Survival following early-stage colon cancer: An ACCENT-based comparison of patients versus a matched international general population

Background: Post-treatment survival experience of early colon cancer (CC) patients is well described in the literature, which states that cure is probable for some patients. However, comparisons of treated patients' survival versus that expected from a matched general population (MGP) are limited. Patients and methods: A total of 32 745 patients from 25 randomized adjuvant trials conducted from 1977 to 2012 in 41 countries were pooled. Observed long-term survival of these patients was compared with expected survival matched on sex, age, country, and year, both overall and by stage (II and III), sex, treatment [surgery, 5-fluorouracil (5-FU), 5-FU + oxaliplatin], age (<70 and 70+), enrollment year (pre/post 2000), and recurrence (yes/no). Comparisons were made at randomization and repeated conditional on survival to 1, 2, 3, and 5 years. CC and MGP equivalence was tested, and observed Kaplan-Meier survival rates compared with expected MGP rates 3 years out from each landmark. Analyses were also repeated in patients without recurrence. Results: Within most cohorts, long-term survival of CC patients remained statistically worse than the MGP, though conditional survival generally improved over time. Among those surviving 5 years, stage II, oxaliplatin-treated, elderly, and recurrence-free patients achieved subsequent 3-year survival rates within 5% of the MGP, with recurrence-free patients achieving equivalence. Conclusions: Conditional on survival to 5 years, long-term survival of most CC patients on clinical trials remains modestly poorer than an MGP, but achieves MGP levels in some subgroups. These findings emphasize the need for access to quality care and improved treatment and follow-up strategies

Sex and adverse events of adjuvant chemotherapy in colon cancer: an analysis of 34,640 patients in the ACCENT database

BACKGROUND: Adjuvant chemotherapy is a standard treatment option for patients with stage III and high-risk stage II colon cancer. Sex is one of several factors responsible for the wide inter-patient variability in drug responses. Amalgamated data on the effect of sex on the toxicity of current standard adjuvant treatment for colorectal cancer are missing. METHODS: The objective of our study was to compare incidence and severity of major toxicities of fluoropyrimidine- (5FU or capecitabine) based adjuvant chemotherapy, with or without oxaliplatin, between male and female patients after curative surgery for colon cancer. Adult patients enrolled in 27 relevant randomized trials included in the ACCENT (Adjuvant Colon Cancer End Points) database, a large, multi-group, international data repository containing individual patient data, were included. Comparisons were conducted using logistic regression models (stratified by study and treatment arm) within each type of adjuvant chemotherapy (5FU, FOLFOX, capecitabine, CAPOX, and FOLFIRI). The following major toxicities were compared (grade III or IV and grade I-IV, according to National Cancer Institute Common Terminology Criteria [NCI-CTC] criteria, regardless of attribution): nausea, vomiting, nausea or vomiting, stomatitis, diarrhea, leukopenia, neutropenia, thrombocytopenia, anemia, and neuropathy (in patients treated with oxaliplatin). RESULTS: Data from 34 640 patients were analyzed. Statistically significant and clinically relevant differences in the occurrence of grade III or IV nonhematological {especially nausea (5FU: odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.90 to 2.87, P < .001; FOLFOX: OR = 2.34, 95% CI = 1.76 to 3.11, P < .001), vomiting (5FU: OR = 2.38, 95% CI = 1.86 to 3.04, P < .001; FOLFOX: OR = 2.00, 95% CI = 1.50 to 2.66, P < .001; CAPOX: OR = 2.32, 95% CI = 1.55 to 3.46, P < .001), and diarrhea (5FU: OR = 1.35, 95% CI = 1.21 to 1.51, P < .001; FOLFOX: OR = 1.60, 95% CI = 1.35 to 1.90, P < .001; FOLFIRI: OR = 1.57, 95% CI = 1.25 to 1.97, P < .001)} as well as hematological toxicities (neutropenia [5FU: OR = 1.55, 95% CI = 1.37 to 1.76, P < .001; FOLFOX: OR = 1.96, 95% CI = 1.71 to 2.25, P < .001; FOLFIRI: OR = 2.01, 95% CI = 1.66 to 2.43, P < .001; capecitabine: OR = 4.07, 95% CI = 1.84 to 8.99, P < .001] and leukopenia [5FU: OR = 1.74, 95% CI = 1.40 to 2.17, P < .001; FOLFIRI: OR = 1.75, 95% CI = 1.28 to 2.40, P < .001]) were observed, with women being consistently at increased risk. CONCLUSIONS: Our analysis confirms that women with colon cancer receiving adjuvant fluoropyrimidine-based chemotherapy are at increased risk of toxicity. Given the known sex differences in fluoropyrimidine pharmacokinetics, sex-specific dosing of fluoropyrimidines warrants further investigation

Outcomes Among Black Patients With Stage II and III Colon Cancer Receiving Chemotherapy: An Analysis of ACCENT Adjuvant Trials

Among patients with resected colon cancer, black patients have worse survival than whites. We investigated whether disparities in survival and related endpoints would persist when patients were treated with identical therapies in controlled clinical trials

Assessment of the consistency and robustness of results from a multicenter trial of remission maintenance therapy for acute myeloid leukemia

<p>Abstract</p> <p>Background</p> <p>Data from a randomized multinational phase 3 trial of 320 adults with acute myeloid leukemia (AML) demonstrated that maintenance therapy with 3-week cycles of histamine dihydrochloride plus low-dose interleukin-2 (HDC/IL-2) for up to 18 months significantly improved leukemia-free survival (LFS) but lacked power to detect an overall survival (OS) difference.</p> <p>Purpose</p> <p>To assess the consistency of treatment benefit across patient subsets and the robustness of data with respect to trial centers and endpoints.</p> <p>Methods</p> <p>Forest plots were constructed with hazard ratios (HRs) of HDC/IL-2 treatment effects versus no treatment (control) for prospectively defined patient subsets. Inconsistency coefficients (I²) and interaction tests (X²) were used to detect any differences in benefit among subsets. Robustness of results to the elimination of individual study centers was performed using "leave-one-center-out" analyses. Associations between treatment effects on the endpoints were evaluated using weighted linear regression between HRs for LFS and OS estimated within countries.</p> <p>Results</p> <p>The benefit of HDC/IL-2 over controls was statistically consistent across all subsets defined by baseline prognostic variables. I²and <it>P</it>-values of X²ranged from 0.00 to 0.51 and 0.14 to 0.91, respectively. Treatment effects were statistically significant in 14 of 28 subsets analyzed. The "leave-one-center-out" analysis confirmed that no single center dominated (<it>P</it>-values ranged from 0.004 to 0.020 [mean 0.009]). The HRs representing the HDC/IL-2 effects on LFS and OS were strongly correlated at the country level (R²= 0.84).</p> <p>Limitations</p> <p>Small sample sizes in some of the subsets analyzed.</p> <p>Conclusions</p> <p>These analyses confirm the consistency and robustness of the HDC/IL-2 effect as compared with no treatment. LFS may be an acceptable surrogate for OS in future AML trials. Analyses of consistency and robustness may aid interpretation of data from multicenter trials, especially in populations with rare diseases, when the size of randomized clinical trials is limited.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00003991">NCT00003991</a></p

Cold Hardiness and Supercooling Capacity in the Overwintering Larvae of the Codling Moth, Cydia pomonella

The codling moth, Cydia pomonella L. (Lepidoptera: Tortricidae), a worldwide apple pest, is classified as a freeze-intolerant organism and one of the most cold-tolerant pests. The objectives of this study were to examine the supercooling point of overwintering and non-diapausing larvae of C. pomonella as an index of its cold hardiness, and to assess larval mortality following 24 h exposure to extreme low temperatures ranging from -5 to -25°C. The mean (±SE) supercooling point for feeding larvae (third through fifth instars) was -12.4 ± 1.1°C. The mean supercooling point for cocooned, non-diapausing larvae (i.e., non-feeding stages) decreased as the days that the arvae were cocooned increased and changed between -15.1 ± 1.2°C for one to two day cocooned arvae and -19.2 ± 1.8°C for less than five day cocooned larvae. The mean (±SE) supercooling point for other non-feeding stages containing pupae and overwintering larvae were -19.9 ± 1.0°C and -20.2 ± 0.2°C, respectively. Mean supercooling points of C. pomonella larvae were significantly lower during the winter months than the summer months, and sex had no effect on the supercooling point of C. pomonella larvae. The mortality of larvae increased significantly after individuals were exposed to temperatures below the mean supercooling point of the population. The supercooling point was a good predictor of cold hardiness

Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high risk, early breast cancer.

BACKGROUND: The randomized, double-blind OlympiA trial compared one year of the oral poly(adenosine diphosphate-ribose) polymerase) inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2 (HER2)-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive-disease-free survival (IDFS) and distant-disease-free survival (DDFS). The olaparib-group had fewer deaths than the placebo-group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. PATIENTS AND METHODS: 1,836 patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy (N)ACT, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone-receptor-positive-cancers. Statistical significance for OS at this IA required P<0.015. RESULTS: With median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib-group relative to the placebo-group (HR, 0.68; 98.5% CI 0.47 to 0.97; P=0.009). Four-year OS was 89.8% in the olaparib-group and 86.4% in the placebo-group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for olaparib-group versus placebo-group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myelogenous leukemia or myelodysplastic syndrome (AML/MDS). CONCLUSION: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals