TNM staging alone does not accurately predict outcome in colon cancer (CC) patients who may be eligible for adjuvant chemotherapy. It is unknown to what extent the molecular markers microsatellite ...instability (MSI) and mutations in BRAF or KRAS improve prognostic estimation in multivariable models that include detailed clinicopathological annotation.
After imputation of missing at random data, a subset of patients accrued in phase 3 trials with adjuvant chemotherapy (n=3016)—N0147 (NCT00079274) and PETACC3 (NCT00026273)—was aggregated to construct multivariable Cox models for 5-year overall survival that were subsequently validated internally in the remaining clinical trial samples (n=1499), and also externally in different population cohorts of chemotherapy-treated (n=949) or -untreated (n=1080) CC patients, and an additional series without treatment annotation (n=782).
TNM staging, MSI and BRAFV600E mutation status remained independent prognostic factors in multivariable models across clinical trials cohorts and observational studies. Concordance indices increased from 0.61–0.68 in the TNM alone model to 0.63–0.71 in models with added molecular markers, 0.65–0.73 with clinicopathological features and 0.66–0.74 with all covariates. In validation cohorts with complete annotation, the integrated time-dependent AUC rose from 0.64 for the TNM alone model to 0.67 for models that included clinicopathological features, with or without molecular markers. In patient cohorts that received adjuvant chemotherapy, the relative proportion of variance explained (R2) by TNM, clinicopathological features and molecular markers was on an average 65%, 25% and 10%, respectively.
Incorporation of MSI, BRAFV600E and KRAS mutation status to overall survival models with TNM staging improves the ability to precisely prognosticate in stage II and III CC patients, but only modestly increases prediction accuracy in multivariable models that include clinicopathological features, particularly in chemotherapy-treated patients.
Since 2004, adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX or FLOX) have been the standard of care for patients with resected colon cancer. Herein we examine the change of outcomes over ...a 10-year period in patients with stage III colon cancer who received this regimen.
Individual patient data from the ACCENT database was used to compare the outcomes in older (1998–2003) and newer (2004–2009) treatment eras for patients with stage III colon cancer who received adjuvant FOLFOX or FLOX. The outcomes were compared between the two groups by the multivariate Cox proportional-hazards model adjusting for age, sex, performance score, T stage, N stage, tumor sidedness, and histological grade.
A total of 6501 patients with stage III colon cancer who received adjuvant FOLFOX or FLOX in six randomized trials were included in the analysis. Patients enrolled in the new era group experienced statistically significant improvement in time to recurrence 3-year rate, 76.1% versus 73.0%; adjusted hazard ratio (HRadj) = 0.83 (95% CI, 0.74–0.92), P = 0.0008, disease-free survival (DFS) 3-year rate, 74.7% versus 72.3%; HRadj = 0.88 (0.79–0.98), P = 0.024, survival after recurrence (SAR) median time, 27.0 versus 17.7 months; HRadj = 0.65 (0.57–0.74), P < 0.0001, and overall survival (OS) 5-year rate, 80.9% versus 75.7%; HRadj = 0.78 (0.69–0.88), P < 0.0001. The improved outcomes remained in patients diagnosed at 45 years of age or older, low-risk patients (T1–3 and N1), left colon, mismatch repair proficient (pMMR), BRAF, and KRAS wild-type tumors.
Improved outcomes were observed in patients with stage III colon cancer enrolled in clinical trials who received adjuvant FOLFOX/FLOX therapy in 2004 or later compared with patients in the older era. Prolonged SAR calls for revalidation of 3-year DFS as the surrogate endpoint of OS in adjuvant clinical trials and reevaluation of optimal follow-up of OS to confirm the trial findings based on the DFS endpoints.
NCT00079274; NCT00096278; NCT00004931; NCT00275210; NCT00265811; NCT00112918.
•Improved outcomes were observed in stage III colon cancer patients who received adjuvant FOLFOX/FLOX therapy after 2004.•Adherence to sufficient lymph nodes examination is continuously recommended for better treatment decision making.•Re-validation of three-year DFS as the surrogate endpoint of OS in adjuvant clinical trials is needed.•Re-evaluation of optimal follow-up of OS to confirm trial findings based on DFS endpoints is needed.
The aim of the study was to determine the prevalence and determinants of chronic non-communicable disease (NCD) risk factors in a rural community in the Limpopo Province of South Africa.
This survey ...was conducted using the WHO "STEPwise approach to the surveillance of non-communicable diseases" (STEPS) methodology. Participants were residents of the Dikgale HDSS site and standardised international protocols were used to measure behavioural risk factors (smoking, alcohol consumption, fruit and vegetable intake and, physical activity) and physical characteristics (weight, height, waist and hip circumferences and blood pressure-BP). Fasting blood glucose, triglyceride, cholesterol and HDL-C were determined in 732 participants. Data were analysed using STATA 12 for Windows.
The prevalence of current smokers amongst the participants was 13.7%, of which 81.3% were daily smokers. Alcohol was consumed by 16.3% of the participants. The majority of participants (88.6%) had low daily intake of fruit and vegetables and low physical activity (66.5%). The prevalence of hypertension amongst the participants was 38.2%. Overweight, obesity and high waist circumference were prevalent in females. The cardio-metabolic risk profile was not significantly different between men and women. People who were older than 40 years, overweight or obese and those who consumed alcohol were more likely to be hypertensive. Smoking was associated significantly with older age, males, never married and divorced people. Alcohol consumption was associated with older age, males, low educational status and low income.
High levels of risk factors for NCDs among adults in the Dikgale HDSS suggest an urgent need for health interventions to control these risk factors at the population level in order to reduce the prevalence of NCDs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Tumor-infiltrating lymphocytes (TILs), tumor budding, and micropapillary architecture may influence tumor growth and metastatic potential, thereby enhancing prognostic stratification. We analyzed ...these features and their relative contribution to overall outcome and in low (T1–3 N1) and high (T4 and/or N2) risk groups that are used to inform the duration of adjuvant chemotherapy in patients with resected stage III colon cancers.
Among 1532 patients treated in a phase III adjuvant trial of FOLFOX-based therapy, intraepithelial TIL densities, tumor budding, and micropapillary features were analyzed and quantified in routine histopathological sections with light microscopy. Optimal cut-points were determined in association with disease-free survival (DFS) in training and validation sets. Associations or relative contributions of individual features or combined variables with DFS were determined using multivariable Cox regression models.
TILs, tumor budding, and micropapillary features were shown to differ significantly by T, N risk groups and by mismatch repair (MMR) status. Low TILs, high budding, and their combined variable hazard ratio = 2.07 (95% CI, 1.50% to 2.88%); Padj < 0.0001, but not micropapillary features, were each significantly associated with poorer DFS in a training data set and confirmed in a validation set. TILs were prognostic in proficient mismatch repair (pMMR) and deficient mismatch repair (dMMR) tumors; budding was prognostic only in pMMR tumors. The percentage relative contribution of budding/TILs to DFS was second only to nodal status overall, was second (24.4%) after KRAS in low-risk patients, and was the most important contributor (45.4%) in high-risk patients.
TIL density and tumor budding were each validated as significant prognostic variables and their combined variable provided robust prognostic stratification by T, N risk groups, being the strongest predictor of DFS among high-risk stage III patients.
NCT00079274.
•The microenvironmental features of TIL density and tumor budding may determine tumor metastatic potential.•In stage III colon cancer patients, TIL density and tumor budding were each validated as significant prognostic variables.•Tumor budding/TIL combined variable provided robust prognostic stratification overall and in both low and high risk groups.•The relative contribution of tumor budding/TILs to DFS was second only to N stage in the overall cohort.•The relative contribution of tumor budding/TILs to DFS was second to KRAS in low risk and first in high risk patients.
This phase II trial examined the addition of ramucirumab, a vascular endothelial growth factor receptor-2 monoclonal antibody, to mFOLFOX6 as front-line therapy for patients with advanced gastric/GEJ ...or esophageal adenocarcinoma. A survival benefit was not observed in the ITT population, but an exploratory analysis suggested a potential benefit for ramucirumab in the gastric/GEJ cancer subgroup.
We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ).
Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure–response analysis was undertaken.
Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS 6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69–1.37) or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure–response analysis indicated that patients with higher ramucirumab exposure had longer OS.
The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population.
NCT01246960.
Tumor-infiltrating lymphocytes (TILs) are a robust and independent prognostic variable in localized colon cancer. Given reported differences in molecular features and prognosis of right- versus ...left-sided tumors, we examined the association of TIL densities with patient survival by primary tumor sidedness in stage III cancers, including clinical low- (T1-3, N1) and high-risk (T4 and/or N2) groups.
In a phase III trial of FOLFOX-based adjuvant chemotherapy, TIL densities were analyzed and dichotomized in colon carcinomas (N = 1532) based on a previously determined cut point optimized for disease-free survival (DFS). Right-sided tumors were defined as proximal to the splenic flexure. Associations of TILs and sidedness with 5-year DFS were examined using Kaplan–Meier methodology along with multivariable modeling and relative contribution analysis by Cox regression.
Lower TIL densities were found in left- versus right-sided tumors (P < 0.0001). The association of TIL densities with DFS differed significantly by tumor sidedness (Pinteraction = 0.045). Overall, patient tumors with low (versus high) TILs had significantly poorer DFS in right-sided (hazard ratio 2.02, 95% confidence interval 1.45-2.82; Padj < 0.0001), but not left-sided tumors (Padj = 0.1731). Among clinical low-risk patients, low (versus high) TILs were adversely prognostic only in right-sided tumors (Padj = 0.0058). Among high-risk patients, low TILs were prognostic independent of sidedness (Padj < 0.025). The relative contribution of TILs to DFS was substantially greater in right- versus left-sided tumors (24% versus 1.5%). In high-risk tumors, TILs had the highest relative contribution to DFS (42%) of all variables. In low-risk tumors, the contribution of TILs (16%) to DFS was second to KRAS.
The association of TIL densities with patient survival differed by primary tumor sidedness and clinical risk group, suggesting that TILs should be interpreted in this context among stage III colon cancers.
NCT00079274; https://clinicaltrials.gov/ct2/show/NCT00079274
•Association of TIL densities with 5-year DFS differed significantly by primary tumor sidedness.•Overall, low versus high TILs were significantly associated with poorer DFS among right-sided, but not left-sided tumors.•Prognostic impact of TILs was limited to right-sided cancers among clinical low-risk tumors.•Relative contribution of TILs to DFS was greater in right- versus left-sided tumors (24% versus 1.5%).•In clinical high-risk tumors, TILs had the highest relative contribution to DFS of all variables.
The prognostic value of KRAS and BRAFV600E mutations in stage III colon cancer (CC) remains controversial and has never been clearly analyzed in patients with microsatellite instability-high (MSI-H) ...tumors due to sample size limitations. Data are also lacking for KRAS submutations and prognosis.
We examined clinicopathological variables and prognosis in patients with surgically resected stage III CC who participated in seven clinical trials from the ACCENT/IDEA databases. Associations between KRAS exon 2 and BRAFV600E mutations and time to recurrence (TTR), overall survival (OS), and survival after recurrence (SAR) were assessed using a Cox model. We also analyzed the prognostic value of KRAS exon 2 submutations.
Among 8460 patients, 11.4% had MSI-H status. In the MSI-H group, BRAFV600E, KRAS exon 2 mutants, and double-wild-type statuses were detected in 40.6%, 18.1%, and 41.3%, respectively, whereas and in the microsatellite stable (MSS) group, these were detected in 7.7%, 38.6%, and 53.8%, respectively. In the MSS group, 5-year TTR rates of 61.8%, 66.3%, and 72.9% were observed among patients with BRAFV600E, KRAS exon 2 mutants, and those who were DWT, respectively adjusted hazard ratio (HR) = 1.58 and 1.31, both P < 0.001. In the MSI-H group, 5-year TTR rates did not differ significantly among the mutated subgroups. Similar results were found for OS. However, survival after relapse was significantly shorter in the KRAS exon 2- and BRAFV600E-mutated patients in both MSS (adjusted HR = 2.06 and 1.15; both P < 0.05) and MSI-H (adjusted HR = 1.99 and 1.81; both P < 0.05) groups. In the MSS group, KRAS exon 2 mutations were associated with TTR, but only p.G12C, p.G12D, and p.G13D were associated with poor outcomes after disease recurrence.
Testing for both KRAS and BRAFV600E mutations in stage III patients should be considered as they can better define individual patient prognosis, and may also enable patient selection for (neo)adjuvant trials dedicated to specific molecular subtypes with poor prognosis.
•KRAS exon 2 and BRAFV600E mutations are associated with shorter TTR in patients resected from a stage III MSS CC.•KRAS exon 2 and BRAFV600E mutations are not associated with shorter TTR in patients resected from a stage III MSI-H CC.•BRAFV600E, KRAS G12C, and G13D mutations are associated with shorter SAR in patients resected from a stage III MSS CC.
Background: PS-341 is a proteasome inhibitor with preclinical activity in pancreatic cancer tumor models and synergistic activity with gemcitabine. This randomized phase II study determined the tumor ...response rate (RR) for PS-341 alone and the 6-month survival and RR for the combination of gemcitabine and PS-341 in patients with metastatic pancreatic adenocarcinoma. Patients and methods: Patients were randomized to receive 3-week cycles of either arm A: PS-341 1.5 mg/m2 i.v. bolus (over 3–5 s) on days 1, 4, 8 and 11 or arm B: PS-341 1.0 mg/m2 (same as arm A otherwise) plus gemcitabine 1000 mg/m2 i.v. on days 1 and 8. Patients progressing on arm A were allowed to receive arm B treatment. Results: Arm A: 42 evaluable patients were enrolled with a confirmed RR of 0% (95% CI 0% to 8%), median survival of 2.5 months (95% CI 2.0–3.3), and median time to progression (TTP) of 1.2 months (95% CI 1.1–1.3). Twelve of 43 evaluable patients (28%) experienced at least one grade 4+ AE. Arm B: 39 evaluable patients yielded a 6-month survival rate of 41% (16/39, 95% CI 29.8% to 67.0%), median survival of 4.8 months (95% CI 2.4–7.4), median TTP of 2.4 months (95% CI 1.5–3.1), and confirmed RR of 10% (4 partial responses/0 complete responses, 95% CI 3% to 24%). Eleven of 43 evaluable patients (26%) experienced at least one grade 4+ AE. One patient had grade 5 hypotension. Conclusion: The use of PS-341 alone or in combination with gemcitabine did not result in an overall survival and RR better than that expected for gemcitabine alone. Based on the lack of efficacy and the toxicity seen in our trial, there does not appear to be a role for PS-341 in pancreatic adenocarcinoma with either of the schedules used in this trial.
Background: Fluorouracil (5-FU), oxaliplatin and irinotecan combinations improve time to tumor progression (TTP), objective response and overall survival (OS) in patients with metastatic colorectal ...cancer (MCRC). Here we identify and describe patients treated on Intergroup study N9741 who initially had inoperable MCRC, but who obtained sufficient chemotherapeutic benefit to allow removal of their metastatic disease. Patients and methods: Patient research records in study arms (A) irinotecan/5-FU/leucovorin (LV) (IFL, n=264), (F) oxaliplatin/5-FU/LV (FOLFOX4, n=267) and (G) oxaliplatin/irinotecan (IROX, n=265) were reviewed. TTP and median OS were calculated. Results: Twenty-four (3.3%) of 795 randomized patients underwent curative metastatic disease resection hepatectomy, 16; radiofrequency-ablation (RFA), six; lung resection, two. Twenty-two out of 24 (92%) resected patients received an oxaliplatin-based regimen (FOLFOX4, 11; IROX, 11). Seven patients (29.2%) remain disease-free; relapses occurred mainly in the resected organ. Median OS in resected patients is 42.4 months, and median TTP is 18.4 months. All six patients treated with RFA have recurred. Four out of five (80%) patients who received chemotherapy following resection are disease-free. Conclusions: Resection of metastatic disease after chemotherapy is possible in a small but important subset of patients with MCRC, particularly after receiving an oxaliplatin-based chemotherapy regimen, with encouraging OS and TTP observed in these highly selected patients.
Gastric cancer incidence and mortality has fallen dramatically over the last 50 years in many regions, but remains the second most common cancer worldwide. Despite a marked decline in fundic and ...distal tumors, there is a rising incidence of adenocarcinomas of the gastroesophageal junction and gastric cardia, particularly in Western nations. This may imply that there are in fact two diseases differing from each other in epidemiology, etiology, pathology and clinical expression. While surgical resection remains the cornerstone of gastric cancer treatment, the optimum extent of nodal resection remains controversial, with randomized studies failing to show that the D2 procedure improves survival when compared with D1 dissection. The high rate of recurrence and poor survival following surgery provides a rationale for the early use of adjuvant treatment. Adjuvant chemotherapy or adjuvant radiotherapy, when used alone, do not improve survival following resection. However, the results of the recent Intergroup 0116 study are promising in showing that the combination of 5-fluorouracil (5-FU)-based chemotherapy with radiotherapy significantly prolongs disease-free and overall survival when compared with no adjuvant treatment. In advanced gastric cancer, chemotherapy enhances quality of life and prolongs survival when compared with best supportive care. There is no agreed standard of treatment in this setting. Of the commonly used regimens, epirubicin plus cisplatin and 5-FU (ECF) probably has the strongest claim to this role. However, there is a pressing need for new agents, both cytotoxic and molecularly targeted, to be assessed in both the advanced and adjuvant settings.