cases with residual kidney dysfunction at 15 days showed a trend to earlier and higher increase in urinary NGAL levels compared to cases with renal function recovery. Conclusion: An early increase in urinary NGAL excretion may help in identifying patients at risk of cisplatin-induced AKI who might benefit from innovative treatments to prevent cisplatin nephrotoxicity. Copyright © 2010 S. Karger AG, Basel [PUBLICATION ABSTRACT]