Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity. METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used. RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

A randomized trial of intensive versus minimal surveillance of patients with resected Dukes B2-C colorectal carcinoma.

BACKGROUND: Colorectal cancer is the third most common and the third most lethal cancer in both men and women in developed countries. About 75% of cases are first diagnosed when the disease is classified as localized or regional, undergo potentially curative treatment and enter a post-treatment surveillance program. Although such programs drain significant resources from health systems, empirical evidence of their efficacy is scanty. PATIENTS AND METHODS: Dukes B2-C colorectal cancer patients who had no evidence of disease at the end of their front-line treatment (surgery and adjuvant radiochemotherapy, if indicated) were eligible for the trial and randomized to two different surveillance programs. These programs differed greatly in the frequency of diagnostic imaging. They had similar schedules of physical examinations and carcinoembryonic antigen (CEA) assessments. Patients received baseline and yearly health-related quality-of-life (HR-QoL) questionnaires. Primary outcomes were overall survival (OS) and QoL. RESULTS: From 1998 to 2006, 1228 assessable patients were randomized, 933 with colon cancer and 295 with rectal cancer. More than 90% of patients had the expected number of diagnostic procedures. Median follow-up duration was 62 months [interquartile range (IQR) 51-86] in the minimal surveillance group and 62 months (IQR 50-85) in the intensive group. At primary analysis, 250 patients had recurred and 218 had died. Intensive surveillance anticipated recurrence, as shown by a significant difference in mean disease-free survival of 5.9 months. Comparison of OS curves of the whole intention-to-treat population showed no statistically significant differences. HR-QoL of life scores did not differ between regimens. CONCLUSION: Our findings support the conclusions of other randomized clinical trials, which show that early diagnosis of cancer recurrence is not associated with OS benefit. CLINICALTRIALSGOV: NCT02409472.

Cisplatin and vinorelbine as second-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) resistant to taxol plus gemcitabine.

The aim of the study was to evaluate the activity of cisplatin (CDDP) plus vinorelbine (VNR) in patients with advanced non-small cell lung cancer (NSCLC) progressing after paclitaxel plus gemcitabine. Treatment consisted of CDDP 80 mg/m(2) administered on day 1 and VNR 25 mg/m(2) administered on day 1 and 8, repeated every 3 weeks. Nine patients who relapsed after partial response and eight patients refractory to prior CT received a minimum of two treatment cycles: three patients achieved a PR (18%; 95% CI: 4-43%), four had stable disease and 10 had disease progression. All responses were observed among the nine patients responsive to prior treatment. Median survival was 35 weeks. No patients required dose-reduction, treatment discontinuation or delay because of toxicity. Our results indicate a reasonable antitumor efficacy and no relevant toxicity of a second-line CDDP-based chemotherapy in patients with advanced NSCLC. We recommend the use of this regimen for patients not refractory to primary treatment.

Infections in haematologic neoplasms: autopsy findings.

BACKGROUND AND METHODS: Infections are the main cause of death in most haematologic malignancies. We studied 95 autopsies of patients who died from haematologic neoplasms in the period 1980-1989 at Niguarda Cà Granda Hospital. RESULTS AND CONCLUSIONS: Infections were the cause of death in 63% of patients. In this group of patients bacterial infections accounted for 43% of deaths; fungal infections were frequent too (28%), mainly among leukemic patients; viral (9%), mycobacterial (7%) and polymicrobic infections (11%) were also documented. Haemorrhages were less frequently fatal (12%) due to the availability of haemocomponents. A high number of fatal haemorrhages were associated with fungal infections. Neoplastic progression was the real cause of death in only a few cases, and cardiovascular and pulmonary complications were fatal in the great majority of the other patients.